MSAC Assessment Report Template



Catheter-free (wireless) ambulatory oesophageal pH monitoring for gastro-oesophageal reflux disease (GORD)February 2014 MSAC application no. 1203Assessment report? Commonwealth of Australia 2014ISBN (online) 978-1-74186-141-9ISSN (online) 1443-7139Publication approval number 10784Internet site work is copyright. You may download, display, print and reproduce this material in unaltered form only (retaining this notice) for your personal, non-commercial use or use within your organisation. Apart from any use as permitted under the Copyright Act 1968, all other rights are reserved. Requests and enquiries concerning reproduction and rights should be addressed to Commonwealth Copyright Administration, Attorney-General's Department, Robert Garran Offices, National Circuit, Barton ACT 2600, or posted at copies of the report can be obtained from the Medical Service Advisory Committee’s internet site at about the content of the report should be directed to the above address.This report was commissioned for use by the Medical Services Advisory Committee (MSAC) to inform its deliberations. MSAC is an independent committee that has been established to provide advice to the Minister for Health on the strength of evidence available on new and existing medical technologies and procedures in terms of their safety, effectiveness and cost-effectiveness. This advice will help to inform government decisions about which medical services should attract funding under Medicare.MSAC’s advice does not necessarily reflect the views of all individuals who participated in the MSAC evaluation.This report was prepared for MSAC by Ms Sharon Kessels, Ms Camille Schubert, Ms Skye Newton and Assoc. Prof. Tracy Merlin from Adelaide Health Technology Assessment (AHTA), the University of Adelaide, with the assistance of Health Expert Standing Panel members Prof. Robert Batey and Prof. Robert Fraser. The report was commissioned by the Australian Government Department of Health. It was edited by Ms Jo Mason of MasonEdit, Adelaide.This report should be referenced as follows:Kessels S, Schubert C, Newton S & Merlin T 2014, Catheter-free (wireless) ambulatory oesophageal pH monitoring for gastro-oesophageal reflux disease (GORD), MSAC Application 1203, Assessment Report, Commonwealth of Australia, Canberra, ACT.Contents TOC \o "1-3" Executive summary PAGEREF _Toc383606889 \h xvAssessment of catheter-free (wireless) ambulatory oesophageal pH monitoring for gastro-oesophageal reflux disease PAGEREF _Toc383606890 \h xvRationale for assessment PAGEREF _Toc383606891 \h xvGastro-oesophageal reflux disease (GORD) and pH monitoring PAGEREF _Toc383606892 \h xvCurrent arrangements for public reimbursement PAGEREF _Toc383606893 \h xviClinical need PAGEREF _Toc383606894 \h xviResults of assessment PAGEREF _Toc383606895 \h xviEconomic and financial considerations PAGEREF _Toc383606896 \h xixOther relevant considerations / discussion PAGEREF _Toc383606897 \h xxiGlossary and abbreviations PAGEREF _Toc383606898 \h 23Introduction PAGEREF _Toc383606899 \h 25Rationale for assessment PAGEREF _Toc383606900 \h 25Background PAGEREF _Toc383606901 \h 26Gastro-oesophageal reflux disease (GORD) PAGEREF _Toc383606902 \h 26pH monitoring PAGEREF _Toc383606903 \h 27The current MBS-approved pH-monitoring test for GORD: catheter-based ambulatory oesophageal pH monitoring (MBS item 11810) PAGEREF _Toc383606904 \h 28Catheter-free (wireless) ambulatory oesophageal pH monitoring PAGEREF _Toc383606905 \h 29Intended purpose PAGEREF _Toc383606906 \h 30Indications PAGEREF _Toc383606907 \h 31Clinical need PAGEREF _Toc383606908 \h 31Other existing tests for GORD PAGEREF _Toc383606909 \h 32Oesophageal impedance testing PAGEREF _Toc383606910 \h 32Marketing status of device/technology PAGEREF _Toc383606911 \h 33Current reimbursement arrangements PAGEREF _Toc383606912 \h 33Proposal for public funding PAGEREF _Toc383606913 \h 34Consumer impact statement PAGEREF _Toc383606914 \h 35Approach to assessment PAGEREF _Toc383606915 \h 36Objective PAGEREF _Toc383606916 \h 36Clinical pathway PAGEREF _Toc383606917 \h 36Comparator PAGEREF _Toc383606918 \h 38The reference standard PAGEREF _Toc383606919 \h 38Research questions PAGEREF _Toc383606920 \h 38Diagnostic assessment framework PAGEREF _Toc383606921 \h 40Review of literature PAGEREF _Toc383606922 \h 41Literature sources and search strategies PAGEREF _Toc383606923 \h 41Selection criteria PAGEREF _Toc383606924 \h 42Search results PAGEREF _Toc383606925 \h 44Data extraction and analysis PAGEREF _Toc383606926 \h 46Appraisal of the evidence PAGEREF _Toc383606927 \h 48Expert advice: Health Expert Standing Panel (HESP) PAGEREF _Toc383606928 \h 54Results of assessment PAGEREF _Toc383606929 \h 55Is it safe? PAGEREF _Toc383606930 \h 55Safety of catheter-free (wireless) pH monitoring PAGEREF _Toc383606931 \h 57Is it effective? PAGEREF _Toc383606932 \h 73Direct evidence of diagnostic effectiveness PAGEREF _Toc383606933 \h 73Linked evidence PAGEREF _Toc383606934 \h 82Other relevant considerations PAGEREF _Toc383606935 \h 107Defining the population and the potential for ‘leakage’ PAGEREF _Toc383606936 \h 107What are the economic considerations? PAGEREF _Toc383606937 \h 108Economic evaluation PAGEREF _Toc383606938 \h 108Overview PAGEREF _Toc383606939 \h 108Economic literature review PAGEREF _Toc383606940 \h 109Populations and settings PAGEREF _Toc383606941 \h 110Structure and rationale of the economic evaluation PAGEREF _Toc383606942 \h 111Inputs to the economic evaluation PAGEREF _Toc383606943 \h 118Outputs from the economic evaluation PAGEREF _Toc383606944 \h 126Financial and costing impact PAGEREF _Toc383606945 \h 132Data sources used in the financial analysis PAGEREF _Toc383606946 \h 132Use and costs of the proposed wireless pH-monitoring strategy PAGEREF _Toc383606947 \h 132Changes in use and cost of current monitoring strategy PAGEREF _Toc383606948 \h 139Financial implications to the Medical Benefits Schedule (MBS) PAGEREF _Toc383606949 \h 141Other Australian healthcare system costs PAGEREF _Toc383606950 \h 142Discussion PAGEREF _Toc383606951 \h 144Safety PAGEREF _Toc383606952 \h 144Effectiveness PAGEREF _Toc383606953 \h 145Economic considerations PAGEREF _Toc383606954 \h 150Estimated cost-effectiveness PAGEREF _Toc383606955 \h 150Estimated financial impact PAGEREF _Toc383606956 \h 151Conclusions PAGEREF _Toc383606957 \h 154Is catheter-free monitoring safe? PAGEREF _Toc383606958 \h 154Is catheter-free monitoring effective? PAGEREF _Toc383606959 \h 154Is catheter-free monitoring cost-effective? PAGEREF _Toc383606960 \h 156Costing PAGEREF _Toc383606961 \h 156Appendix AHealth Expert Standing Panel and Assessment Group PAGEREF _Toc383606962 \h 158Health Expert Standing Panel (HESP) PAGEREF _Toc383606963 \h 158Assessment group PAGEREF _Toc383606964 \h 158Appendix BSearch strategies PAGEREF _Toc383606965 \h 159Bibliographic databases PAGEREF _Toc383606966 \h 162Additional sources of literature PAGEREF _Toc383606967 \h 162Additional databases searched for economic evaluations PAGEREF _Toc383606968 \h 162Specialty websites PAGEREF _Toc383606969 \h 163Appendix CStudies included in the review PAGEREF _Toc383606970 \h 164Study profiles of included studies on safety PAGEREF _Toc383606971 \h 164Study profiles of included studies on direct effectiveness PAGEREF _Toc383606972 \h 183Study profiles of included studies on linked evidence PAGEREF _Toc383606973 \h 202Appendix DExcluded studies PAGEREF _Toc383606974 \h 224Conference abstracts PAGEREF _Toc383606975 \h 224Incorrect/irrelevant intervention PAGEREF _Toc383606976 \h 227Irrelevant outcomes PAGEREF _Toc383606977 \h 227Unable to retrieve full text PAGEREF _Toc383606978 \h 227Not in English, and not of a higher level of evidence than the English language literature PAGEREF _Toc383606979 \h 228Irrelevant or incorrect study design PAGEREF _Toc383606980 \h 228Did not meet inclusion criteria regarding population PAGEREF _Toc383606981 \h 230Appendix E Safety data PAGEREF _Toc383606982 \h 231Appendix F Non-comparative technical efficacy data PAGEREF _Toc383606983 \h 241Appendix G Day-to-day variability in oesophageal acid exposure PAGEREF _Toc383606984 \h 246Appendix H Non-comparative diagnostic yield PAGEREF _Toc383606985 \h 251Appendix I MBS items for anti-reflux surgery PAGEREF _Toc383606986 \h 253Appendix JEconomic literature search PAGEREF _Toc383606987 \h 254Appendix KAdditional information relating to the economic evaluation PAGEREF _Toc383606988 \h 255Appendix LAdditional information for the financial and costing analysis PAGEREF _Toc383606989 \h 257References PAGEREF _Toc383606990 \h 258Tables TOC \f F \c "Table" Table 1Catheter-free monitoring device listed on the ARTG PAGEREF _Toc383607099 \h 33Table 2Relevant MBS item for the currently reimbursed test for GORD PAGEREF _Toc383607100 \h 33Table 3Proposed MBS item descriptor PAGEREF _Toc383607101 \h 35Table 4Electronic databases searched PAGEREF _Toc383607102 \h 41Table 5Search terms used PAGEREF _Toc383607103 \h 41Table 6Search terms used to identify studies for the last step of the linked analysis (health outcomes) PAGEREF _Toc383607104 \h 42Table 7Diagnostic accuracy data extraction for GORD PAGEREF _Toc383607105 \h 47Table 8Evidence dimensions PAGEREF _Toc383607106 \h 49Table 9Designations of levels of evidence according to type of research question (including table notes) PAGEREF _Toc383607107 \h 50Table 10Grading system used to rank included studies PAGEREF _Toc383607108 \h 51Table 11Body of evidence matrix PAGEREF _Toc383607109 \h 53Table 12Chest discomfort or chest pain resulting from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607110 \h 58Table 13Chest pain or chest discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607111 \h 59Table 14Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in children PAGEREF _Toc383607112 \h 60Table 15A foreign-body sensation resulting from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607113 \h 60Table 16A foreign-body sensation resulting from catheter-free (wireless) oesophageal pH monitoring in adults PAGEREF _Toc383607114 \h 60Table 17 Nose and throat pain or discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607115 \h 62Table 18Nose and throat pain or discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607116 \h 63Table 19Throat pain and epistaxis resulting from catheter-free (wireless) oesophageal pH monitoring in adults PAGEREF _Toc383607117 \h 63Table 20Dysphagia resulting from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607118 \h 64Table 21Eating and drinking difficulties resulting from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607119 \h 65Table 22Eating and drinking difficulties resulting from catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607120 \h 66Table 23Impact on daily life from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607121 \h 67Table 24Impact on daily life from catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607122 \h 69Table 25Overall discomfort and satisfaction from catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607123 \h 69Table 26Overall discomfort and satisfaction from catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607124 \h 71Table 27Failure rates / recording efficacy of catheter-free monitoring compared with catheter-based monitoring PAGEREF _Toc383607125 \h 76Table 28Diagnostic accuracy of catheter-free monitoring compared with catheter-based monitoring for diagnosing GORD in adults PAGEREF _Toc383607126 \h 86Table 29Diagnostic accuracy of catheter-free monitoring compared to clinical diagnosis for diagnosing GORD in adults PAGEREF _Toc383607127 \h 87Table 30Concordance of acid exposure times using both monitoring tests in adults PAGEREF _Toc383607128 \h 90Table 31Concordance of acid exposure times using both monitoring tests in children PAGEREF _Toc383607129 \h 92Table 32Number of reflux events in catheter-free monitoring compared with catheter-based monitoring PAGEREF _Toc383607130 \h 93Table 33Diagnostic yield using catheter-free monitoring compared to catheter-based monitoring PAGEREF _Toc383607131 \h 94Table 34Yield comparison between 24 hours and 48 hours with catheter-free monitoring PAGEREF _Toc383607132 \h 95Table 35Concordance between results of the test and treatment for GORD PAGEREF _Toc383607133 \h 98Table 36Specific management changes after wireless oesophageal pH monitoring PAGEREF _Toc383607134 \h 98Table 37Prevalence of symptoms at 5-year follow-up of LOTUS and REFLUX trials PAGEREF _Toc383607135 \h 104Table 38Summary of the economic evaluation (applies to both models) PAGEREF _Toc383607136 \h 113Table 39Implications for true positive and true negative test results for patients in the economic evaluation (base-case) PAGEREF _Toc383607137 \h 120Table 40Additional implications for false positive and false negative patients in the supplementary economic evaluation PAGEREF _Toc383607138 \h 120Table 41Health outcomes associated with treatment pathways in the model PAGEREF _Toc383607139 \h 123Table 42Testing-related healthcare resources used in the economic model PAGEREF _Toc383607140 \h 124Table 43Health state utilities used in the economic evaluation PAGEREF _Toc383607141 \h 125Table 44Utility adjustments used in the economic evaluation PAGEREF _Toc383607142 \h 126Table 45 Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERD PAGEREF _Toc383607143 \h 127Table 46 Model 2: Cost-effectiveness of wireless pH monitoring vs catheter-based pH monitoring in patients with refractory NERD PAGEREF _Toc383607144 \h 127Table 47 Societal ICERs following the proposed listing, allowing for various levels of leakage to include patients tolerant of catheter-based pH monitoring accessing wireless monitoring PAGEREF _Toc383607145 \h 128Table 48Sensitivity analyses around wireless pH-test accuracy for Model 1 PAGEREF _Toc383607146 \h 129Table 49Sensitivity analyses around the assumption of PPI discontinuation for Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERD PAGEREF _Toc383607147 \h 130Table 50Sensitivity analyses around the time horizon measured in Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERD PAGEREF _Toc383607148 \h 130Table 51Sensitivity analyses around the accuracy of wireless pH monitoring and catheter-based monitoring in Model 2 PAGEREF _Toc383607149 \h 131Table 52Additional MBS item resources expected to be used concurrently with all occasions of the proposed intervention PAGEREF _Toc383607150 \h 134Table 53 Other resources expected to be used concurrently with all occasions of the proposed intervention PAGEREF _Toc383607151 \h 134Table 54 Additional MBS item resources expected to be used concurrently in approximately 5%–10% of the proposed interventions PAGEREF _Toc383607152 \h 135Table 55 Total costs directly associated with a service of wireless pH monitoring under the proposed MBS listing PAGEREF _Toc383607153 \h 135Table 56Projected number of wireless pH tests annually under the proposed listing (base-case estimates) PAGEREF _Toc383607154 \h 136Table 57Sensitivity analyses for the projected number of wireless pH tests under the proposed listing PAGEREF _Toc383607155 \h 137Table 58 Total cost of the proposed intervention to the MBS (base-case) PAGEREF _Toc383607156 \h 138Table 59 Sensitivity analysis: Projected MBS costs associated with wireless pH monitoring if patient numbers grow at increased annual rate of 8% PAGEREF _Toc383607157 \h 138Table 60 Sensitivity analysis: Projected MBS costs associated with potential leakage (upper plausible extent) of wireless pH monitoring beyond the restriction (i.e. use in 90% of patients who are tolerant to catheter-based monitoring) PAGEREF _Toc383607158 \h 139Table 61 Sensitivity analysis: Changes in MBS costs of catheter-based monitoring associated with upper plausible limit of potential leakage to wireless pH monitoring beyond the restriction PAGEREF _Toc383607159 \h 140Table 62 Sensitivity analysis: Net changes in MBS costs associated with the proposed listing of wireless pH monitoring (including cost offsets associated with catheter-based monitoring) assuming the upper plausible extent of leakage to wireless pH monitoring beyond the restriction PAGEREF _Toc383607160 \h 141Table 63Costs of hospitalisation incurred by private insurer or patient (base-case) PAGEREF _Toc383607161 \h 142Table 64 Costs of hospitalisation incurred by private insurer or patient—alternative scenarios PAGEREF _Toc383607162 \h 142Table 65 Total Australian healthcare system costs (base-case) PAGEREF _Toc383607163 \h 143Table 66Total Australian healthcare system costs—alternative scenarios PAGEREF _Toc383607164 \h 143Table 67Body of evidence matrix PAGEREF _Toc383607165 \h 149Table 68Financial impact on the MBS, patients and private health insurers, assuming use is strictly limited to patients who cannot tolerate catheter-based monitoring PAGEREF _Toc383607166 \h 152Table 69Financial impact on the MBS, patients and private health insurers, assuming extensive use of wireless monitoring in patients who would otherwise have a catheter-based pH test PAGEREF _Toc383607167 \h 153Table 70Complications and adverse events of catheter-free monitoring compared with catheter-based monitoring in adults PAGEREF _Toc383607168 \h 231Table 71Complications and adverse events of catheter-free monitoring compared with catheter-based monitoring in children PAGEREF _Toc383607169 \h 234Table 72Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in adults PAGEREF _Toc383607170 \h 235Table 73Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in children PAGEREF _Toc383607171 \h 238Table 74Case reports reporting complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring PAGEREF _Toc383607172 \h 238Table 75Chest discomfort / complications resulting from catheter-free (wireless) oesophageal pH monitoring in adults PAGEREF _Toc383607173 \h 239Table 76Technical efficacy of catheter-free (wireless) oesophageal pH monitoring in adults PAGEREF _Toc383607174 \h 241Table 77Technical efficacy of catheter-free (wireless) oesophageal pH monitoring in children PAGEREF _Toc383607175 \h 245Table 78Day-to-day variability in oesophageal acid exposure with catheter-free monitoring in adults PAGEREF _Toc383607176 \h 246Table 79Day-to-day variability in oesophageal acid exposure with catheter-free monitoring in children PAGEREF _Toc383607177 \h 250Table 80Non-comparative diagnostic yield with catheter-free monitoring in adults PAGEREF _Toc383607178 \h 251Table 81Non-comparative diagnostic yield with catheter-free monitoring in children PAGEREF _Toc383607179 \h 252Table 82Anti-reflux surgery MBS item descriptors and claims from July 2012 to June 2013 PAGEREF _Toc383607180 \h 253Table 83Literature search in PubMed 21 November 2013 PAGEREF _Toc383607181 \h 254Table 84Literature containing economic models relating to pH monitoring and management of GORD symptoms PAGEREF _Toc383607182 \h 254Table 85A summary of variables used in the model PAGEREF _Toc383607183 \h 255Table 86Scenario/sensitivity tests around other inputs into the economic model (Model 1 vs empirical treatment) PAGEREF _Toc383607184 \h 256Table 87ASGE Technology Status Evaluation Report: wireless oesophageal pH-monitoring system PAGEREF _Toc383607185 \h 257 Boxes TOC \h \z \c "Box" Box 1Inclusion criteria for studies assessing the safety of catheter-free (wireless) oesophageal pH monitoring PAGEREF _Toc383607078 \h 56Box 2Eligibility criteria for identification of studies relevant to an assessment of effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring PAGEREF _Toc383607079 \h 73Box 3Eligibility criteria for identification of studies relevant to an assessment of the technical efficacy of catheter-free (wireless) ambulatory oesophageal pH monitoring PAGEREF _Toc383607080 \h 75Box 4Inclusion criteria for identification of studies relevant to an assessment of the accuracy of catheter-free (wireless) ambulatory oesophageal pH monitoring PAGEREF _Toc383607081 \h 83Box 5Inclusion criteria for identification of studies relevant to an assessment of change in management following catheter-free (wireless) ambulatory oesophageal pH monitoring PAGEREF _Toc383607082 \h 97Box 6Inclusion criteria for identification of studies relevant to an assessment of health outcomes following a change in management PAGEREF _Toc383607083 \h 101Figures TOC \f \c "Figure" Figure 1Catheter-based pH monitoring PAGEREF _Toc383607084 \h 29Figure 2Usage of catheter-based pH monitoring, July 2012 – June 2013 PAGEREF _Toc383607085 \h 34Figure 3Clinical management algorithm for the proposed new intervention PAGEREF _Toc383607086 \h 37Figure 4Summary of the process used to identify and select studies for the review (in first search) PAGEREF _Toc383607087 \h 44Figure 5Summary of the process used to identify and select studies for the review (in search 'true positives') PAGEREF _Toc383607088 \h 45Figure 6Summary of the process used to identify and select studies for the review (in search 'false negatives and false positives') PAGEREF _Toc383607089 \h 46Figure 7Meta-analysis of technical efficacy of catheter-free monitoring compared with catheter-based monitoring PAGEREF _Toc383607090 \h 78Executive summaryAssessment of catheter-free (wireless) ambulatory oesophageal pH monitoring for gastro-oesophageal reflux diseaseRationale for assessmentAn application requesting Medicare Benefits Schedule (MBS) listing of catheter-free (wireless) ambulatory oesophageal pH monitoring for gastro-oesophageal reflux disease (GORD) was received from Given Imaging Pty Ltd (the applicant) by the Department of Health in January 2012. Catheter-free monitoring is proposed for patients who have previously failed catheter-based monitoring or in whom the use of the latter is anatomically inappropriate. Gastro-oesophageal reflux disease (GORD) and pH monitoringGastric acid reflux in the oesophagus is a normal physiological event and it usually occurs after the consumption of a meal. Acid reflux can lead to impairment in quality of life or physical complications such as oesophagitis, Barrett’s oesophagus or oesophageal adenocarcinoma. Although there is no clear internationally applied definition for GORD, one of the accepted definitions is: ‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications’. Reflux is considered to impact on quality of life when symptoms are present on two or more days a week. When a GORD patient’s symptoms are resistant to acid suppression therapy, endoscopy is the primary test to exclude reflux disease and identify other causes. If the endoscopy result is negative, oesophageal pH monitoring is widely used to provide additional information. Oesophageal pH-monitoring measures the exposure of the oesophagus to acid reflux over a defined period of time, whereas endoscopy can only provide information at a single point in time. Currently, the 24-hour catheter-based pH-monitoring test is the most commonly used method of oesophageal pH monitoring. Catheter-based monitoring quantifies the time the oesophagus is exposed to acid and analyses the association between symptoms and reflux events. However, not every patient is able to tolerate catheter-based monitoring, e.g. due to gagging or anatomical challenges; as a consequence, they do not receive any pH monitoring.Catheter-free (wireless) ambulatory oesophageal pH monitoring is a system that consists of a small capsule that is usually delivered transorally during an oesophagoscopy, and a wireless receiver. The pH-monitoring capsule is temporarily attached to the oesophageal wall to measure and transmit pH information for at least 48 hours, sending it to the receiver and thereby circumventing the need for an oesophageal catheter.The primary comparator for catheter-free monitoring is ‘no pH monitoring’, although the Protocol Advisory Sub-Committee (PASC) of the Medicare Services Advisory Committee (MSAC) requested that the accuracy of catheter-free monitoring be compared against 'catheter-based monitoring’. Current arrangements for public reimbursementThere have been no previous MSAC considerations of catheter-free monitoring. The current test for GORD, 24-hour catheter-based monitoring, is listed on the MBS (item 11810) (see REF _Ref350151252 \h \* MERGEFORMAT Table 2). There were 3,590 claims for catheter-based monitoring from July 2012 to June 2013. The device used in catheter-free monitoring was listed on the Australian Register of Therapeutic Goods (ARTG) by the Therapeutic Goods Administration (TGA), and is currently classified as a Medical Device Class IIa (see REF _Ref364240778 \h Table 1). Its use in Australia is still limited: only 27, 22 and 46 catheter-free monitoring capsules were sold to Australian sites in 2011, 2012 and 2013, respectively. Clinical needReflux disease is common. Of patients attending GPs, 10.4% have GORD ADDIN EN.CITE <EndNote><Cite><Author>Knox</Author><Year>2008</Year><RecNum>36</RecNum><DisplayText>(Knox et al. 2008)</DisplayText><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">36</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knox, S. A.</author><author>Harrison, C. M.</author><author>Britt, H. C.</author><author>Henderson, J. V.</author></authors></contributors><auth-address>Family Medicine Research Centre, School of Public Health, University of Sydney, Sydney, NSW, Australia.</auth-address><titles><title>Estimating prevalence of common chronic morbidities in Australia</title><secondary-title>Med J Aust</secondary-title><alt-title>The Medical journal of Australia</alt-title></titles><periodical><full-title>Med J Aust</full-title><abbr-1>The Medical journal of Australia</abbr-1></periodical><alt-periodical><full-title>Med J Aust</full-title><abbr-1>The Medical journal of Australia</abbr-1></alt-periodical><pages>66-70</pages><volume>189</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Australia/epidemiology</keyword><keyword>Cardiovascular Diseases/epidemiology</keyword><keyword>Chronic Disease/*epidemiology</keyword><keyword>Female</keyword><keyword>Gastroesophageal Reflux/epidemiology</keyword><keyword>Health Surveys</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Morbidity</keyword><keyword>Prevalence</keyword><keyword>Pulmonary Disease, Chronic Obstructive/epidemiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul 21</date></pub-dates></dates><isbn>0025-729X (Print)&#xD;0025-729X (Linking)</isbn><accession-num>18637769</accession-num><urls><related-urls><url>;(Knox et al. 2008). Studies indicate that between 14% and 25% of adults experience reflux symptoms at least once a week. Although the prevalence of GORD is high, there is a relatively low usage of MBS item 11810 (catheter-based pH monitoring), so it would appear that pH monitoring is not often used for the study of this condition. The new intervention (catheter-free or wireless monitoring) will be used in patients who either fail catheter-based monitoring or in whom its use is anatomically inappropriate. It may avoid lengthy periods of unnecessary pharmacologic therapy in this group, expected to be 5–10% of the patients eligible for pH monitoring. An algorithm outlining the clinical management of patients with GORD, including the use of pH monitoring, can be found on page 37, ( REF _Ref379455005 \h \* MERGEFORMAT Figure 3).Results of assessmentSafety: Only one study was identified that assessed the safety of catheter-free monitoring compared with no monitoring. The findings indicated that chest pain was more likely to occur in those undergoing catheter-free monitoring than in those who did not undergo monitoring (RR=2.33, 95%CI 0.81, 6.76). Twelve studies compared the safety of catheter-free monitoring with catheter-based monitoring. No deaths or life-threatening events caused by pH monitoring were reported. Chest pain was significantly more prevalent in patients undergoing catheter-free monitoring compared with catheter-based monitoring, possibly due to the attachment of the capsule to the oesophageal wall. In a high-quality randomised controlled trial by Andrews et al. (2012), the median chest pain score during the pH test was 29?±?4?mm on a 100-point visual analogue scale (VAS) in the catheter-free monitoring group, compared with only 14?±?3?mm in the catheter-based monitoring group (p=0.001). The difference is likely to be clinically meaningful. However, other adverse events such as nose and throat pain, dysphagia, eating and drinking difficulties, and headache were more prevalent with catheter-based monitoring. Furthermore, catheter-based monitoring caused more overall discomfort and had a greater negative impact on normal daily activities and work attendance. Twenty-nine non-comparative studies of level IV interventional evidence were included to determine the rate of other complications and/or adverse events caused by catheter-free monitoring. Most adverse events reported were related to discomfort caused by the capsule attaching to the oesophageal mucosa, e.g. pharyngeal irritation, retrosternal discomfort and throat pain. More-severe complications from catheter-free monitoring, such as a rupture in the oesophageal mucosa, were rare. Effectiveness: Studies assessing the direct health impact of catheter-free monitoring versus no monitoring in the selected study population were not available. Two studies that did not meet the pre-specified inclusion criteria, but reported on the health effects of catheter-free monitoring, were included in the absence of more relevant data. One comparative study reported an improvement or disappearance of the principal symptom in 73% of patients in the wireless group (n=51) and 69% in the catheter-based group (n=51). A case series reported 9 patients with a good or moderate improvement in symptoms, out of 26 patients who received medical therapy or conservative advice after a catheter-free monitoring test.The sensitivity and specificity of catheter-free monitoring could be calculated from eight studies. In three of these studies the reference standard was catheter-based monitoring. The highest quality study, of level II diagnostic accuracy, indicated that a catheter-free monitoring test with a diagnostic cut-off point of 4.4% of the time that pH <4 had good sensitivity and specificity, with rates of 86.4% and 77.8%, respectively. The accuracy of catheter-free monitoring in the two other studies was similar, although test sensitivity was slightly lower and specificity slightly higher. Five diagnostic case-control studies, of level III-3 diagnostic accuracy, used clinical diagnosis as a reference standard. The study with the largest patient population reported sensitivity ranging between 59% and 88% and specificity between 75% and 96%, depending on which cut-off value was used (between 1.9% and 4.4% of the time that pH <4). There were nine studies that reported on oesophageal acid exposure times during catheter-free monitoring in adults. Most (five out of eight) of the studies reporting on adults found no difference between the two measurement methods. There was one study that reported concordance data on oesophageal acid exposure in children, finding significantly more reflux with wireless monitoring compared with catheter-based monitoring (p=0.01). Three of four available studies reported significantly more reflux events with the catheter-based monitoring system. Monitoring time was increased in the wireless-based compared with the catheter-based method. Six studies compared the yield of GORD diagnoses after 24 and 48?hours of catheter-free monitoring, and reported an additional yield on day 2 of monitoring, varying from 2.0% to 15.6% with a median of 7.8%.Nine studies reported on the technical efficacy of the wireless system. A meta-analysis was conducted and showed that there was over three times the risk (RR=3.3, 95%CI 1.63, 6.81) of having technical problems with the catheter-free monitoring system compared with catheter-based monitoring in adults. The risk decreased slightly (RR=2.87, 95%CI 1.47, 5.62) when used in a combined population of adults and children. The most commonly reported technical failures associated with catheter-free monitoring were early capsule detachments, causing incomplete data capture, and errors in placement of the system, i.e. in the wrong place in the oesophagus or where the capsule fails to attach to the oesophageal mucosa. On average, problems occurred more often during insertion or placement of the catheter-free system (median 7.5% of procedures, range 0–12%) than the catheter-based system (median 0.9% of procedures, range 0–4%). In most studies (15/20) the oesophageal acid exposure remained the same across 2?days of catheter-free monitoring in adults.Five studies reported on change in patient management after catheter-free monitoring, in patients who were suspected of GORD but who could have potentially tolerated a catheter-based test. The results of these studies were described due to a lack of more-relevant data in patients unable to tolerate a catheter-based test. One study reported that 42.2% (38/90) of patients continued to take proton pump inhibitors (PPIs) despite a negative pH test result. A second study reported that medical therapy or conservative advice was pursued in 68% of cases at a median of 2?years after the test, and two other studies showed that monitoring led to a change in management in 63% of adults and 88% of children. Finally, one other study stated that concordance between the test and treatment was higher after catheter-free monitoring than catheter-based monitoring: 78% vs 58% (p<0.05).To answer the question whether a change in management leads to better health outcomes, a second literature search was conducted. No evidence was found to determine the psychological or physical impact of a false negative test result. For people initially suspected of having GORD but eventually given an alternative diagnosis (i.e. true negatives), it was assumed that their management had been optimised as a result of obtaining the correct diagnosis. However, two retrospective case series reported poorer outcomes and worse treatment responses in infants with infantile spasms misdiagnosed as GORD (false positive test results) compared with infants with no treatment lag. Two systematic reviews comparing medical treatment with anti-reflux surgery reported that surgery was more effective than medical management at treating GORD symptoms, at least in the short to medium term.Two randomised controlled trials (RCTs) have been published since the high-quality Wileman et al. (2010) review was published. After 5?years laparoscopic fundoplication continued to provide better relief of GORD symptoms than medical management. Economic and financial considerationsTwo economic models were constructed to determine: the cost-effectiveness of catheter-free pH monitoring vs no monitoring (empirical treatment) in an Australian population who cannot tolerate catheter-based monitoring; and the cost-effectiveness (or not) of catheter-free monitoring vs catheter-based monitoring should use of the proposed listing ‘leak’ to include patients who are not intolerant of catheter-based monitoring.Characteristics of the cost–utility models, which assume a health system perspective from public and private healthcare providers and defined patient contributions are outlined in REF _Ref379483368 \h Table ES 1.Table ES 1Summary of the economic evaluation (applies to both models)Time horizonBase-case analysis of 15 yearsOutcomesQuality-adjusted life yearsMethods used to generate resultsMarkov model with half-cycle correctionCycle length1 yearDiscount rate5% for both costs and outcomesSoftware packages usedTreeAge Pro and Excel (hybrid)Key structural assumptions were: that a positive pH test result provided patients the option of surgery to treat GORD symptoms; and that a negative result would prompt investigation for other diagnoses and reduce the use of ongoing high-dose PPIs. When modelling, it was considered that inclusion of the accuracy of wireless pH monitoring when measured against catheter-based monitoring—an imperfect reference standard—would distort the results; therefore, the base-case assumes wireless pH monitoring, catheter-based monitoring and a trial of empirical treatment (high-dose PPIs) to be equally accurate. Sensitivity analyses explore alternative test accuracy values.The base-case analysis found that wireless pH monitoring vs no pH monitoring had an incremental cost-effectiveness ratio of $14,457 per quality-adjusted life year (QALY) gained. However, when compared against catheter-based monitoring, wireless monitoring was dominated—it had a higher cost and was less effective, with the lesser effectiveness due to an increased technical failure rate. Thus, if catheter-free monitoring were to be MBS listed, leakage of use into patients who could otherwise tolerate catheter-based monitoring may substantially reduce the assumed cost-effectiveness. The overall cost-effectiveness of an MBS listing is dependent on the predicted extent of leakage, with 30% leakage into cohorts of patients who are able to tolerate, or do not fail, catheter-based monitoring increasing the overall incremental cost-effectiveness ratio (ICER) to $58,429/QALY.Other key areas of uncertainty in the cost–utility models relate to: the assumed accuracy of the test—where imperfect sensitivity and specificity values are incorporated, sensitivity analyses showed that wireless monitoring was dominated, with sensitivity values ≤90%; and the assumption that, in the absence of a pH test (which incorporates a follow-up assessment of results), some patients will be trialled on high-dose PPIs and inappropriately remain on this treatment indefinitely. That this occurs is supported by the literature and expert opinion, but quantification is highly uncertain. If the assumption is removed altogether, wireless pH monitoring is dominated by an empirical trial of high-dose medication. The base-case assumes that inappropriate ongoing high-dose PPI use occurs in 1 in 10 patients diagnosed with non-erosive reflux disease (NERD)-like symptoms but who actually have a non-acid related condition.It is estimated that the ‘true’ catheter-intolerant patient population who would benefit from wireless monitoring would be approximately 400 patients per year (2015–16 estimate = 404), increasing by 4%–8% per year, based on the current extent and growth of catheter-based pH monitoring MBS claims. This estimate would result in MBS costs of approximately $369,000 directly associated with the new item number, and a further $67,000 in associated MBS-funded anaesthesia items, per year (with annual growth). There are no MBS cost offsets in this patient population. Of this expenditure of $436,000, patients are expected to pay approximately $100,000.The overall financial impact of the proposed listing is also highly dependent on the extent of predicted use beyond the intended catheter-intolerant population, and it is noted that the proposed fee, in including an ‘equipment depreciation’ component, provides an incentive that encourages increased servicing.If 90% (an extreme upper plausible limit) of patients who are tolerant to catheter-based monitoring ‘switched’ to wireless monitoring, the net MBS impacts, including cost offsets of ‘unused’ catheter-based monitoring, would exceed $3.5?million per year, of which approximately $880,000 would be paid through patient contributions.Other non-MBS costs incurred are private hospital costs, which may range from $275,000 to $2.5?million across the population, depending on leakage.Other relevant considerations / discussionThe catheter-free monitoring test is seen as more convenient and has less impact on daily activities than catheter-based monitoring. It can be difficult to determine who is ‘unable’ to tolerate a catheter. Physicians might therefore be inclined to give more patients catheter-free monitoring than catheter-based monitoring to avoid discomfort and embarrassment. Thus, it is possible that the population using catheter-free monitoring may expand beyond the population currently being considered for eligibility for the device, and this ‘leakage’ could lead to extra costs (see ‘Economic and financial considerations’).The validity of catheter-based monitoring as a reference standard to determine the diagnostic accuracy of catheter-free monitoring is questionable. First, catheter-free monitoring is able to monitor acid reflux for 48?hours instead of the 24?hours used with catheter-based monitoring; this leads to increased diagnostic yield. Second, many of the short reflux events that are measured by catheter-based monitoring and not by catheter-free monitoring could be artefacts that are not related to GORD. It is possible that catheter-free monitoring is more accurate than catheter-based monitoring.There are other limitations with the reported test accuracy data. There was considerable variation and a lack of consensus across the studies in the evidence-base with regard to diagnostic thresholds (cut-off points), defining a positive test result (worst day analysis, positive value on both days, reflux symptom correlation) and determining the optimal position of the capsule in the oesophagus. There is therefore a considerable lack of certainty with regard to the reported test accuracy results. Glossary and abbreviations TermDescriptionAHTAAdelaide Health Technology AssessmentARTGAustralian Register of Therapeutic Goodscatheter-based monitoringcatheter-based pH monitoringcatheter-free monitoringcatheter-free (wireless) pH monitoringCBPMcatheter-based pH monitoringCFPMcatheter-free (wireless) pH monitoringCIconfidence intervalDAPdecision analytic protocolFHfunctional heartburnGOJgastro-oesophageal junctionGORDgastro-oesophageal reflux diseaseH. pyloriHelicobacter pyloriH2histamine 2 (receptor)HESPHealth Expert Standing PanelHOhypersensitive oesophagusICERincremental cost-effectiveness ratioLOSlower oesophageal sphincterLR+likelihood ratio positiveLR–likelihood ratio negativeMBSMedicare Benefits ScheduleMIImultichannel intraluminal impedanceMSACMedical Services Advisory CommitteeNERDnon-erosive reflux diseaseNHMRCNational Health and Medical Research CouncilNPVnegative predictive valueNSnot significantOeOoesinophilic oeosphagitisPASCProtocol Advisory Sub-Committee (of MSAC)PBSPharmaceutical Benefits SchemePPIsproton pump inhibitorsPPVpositive predictive valueQALYquality-adjusted life yearQoLquality of lifeRCTrandomised controlled trialSCJsquamo-columnar junctionVASvisual analogue scaleIntroductionThis assessment report is intended for the Medical Services Advisory Committee (MSAC). MSAC evaluates new and existing health technologies and procedures for which funding is sought under the Medicare Benefits Schedule (MBS) in terms of their safety, effectiveness and cost-effectiveness, while taking into account other issues such as access and equity. MSAC adopts an evidence-based approach to its assessments, based on reviews of the scientific literature and other information sources, including clinical expertise.Adelaide Health Technology Assessment (AHTA), School of Population Health, University of Adelaide, has been commissioned by the Australian Government Department of Health to conduct a systematic literature review and economic evaluation of the use of catheter-free (wireless) oesophageal pH monitoring in the diagnosis of gastro-oesophageal reflux disease (GORD). This evaluation has been undertaken in order to inform MSAC’s decision-making regarding public funding of the intervention. The proposed use of catheter-free (wireless) oesophageal pH monitoring in Australian clinical practice was outlined in a decision analytical protocol (DAP) that guided the evaluation undertaken by AHTA. The DAP was released for public comment on 28 May 2012 and closed for comments on 5 July 2012. No public consultation responses were received. The DAP was finalised as a result of PASC deliberation on 16–17 August 2012.Rationale for assessmentGiven Imaging Pty Ltd (the applicant) submitted an application to the Department of Health in January 2012, requesting an MBS listing for catheter-free (wireless) ambulatory oesophageal pH monitoring for the diagnosis of GORD. Its use is proposed in patients who have previously failed catheter-based monitoring or in whom the use of the latter is anatomically inappropriate. BackgroundGastro-oesophageal reflux disease (GORD)Gastric acid reflux in the oesophagus is a normal physiological event and it usually occurs after the consumption of a meal. GORD occurs when acid reflux impairs a person’s quality of life or when it leads to a risk of physical complications such as oesophagitis, Barrett’s oesophagus or oesophageal adenocarcinoma ADDIN EN.CITE <EndNote><Cite><Year>2011</Year><RecNum>14</RecNum><DisplayText>(Gastroenterological Society of Australia 2011)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">14</key></foreign-keys><ref-type name="Pamphlet">24</ref-type><contributors><authors><author>Gastroenterological Society of Australia,</author></authors><secondary-authors><author>Gastroenterological Society of Australia</author></secondary-authors></contributors><titles><title>Gastro-oesophageal Reflux Disease in Adults (5th ed)</title></titles><dates><year>2011</year></dates><publisher>Gastroenterological Society of Australia, Digestive Health Foundation</publisher><urls></urls></record></Cite></EndNote>(Gastroenterological Society of Australia 2011). 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ADDIN EN.CITE.DATA (Dent et al. 2005; Katz, Gerson & Vela 2012). The current definition of the disorder being used by the International Foundation of Functional Gastrointestinal Disorders (IFFGD) and the American Gastroenterological Association is: ‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications’ PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JRkZHRDwvQXV0aG9yPjxSZWNOdW0+NTg2PC9SZWNOdW0+

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ADDIN EN.CITE.DATA (IFFGD 2014; Kahrilas 2008; Kahrilas, Shaheen & Vaezi 2008). Reflux is considered to impact on quality of life when symptoms are present on two or more days a week. The definition used by the Gastroenterological Society of Australia (2013) is ‘persistent reflux that occurs more than twice a week’. Oesophagitis, which is present in about one-third of GORD patients, occurs when excessive reflux of acid and pepsin results in necrosis of surface layers of the oesophageal mucosa, causing erosions and ulcers. Although the absolute risk of oesophageal cancer in an individual with GORD is small ADDIN EN.CITE <EndNote><Cite><Year>2011</Year><RecNum>14</RecNum><DisplayText>(Gastroenterological Society of Australia 2011)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">14</key></foreign-keys><ref-type name="Pamphlet">24</ref-type><contributors><authors><author>Gastroenterological Society of Australia,</author></authors><secondary-authors><author>Gastroenterological Society of Australia</author></secondary-authors></contributors><titles><title>Gastro-oesophageal Reflux Disease in Adults (5th ed)</title></titles><dates><year>2011</year></dates><publisher>Gastroenterological Society of Australia, Digestive Health Foundation</publisher><urls></urls></record></Cite></EndNote>(Gastroenterological Society of Australia 2011), oesophageal adenocarcinoma is epidemiologically linked to GORD and the incidence of both is increasing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWhyaWxhczwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

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ADDIN EN.CITE.DATA (Kahrilas 2008; Lagergren et al. 1999). Up to 15% of patients with chronic reflux disease undergoing endoscopy may be shown to develop Barrett’s oesophagus. This condition involves the development of columnar metaplasia in place of the normal squamous epithelium, and is a risk factor for the development of oesophageal adenocarcinoma PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFoZWVuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

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ADDIN EN.CITE.DATA (Gastroenterological Society of Australia 2011; Kahrilas 2008). Also, the following specific patient groups are at higher risk of GORD and its complications ADDIN EN.CITE <EndNote><Cite><Year>2011</Year><RecNum>14</RecNum><DisplayText>(Gastroenterological Society of Australia 2011)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">14</key></foreign-keys><ref-type name="Pamphlet">24</ref-type><contributors><authors><author>Gastroenterological Society of Australia,</author></authors><secondary-authors><author>Gastroenterological Society of Australia</author></secondary-authors></contributors><titles><title>Gastro-oesophageal Reflux Disease in Adults (5th ed)</title></titles><dates><year>2011</year></dates><publisher>Gastroenterological Society of Australia, Digestive Health Foundation</publisher><urls></urls></record></Cite></EndNote>(Gastroenterological Society of Australia 2011): patients with connective tissue diseases such as sclerodermapatients with chronic respiratory diseases such as asthma and cystic fibrosispeople who are institutionalised and/or intellectually handicappedpatients nursed in a supine position for prolonged periods. Most GORD patients experience a burning feeling rising up from the stomach or lower chest towards the neck, known as heartburn. However, the symptoms of GORD, ulcer disease, irritable bowel syndrome (IBS) and dyspepsia are often similar. When a patient exhibits typical GORD symptoms and responds to therapy, no additional diagnostic tests are necessary. Diagnostic testing is usually done to avert misdiagnosis, identify complications of GORD and evaluate treatment failures. Other diagnoses that could be considered when GORD treatment fails include coronary heart disease; gallbladder disease; gastric or oesophageal cancer; peptic ulcer disease; oesophageal motility disorders; and oesinophilic, infectious or pill oesophagitis ADDIN EN.CITE <EndNote><Cite><Author>Kahrilas</Author><Year>2008</Year><RecNum>587</RecNum><IDText>1700-7</IDText><DisplayText>(Kahrilas 2008)</DisplayText><record><rec-number>587</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">587</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kahrilas, P. J.</author></authors></contributors><auth-address>Division of Gastroenterology, Feinberg School of Medicine, Chicago IL 60611-2951, USA. p-kahrilas@northwestern.edu</auth-address><titles><title>Clinical practice. Gastroesophageal reflux disease</title><secondary-title>N Engl J Med</secondary-title><alt-title>The New England journal of medicine</alt-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><alt-periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></alt-periodical><pages>1700-7</pages><volume>359</volume><number>16</number><keywords><keyword>Esophagus/pathology</keyword><keyword>*Fundoplication</keyword><keyword>Gastroesophageal Reflux/complications/diagnosis/*therapy</keyword><keyword>Histamine Antagonists/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Proton Pump Inhibitors/*therapeutic use</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct 16</date></pub-dates></dates><isbn>1533-4406 (Electronic)&#xD;0028-4793 (Linking)</isbn><accession-num>18923172</accession-num><urls><related-urls><url>;(Kahrilas 2008). When the patient’s symptoms are resistant to acid suppression therapy, endoscopy is the primary test to exclude reflux disease and to diagnose other causes. However, the yield of endoscopy is low because of the poor correlation between symptoms of GORD and oesophagitis, the likelihood that oesophagitis may already have been resolved with previous therapy, and its poor sensitivity at detecting motility disorders. If the endoscopy result is negative, other physiological testing can be considered, such as oesophageal manometry to detect motility disorders, ambulatory pH monitoring to demonstrate abnormal exposure to acid (see below), or impedance monitoring to identify reflux events regardless of acidic content PEVuZE5vdGU+PENpdGU+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjE0PC9SZWNOdW0+PERpc3Bs

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ADDIN EN.CITE.DATA (Gastroenterological Society of Australia 2011; Kahrilas 2008). Treatments for GORD depend on symptom severity and include lifestyle modification, pharmacologic therapy [proton pump inhibitors (PPIs), H2 (histamine 2) antagonists] and surgical intervention. PPIs and H2 antagonists both reduce gastric acid production, although PPIs seem to be more effective than H2 antagonists PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fcmlrc3NvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+

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ADDIN EN.CITE.DATA (Eriksson et al. 1995). Reflux disease patients with severe oesophagitis may be treated with a standard dose of PPIs on an ongoing basis. A surgical intervention, usually laparoscopic fundoplication, is indicated in patients whose GORD symptoms cannot be controlled using medical therapy, or who wish to avoid being medicated over the long term and accept the risks associated with a surgical procedure. pH monitoringOesophageal pH monitoring is widely used to monitor GORD after a negative endoscopy result. It provides additional information by monitoring acid reflux over a period of time rather than, in the case of endoscopy, at one point in time. It is useful when the relationship between symptoms and reflux aetiology remains unclear. A pH-monitoring study may reveal PPI failure and associated ongoing acid reflux, which may require dose escalation of therapy, adequate acid control or no reflux. When the pH study in refractory GORD patients is negative, those with heartburn may be classified as having ‘functional heartburn’; and in those with other ongoing, atypical symptoms, other diagnoses may be considered ADDIN EN.CITE <EndNote><Cite><Author>Katz</Author><Year>2012</Year><RecNum>239</RecNum><DisplayText>(Katz, Gerson &amp; Vela 2012)</DisplayText><record><rec-number>239</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">239</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Katz, P. O.</author><author>Gerson, L. B.</author><author>Vela, M. F.</author></authors></contributors><auth-address>Division of Gastroenterology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.</auth-address><titles><title>Guidelines for the diagnosis and management of gastroesophageal reflux disease</title><secondary-title>Am J Gastroenterol</secondary-title><alt-title>The American journal of gastroenterology</alt-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><alt-periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></alt-periodical><pages>308-28</pages><volume>108</volume><number>3</number><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>23419381</accession-num><urls><related-urls><url>;(Katz, Gerson & Vela 2012). The current MBS-approved pH-monitoring test for GORD: catheter-based ambulatory oesophageal pH monitoring (MBS item 11810)Currently, the 24-hour catheter-based pH-monitoring system is commonly used to objectively diagnose GORD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWJlcjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Weber, Davis & Fisichella 2011). Before the measurement starts, a pH-measuring sensor with a catheter is passed transnasally and placed with manometric guidance. This is often a cause of discomfort for the patient. The catheter is then taped to the patient’s nose, and the patient returns to the hospital or rooms of the specialist 24?hours later to have the catheter removed and the data analysed.Although catheter-based monitoring quantifies the time the oesophagus is exposed to acid and measures the association between symptoms and reflux events, it does have some disadvantages. It is claimed that poor patient tolerance is the main drawback, as it leads to patient discomfort, social embarrassment, and alteration of daily activities and eating habits during the monitoring period ( REF _Ref379455158 \h Figure 1). Other claimed disadvantages include variable test accuracy and a limited observation period that leads to less-reproducible results. It is very important that the sensors are correctly placed in order for the results to be valid PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Lee 2012; Weber, Davis & Fisichella 2011). The information from the sensor is used to guide or reassess treatment strategies for patients.Figure 1Catheter-based pH monitoring Source: [accessed August 2013]Catheter-free (wireless) ambulatory oesophageal pH monitoringCatheter-free (wireless) ambulatory oesophageal pH monitoring for use in the confirmatory diagnosis of GORD is a system that consists of a small capsule (which is usually delivered transorally during an oesophagoscopy or sometimes transnasally during manometry) plus a wireless receiver that the patient wears on his or her belt. The radiotelemetry pH-monitoring capsule is temporarily attached to the oesophagus wall to measure and transmit pH information every 6?seconds for at least 48?hours, sending it to the receiver and thereby circumventing the need for an oesophageal catheter PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWJlcjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Maerten et al. 2007; Weber, Davis & Fisichella 2011). The wireless capsule is invisible, so the patient should be better able to carry out his/her normal daily activities, which should lead to more reliable and accurate results. The procedureFirst, the capsule is calibrated by submersion in pH buffer solutions, and is then placed through the mouth, and sometimes the nose, into the oesophagus via endoscopic guidance. The distal end of the capsule is placed approximately 6?cm above the squamo-columnar junction (SCJ) or 5?cm above the proximal border of the LOS via manometric guidance. The LOS is usually localised before capsule placement PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OdXNyYXQ8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Nusrat, Roy & Bielefeldt 2012). The capsule itself measures 6?x?5.5?x?25?mm and contains a 3.5?mm-deep well that is connected to an external vacuum unit. When the capsule is being placed, suction is applied through the suction channel, causing the adjacent mucosa to be drawn into the well of the capsule. At this point a spring-loaded mechanism puts a little stainless steel pin through the well of the capsule, securing the mucosa in the well and attaching the capsule to the oesophageal wall. The delivery system is then removed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWVydGVuPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA (Maerten et al. 2007; Pandolfino et al. 2003). The single-use capsule makes catheter-free monitoring more expensive than the traditional catheter-based monitoring, which usually uses a reusable catheter, although single-use catheters are also available. During the pH recording days, patients keep a diary where they record food intake, symptoms and activities, including changes in their position. After 48?hours the patient returns to the hospital or specialist’s rooms, and the information on the receiver is uploaded to a computer and interpreted by a physician. AccuView is the software used to review and analyse the test results. Recent versions of the software are compatible with both the Bravo pH (catheter-free) and Digitrapper pH-Z (catheter-based) monitoring systems, eliminating the need to learn and maintain separate systems. The information in the diary is used to interpret the pH data. The capsule usually spontaneously dislodges from the oesophageal mucosa within 15?days. However, in some cases it does not spontaneously detach and needs to be endoscopically removed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5kb2xmaW5vPC9BdXRob3I+PFllYXI+MjAwMzwvWWVh

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ADDIN EN.CITE.DATA (Sweis et al. 2009). Early referral for pH monitoring, and pH monitoring of patients who fail catheter-based monitoring, may avoid lengthy periods of unnecessary medical therapy ADDIN EN.CITE <EndNote><Cite><Author>Kleiman</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(Kleiman et al. 2012)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kleiman, D. A.</author><author>Sporn, M. J.</author><author>Beninato, T.</author><author>Metz, Y.</author><author>Crawford, C.</author><author>Fahey, T. J., 3rd</author><author>Zarnegar, R.</author></authors></contributors><auth-address>Division of Endocrine and Minimally Invasive Surgery, Department of Surgery, New York Presbyterian Hospital - Weill Cornell Medical College, 525 East 68th Street, F-2024, New York, NY, 10065, USA, dak2011@.</auth-address><titles><title>Early referral for 24-h esophageal pH monitoring may prevent unnecessary treatment with acid-reducing medications</title><secondary-title>Surg Endosc</secondary-title><alt-title>Surgical endoscopy</alt-title></titles><periodical><full-title>Surg Endosc</full-title><abbr-1>Surgical endoscopy</abbr-1></periodical><alt-periodical><full-title>Surg Endosc</full-title><abbr-1>Surgical endoscopy</abbr-1></alt-periodical><dates><year>2012</year><pub-dates><date>Dec 12</date></pub-dates></dates><isbn>1432-2218 (Electronic)&#xD;0930-2794 (Linking)</isbn><accession-num>23232999</accession-num><urls><related-urls><url>;(Kleiman et al. 2012). The expectation is that pH monitoring will change management in patients suspected of GORD in approximately 50% of cases, although such changes are not always maintained, and this may lead to an increased quality of life for this patient group PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FY2thcmR0PC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48

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ADDIN EN.CITE.DATA (Eckardt, Dilling & Bernhard 1999; Hirano, Richter & Practice Parameters Committee of the American College of 2007; Netzer et al. 1999).IndicationsThe American College of Gastroenterology documented the usefulness of pH monitoring in GORD patients and its impact on patient management PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaXJhbm88L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Hirano, Richter & Practice Parameters Committee of the American College of 2007; Katz, Gerson & Vela 2012). They determined that pH monitoring is useful to:quantify reflux and assess the relationship between reflux episodes and the patient’s symptomsdocument abnormal oesophageal acid exposure in endoscopy-negative individuals being considered for a surgical anti-reflux procedureevaluate endoscopy-negative patients with typical or atypical reflux symptoms that are refractory to PPI therapy document the adequacy of PPI therapy in oesophageal acid control in patients with complications of GORD that include Barrett’s oesophagus.Of these patients, catheter-free monitoring would be indicated for those in whom catheter-based monitoring has failed or is anatomically inappropriate.Contraindications for catheter-free (wireless) ambulatory oesophageal pH monitoring include the following (Maerten et al. 2007):haemorrhagic diathesisoesophageal varicessevere oesophagitisoesophageal strictures or diverticulahaving a pacemaker or defibrillatorpregnancy.Clinical need Reflux disease is common. Knox et al. (2008) estimated the prevalence of GP-diagnosed GORD in Australia to be around 10.4% of patients. The prevalence in the Australian population was estimated at 9.2%, which equates to approximately 2?million Australians with GORD. Knox et al. reported on the percentage of patients who were currently under clinical management, which means that this study probably underestimated the total GORD prevalence. Other studies report higher prevalence rates, ranging between 14% and 25% of adults experiencing symptoms of reflux at least once a week PEVuZE5vdGU+PENpdGU+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjE0PC9SZWNOdW0+PERpc3Bs

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ADDIN EN.CITE.DATA (Gastroenterological Society of Australia 2011; Kahrilas 2008; Miller & Pan 2009). The lower prevalence recorded from GP-encounter data compared with community-based studies may indicate that there is a significant level of unmet need for management of this disease in the Australian community.There is a lack of epidemiological data on GORD in infants and children. However, one American study reported that at least one episode of regurgitation a day occurs in approximately half of infants aged 0–3?months, and heartburn and regurgitation were reported on a weekly basis in about 2% of 3–9 year old children and 5%–8% of 10–17 year old children ADDIN EN.CITE <EndNote><Cite><Author>Nelson</Author><Year>2000</Year><RecNum>607</RecNum><IDText>150-4</IDText><DisplayText>(Nelson et al. 2000)</DisplayText><record><rec-number>607</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">607</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nelson, S. P.</author><author>Chen, E. H.</author><author>Syniar, G. M.</author><author>Christoffel, K. K.</author></authors></contributors><auth-address>Division of Gastroenterology, Northwestern University Medical School and Children&apos;s Memorial Medical Center, Chicago, IL 60614, USA. snelson@nwu.edu</auth-address><titles><title>Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Pediatric Practice Research Group</title><secondary-title>Arch Pediatr Adolesc Med</secondary-title><alt-title>Archives of pediatrics &amp; adolescent medicine</alt-title></titles><periodical><full-title>Arch Pediatr Adolesc Med</full-title><abbr-1>Archives of pediatrics &amp; adolescent medicine</abbr-1></periodical><alt-periodical><full-title>Arch Pediatr Adolesc Med</full-title><abbr-1>Archives of pediatrics &amp; adolescent medicine</abbr-1></alt-periodical><pages>150-4</pages><volume>154</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Chicago/epidemiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Female</keyword><keyword>Gastroesophageal Reflux/*epidemiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Prevalence</keyword></keywords><dates><year>2000</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1072-4710 (Print)&#xD;1072-4710 (Linking)</isbn><accession-num>10665601</accession-num><urls><related-urls><url>;(Nelson et al. 2000). GORD occurs more often in developed countries and may be associated with reduction of Helicobacter pylori (H. pylori) colonisation of the gastric mucosa due to better hygiene, a greater use of antibiotics, and the increasing frequency of obesity in the community ADDIN EN.CITE <EndNote><Cite><Author>Knox</Author><Year>2008</Year><RecNum>36</RecNum><DisplayText>(Knox et al. 2008)</DisplayText><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">36</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knox, S. A.</author><author>Harrison, C. M.</author><author>Britt, H. C.</author><author>Henderson, J. V.</author></authors></contributors><auth-address>Family Medicine Research Centre, School of Public Health, University of Sydney, Sydney, NSW, Australia.</auth-address><titles><title>Estimating prevalence of common chronic morbidities in Australia</title><secondary-title>Med J Aust</secondary-title><alt-title>The Medical journal of Australia</alt-title></titles><periodical><full-title>Med J Aust</full-title><abbr-1>The Medical journal of Australia</abbr-1></periodical><alt-periodical><full-title>Med J Aust</full-title><abbr-1>The Medical journal of Australia</abbr-1></alt-periodical><pages>66-70</pages><volume>189</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Australia/epidemiology</keyword><keyword>Cardiovascular Diseases/epidemiology</keyword><keyword>Chronic Disease/*epidemiology</keyword><keyword>Female</keyword><keyword>Gastroesophageal Reflux/epidemiology</keyword><keyword>Health Surveys</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Morbidity</keyword><keyword>Prevalence</keyword><keyword>Pulmonary Disease, Chronic Obstructive/epidemiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul 21</date></pub-dates></dates><isbn>0025-729X (Print)&#xD;0025-729X (Linking)</isbn><accession-num>18637769</accession-num><urls><related-urls><url>;(Knox et al. 2008). However, the relationship between H. pylori infection and GORD is still controversial ADDIN EN.CITE <EndNote><Cite><Author>Katz</Author><Year>2012</Year><RecNum>239</RecNum><DisplayText>(Katz, Gerson &amp; Vela 2012)</DisplayText><record><rec-number>239</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">239</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Katz, P. O.</author><author>Gerson, L. B.</author><author>Vela, M. F.</author></authors></contributors><auth-address>Division of Gastroenterology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.</auth-address><titles><title>Guidelines for the diagnosis and management of gastroesophageal reflux disease</title><secondary-title>Am J Gastroenterol</secondary-title><alt-title>The American journal of gastroenterology</alt-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><alt-periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></alt-periodical><pages>308-28</pages><volume>108</volume><number>3</number><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>23419381</accession-num><urls><related-urls><url>;(Katz, Gerson & Vela 2012). It is known that GORD patients with daily or weekly symptoms are more likely to have time off work, a decrease in work productivity, lower quality sleep and a decrease in physical functioning. Nocturnal GORD has an even greater impact on quality of life compared with daytime symptoms ADDIN EN.CITE <EndNote><Cite><Author>Katz</Author><Year>2012</Year><RecNum>239</RecNum><DisplayText>(Katz, Gerson &amp; Vela 2012)</DisplayText><record><rec-number>239</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">239</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Katz, P. O.</author><author>Gerson, L. B.</author><author>Vela, M. F.</author></authors></contributors><auth-address>Division of Gastroenterology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.</auth-address><titles><title>Guidelines for the diagnosis and management of gastroesophageal reflux disease</title><secondary-title>Am J Gastroenterol</secondary-title><alt-title>The American journal of gastroenterology</alt-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><alt-periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></alt-periodical><pages>308-28</pages><volume>108</volume><number>3</number><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>23419381</accession-num><urls><related-urls><url>;(Katz, Gerson & Vela 2012). Other existing tests for GORDOesophageal impedance testingIn 1991 multichannel intraluminal impedance (MII) was first described. It is a technology that is able to detect refluxate moving from the stomach into the oesophagus, independent of the content. With this method it is possible to determine the composition, distribution and clearance of gastro-oesophageal reflux, differentiating between the refluxate of liquid, gas, and combined liquid and gas. Impedance depends on the conductivity of material through which current travels; this means that MII measures the electrical conductivity across a pair of electrodes in the oesophageal lumen, and changes in conductivity as a result of intraoesophageal materials moving will be recorded. It can detect movement in both the retrograde (reflux) and the anterograde (swallow) direction. This test uses a catheter and can be combined with catheter-based monitoring. 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ADDIN EN.CITE.DATA (Hirano 2006; Tutuian 2008; Weber, Davis & Fisichella 2011; Wilson & Vela 2008).Marketing status of device/technologyAll therapeutic products marketed in Australia require listing on the Australian Register of Therapeutic Goods (ARTG). The device for catheter-free monitoring is listed on the ARTG under the item shown in REF _Ref364240778 \h \* MERGEFORMAT Table 1. It is stated that ‘the Bravo pH-monitoring system is intended to be used for gastro-oesophageal pH measurement and monitoring of gastric reflux’. Table 1Catheter-free monitoring device listed on the ARTGARTG no.Product no.Product descriptionProduct categorySponsor20579558357Gastrointestinal telemetric monitoring systemMedical Device Class IIaGiven Imaging Pty LimitedSource: Therapeutic Goods Administration, [accessed 14 August 2013]Current reimbursement arrangementsCurrently, there is no listing on the MBS for catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD. As a result, its use in Australia is limited: only 27, 22 and 46 capsules were sold to Australian sites in 2011, 2012 and 2013, respectively.The diagnostic test for GORD currently listed on the MBS—24-hour ambulatory catheter-based pH monitoring—is shown in REF _Ref350151252 \h \* MERGEFORMAT Table 2. Table 2Relevant MBS item for the currently reimbursed test for GORDCategory 2 – Diagnostic procedures and interventionsMBS 11810CLINICAL ASSESSMENT of GASTRO-OESOPHAGEAL REFLUX DISEASE involving 24 hour pH monitoring, including analysis, interpretation and report and including any associated consultation Fee: $174.45 Benefit: 75% = $130.85 85% = $148.30Although GORD is relatively common, there is fairly low usage of the current MBS item for pH monitoring; there were only 3,590 claims for catheter-based monitoring from July 2012 until June 2013 ( REF _Ref379455256 \h \* MERGEFORMAT Figure 2). It is claimed that part of the low usage for the current test could reflect the discomfort and inconvenience of having a catheter in place for 24?hours, so that use of pH-monitoring devices might increase if catheter-free monitoring is publicly funded on the MBS.Figure 2Usage of catheter-based pH monitoring, July 2012 – June 2013 Source: Medicare (2013)Surgical treatments for GORD are listed under five different MBS item numbers: 43951, 43954, 31464, 30527 and 30530. A total of 1,834 anti-reflux procedures were claimed from July 2012 to June 2013 ADDIN EN.CITE <EndNote><Cite><Author>Medicare</Author><Year>2013</Year><RecNum>240</RecNum><DisplayText>(Medicare 2013)</DisplayText><record><rec-number>240</rec-number><foreign-keys><key app="EN" db-id="5dedfdstldtwtle05ahpwf0cv25ze0ef2e5v">240</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Medicare</author></authors></contributors><titles><title>Medicare Item Reports</title></titles><dates><year>2013</year></dates><pub-location>Canberra</pub-location><publisher>Australian Government</publisher><urls></urls></record></Cite></EndNote>(Medicare 2013). For the description and usage of each individual item number, see REF _Ref375317101 \h \* MERGEFORMAT Appendix I. Proposal for public fundingThe proposed MBS item is summarised in REF _Ref373485347 \h \* MERGEFORMAT Table 3. The fee was suggested by the applicant. It includes a $350 fee for professional time for performing the test, $430.40 for the capsule itself and $133.25 for the reader system. The proposed item descriptor makes it clear that it is a requirement that all individuals undergoing catheter-free monitoring have previously failed catheter-based monitoring or are anatomically inappropriate for a catheter-based system. Furthermore, the test should only be performed by a specialist or consultant physician with endoscopic training that is recognised by the Conjoint Committee for the Recognition of Training in Gastrointestinal Endoscopy.Table 3Proposed MBS item descriptorCategory 2 – Diagnostic procedures and interventionsCLINICAL ASSESSMENT of GASTRO-OESOPHAGEAL REFLUX DISEASE that involves 48 hour catheter-free wireless ambulatory oesophageal pH monitoring including administration of the device and any endoscopy associated with this, analysis and interpretation of the data and all attendances providing the service, ifThe service is performed by a specialist or consultant physician with endoscopic training that is recognised by the Conjoint Committee for the Recognition of Training in Gastrointestinal Endoscopy; andThe patient has previously failed (rather than intolerant of) a catheter-based ambulatory oesophageal pH-monitoring or is anatomically inappropriate for a catheter-based-systemFee: $913.64Consumer impact statementPASC received one response from the public when the DAP was put out for public consultation—from the professional body, the Gastroenterological Society of Australia (GESA). Approach to assessment The purpose of a DAP is to describe in detail a limited set of decision option(s) associated with the possible public funding of a proposed medical service. A DAP also accurately captures current clinical practice, reflects likely future practice with the proposed?medical service, and describes all potentially affected healthcare resources. A DAP was developed prior to the commencement of this assessment, and was approved by the PASC of MSAC. The guiding framework of the DAP was used throughout this assessment.ObjectiveTo determine whether there is sufficient evidence, in relation to safety, effectiveness and cost-effectiveness, to have catheter-free monitoring for GORD listed on the MBS for patients who have previously failed a catheter-based test or for whom catheter-based monitoring is anatomically inappropriate.Clinical pathwayA flowchart can help define the place of a new intervention in the clinical management of a patient. The solid lines in REF _Ref379455005 \h \* MERGEFORMAT Figure 3 indicate the current clinical management pathway, whereas the dashed lines show the proposed change in management if catheter-free monitoring becomes available. The tests prior to pH monitoring are also shown in the pathway, and the relevant population being targeted by catheter-free monitoring can be found in the shaded box.The proposed pathway indicates that there would be more diagnostic options for patients who have either failed a catheter-based pH test or in whom it is anatomically inappropriate to use the currently available test (i.e. as an alternative to no pH monitoring). Instead of no further testing and continuation of potentially ineffective PPI treatment, patients are able to undergo a pH-monitoring test that would lead to other treatment options such as surgery or different medication. Figure SEQ Figure \* ARABIC 3Clinical management algorithm for the proposed new interventionComparatorComparators are usually selected by determining the diagnostic test that is most likely to be replaced, or added to, by the technology submitted for a new MBS item number. As catheter-free monitoring (the index test) is indicated for people that currently have no monitoring due to a failed catheter-based test or people for whom a catheter-based test is anatomically inappropriate, the appropriate comparator is ‘no pH monitoring’ and empirical therapy. However, for catheter-free monitoring to be implemented in this group, PASC determined that it should be demonstrated that the diagnostic sensitivity, specificity and safety of the proposed new test is at least equivalent to catheter-based monitoring. Thus, to establish diagnostic accuracy and safety, the selected comparator was catheter-based monitoring.The reference standard Oesophageal pH monitoring is used to diagnose GORD. In this assessment the accuracy of catheter-free monitoring in diagnosing GORD was benchmarked against the evidentiary standard as agreed to by PASC in August 2012—catheter-based pH monitoring. Patients usually have a GORD diagnosis if they respond to anti-reflux medication therapy, i.e. symptoms disappear completely or decrease by at least 50%. Clinical diagnosis based on response to treatment (which is the ‘gold standard’ in diagnosing GORD) has therefore also been used as a secondary reference standard. Research questionsIn the event that direct evidence was available to assess the safety, effectiveness and cost-effectiveness of catheter-free monitoring, the following research question was to be addressed by this evaluation:What is the safety, effectiveness and cost-effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD, compared with no pH monitoring, in patients who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?In the event that linked evidence (see ‘ REF _Ref375553651 \h \* MERGEFORMAT Diagnostic assessment framework’ on page 40) was the only evidence available to assess the safety, effectiveness and cost-effectiveness of catheter-free monitoring, the following research questions were also to be addressed:Safety:Is catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD as safe as, or safer than, no pH monitoring?Is catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD as safe as, or safer than, catheter-based oesophageal pH monitoring?Accuracy:What is the diagnostic accuracy of catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD compared with catheter-based oesophageal pH monitoring?Effectiveness / patient management:Compared with no pH monitoring, does catheter-free (wireless) ambulatory oesophageal pH monitoring change the clinical management or treatment options available for patients with suspected GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?Effectiveness / health outcomes, in case of a change in management:Do alterations in clinical management and treatment options have an impact on the health outcomes of patients with suspected GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?Do alterations in clinical management and treatment options have an impact on the health outcomes of patients with GORD (true positives)?Do alterations in clinical management and treatment options have an impact on the health outcomes of patients who were initially suspected of GORD but who received an incorrect diagnosis after catheter-free monitoring (false positives and false negatives)?Cost-effectiveness:What is the cost-effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring compared with no pH monitoring for patients with suspected GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?What is the cost-effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring compared with catheter-based oesophageal pH monitoring in patients with symptoms of GORD?Diagnostic assessment frameworkThis assessment uses the theoretical framework outlined in the MSAC Guidelines for the assessment of diagnostic technologies ADDIN EN.CITE <EndNote><Cite><Author>MSAC</Author><Year>2005</Year><RecNum>42</RecNum><DisplayText>(MSAC 2005b)</DisplayText><record><rec-number>42</rec-number><ref-type name="Electronic Source">12</ref-type><contributors><authors><author>MSAC</author></authors></contributors><titles><title>Guidelines for the assessment of diagnostic technologies</title></titles><pages>1-93</pages><dates><year>2005</year><pub-dates><date>August 2005</date></pub-dates></dates><pub-location>Canberra, ACT</pub-location><publisher>Medical Services Advisory Committee, Commonwealth of Australia</publisher><work-type>Internet</work-type><urls><related-urls><url>.au</url></related-urls></urls></record></Cite></EndNote>(MSAC 2005b).This means that evidence of the clinical effectiveness of catheter-free monitoring requires either the first or, if not available, the second of the following: evidence of the effectiveness of catheter-free monitoring from high-quality comparative studies evaluating its use and subsequent treatment compared with no monitoring and treatment (direct evidence); randomised controlled trials (RCTs) provide the highest quality evidence for this comparison. evidence of treatment effectiveness from high-quality comparative studies evaluating the treatment for GORD, linked with applicable and high-quality evidence of the accuracy of catheter-free monitoring to diagnose GORD compared with catheter-based monitoring or no monitoring; this is called ‘linked evidence’. There was limited, low-quality direct evidence available that assessed the impact of catheter-free monitoring, so in this assessment the available direct evidence was supplemented with a linked evidence approach. This means that evidence from studies that report on diagnostic test performance (diagnostic accuracy), the impact on clinical decision-making and the impact of the treatment of diagnosed patients on health outcomes was narratively linked in order to infer the effect of the diagnostic test on patient health outcomes. For the last step of the linked analysis, to answer the questions, two separate searches were conducted ( REF _Ref371687271 \h \* MERGEFORMAT Table 6): Evidence-based guidelines and/or systematic reviews providing evidence on treatment effectiveness in patients with GORD was collated, as this provides data on the health outcomes of those who are correctly diagnosed (i.e. true positives). For people initially suspected of GORD but who are eventually given an alternative diagnosis, it was assumed that their management/treatment would be optimised as a consequence of obtaining the correct diagnosis. To address the implications associated with either inappropriately treating people who are incorrectly diagnosed with GORD (i.e. false positives) or not properly treating people who are incorrectly given an alternative diagnosis to GORD (i.e. false negatives), a second separate literature search was conducted.Review of literature Literature sources and search strategiesThe medical literature was searched to identify relevant studies and reviews for the period between 2001 and September 2013, as catheter-free monitoring became available in 2001. Searches were conducted via the databases described in REF _Ref363131254 \h \* MERGEFORMAT Table 4. Search terms are described in REF _Ref379483486 \h Table 5 and REF _Ref371687785 \h \* MERGEFORMAT Table 6. REF _Ref371687785 \h \* MERGEFORMAT Table 6 contains the search terms for the last step of the linked analysis.Table 4Electronic databases searchedElectronic databasePeriod coveredCochrane Library – including, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials (CENTRAL), the Health Technology Assessment Database, the NHS Economic Evaluation Database2001 – 9/2013Current Contents 2001 – 9/2013Embase 2001 – 9/2013PubMed2001 – 9/2013Web of Science – Science Citation Index Expanded2001 – 9/2013Cinahl2001 – 9/2013Econlit2001 – 9/2013Scopus2001 – 9/2013Table 5Search terms usedElement of clinical questionSearch termsPopulationGastroesophageal reflux [MeSH] OR Gastric Acid [MeSH] OR heartburn [MeSH] OR (GORD OR GERD OR Heartburn OR gastro oesophageal reflux disease OR gastro esophageal reflux disease OR gastroesophageal reflux diseaseIntervention((hydrogen-ion concentration [MeSH]) OR hydrogen-ion concentration OR pH) AND(Esophageal pH monitoring [MeSH] OR Gastric Acidity Determination /instrumentation [MeSH] OR “catheter free” OR catheterless OR wireless OR tubeless OR telemetry [MeSH] OR telemetry OR (radio transmit*) OR (radio transmis*) OR radiotransmit* OR radiotransmis* OR bravo)Comparator (if applicable)N/AOutcomes (if applicable)N/ALimits2001–2013MeSH = Medical Subject Heading, based on a Medline/PubMed platformTable SEQ Table \* ARABIC 6Search terms used to identify studies for the last step of the linked analysis (health outcomes)Element of clinical questionTrue positivesFalse negatives and false positivesPopulationGastroesophageal reflux [MeSH] OR Gastric Acid [MeSH] OR heartburn [MeSH] OR (GORD OR GERD OR heartburn OR "gastro oesophageal reflux disease" OR "gastro esophageal reflux disease" OR "gastroesophageal reflux disease")(Gastroesophageal reflux [MeSH] OR Gastric Acid [MeSH] OR heartburn [MeSH] OR (GORD OR GERD OR heartburn OR "gastro oesophageal reflux disease" OR "gastro esophageal reflux disease" OR "gastroesophageal reflux disease") Intervention(Omeprazole OR lansoprazole OR dexlansoprazole OR esomeprazole OR pantoprazole OR rabeprazole OR ilaprazole OR “proton pump inhibitor” OR PPI OR “proton pump inhibitors”) OR (cimetidine OR rantidine OR famotidine OR nizatidine OR (H2 receptor antagonist*) OR (H2 antagonist*)) (untreated OR "not treated" OR "no treatment" OR "delayed treatment" OR "non-optimal treatment" OR "inappropriate treatment") OR (“wrong diagnosis” OR “missed diagnosis” OR misdiagnosis) OR “false negative” OR “false negatives” OR “false reassurance” OR “false positive” OR “false positives” OR “false alarm” OR "Diagnostic Errors"[Mesh]Comparator (if applicable)--Outcomes (if applicable)--“Systematic review” OR guideline OR guidelines-MeSH = Medical Subject Heading, based on a Medline/PubMed platformSelection criteriaIn general, studies were excluded (Figures 4, 5 and 6) if they: did not provide information on the pre-specified target populationdid not address one of the pre-specified outcomes and/or provided inadequate data on these outcomeswere in a language other than English and were of a lower level of evidence than the studies in Englishdid not have an eligible study designused impedance monitoring as a comparatorincluded a non-Bravo wireless pH-monitoring device as the index test.If the same data were duplicated in multiple articles, only results from the most comprehensive or most recent article were included. Search resultsPRISMA flowchartFigure 4Summary of the process used to identify and select studies for the review (in first search)Figure 5Summary of the process used to identify and select studies for the review (in search 'true positives')Figure 6Summary of the process used to identify and select studies for the review (in search 'false negatives and false positives')Data extraction and analysisA profile of key characteristics was developed for each included study (see REF _Ref364237249 \h \* MERGEFORMAT Appendix C). Each study profile described the level of evidence, design and quality of the study, authors, publication year, location, criteria for including/excluding patients, study population characteristics, type of intervention, comparator intervention and/or reference standard (where relevant), and outcomes assessed. Studies that could not be retrieved or that met the inclusion criteria but contained insufficient or inadequate data for inclusion are listed in REF _Ref364237293 \h \* MERGEFORMAT Appendix D. Definitions of all technical terms and abbreviations are provided in the Glossary (page PAGEREF _Ref363826811 \h 23). Descriptive statistics were extracted or calculated for all safety and effectiveness outcomes in the individual studies.Assessing diagnostic accuracyTo assess the diagnostic accuracy of catheter-free monitoring, where possible the sensitivity, specificity, negative and positive predictive values (NPV, PPV) and likelihood ratios of the tests were calculated with corresponding 95% confidence intervals (CIs). Data were extracted into a classic 2? 2 table, in which the results of the index diagnostic test were cross-classified (Table 7) against the results of the reference standard ADDIN EN.CITE <EndNote><Cite><Author>Armitage</Author><Year>2002</Year><RecNum>83</RecNum><DisplayText>(Armitage, Berry &amp; Matthews 2002; Deeks 2001)</DisplayText><record><rec-number>83</rec-number><ref-type name="Book">6</ref-type><contributors><authors><author>Armitage, P.</author><author>Berry,G.</author><author>Matthews, J.N.S</author></authors></contributors><titles><title>Statistical methods in medical research</title></titles><edition>Fourth Edition</edition><dates><year>2002</year></dates><pub-location>Oxford</pub-location><publisher>Blackwell Science</publisher><urls></urls><custom1>yes</custom1></record></Cite><Cite><Author>Deeks</Author><Year>2001</Year><RecNum>84</RecNum><record><rec-number>84</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deeks, J.J.</author></authors></contributors><titles><title>Systematic reviews of evaluations of diagnostic and screening tests</title><secondary-title>British Medical Journal</secondary-title><alt-title>British Medical Journal (Education and Debate)</alt-title></titles><pages>157-162</pages><volume>323</volume><number>21 July</number><keywords><keyword>Review literature</keyword><keyword>Meta-analysis</keyword><keyword>Mass-screening</keyword><keyword>Diagnostic techniques</keyword><keyword>Sensitivity-and-Specificity</keyword><keyword>Predictive-Value-of-Tests</keyword><keyword>ROC-Curve</keyword></keywords><dates><year>2001</year></dates><label>Methodology; SR; diagnostic test; screening;SR</label><urls></urls></record></Cite></EndNote>(Armitage, Berry & Matthews 2002; Deeks 2001), and Bayes’ Theorem was applied:Table 7Diagnostic accuracy data extraction for GORDReference standard(catheter-based oesophageal pH monitoring or clinical diagnosis)Disease +Disease –Index test(catheter-free [wireless] ambulatory oesophageal pH monitoring)Test +true positivefalse positiveTotal test positiveTest –false negativetrue negativeTotal test negativeTotal with GORDTotal without GORDPrimary measuresTest sensitivity was calculated as the proportion of people with GORD, as determined by catheter-based monitoring or clinical diagnosis, who had a positive test result on catheter-free monitoring:Sensitivity (true positive rate) = number with true positive result / total with GORDTest specificity was calculated as the proportion of people without GORD, as determined by catheter-based monitoring or clinical diagnosis, who had a normal test result on catheter-free monitoring:Specificity (true negative rate) = number with true negative result / total without GORDWhere possible, the PPV and NPV were also provided. A PPV is the proportion of positive test results that are true positives, and the NPV is the proportion of negative test results that are true negatives. They reflect the probability that a positive (or negative) test result corresponds with having (or not having) GORD. However, the values depend on the prevalence of GORD.PPV = number true positive / total test positiveNPV = number true negative / total test negativeWhen a 95%CI was not provided, it was calculated by exact binomial methods.Summary measuresPositive and negative likelihood ratios (LRs) were reported if available. These ratios measure the probability of the test result in patients with GORD compared with those without GORD. LR+ = sensitivity / 1–specificityLR– = 1–sensitivity / specificityA likelihood ratio of 1 means that the test does not provide any useful diagnostic information, whereas LR+ >5 and LR– <0.2 can suggest strong diagnostic ability ADDIN EN.CITE <EndNote><Cite><Author>MSAC</Author><Year>2005</Year><RecNum>260</RecNum><DisplayText>(MSAC 2005a)</DisplayText><record><rec-number>260</rec-number><foreign-keys><key app="EN" db-id="5fztv099mfwwx7e0pse5vxeozd5aa2d59rpz">260</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>MSAC,</author></authors></contributors><titles><title>Gruidelines for the Assessment of Diagnostic Technologies</title></titles><dates><year>2005</year></dates><pub-location>Canberra</pub-location><publisher>Commonwealth of Australia</publisher><urls></urls></record></Cite></EndNote>(MSAC 2005a). The summary receiver–operator characteristic curve plots the estimated sensitivity versus 1–specificity from different studies to produce a global measure of test accuracy.All statistical calculations were undertaken using the biostatistical computer package Stata version 12.0.Meta-analysis of diagnostic accuracy results was not conducted owing to the heterogeneous nature of the available evidence-base assessing the test performance of GORD; specifically, different thresholds for diagnosis were used and there were not enough studies reporting data within each threshold to stratify and meta-analyse the results by cut-point. Meta-analysis of technical failure data was conducted using the metan command in Stata version 12.0 and specifying a random-effects model. Subgroup analyses were not performed.A narrative meta-synthesis of the data was undertaken where meta-analysis could not be performed.Appraisal of the evidenceAppraisal of the evidence was conducted in three stages:Stage 1: Appraisal of the applicability and quality of individual studies included in the review (strength of the evidence).Stage 2: Appraisal of the precision, size of effect and clinical importance of the results for primary outcomes in individual studies—used to determine the safety and effectiveness of the intervention. Stage 3: Integration of this evidence for conclusions about the net clinical benefit of the intervention in the context of Australian clinical practice. The evidence presented in the selected studies was assessed and classified using the dimensions of evidence defined by the National Health and Medical Research Council (NHMRC 2000). These dimensions ( REF _Ref206478845 \h \* MERGEFORMAT Table 8) consider important aspects of the evidence supporting a particular intervention and include three main domains: strength of the evidence, size of the effect and relevance of the evidence. The first domain is derived directly from the literature identified as informing a particular intervention; the last two each requires expert clinical input as part of its determination.Table SEQ Table \* ARABIC 8Evidence dimensionsType of evidenceDefinitionStrength of the evidence:LevelQualityStatistical precisionThe study design used, as an indicator of the degree to which bias has been eliminated by design.aThe methods used by investigators to minimise bias within a study design.The p-value or, alternatively, the precision of the estimate of the effect. It reflects the degree of certainty about the existence of a true effect.Size of effectThe distance of the study estimate from the ‘null’ value and the inclusion of only clinically important effects in the confidence interval.Relevance of evidenceThe usefulness of the evidence in clinical practice, particularly the appropriateness of the outcome measures used.aSee REF _Ref206478826 \h \* MERGEFORMAT Table 9Stage 1: strength of the evidenceThe three sub-domains—level, quality and statistical precision—are collectively a measure of the strength of the evidence. The ‘level’ of evidence reflects the effectiveness of a study design to answer a particular research question. Effectiveness is based on the probability that the design of the study has reduced or eliminated the impact of bias on the results. The NHMRC evidence hierarchy provides a ranking of various study designs (‘levels of evidence’) by the type of research question being addressed ( REF _Ref206478826 \h \* MERGEFORMAT Table 9).Table SEQ Table \* ARABIC 9Designations of levels of evidence according to type of research question (including table notes) LevelIntervention aDiagnostic accuracy bI cA systematic review of level II studiesA systematic review of level II studiesIIA randomised controlled trialA study of test accuracy with: an independent, blinded comparison with a valid reference standard,d among consecutive persons with a defined clinical presentation eIII-1A pseudo-randomised controlled trial(i.e. alternate allocation or some other method)A study of test accuracy with: an independent, blinded comparison with a valid reference standard,d among non-consecutive persons with a defined clinical presentation eIII-2A comparative study with concurrent controls:? non-randomised, experimental trial f? cohort study? case-control study? interrupted time series with a control groupA comparison with reference standard that does not meet the criteria required for level II and III-1 evidenceIII-3A comparative study without concurrent controls:? historical control study? two or more single arm studies g ? interrupted time series without a parallel control groupDiagnostic case-control study eIVCase series with either post-test or pre-test/post-test outcomesStudy of diagnostic yield (no reference standard) hSources: Merlin et al. (2009); hierarchies adapted and modified from: NHMRC 1999; Bandolier 1999; Lijmer et al. 1999; Phillips et al. 2001Explanatory notes:a Definitions of these study designs are provided in NHMRC (2000; pp. 7–8) and in the Glossary accompanying Merlin et al. (2009).b These levels of evidence apply only to studies assessing the accuracy of diagnostic or screening tests. To assess the overall effectiveness of a diagnostic test there also needs to be a consideration of the impact of the test on patient management and health outcomes (MSAC 2005; Sackett & Haynes 2002). The evidence hierarchy given in the ‘Intervention’ column should be used when assessing the impact of a diagnostic test on health outcomes relative to an existing method of diagnosis or comparator test(s). The evidence hierarchy given in the ‘Screening’ column should be used when assessing the impact of a screening test on health outcomes relative to no screening or alternative screening methods.c A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of level II evidence. Systematic reviews of level II evidence provide more data than the individual studies and any meta-analyses will increase the precision of the overall results, reducing the likelihood that the results are affected by chance. Systematic reviews of lower level evidence present results of likely poor internal validity and thus are rated on the likelihood that the results have been affected by bias, rather than whether the systematic review itself is of good quality. Systematic review quality should be assessed separately. A systematic review should consist of at least two studies. In systematic reviews that include different study designs, the overall level of evidence should relate to each individual outcome/result, as different studies and study designs might contribute to each different outcome.d The validity of the reference standard should be determined in the context of the disease under review. Criteria for determining the validity of the reference standard should be pre-specified. This can include the choice of the reference standard(s) and its timing in relation to the index test. The validity of the reference standard can be determined through quality appraisal of the study (Whiting et al. 2003).e Well-designed population-based case-control studies (e.g. screening studies where test accuracy is assessed on all cases, with a random sample of controls) do capture a population with a representative spectrum of disease and thus fulfil the requirements for a valid assembly of patients. However, in some cases the population assembled is not representative of the use of the test in practice. In diagnostic case-control studies a selected sample of patients already known to have the disease is compared with a separate group of normal/healthy people known to be free of the disease. In this situation patients with borderline or mild expressions of the disease, and conditions mimicking the disease, are excluded, which can lead to exaggeration of both sensitivity and specificity. This is called spectrum bias or spectrum effect because the spectrum of study participants will not be representative of patients seen in practice (Mulherin & Miller 2002).f This also includes controlled before-and-after (pre-test/post-test) studies as well as adjusted indirect comparisons, i.e. utilising A vs B and B vs C to determine A vs C, with statistical adjustment for B.gComparing single arm studies, i.e. case series from two studies. This would also include unadjusted indirect comparisons, i.e. utilising A vs B and B vs C to determine A vs C, but where there is no statistical adjustment for B.hStudies of diagnostic yield provide the yield of diagnosed patients, as determined by an index test, without confirmation of the accuracy of this diagnosis by a reference standard. These may be the only alternative when there is no reliable reference standard.Note A: Assessment of comparative harms/safety should occur according to the hierarchy presented for each of the research questions, with the proviso that this assessment occurs within the context of the topic being assessed. Some harms (and other outcomes) are rare and cannot feasibly be captured within randomised controlled trials, in which case lower levels of evidence may be the only type of evidence that is practically achievable; both physical and psychological harms may need to be addressed by different study designs; harms from diagnostic testing include the likelihood of false positive and false negative results; harms from screening include the likelihood of false alarms and false reassurance results.Note B: When a level of evidence is attributed in the text of a document, it should also be framed according to its corresponding research question, e.g. level II intervention evidence; level IV diagnostic evidence; level III-2 prognostic evidence.Note C: Each individual study that is attributed a ‘level of evidence’ should be rigorously appraised using validated or commonly used checklists or appraisal tools to ensure that factors other than study design have not affected the validity of the results.Individual studies assessing diagnostic effectiveness were graded according to pre-specified quality and applicability criteria (MSAC 2005), as shown in REF _Ref206477516 \h \* MERGEFORMAT Table 10.Table SEQ Table \* ARABIC 10Grading system used to rank included studiesValidity criteriaDescriptionGrading systemAppropriate comparisonDid the study evaluate a direct comparison of the index test strategy versus the comparator test strategy?C1 direct comparison CX other comparison Applicable populationDid the study evaluate the index test in a population that is representative of the subject characteristics (age and sex) and clinical setting (disease prevalence, disease severity, referral filter and sequence of tests) for the clinical indication of interest?P1 applicable P2 limited P3 different population Quality of studyWas the study designed to avoid bias?High quality = no potential for bias based on pre-defined key quality criteria Medium quality = some potential for bias in areas other than those pre-specified as key criteriaPoor quality = poor reference standard and/or potential for bias based on key pre-specified criteriaQ1 high quality Q2 medium Q3 poor reference standardpoor quality or insufficient informationThe appraisal of intervention studies pertaining to treatment safety and effectiveness was undertaken using the Downs and Black (1998) checklist, which was used for trials and cohort studies. Uncontrolled before-and-after case series are a poorer level of evidence with which to assess effectiveness. The quality of this type of study design was assessed according to a checklist developed by the UK National Health Service (NHS) Centre for Reviews and Dissemination ADDIN EN.CITE <EndNote><Cite><Author>Khan</Author><Year>2001</Year><RecNum>27</RecNum><DisplayText>(Khan et al. 2001)</DisplayText><record><rec-number>27</rec-number><ref-type name="Report">27</ref-type><contributors><authors><author>Khan, K.S.</author><author>Ter Riet, G.</author><author>Glanville, J.M.</author><author>Sowden, A.J.</author><author>Kleijnen, J.</author></authors></contributors><titles><title>Undertaking systematic reviews of research on effectiveness. CRD&apos;s guidance for those carrying out or commissioning reviews</title></titles><dates><year>2001</year><pub-dates><date>2001 (second edition)</date></pub-dates></dates><pub-location>York</pub-location><publisher>NHS Centre for Reviews and Dissemination, University of York</publisher><isbn>CRD Report Number 4 (second edition)</isbn><call-num>TRACY</call-num><label>evidence ; sr ; health information ; research ; LR</label><work-type>CRD Report</work-type><urls></urls></record></Cite></EndNote>(Khan et al. 2001). Studies of diagnostic accuracy were assessed using the QUADAS-2 quality assessment tool ADDIN EN.CITE <EndNote><Cite><Author>Whiting</Author><Year>2011</Year><RecNum>18735</RecNum><IDText>529-36</IDText><DisplayText>(Whiting, Rutjes, Westwood, Mallett, Deeks, Reitsma, Leeflang, Sterne, Bossuyt, et al. 2011)</DisplayText><record><rec-number>18735</rec-number><foreign-keys><key app="EN" db-id="5exd9tre4x0dwoefarq5epd0f5vx52s59paf">18735</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Whiting, P. F.</author><author>Rutjes, A. W.</author><author>Westwood, M. E.</author><author>Mallett, S.</author><author>Deeks, J. J.</author><author>Reitsma, J. B.</author><author>Leeflang, M. M.</author><author>Sterne, J. A.</author><author>Bossuyt, P. M.</author><author>Quadas- Group</author></authors></contributors><auth-address>University of Bristol, United Kingdom. penny.whiting@bristol.ac.uk</auth-address><titles><title>QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies</title><secondary-title>Ann Intern Med</secondary-title><alt-title>Annals of internal medicine</alt-title></titles><periodical><full-title>Ann Intern Med</full-title></periodical><alt-periodical><full-title>Annals of Internal Medicine</full-title></alt-periodical><pages>529-36</pages><volume>155</volume><number>8</number><keywords><keyword>Bias (Epidemiology)</keyword><keyword>*Diagnosis</keyword><keyword>Evidence-Based Medicine</keyword><keyword>Humans</keyword><keyword>Patient Selection</keyword><keyword>Quality Control</keyword><keyword>*Questionnaires</keyword><keyword>Reference Standards</keyword><keyword>*Review Literature as Topic</keyword><keyword>Time Factors</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct 18</date></pub-dates></dates><isbn>1539-3704 (Electronic)&#xD;0003-4819 (Linking)</isbn><accession-num>22007046</accession-num><urls><related-urls><url>;(Whiting et al. 2011), whereas systematic reviews included in the last step of the linked analysis were assessed with the PRISMA checklist ADDIN EN.CITE <EndNote><Cite><Author>Liberati</Author><Year>2009</Year><RecNum>616</RecNum><IDText>b2700</IDText><DisplayText>(Liberati et al. 2009)</DisplayText><record><rec-number>616</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">616</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liberati, A.</author><author>Altman, D. G.</author><author>Tetzlaff, J.</author><author>Mulrow, C.</author><author>Gotzsche, P. C.</author><author>Ioannidis, J. P.</author><author>Clarke, M.</author><author>Devereaux, P. J.</author><author>Kleijnen, J.</author><author>Moher, D.</author></authors></contributors><auth-address>Universita di Modena e Reggio Emilia, Modena, Italy.</auth-address><titles><title>The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration</title><secondary-title>BMJ</secondary-title><alt-title>Bmj</alt-title></titles><periodical><full-title>BMJ</full-title><abbr-1>Bmj</abbr-1></periodical><alt-periodical><full-title>BMJ</full-title><abbr-1>Bmj</abbr-1></alt-periodical><pages>b2700</pages><volume>339</volume><keywords><keyword>Evidence-Based Medicine/standards</keyword><keyword>Humans</keyword><keyword>*Meta-Analysis as Topic</keyword><keyword>Publishing/*standards</keyword><keyword>Quality Control</keyword><keyword>*Review Literature as Topic</keyword><keyword>Terminology as Topic</keyword></keywords><dates><year>2009</year></dates><isbn>1756-1833 (Electronic)&#xD;0959-535X (Linking)</isbn><accession-num>19622552</accession-num><urls><related-urls><url>;(Liberati et al. 2009).Stage 2: precision, size of effect and clinical importance Statistical precision was determined using statistical principles. Small CIs and p-values give an indication as to the probability that the reported effect is real and not attributable to chance ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2000</Year><RecNum>25</RecNum><DisplayText>(NHMRC 2000)</DisplayText><record><rec-number>25</rec-number><ref-type name="Report">27</ref-type><contributors><authors><author>NHMRC,</author></authors></contributors><titles><title>How to use the evidence: assessment and application of scientific evidence</title></titles><pages>84</pages><keywords><keyword>Practice guidelines</keyword><keyword>Review literature</keyword><keyword>Australia</keyword><keyword>Evidence-Based Medicine</keyword></keywords><dates><year>2000</year><pub-dates><date>February 2000</date></pub-dates></dates><pub-location>Canberra</pub-location><publisher>National Health and Medical Research Council</publisher><call-num>SHELF 7</call-num><label>evidence ; treatment path ; clinical decisions ; guidelines; methodology; health technology;</label><work-type>Handbook series on preparing clinical practice guidelines</work-type><urls></urls></record></Cite></EndNote>(NHMRC 2000). Studies need to be appropriately powered to ensure that a real difference between groups will be detected in the statistical analysis.For intervention studies it was important to assess whether statistically significant differences between patients receiving catheter-free monitoring and those receiving no pH monitoring or catheter-based monitoring were also clinically important. The size of the effect needed to be determined, as well as whether the 95%CI included only clinically important effects. The outcomes being measured in this report were assessed as to whether they were appropriate and clinically relevant ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2000</Year><RecNum>25</RecNum><DisplayText>(NHMRC 2000)</DisplayText><record><rec-number>25</rec-number><ref-type name="Report">27</ref-type><contributors><authors><author>NHMRC,</author></authors></contributors><titles><title>How to use the evidence: assessment and application of scientific evidence</title></titles><pages>84</pages><keywords><keyword>Practice guidelines</keyword><keyword>Review literature</keyword><keyword>Australia</keyword><keyword>Evidence-Based Medicine</keyword></keywords><dates><year>2000</year><pub-dates><date>February 2000</date></pub-dates></dates><pub-location>Canberra</pub-location><publisher>National Health and Medical Research Council</publisher><call-num>SHELF 7</call-num><label>evidence ; treatment path ; clinical decisions ; guidelines; methodology; health technology;</label><work-type>Handbook series on preparing clinical practice guidelines</work-type><urls></urls></record></Cite></EndNote>(NHMRC 2000). Stage 3: Assessment of the body of evidenceAppraisal of the body of evidence was conducted along the lines suggested by the NHMRC in their guidance on clinical practice guideline development ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2008</Year><RecNum>132</RecNum><DisplayText>(NHMRC 2008)</DisplayText><record><rec-number>132</rec-number><ref-type name="Electronic Source">12</ref-type><contributors><authors><author>NHMRC</author></authors></contributors><titles><title>NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Stage 2 consultation.</title></titles><number>11/03/08</number><dates><year>2008</year></dates><publisher>National Health and Medical Research Council, Australian Government</publisher><work-type>Internet</work-type><urls><related-urls><url>.au/consult/index.htm</url></related-urls></urls></record></Cite></EndNote>(NHMRC 2008). Five components are considered essential by the NHMRC when judging the body of evidence: the evidence-base—which includes the number of studies sorted by their methodological quality and relevance to patients;the consistency of the study results—whether the better quality studies had results of a similar magnitude and in the same direction, i.e. homogeneous or heterogeneous findings;the potential clinical impact—appraisal of the precision, size and clinical importance or relevance of the primary outcomes used to determine the safety and effectiveness of the test;the generalisability of the evidence to the target population; andthe applicability of the evidence—integration of this evidence for conclusions about the net clinical benefit of the intervention in the context of Australian clinical practice.A matrix for assessing the body of evidence for each research question, according to the components above, was used for this assessment ( REF _Ref362269843 \h \* MERGEFORMAT Table 11).Table 11Body of evidence matrix ComponentABCD-ExcellentGoodSatisfactoryPoorEvidence-base aOne or more level I studies with a low risk of bias or several level II studies with a low risk of biasOne or two level II studies with a low risk of bias or an SR or several level III studies with a low risk of biasOne or two level III studies with a low risk of bias, or level I or II studies with a moderate risk of biasLevel IV studies, or level I to III studies/SRs with a high risk of biasConsistency bAll studies consistentMost studies consistent and inconsistency may be explainedSome inconsistency reflecting genuine uncertainty around clinical questionEvidence is inconsistentClinical impactVery largeSubstantialModerateSlight or restrictedGeneralisabilityPopulation(s) studied in body of evidence are the same as target population Population(s) studied in body of evidence are similar to target population Population(s) studied in body of evidence differ from target population for guideline but it is clinically sensible to apply this evidence to target population cPopulation(s) studied in body of evidence differ from target population and it is hard to judge whether it is sensible to generalise to target populationApplicabilityDirectly applicable to Australian healthcare contextApplicable to Australian healthcare context with few caveatsProbably applicable to Australian healthcare context with some caveatsNot applicable to Australian healthcare contextSource: adapted from ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2008</Year><RecNum>132</RecNum><DisplayText>(NHMRC 2008)</DisplayText><record><rec-number>132</rec-number><ref-type name="Electronic Source">12</ref-type><contributors><authors><author>NHMRC</author></authors></contributors><titles><title>NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Stage 2 consultation.</title></titles><number>11/03/08</number><dates><year>2008</year></dates><publisher>National Health and Medical Research Council, Australian Government</publisher><work-type>Internet</work-type><urls><related-urls><url>.au/consult/index.htm</url></related-urls></urls></record></Cite></EndNote>NHMRC (2008)aLevel of evidence determined from the NHMRC evidence hierarchy (Table 9) bIf there is only one study, rank this component as ‘not applicable’. cFor example, results in adults that are clinically sensible to apply to children OR psychosocial outcomes for one cancer that may be applicable to patients with another cancerSR = systematic review; several = more than two studiesExpert advice: Health Expert Standing Panel (HESP) The Health Expert Standing Panel (HESP) has been established as a panel of the MSAC and is a pool of experts collated from various medical fields who are nominated by their associated professional body or by applicants. HESP members are engaged to provide practical, professional advice to evaluators that directly relates to each application and the service being proposed for the MBS. HESP members are not members of either MSAC or its subcommittees. Their role is limited to providing input and guidance to the assessment groups to ensure that the pathway is clinically relevant and takes into account consumer interests. HESP members’ advice is used to inform the deliberations that MSAC presents to the Federal Minister for Health.Results of assessment Is it safe? Summary—Is catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD as safe as, or safer than, no pH monitoring?Only one study was identified that assessed the safety of catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD compared with no pH monitoring. This RCT found that chest pain was more likely to occur in those undergoing catheter-free monitoring (66%) than those undergoing no monitoring (28%) (RR=2.33, 95%CI 0.81, 6.76). Chest pain is likely to be attributed to the placement of the capsule.Summary—Is catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD as safe as, or safer than, catheter-based oesophageal pH monitoring?Twelve comparative studies were identified that reported on complications of catheter-free monitoring compared with catheter-based monitoring. Included were four RCTs, one pseudo-RCT, three cohort studies, two non-randomised controlled trials and two case-control studies.No deaths or life-threatening events caused by pH monitoring were reported in the comparative studies. Chest pain was significantly more prevalent in patients undergoing catheter-free monitoring compared with catheter-based monitoring, as reported in four out of seven studies. In a high-quality RCT by Andrews et al. (2012), the median chest pain score during the pH test was 29?±?4?mm on a 100-point VAS in the catheter-free monitoring group, compared with only 14?±?3?mm in the catheter-based monitoring group (p=0.001). The difference is likely to be clinically meaningful. On the other hand, other adverse events such as nose and throat pain, dysphagia, eating and drinking difficulties, and headache were significantly more prevalent in catheter-based monitoring compared with catheter-free monitoring. Catheter-based monitoring tends to produce more overall discomfort than catheter-free monitoring and is more likely to have a negative impact on normal daily activities and work attendance. In addition to the comparative studies, 29 non-comparative level IV studies were included to determine other complications and/or adverse events caused by catheter-free monitoring. The most common reported adverse events were chest pain and foreign-body sensation. Other complications included diminished appetite, extreme gagging, nausea, epistaxis, pharyngeal irritation, retrosternal discomfort on swallowing, throat pain, back pain, rash, mucosal abrasion with (minor) haemorrhage, capsule dislodgement, capsule detachment failure, laryngospasm, vasovagal reaction, poor capsule tolerance with vomiting, and a dizzy spell during insertion.In children, two oesophageal tears were reported, at least one due to a capsule release failure. Less-severe adverse events in children were overall discomfort, mild chest discomfort, coughing and dysphagia.Finally, seven case reports were identified that reported some additional (rare) complications resulting from catheter-free monitoring, such as capsule dislodgment and/or aspiration, retention of the capsule in a colonic diverticulum and oesophageal perforation.In conclusion, most complications reported were mild and did not require medical therapy. However, some (rare) complications can become severe when left untreated.Studies were included to assess the safety of catheter-free (wireless) oesophageal pH monitoring according to criteria outlined a priori in REF _Ref360536329 \h \* MERGEFORMAT Box 1.Box 1Inclusion criteria for studies assessing the safety of catheter-free (wireless) oesophageal pH monitoringSelection criteriaInclusion criteriaPopulationPatients with symptoms of GORD for whom pH monitoring is indicatedPatients with symptoms of GORD in whom catheter-based pH monitoring has failed or in whom it is anatomically inappropriate Subgroups: adults versus childrenInterventionCatheter-free (wireless) ambulatory oesophageal pH monitoringComparatorsNo pH monitoringCatheter-based oesophageal pH monitoringOutcomesAny adverse events arising from monitoring including:oesophageal injurychest painlate detachmentstricturenaso-pharyngeal discomfortnauseaAny adverse events arising from (incorrect) treatment (as a result of no monitoring), such as:worsening of or no decrease in reflux complaintsBarrett’s oesophagus / oesophageal adenocarcinomaPublication typeRandomised or non-randomised controlled trials, cohort studies, registers, case series, case reports or systematic reviews of these study designsSearch period2001 – 5/2013LanguageNon-English language articles were excluded unless they provided a higher level of evidence than the English language articles identifiedThere were 48 studies that met the selection criteria that reported on the safety of catheter-free monitoring. There was 1 comparative study on the safety of (proximal) catheter-free monitoring compared with no monitoring, and 12 studies compared catheter-based monitoring with catheter-free monitoring in terms of safety. The remaining studies were case series or case reports. There were no deaths or life-threatening events reported as a direct result of either catheter-free or catheter-based monitoring. Safety of catheter-free (wireless) pH monitoring Safety results have been divided into the commonly reported outcomes of chest pain, foreign-body sensation, nose and throat pain, dysphagia, eating and drinking difficulties, impact on daily life, overall discomfort and satisfaction, and ‘other’. Within each table of results per outcome, studies are listed in order of methodological quality and sample size. For the complete overview of safety data extracted per study, including non-significant results, see REF _Ref364237359 \h \* MERGEFORMAT Appendix E (page PAGEREF _Ref366248166 \h 231). Chest pain One randomised blinded controlled trial ADDIN EN.CITE <EndNote><Cite><Author>Francis</Author><Year>2012</Year><RecNum>236</RecNum><IDText>91-97</IDText><DisplayText>(Francis, DO et al. 2012)</DisplayText><record><rec-number>236</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">236</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, D. O.</author><author>Sumner, E.</author><author>Goutte, M.</author><author>Slaughter, J. C.</author><author>Garrett, C. G.</author><author>Hagaman, D.</author><author>Vaezi, M. F.</author></authors></contributors><titles><title>Feasibility of Dual Wireless Esophageal pH Monitoring: Randomized Blinded Sham-Controlled Trial</title><secondary-title>Otolaryngology-Head and Neck Surgery</secondary-title></titles><periodical><full-title>Otolaryngology-Head and Neck Surgery</full-title></periodical><pages>91-97</pages><volume>147</volume><number>1</number><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0194-5998</isbn><accession-num>CCC:000314267600016</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000314267600016</url><url>;(Francis et al. 2012) reported on chest discomfort during proximal (16?cm above the SCJ) catheter-free pH monitoring compared with no proximal monitoring (Table 12). All patients had a wireless pH-monitoring capsule positioned 6?cm proximal to the gastro-oesophageal junction (GOJ), and 48?hours later they were randomised into proximal capsule placement (i.e. another capsule placed 16?cm above the SCJ) or sham capsule placement. Patients were blinded regarding whether the second capsule was deployed and there were 11 patients in each group. In the intervention group 66% reported chest pain scores of 3 or greater on a 10-point VAS where higher scores indicate more pain, compared with only 28% in the control group (RR=2.33, 95%CI 0.81, 6.76). For higher levels of chest discomfort, 32% reported a chest pain score of ≥7 in the intervention group, compared with 8% in the sham group. Multivariate analysis showed an increased odds of severe chest pain in the intervention group when comparing subjects with the same chest pain score during the first monitoring period (adjusted OR=8.44; 95%CI 1.35, 52.6). Four (three level II and one level III-2) intervention studies reported significantly more chest pain or oesophageal discomfort with catheter-free monitoring than with catheter-based monitoring in adults. In a high-quality RCT by Andrews et al. (2012), the median chest pain score during the pH test was 29?±?4?mm on a 100-point VAS in the catheter-free monitoring group, compared with only 14?±?3?mm in the catheter-based monitoring group (p=0.001) This difference is likely to be clinical meaningful. An RCT by Wong et al. (2005) reported 9/25 patients (36%) with chest discomfort with catheter-free monitoring, compared with only 2/25 patients (8%) in the catheter-based monitoring group (RR=4.5, 95%CI 1.08, 18.77, p=0.037, p=0.037). More chest discomfort (RR=1.95, 95%CI 1.47, 2.60) and chest pain (RR=1.76, 95%CI 1.2, 2.57) in the catheter-free monitoring group, relative to the catheter-based monitoring group, was also reported in a cohort study by Bradley et al. (2011). In one average-quality case-control study (Pandolfino et al. 2003) 34% of the patients undergoing catheter-free monitoring had oesophageal discomfort, compared with only 17% of those undergoing catheter-based monitoring. Three studies (Schneider et al. 2007; Grigolon et al. 2007; Wenner, Johnsson et al. 2007) did not report significant differences in chest pain or oesophageal discomfort.Table 12Chest discomfort or chest pain resulting from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI] (p-value)Wenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median 10 cm VAS (IQR) Chest symptoms: 2.4 (0.3–5.9)Patients’ experience, median 10 cm VAS (IQR) Chest symptoms: 1.1 (0.3 – 2.9)(0.084)aAndrews et al. (2012)Level IIQuality: 19/26Dual centre, randomised, non-blinded trial43 participants, catheter group43 participants, wireless grouppH placement discomfort (100 mm VAS ± SE)Chest: 14 ± 3pH-test discomfort (mm VAS ± SE)Chest: 29 ± 4pH placement discomfort (100 mm VAS ± SE)Chest: 13 ± 3pH-test discomfort (mm VAS ± SE)Chest: 14 ± 3(0.968)b(0.001)bWong et al. (2005)Level IIQuality: 16.5/26Randomised controlled trial25 participants, catheter group25 participants, wireless groupChest discomfort: 9/25 (36%)Chest discomfort: 2/25 (8%)4.5 [1.08, 18.77] (0.037)Grigolon et al. (2007)Level III-1Quality: 13.5/26Pseudo-randomised controlled trial78 participants, catheter group55 participants, wireless groupChest discomfort: 17/55 (30.9%)Not stated-Bradley et al. (2011)Level III-2Quality: 15/26Cohort study106 participants, catheter group234 participants, wireless groupChest discomfort: 54/106 (51%)Chest pain: 35/106 (33%)Chest discomfort: 61/234 (26%)Chest pain: 44/234 (19%)1.95 [1.47, 2.60](<0.001)1.76 [1.2, 2.57](0.009)Pandolfino et al. (2003)Level III-2Quality: 11.5/26Case-control study30 participants, catheter group29 participants, wireless groupOesophageal discomfort: 10/29 (34.5%)Severe discomfort leading to capsule removal: 2/29 (6.9%)Moderate chest pain: 4/29 (13.8%)Oesophageal discomfort: 5/30 (16.7%)2.07 [0.80, 5.32](<0.05)Schneider et al. (2007)Level III-2Quality: 9/26Non-randomised controlled trial78 participants, wireless group55 participants, catheter groupOesophagus discomfort: 14/78 (17.9%)Oesophagus discomfort: 18/55 (32.7%)0.55, [0.30, 1.01](NS)NS = not significantaAnalysis was done using the Mann-Whitney U-test.bAnalysis was done using the Student t-test.Chest pain was reported in 21/31 non-comparative studies and was the most reported adverse event resulting from catheter-free monitoring. In the studies that reported chest pain or discomfort as an adverse event, rates varied between 0.27% and 45%, with a median of 17.19%. Severe or intolerable chest pain was reported in 6 of the 21 studies and occurred in 0.52% to 5.13% of cases, with a median of 1.44% (see REF _Ref383766707 \h \* MERGEFORMAT Table 75 in REF _Ref364237359 \h \* MERGEFORMAT Appendix E).Children had six times more chest pain undergoing catheter-free monitoring (39%) compared with catheter-based monitoring (6%; p=0.02) (Croffie et al. 2007). Of the four non-comparative studies on complications of catheter-free monitoring in children, one study (Gunnarsdottir, Stenstrom & Arnbjornsson 2007, 2008) reported a case of mild chest discomfort ( REF _Ref366833236 \h \* MERGEFORMAT Table 13 and REF _Ref375124857 \h \* MERGEFORMAT Table 14). Table 13Chest pain or chest discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI] (p-value)Croffie et al. (2007)Level IIQuality: 14.5/25Randomised controlled trial16 participants, catheter group18 participants, wireless groupChest pain 7/18 (39%)Chest pain 1/16 (6%)6.22 [0.86, 45.25](0.02)Table 14Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in childrenStudyLevel and qualityPopulation Complications per procedureGunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008)Level IVQ1Case series58 children 1/58 procedures1 mild chest discomfortForeign-body sensationA foreign-body sensation during monitoring was reported in one comparative study and nine non-comparative studies. Bradley et al. (2011) reported significantly more chest foreign-body sensation in patients with catheter-free monitoring compared with catheter-based monitoring ( REF _Ref361063962 \h \* MERGEFORMAT Table 15).In a large case series by Crowell et al. (2009) the foreign-body sensation rate was as high as 50% (147/294) ( REF _Ref379483586 \h Table 16). Other smaller studies reported a lower rate of globus sensation (i.e. feeling a lump or foreign body in their throat): the proportion of procedures associated with this sensation ranged from 0.22% to 22.97%, with a median of 5.9%.Table 15A foreign-body sensation resulting from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI] (p-value)Bradley et al. (2011)Level III-2Quality: 15/26Cohort study106 participants, catheter group234 participants, wireless groupForeign body chest: 66/106 (62)%Foreign body throat: 22/106 (21%)Foreign body chest: 80/234 (34% )Foreign body throat: 51/234 (22%)1.82 [1.44, 2.30](<0.001)0.95 [0.61, 1.48](0.887)Table 16A foreign-body sensation resulting from catheter-free (wireless) oesophageal pH monitoring in adultsStudyLevel and qualityPopulation Chest discomfort / complications per procedureCrowell et al. (2008)Level IVQ1Case series294 patients147/294 procedures147 foreign-body sensationTseng et al. (2005)Level IVQ1Retrospective case series190 procedures, 186 patientsMost patients noted a foreign-body sensationRemes-Troche et al. (2005)Level IVQ1Prospective case series77 patients11/77 procedures11 foreign-body sensationPrakash et al. (2006)Level IVQ2Retrospective case series452 patients1/452 procedures (but this only gives the major side effects of the patients who requested removal of the capsule)1 severe foreign-body sensationDomingues, Moraes-Filho & Domingues (2011)Level IVQ2Retrospective case series74 patients17/74 procedures17 mild foreign-body sensationGarrean et al. (2008)Level IVQ2Post-test case series60 patients1/60 procedures1 globus sensationBelafsky et al. (2004)Level IVQ2Prospective case series46 patients4/46 procedures4 foreign-body sensationPandolfino et al. (2006)aLevel IVQ2Case-control study10 control subjects and 10 patients with GORD7/20 7 mild chest discomfort or foreign-body sensationaThis study is not a case series but is still included as level IV safety evidence because it does not report a(n) (appropriate) comparison regarding complications or adverse events. Nose and throat painIn contrast to the findings for chest pain and discomfort, other complications and discomforts from pH monitoring were more common with catheter-based monitoring compared with catheter-free monitoring. Five studies reported on nose and/or throat pain or discomfort, and in all studies this was significantly more severe in patients receiving catheter-based monitoring ( REF _Ref361044607 \h \* MERGEFORMAT Table 17). Wenner, Johnsson et al. (2007) reported a median score of 0.2?cm on a 10?cm VAS scale for nose/throat symptoms in patients undergoing catheter-free monitoring, compared with a score of 6.5?cm for patients in the catheter-based monitoring group (p<0.0001)—a clinically significant difference. Andrews et al. (2012) noted a greater difference in nasal discomfort than throat discomfort between the two pH-monitoring technologies, with results favouring catheter-free monitoring. Nasal pain was halved in patients receiving catheter-free monitoring compared with catheter-based monitoring in Wong et al. (2005). The differences in throat pain and discomfort between the two pH tests in Wong et al. (2005), Pandolfino et al. (2003) and Schneider et al. (2007) was much greater than in Andrews et al. (2012), with relative risk reductions favouring catheter-free monitoring that ranged from 67% to 96%. Croffie et al. (2007) reported that throat pain in children was also significantly more common during catheter-based monitoring ( REF _Ref379483635 \h Table 18).Table 17 Nose and throat pain or discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI] (p-value)Wenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median cm VAS (IQR) Nose/throat symptoms: 0.2 (0.0–1.9)Patients’ experience, median cm VAS (IQR) Nose/throat symptoms: 6.5 (1.5–8.0)(<0.0001) aAndrews et al. (2012)Level IIQuality: 19/26Dual centre, randomised, non-blinded trial43 participants, catheter group43 participants, wireless grouppH placement discomfort (mm VAS ± SE)Nasal: 6 ± 2Throat: 32 ± 4pH-test discomfort (mm VAS ± SE)Nasal: 10 ± 3Throat: 19 ± 4pH placement discomfort (mm VAS ± SE)Nasal: 36 ± 4Throat: 37 ± 3pH-test discomfort (mm VAS ± SE)Nasal: 39 ± 3Throat: 43 ± 4(<0.001) b(0.317) b(<0.001) b(<0.001) bWong et al. (2005)Level IIQuality: 16.5/26Randomised controlled trial25 participants, catheter group25 participants, wireless groupNose pain: 8/25 (32%)Runny nose: 13/25 (52%)Nose bleeding: 1/25 (4%)Throat pain: 4/25 (16%)Throat discomfort: 12/25 (48%)Nose pain: 15/25 (60%)Runny nose: 24/25 (96%)Nose bleeding: 0/25 (0%)Throat pain: 12/25 (48%)Throat discomfort: 23/25 (92%)0.53 [0.28, 1.03] (0.047)0.54 [0.37, 0.8] (0.001)(1.0)0.33 [0.12, 0.89] (0.032) 0.52 [0.34, 0.8] (0.001)Pandolfino et al. (2003)Level III-2Quality: 11.5/26Case-control study30 participants, catheter group29 participants, wireless groupThroat discomfort: 4/29 (13.8%)Throat discomfort: 22/30 (73.3%)0.19 [0.07, 0.48] (<0.001)Schneider et al. (2007)Level III-2Quality: 9/26Non-randomised controlled trial55 participants, catheter group78 participants, wireless groupThroat discomfort: 3/78 (3.8%)Throat discomfort: 52/55 (94.5%) 0.04 [0.01, 0.12] (0.001)aAnalysis was done using the Mann-Whitney U-test.bAnalysis was done using the Student t-test.Table 18Nose and throat pain or discomfort resulting from catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI](p-value)Croffie et al. (2007)Level IIQuality: 14.5/25Randomised controlled trial16 participants, catheter group18 participants, wireless group Throat pain 8/18 (44%)Throat pain 15/16 (94%) 0.47 [0.28, 0.81] (0.001)Three case series reported throat pain during catheter-free monitoring ( REF _Ref361045484 \h \* MERGEFORMAT Table 19). Throat pain was reported in 9.3% of cases in the study by Karamanolis et al. (2012), 5.0% of cases by Garrean et al. (2008) and 32.8% of patients by Sofi et al. (2011). No case series mentioned nose pain or discomfort as a side effect from catheter-free monitoring; however, some cases of epistaxis were reported ( REF _Ref361045484 \h \* MERGEFORMAT Table 19).Table 19Throat pain and epistaxis resulting from catheter-free (wireless) oesophageal pH monitoring in adultsStudyLevel and qualityPopulation Throat pain per procedureKaramanolis et al. (2012)Level IVQ1Post-test case series32 patients3/32 procedures3 throat painGarrean et al. (2008)Level IVQ2Post-test case series60 patients3/60 procedures3 throat painSofi et al. (2011)Level IVQ3Retrospective case series58 patients19/58 procedures19 sore throatdes Varannes et al. (2005)aLevel IVQ1In-subject simultaneous recording study40 patients1/40 procedures1 epistaxisMarchese et al. (2006)Level IVQ1Prospective case series39 patients2/39 procedures2 mild epistaxisBelafsky et al. (2004)Level IVQ2Prospective case series46 patients2/46 procedures2 epistaxisaThis study is not a case series but is still included as level IV safety evidence because it does not report a(n) (appropriate) comparison regarding complications or adverse events. DysphagiaDysphagia (difficulty swallowing) was also mentioned as a common adverse effect from pH monitoring. Francis et al. (2012) compared proximal wireless pH monitoring with no proximal pH monitoring (48?hours after the start of distal wireless pH monitoring) during a blinded RCT. They reported increased odds of dysphagia (adjusted OR=14.3; 95%CI 2.12, 96.6; p=0.006) and odynophagia (painful swallowing) (adjusted OR=49.5; 95%CI 4.70, 520; p=0.001) in the intervention group, i.e. those receiving catheter-free monitoring. Wenner, Johnsson et al. (2007) compared swallow-induced symptoms in patients receiving catheter-free and catheter-based monitoring, and reported a median score of 5.2 on a 10?cm VAS scale (IQR=2.1–6.7) in the catheter-based monitoring group, compared with a score of only 2.1 (IQR=0.5–5.0) in the catheter-free monitoring group (p=0.033). Swallowing difficulties were a lot more common in patients undergoing catheter-based, as opposed to catheter-free, monitoring and were approximately halved in a cohort study by Bradley et al. (2011). This study also reported a significant difference in painful swallowing ( REF _Ref379466243 \h \* MERGEFORMAT Table 20). In children the results were similar, with one high-quality case series by Gunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008) reporting that 3 out of 58 (5.2%) children undergoing catheter-free monitoring had dysphagia (see REF _Ref364237359 \h \* MERGEFORMAT Appendix E).Table 20Dysphagia resulting from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNDysphagia, wireless pH monitoringDysphagia, catheter-based pH monitoringRR [95%CI](p-value)Wenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median cm VAS (IQR) Swallow-induced symptoms: 2.1 (0.5–5.0)Patients’ experience, median cm VAS (IQR) Swallow-induced symptoms: 5.2 (2.1–6.7)0.033 aBradley et al. (2011)Level III-2Quality: 15/26Cohort study106 participants, catheter group234 participants, wireless groupDifficulty swallowing: 98/234 (42%)Painful swallowing: 103/234 (44%)Difficulty swallowing: 96/106 (91%)Painful swallowing: 66/106 (62%)0.46 [0.39, 0.54](<0.001)0.71 [0.57, 0.87](0.002)aAnalysis was done using the Mann-Whitney U-test.Eating and drinking difficultiesSix studies reported that pH monitoring affects diet or appetite ( REF _Ref361059257 \h \* MERGEFORMAT Table 21 and REF _Ref379483689 \h \* MERGEFORMAT Table 22). Andrews et al. (2012) reported that patients in the catheter-free monitoring group were more likely to be able to eat and drink without difficulties than those undergoing catheter-based monitoring, with scores of 75?±?5 and 51?±?4 on a VAS-scale, respectively (p<0.001). Catheter-based monitoring affected the diet of 47% of patients in the study by Pandolfino et al. (2003). In comparison, only 3% of the patients receiving catheter-free monitoring in the same study had their diet affected (p<0.001). Wenner, Johnsson et al. (2007) reported a median food intake interference of 1.4 with the catheter-free (wireless) test and 4.0 with the catheter-based test (on a 10-point VAS, where 0 was defined as no interference at all and 10 the worst possible interference). Although a difference of this size would likely be considered clinically significant, the sample was too small for this to be so. Bradley et al. (2011) also did not report any significant differences regarding early fullness or diminished appetite comparing the two pH tests. In children the results were again consistent, with patients undergoing catheter-free monitoring shown to have more appetite than those undergoing catheter-based monitoring (Croffie et al. 2007; REF _Ref379483689 \h \* MERGEFORMAT Table 22).One non-comparative study, a large case series, addressed eating and drinking during catheter-free monitoring, and reported that 82/294 (27.9%) of the patients had a diminished appetite (Crowell et al. 2008; see REF _Ref364237359 \h \* MERGEFORMAT Appendix E). Table 21Eating and drinking difficulties resulting from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI](p-value)Wenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median cm VAS (IQR) Interference food intake: 1.4 (0.2–4.9)Patients’ experience, median cm VAS (IQR) Interference food intake: 4.0 (1.8–7.0)(0.056) aAndrews et al. (2012)Level IIQuality: 19/26Dual centre, randomised, non-blinded trial43 participants, catheter group43 participants, wireless grouppH-test discomfort (mm VAS ± SE)Eating/drinking: 75 ± 5 pH-test discomfort (mm VAS ± SE)Eating/drinking: 51 ± 4(<0.001) bGrigolon et al. (2007)Level III-1Quality: 13.5/26Pseudo-randomised controlled trial78 participants, catheter group55 participants, wireless groupLimitation of food intake (score 0–3)0.4 ± 0.1Limitation of food intake (score range 0–3)0.9 ± 0.1(<0.05)b Bradley et al. (2011)Level III-2Quality: 15/26Cohort study106 participants, catheter group234 participants, wireless groupEarly fullness: 68/234 (29%)Diminished appetite: 56/234 (24%)Early fullness: 23/106 (22%)Diminished appetite: 34/106 (32%)1.33 [0.89, 2.02](0.188)0.75 [0.52, 1.07](0.144) Pandolfino et al. (2003)Level III-2Quality: 11.5/26Case-control study30 participants, catheter group29 participants, wireless groupAffected diet: 1/29 (3%)Affected diet: 14/30 (47%)0.07 [0.01, 0.53](<0.001)aAnalysis was done using the Mann-Whitney U-test, 10?cm VAS.bAnalysis was done using the Student t-test, 100?mm VAS.Table 22Eating and drinking difficulties resulting from catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringp-valueCroffie et al. (2007)Level IIQuality: 14.5/25Randomised controlled trial16 participants, catheter group18 participants, wireless groupAppetite on scale of 1–5: mean 3.54Appetite on scale of 1–5: mean 2.720.029a aAnalysis was done using the Student t-test.Impact on daily life Oesophageal pH monitoring can have an impact on daily activities. All seven studies reported a significant difference in interference in daily activities when comparing the two different tests, favouring catheter-free monitoring ( REF _Ref366245099 \h \* MERGEFORMAT Table 23 and REF _Ref366244904 \h \* MERGEFORMAT Table 24). On a scale of 0– 10—where 0 means no interference, and 10 means maximum interference, with physical activities—Wenner, Johnsson et al. (2007) reported a median score of 0.6 (IQR=0.2–2.7) with catheter-free monitoring, compared with a score of 5.0 (IQR=2.6–8.5) in the catheter-based monitoring group (Mann-Whitney U test p<0.0001). Interference with normal daily life was also assessed in this study and similar results were obtained. Andrews et al. (2012) assessed whether patients with wireless monitoring were better able to maintain their usual activities than patients with a catheter inserted, and found this was the case. Grigolon et al. (2007), Pandolfino et al. (2003) and Schneider et al. (2007) reported similar results ( REF _Ref366245099 \h \* MERGEFORMAT Table 23). Gillies et al. (2005) reported that catheter-based monitoring seemed to affect work attendance significantly more than wireless monitoring: 82% of patients in the catheter-based group did not attend work, compared with only 14% in the catheter-free group (p<0.0001); and interference with work activities was also significantly less with catheter-free monitoring than with catheter-based monitoring in the study by Wenner, Johnsson et al. (2007).Table 23Impact on daily life from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI](p-value)Wenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median cm VAS (IQR) Interference work activities: 0.3 (0.0–1.4)Interference physical activities: 0.6 (0.2–2.7)Interference normal daily life: 0.7 (0.2–3.4)Patients’ experience, median cm VAS (IQR) Interference work activities: 6.8 (1.7–9.0)Interference physical activities: 5.0 (2.6–8.5)Interference normal daily life: 5.7 (2.3–8.0)(0.005) a(<0.0001) a(<0.0001) aAndrews et al. (2012)Level IIQuality: 19/26Dual centre, randomised, non-blinded trial43 participants, catheter group43 participants, wireless grouppH-test discomfort (mm VAS ± SE)Ability usual activities:92 ± 2pH-test discomfort (mm VAS ± SE)Ability usual activities: 75 ± 5(<0.001) bGrigolon et al. (2007)Level III-1Quality: 13.5/26Pseudo-randomised controlled trial78 participants, catheter group55 participants, wireless groupLimitation of daily activities (score 0–3, mean ± SEM)0.2 ± 0.1Limitation of daily activities (score 0–3, mean ± SEM)1.2 ± 0.1(<0.001) bGillies et al. (2007)Level III-2Quality: 13.5/26Non-randomised controlled trial 100 participants, catheter group 85 participants, wireless group (but 100 studies)Impact on work attendance: 14/100 (14%) Impact on work attendance: 82/100 (82%) 0.17[0.10, 0.28](<0.0001)Pandolfino et al. (2003)Level III-2Quality: 11.5/26Case-control study30 participants catheter group,29 participants, wireless groupChange daily routine: 0/29 (0%)Affected activity: 0%Change daily routine: 11/30 (37%)Affected activity: 60%(<0.001)Schneider et al. (2007)Level III-2Quality: 9/26Non-randomised controlled trial55 participants, catheter group78 participants, wireless groupReduced activities: 5/78 (6.4%)Reduced activities: 55/55 (100%)0.12[0.05, 0.29](0.0001)aAnalysis was done using the Mann-Whitney U-test.bAnalysis was done using the Student t-test.In children the results were similar to those described in adults ( REF _Ref366244904 \h \* MERGEFORMAT Table 24).Table 24Impact on daily life from catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringp-valueCroffie et al. (2007)Level IIQuality: 14.5/25Randomised controlled trial16 participants catheter group18 participants wireless group Mean activity on scale of 1–5: 3.66 Mean activity on scale of 1–5: 2.330.001 aaAnalysis was done using the Student t-test.Overall discomfort and satisfactionOverall placement discomfort was not significantly different between the two pH monitoring tests, when Andrews et al. (2012) and Grigolon et al. (2007) reported on this outcome. Overall discomfort during the period of monitoring was higher when a catheter was used. Overall discomfort scores on a VAS—where 0 means no discomfort and 100 means worst possible discomfort—ranged from 21 to 29 in patients undergoing catheter-free monitoring and from 33 to 51 in those undergoing catheter-based monitoring (Wenner, Johnsson et al. 2007; Andrews et al. 2012; Grigolon et al. 2007; p-values ≤0.012). Gilles et al. (2007) reported that 27% of the patients undergoing catheter-free monitoring experienced no overall discomfort, compared with only 3% undergoing catheter-based monitoring (p<0.0001). In the same patient population 23% in the catheter-free group and 45% in the catheter-based group reported discomfort scores >5 on a scale of 0–10. This difference was not considered statistically significant. Overall satisfaction scores were higher in patients who underwent catheter-free monitoring than catheter-based monitoring (Pandolfino et al. 2003; Sweis et al. 2009; REF _Ref361134190 \h \* MERGEFORMAT Table 25). Table 25Overall discomfort and satisfaction from catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringRR [95%CI]p-valueWenner, Johnsson et al. (2007) Level IIQuality: 20/26Randomised crossover trial31 participants, catheter group31 participants, wireless groupPatients’ experience, median cm VAS (IQR) All adverse symptoms: 2.1 (0.5–4.6)Patients’ experience, median cm VAS (IQR) All adverse symptoms: 5.1 (2.0–6.6)(<0.001) aAndrews et al. (2012)Level IIQuality: 19/26Dual centre, randomised, non-blinded trial43 participants, catheter group43 participants, wireless grouppH placement discomfort (mm VAS ± SE)Overall: 29 ± 4pH-test discomfort (mm VAS ± SE)Overall: 26 ± 4pH placement discomfort (mm VAS ± SE)Overall: 33 ± 4pH-test discomfort (mm VAS ± SE)Overall: 39 ± 4(0.406) b(0.012) bGrigolon et al. (2007)Level III-1Quality: 13.5/26Pseudo-randomised controlled trial78 participants, catheter group55 participants, wireless groupMean placement discomfort (mm VAS ± SE) 29 ± 4Discomfort during whole test (mm VAS ± SE)22 ± 3None to mild discomfort: 41/55 (74.5%)Mean placement discomfort (mm VAS ± SE) 32 ± 3Discomfort during whole test (mm VAS ± SE)37 ± 3None to mild discomfort: 40/78 (51.3%)NS(<0.001) b(<0.05) bSweis et al. (2009)Level III-2Quality: 15/26Cohort study110 participants, catheter group134 participants, wireless groupOverall satisfaction: 4.4/5Overall satisfaction: 3.5/5(<0.001) bGillies et al. (2007)Level III-2Quality: 13.5/26Non-randomised controlled trial 100 participants, catheter group 85 participants, wireless group (but 100 studies)73/100 (73%) overall discomfortMedian discomfort: 3Discomfort score >5: 23/100 (23%)97/100 (97%) overall discomfortMedian discomfort: 5Discomfort score >5: 45/100 (45%)0.85 [0.68, 1.07](<0.0001) a0.60 [0.39, 0.94]Pandolfino et al. (2003)Level III-2Quality: 11.5/26Case-control study30 participants, catheter group29 participants, wireless groupSatisfaction (the lower the better): 0.8 ± 0.1Satisfaction (the lower the better): 1.9 ± 0.2(<0.001) bNS = not significantaAnalysis was done using the Mann-Whitney U-test.bAnalysis was done using the Student t-test.In children the results were similar to those found in adults ( REF _Ref361134205 \h \* MERGEFORMAT Table 26).Table 26Overall discomfort and satisfaction from catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringp-valueCroffie et al. (2007)Level IIQuality: 14.5/25Randomised controlled trial16 participants, catheter group18 participants, wireless group Overall satisfaction on scale of 1–5: 4.31Overall satisfaction on scale of 1–5: 3.110.003 aaAnalysis was done using the Student t-test.Other reported side effects and complicationsWong et al. (2005) reported other fairly prevalent side effects such as coughing (20% in catheter-free and 28% in catheter-based monitoring) and headaches (20% in catheter-free and 56% in catheter-based monitoring, p=0.009). Furthermore, 19% experienced abdominal pain and 18% nausea, and 6% had to vomit during the wireless test, compared with 14%, 20% and 6%, respectively, in the catheter group in the study by Bradley et al. (2011); but these results were not significantly different. In the study by Pandolfino et al. (2003) 9% of patients undergoing catheter-free monitoring reported disrupted sleep, compared with 30% undergoing catheter-based monitoring; this difference was not considered statistically significant (see REF _Ref364237359 \h \* MERGEFORMAT Appendix E).In the non-comparative studies, other adverse events or complications resulting from wireless pH monitoring were extreme gagging (1/190); coughing (6/58); nausea (5/77); pharyngeal irritation (3/39); back pain (5.0% to 6.3%); rash (1/203); mucosal abrasion with minor haemorrhage (1/30); capsule dislodgement in the mouth, pyriform sinus or stomach (3/76); detachment failure of the capsule (1/66); laryngospasm (2/46); vasovagal reaction (1/46); poor tolerance with vomiting (2/40); and dizzy spell during insertion (1/40).Four case series reported adverse events of catheter-free monitoring in children. There were two oesophageal tears reported, at least one due to a capsule release failure. A less severe adverse event reported was coughing (1/58). Case reports were also included but provided less information than case series because it was impossible to determine the denominator, i.e. how many patients received the test and were at risk of harm but did not have any adverse effects. Case reports only provide descriptive information as to the possible types of adverse events and can be useful for describing rare complications. The case reports’ results are shown in REF _Ref364237359 \h \* MERGEFORMAT Appendix E. Serious complications of catheter-free monitoring mentioned in these case reports and not anywhere else were: a retention of the capsule in a colonic diverticulum for over 2?years, a capsule aspiration followed by decreased oxygen saturation, an oesophageal perforation, and different capsule dislodgements—one in the left pyriform sinus and one in the mainstem bronchus. Capsule aspirations and dislodgements can lead to pain, breathing difficulties and choking, depending on where the capsules dislodge, and can therefore become a severe complication. Oesophageal perforations can lead to further complications such as permanent damage to the oesophagus, abscess formation, infection in and around the lungs, and can progress to shock and even death if remain untreated. Is it effective? Direct evidence of diagnostic effectivenessDoes catheter-free monitoring improve health outcomes?Summary—What is the effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD in patients who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate? Does catheter-free monitoring improve health outcomes?No studies were identified that assessed the direct health impact of catheter-free monitoring versus no monitoring in the selected study population. However, one matched-pairs study found that just slightly more patients who were monitored by the wireless system had an improvement or disappearance of the principal symptom, compared with those monitored by the catheter-based system (73% in the wireless group versus 69% in the catheter-based group (n=51 in each group)). A before-and-after study reported that out of 26 patients who received medical therapy or conservative advice after a catheter-free monitoring test, 9 patients had a good or moderate improvement in symptoms.In a meta-analysis, catheter-free monitoring in adults was found to have over three times the risk (RR=3.3, 95%CI 1.63, 6.81) of having technical problems compared with catheter-based monitoring. A similar comparative risk of technical problems was seen in a trial of pH monitoring in adults and children combined (RR=2.87, 95%CI 1.47, 5.62). Most studies (15/20) reported only minimal day-to-day variability in oesophageal acid exposure across the 2?days of monitoring, suggesting that catheter-free monitoring is a reliable means of monitoring pH levels. Studies were included to assess the effectiveness of catheter-free (wireless) oesophageal pH monitoring according to the criteria outlined a priori in REF _Ref360542369 \h \* MERGEFORMAT Box 2.Box 2Eligibility criteria for identification of studies relevant to an assessment of effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoringSelection criteriaInclusion criteriaPopulationPatients with symptoms of GORD in whom catheter-based pH monitoring has failed or in whom it is anatomically inappropriate InterventionCatheter-free (wireless) ambulatory oesophageal pH monitoringComparatorsNo pH monitoringOutcomesPatient relevant outcomes: quality of life, reduction in progression to Barrett’s oesophagus and/or oesophageal cancer, symptom resolution or symptom reductionPublication typeRandomised or non-randomised controlled trials, cohort studies or systematic reviews of these study designsSearch period2001 – 5/2013LanguageNon-English language articles were excluded unless they provided a higher level of evidence than the English language articles identifiedNo studies were identified that assessed the direct health impact of catheter-free monitoring versus no monitoring in the selected study population. Two studies reported on the reduction in GORD symptoms after catheter-free monitoring. However, these studies did not include patients who had either failed a catheter-based test or in whom catheter-based monitoring was anatomically inappropriate. Furthermore, they did not have ‘no pH monitoring’ as a comparator, and therefore did not meet the inclusion criteria specified a priori. However, in the absence of more relevant data, results from these studies are presented. A matched-pairs retrospective cohort study by Grigolon et al. (2011) evaluated the usefulness of a 96-hour catheter-free monitoring test in patients’ clinical management, comparing outcomes of 51 patients studied with the wireless technique and 51 patients studied with the traditional catheter-based 24-hour test. The percentage of patients with an improvement in or disappearance of the principal GORD symptom was 73% in the catheter-free group and 69% in the catheter-based group. The average satisfaction score was 7.0 in the catheter-free group compared with 6.5 in the catheter-based group, on a scale of 0 to 10; as expected, the average score for satisfaction increased progressively (p<0.001) in the two groups as their symptoms improved.Sweis et al. (2011) assessed the clinical impact of prolonged, 96-hour catheter-free pH monitoring at clinical follow-up (6–36?months) in patients with negative 24-hour catheter-based monitoring referred for a second opinion due to ongoing symptoms suggestive of GORD. Follow-up data from at least 6?months after initiation of therapy were available for 33 out of 38 patients (87%). Twenty-six of these patients received medical therapy or conservative advice, with median follow-up at 24?months. Nine of these patients had a moderate or good improvement in symptoms and 17 had a poor outcome or were lost to follow-up. In these groups all 9 (100%) in the improvement group and 9 out of the 17 (53%) in the poor-outcome group had a GORD diagnosis on the basis of pathologic acid exposure or a positive association with GORD symptoms during catheter-free monitoring (p=0.361).Technical efficacy Studies were included to assess the technical efficacy of catheter-free (wireless) oesophageal pH monitoring according to the criteria outlined in REF _Ref360615021 \h \* MERGEFORMAT Box 3.Box 3Eligibility criteria for identification of studies relevant to an assessment of the technical efficacy of catheter-free (wireless) ambulatory oesophageal pH monitoringSelection criteriaInclusion criteriaPopulationPatients with symptoms of GORD in whom catheter-based pH monitoring has failed or in whom it is anatomically inappropriate Patients with symptoms of GORD for whom pH monitoring is indicated InterventionCatheter-free (wireless) ambulatory oesophageal pH monitoringComparatorsNo pH monitoringCatheter-based oesophageal pH monitoring OutcomesTechnical efficacy: operative success and early detachment or hardware malfunctionsPublication typeRandomised or non-randomised controlled trials, cohort studies, registers, case series, case reports or systematic reviews of these study designs Search period2001 – 5/2013LanguageNon-English language articles were excluded unless they provided a higher level of evidence than the English language articles identifiedCatheter-free monitoring versus catheter-based monitoringNine studies were included that reported not only the technical efficacy of catheter-free monitoring, but also catheter-based monitoring failure rates. There were no statistically significant differences in failure rates or recording efficacy when the two pH-measuring systems were compared. However, all eight studies conducted in adults reported a higher percentage of technical problems with the new catheter-free system compared with the traditional catheter-based system ( REF _Ref361145268 \h \* MERGEFORMAT Table 27). No differences were found between the two systems when used in children (Croffie et al. 2007). A meta-analysis was conducted to determine the overall risk of technical failures of both systems when used in adults ( REF _Ref361236783 \h \* MERGEFORMAT Figure 7). The risk of having technical problems with catheter-free monitoring was over three times higher than with catheter-based monitoring (RRp=3.3; 95%CI 1.63, 6.81; I2=0%, p=0.906; k = 8 studies). Results of studies included in this meta-analysis were fairly consistent.Other (non-comparative) technical efficacy results of catheter-free monitoring have been divided and described per outcome; for the complete overview of non-comparative technical efficacy data extracted by each study, see REF _Ref379483855 \h \* MERGEFORMAT Appendix F . Studies are listed in order of level of evidence, quality and sample size.Table 27Failure rates / recording efficacy of catheter-free monitoring compared with catheter-based monitoring StudyLevel and qualityNCatheter-free monitoring Catheter-based monitoring RR[95%CI]des Varannes et al. (2005)Level: II Quality: 20/26In-subject simultaneous recording study40 patientsAdults7/40 procedures (17.5%)1 dysfunction of the capsule2 insertion intolerances1 detachment failure from the delivery system1 recording failure 2 early detachments1/40 procedures (2.5%)1 recording failure7.00[0.90, 54.32]Wenner, Johnsson et al. (2007)Level: IIQuality: 20/26Randomised crossover trial35 patientsAdults2/35 procedures (5.7%)2 technical problems0/35 procedures (0%)5.00[0.25, 100.53]Andrews et al. (2012)Level: IIQuality: 19/26Dual centre, randomised, non-blinded trial43 patients in the wireless group 43 patients in the catheter groupAdults5/43 procedures (12%)2 failed capsule calibrations2 early detachments1 insertion intolerance3/43 procedures (7%)1 equipment malfunction after the patient dropped the recorder2 catheter intolerances with early probe removal1.67 [0.42, 6.54]Azzam et al. (2012)Level: II Quality: 17/26In-subject simultaneous recording study25 patientsAdults1/25 procedures (4.0%)1 early detachment0/25 procedures (0%)3.00[0.13, 70.30]Wong et al. (2005)Level: IIQuality: 16.5/26Randomised controlled trial25 patients in the wireless group 25 patients in the catheter groupAdults2/25 procedures (8.0%)2 failures of transnasal insertion1/25 procedures (4.0%)1 catheter intolerance2.00 [0.19, 20.67]Grigolon et al. (2007)Level: III-1Quality: 13.5/26Pseudo-randomised controlled trial55 patients in the wireless group 78 patients in the catheter groupAdults1/55 procedures (1.8%)1 early detachment95.5% (91.5–97) recording time0/78 procedures (0%)98% (94–99) recording time4.23[0.18, 102.00]Bradley et al. (2011)Level: III-2Quality: 15/26Cohort study234 patients in the wireless group 106 patients in the catheter groupAdults5/234 procedures (2.1%)2 early detachments3 endoscopic removals due to severe discomfort1/106 procedures (0.9%)1 catheter intolerance 2.26 [0.27, 19.15]Hakanson et al. (2009)Level: III-2Quality: 14/26Case-control study with in-subject simultaneous recording53 volunteers and 55 patientsAdults13/108 procedures (12.0%)5 attachment failures4 early detachments3 immediate detachments1 recording failure2/108 procedures (1.9%)1 sensor displacement in the stomach1 catheter intolerance6.50[1.5, 28.12]Croffie et al. (2007)Level: IIQuality:14.5/26Randomised controlled trial30 patients in wireless + catheter group, 18 patients in wireless group and 18 in catheter groupChildren2/48 procedures (4.2%)1 recording failure1 early detachment2/48 procedures (4.2%)1 recording failure1 catheter intolerance1.00[0.15, 6.81]Figure 7Meta-analysis of technical efficacy of catheter-free monitoring compared with catheter-based monitoringInsertion and placement of the catheter-free (wireless) systemSix studies reported on the rate of problems associated with the insertion and placement of both the catheter-free and catheter-based monitoring systems ( REF _Ref361145268 \h \* MERGEFORMAT Table 27). On average, problems occurred more often during insertion or placement of the catheter-free (median 7.5% procedures, range 0%–12%) than the catheter-based monitoring system (median 0.9% procedures, range 0%–4%) ( REF _Ref361145268 \h \* MERGEFORMAT Table 27). Reported insertion and placement problems with the catheter-based system were catheter intolerance or sensor displacement. REF _Ref379483855 \h Appendix F outlines the errors during insertion and placement of the wireless system, which were reported in 24 studies for a total of 1,933 patients. The most common errors during insertion and placement of the wireless system were:an error in placement: either in the cardia or in the wrong place on the oesophagus wall (63–73 times).attachment failure: the capsule does not attach (properly) to the oesophageal mucosa (28–38 times).4detachment failure: the capsule fails to deploy from the delivery system (6–10 times).insertion failure: the inability to insert the system, either due to intolerance or anatomical abnormalities (9 times).immediate detachment: detachment of the capsule from the oesophageal wall immediately after insertion, sometimes followed by aspiration of the capsule (4 times).failed capsule calibration or device malfunction: inability to correctly calibrate the capsule before the monitoring period, or malfunction of the device when inserting (2 and 2 times, respectively).Most insertion and placement errors that occur with wireless monitoring are bothersome and inconvenient for the patient, since they have to return for another try or have the catheter inserted twice in the same sitting. However, insertion failures due to intolerance or anatomical abnormalities would occur in both catheter-free and catheter-based monitoring situations, because both systems are inserted using a catheter. The only difference would be that the catheter could be inserted transnasally or transorally in catheter-free monitoring, whereas it has to be inserted transnasally in catheter-based monitoring.Technical failures during data recordingThe only complications reported in catheter-based monitoring in comparative studies during data recording were recording failures (recorded once in a child and once in an adult) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9mZmllPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA (Croffie et al. 2007; des Varannes et al. 2005). Technical failures during the (usually 48-hour) catheter-free monitoring period in adults were reported in 36 comparative and non-comparative studies with a total of 3,629 patients. The most commonly reported complication influencing technical efficacy was early capsule detachment (reported 133 times). When the capsule detaches from the oesophageal mucosa early, it passes through the stomach, which leads to unreliable data. The commonly reported errors leading to incomplete data were:early capsule detachment (133 times)incomplete data capture (58 times) recording failure or receiver malfunction (11 times)transmission failure (7 times)errors in data retrieval (4 times)poor data reception (3 times).Furthermore, ‘technical failures’ were reported in 7 cases and the capsule malfunctioned in 2 patients. One patient lost his/her data recorder and therefore no analysis was possible (see REF _Ref361145268 \h \* MERGEFORMAT Table 27 and REF _Ref379483855 \h Appendix F ).In children technical errors occurring during monitoring were similar to those with adults. Incomplete data capture was reported in 21/289 children by Cabrera et al. (2011). Furthermore, early detachment occurred in 5 children PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWJyZXJhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA (Cabrera et al. 2011; Croffie et al. 2007), and there were 4 shorter monitoring periods of unknown cause, 2 recording failures and 1 transmission failure during the wireless monitoring period (see REF _Ref361145268 \h \* MERGEFORMAT Table 27 and REF _Ref379483855 \h Appendix F ).Day-to-day variability in oesophageal acid exposureWith catheter-free monitoring it is possible to monitor pH for more than 24?hours: in most cases there is a 48-hour monitoring period. There is a concern that sedation used during insertion of the system may influence the results of the first 24?hours of monitoring, and oesophageal acid exposure has been reported to exhibit day-to-day variability ADDIN EN.CITE <EndNote><Cite><Author>Wiener</Author><Year>1988</Year><RecNum>609</RecNum><IDText>1127-33</IDText><DisplayText>(Wiener et al. 1988)</DisplayText><record><rec-number>609</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">609</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wiener, G. J.</author><author>Morgan, T. M.</author><author>Copper, J. B.</author><author>Wu, W. C.</author><author>Castell, D. O.</author><author>Sinclair, J. W.</author><author>Richter, J. E.</author></authors></contributors><auth-address>Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27103.</auth-address><titles><title>Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters</title><secondary-title>Dig Dis Sci</secondary-title><alt-title>Digestive diseases and sciences</alt-title></titles><periodical><full-title>Dig Dis Sci</full-title><abbr-1>Digestive diseases and sciences</abbr-1></periodical><alt-periodical><full-title>Dig Dis Sci</full-title><abbr-1>Digestive diseases and sciences</abbr-1></alt-periodical><pages>1127-33</pages><volume>33</volume><number>9</number><keywords><keyword>Adult</keyword><keyword>Ambulatory Care</keyword><keyword>Female</keyword><keyword>*Gastric Acidity Determination</keyword><keyword>Gastroesophageal Reflux/*diagnosis/physiopathology</keyword><keyword>Humans</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Monitoring, Physiologic</keyword><keyword>Prospective Studies</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0163-2116 (Print)&#xD;0163-2116 (Linking)</isbn><accession-num>3044715</accession-num><urls><related-urls><url>;(Wiener et al. 1988). If this is the case, monitoring for 48 hours instead of 24?hours, as with traditional catheter-based monitoring, would give truer and more-accurate results, and this may have clinical advantages. Twenty studies reported on the day-to-day variability in oesophageal acid exposure with catheter-free monitoring in adults (see Table 78 in Appendix G).Two large case series of 124 and 77 patients reported significantly more reflux episodes on the second day of monitoring PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFuZGVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (Chander et al. 2012; Remes-Troche et al. 2005). Three other quality case series of 203, 148 and 26 patients reported more reflux on day 1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWNodG9sZDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

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ADDIN EN.CITE.DATA (Bechtold et al. 2007; Bhat, McGrath & Bielefeldt 2006; Turner et al. 2007). The remaining 14 studies did not report a significant difference in oesophageal acid exposure when comparing the first day with the second day of monitoring. In children one out of three studies (n=44) reporting on day-to-day variability noted significantly more reflux on day 1 of monitoring PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2NobWFuPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2NobWFuPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

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ADDIN EN.CITE.DATA (Hochman & Favaloro-Sabatier 2005). However, in the higher quality RCT and the case series with 27 and 58 included children, respectively, there were no significant differences in reflux reported when comparing the first 24 to the second 24?hours PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5uYXJzZG90dGlyPC9BdXRob3I+PFllYXI+MjAwNzwv

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ADDIN EN.CITE.DATA (Croffie et al. 2007; Gunnarsdottir, Stenstrom & Arnbjornsson 2007). See REF _Ref361820725 \h \* MERGEFORMAT Table 79 in REF _Ref379480322 \h Appendix G for the full results.Linked evidenceIs it accurate?Summary—What is the diagnostic accuracy of catheter-free (wireless) ambulatory oesophageal pH monitoring for GORD compared with catheter-based oesophageal pH monitoring?There was no consensus in the literature regarding what cut-offs should be used when pH monitoring is used to diagnose GORD. In the highest quality study available, a diagnosis of GORD was given if patients had a pH <4 for more than, or equal to, 4.4% of the time. Using these criteria, the catheter-free monitoring test had reasonable sensitivity (86.4%) and specificity (77.8%) when catheter-based monitoring was used as a reference standard. The two other studies that used this reference standard reported similar accuracy results, with slightly lower sensitivity and slightly higher specificity (variable cut-off points). Five diagnostic case-control studies used clinical diagnosis as the reference standard. The study with the largest patient population reported test sensitivity between 59% and 88% and test specificity between 75% and 96%, depending on which cut-off value was used (between 1.9% and 4.4% of the time that patients had pH <4). The remaining studies used thresholds between 4.4% and 5.3% for ‘proximal’ oesophageal pH monitoring. The sensitivity and specificity in these studies varied from 67% to 100% and from 66% to 100%, respectively. No studies compared the accuracy of both catheter-free and catheter-based monitoring against the reference standard of clinical diagnosis. Nine studies of adults reported on the time that the oesophagus was exposed to acid, rather than using a diagnostic cut-off, during pH monitoring. In four of the studies both tests were conducted in the same patient population, and therefore variations in results can be attributed with more certainty to the pH-monitoring method, rather than being associated with the use of two different samples of patients. However, the results were mixed, with two studies reporting that catheter-based monitoring detected more acid exposure time and one study reporting that catheter-free monitoring detected more acid exposure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BenphbTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Azzam et al. 2012). The remaining five studies reported no significant differences between the two measurement methods. One study reported on oesophageal acid exposure in children, finding significantly more reflux with wireless monitoring compared with catheter-based monitoring (p=0.01). Four studies reported not only on acid exposure time concordance, but also on variation in the number of reflux events. Three of the four studies—two level II and one level III-2—reported significantly more reflux events with the catheter-based monitoring system.Two comparative diagnostic yield studies reported that significantly more patients were diagnosed with catheter-free monitoring compared with catheter-based monitoring (p<0.001). One reported advantage of catheter-free monitoring is that it allows a longer monitoring period than catheter-based monitoring, i.e. 48 rather than 24?hours. Six studies reported that the additional day of monitoring increased diagnosed yield with a median of 7.8%.Studies were included to assess the accuracy of catheter-free (wireless) oesophageal pH monitoring according to criteria outlined in REF _Ref361041769 \h \* MERGEFORMAT Box 4.Box 4Inclusion criteria for identification of studies relevant to an assessment of the accuracy of catheter-free (wireless) ambulatory oesophageal pH monitoringSelection criteriaInclusion criteriaPopulationPatients with symptoms of GORD for whom pH monitoring is indicatedInterventionCatheter-free (wireless) ambulatory oesophageal pH monitoringReference standard (1)Catheter-based oesophageal pH monitoringReference standard (2)Clinical diagnosisOutcomesSensitivitySpecificityPositive/negative predictive valueLevel of agreement (concordance of data)Diagnostic yield Publication typeAll study designs listed in the ‘Diagnostic accuracy’ column of REF _Ref206478826 \h \* MERGEFORMAT Table 9Search period2001 – 5/2013LanguageNon-English language articles were excluded unless they provided a higher level of evidence than the English language articles identifiedOnly eight studies met the inclusion criteria for assessing the accuracy of catheter-free monitoring and provided sufficient data to determine its sensitivity and specificity. In three studies the reference standard used was catheter-based monitoring. Among them, two level II studies (a randomised crossover trial and an in-subject simultaneous recording study) and one level III-3 diagnostic accuracy study (a case-control study with in-subject simultaneous recording) were identified. All three studies with catheter-based monitoring as a reference standard scored high on flow and timing—the flow of patients through the study, and the timing of the index test(s) and reference standard—mostly because the index test and reference standard were performed almost simultaneously. Patient selection had an unknown to high risk of bias, depending on how patients enrolled and if there was the possibility of bias. The risk of bias regarding the index test and the reference standard varied depending on how the results were interpreted. The results of these studies are presented in REF _Ref361833867 \h \* MERGEFORMAT Table 28. All three studies included patients who were suspected of GORD and in whom pH monitoring was indicated, although one study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWthbnNvbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

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ADDIN EN.CITE.DATA (Hakanson et al. 2009) also included 45 volunteers—people without a history of GORD or any other pathology of the upper gastrointestinal tract. The highest quality study available (level II diagnostic evidence) indicated that a catheter-free monitoring test with a cut-off point of 4.4% of the time that pH <4 had good sensitivity and specificity (86.4% and 77.8%, respectively). The accuracy of the two other studies was in the same range, although their sensitivity was slightly lower and their specificity slightly higher. There is no consensus on which cut-off value should be used, so the cut-off values for diagnosing GORD in both catheter-free and catheter-based monitoring are different in all studies, making it difficult to interpret the accuracy data.Five studies used clinical diagnosis as a reference standard ( REF _Ref361907349 \h \* MERGEFORMAT Table 29). These were all diagnostic case-control studies (level III-3). This means that most of those included in the patient groups were GORD patients who had responded to therapy, because response to PPI therapy is a clear indication of having GORD and is widely used to diagnose the disease. Furthermore, the control groups consisted of patients who did not have GORD symptoms, so the applicability of the results based on these populations is questionable, since they do not match the target population, i.e. patients suspected of GORD who do not respond to PPIs. Most of these studies had a high risk of bias for patient selection when quality was assessed using the QUADAS-2 tool, and a medium to high risk of bias for flow and timing of the studies. Different cut-off values were used for diagnosis, varying from 1.9% to 10.6% of the time that oesophageal pH <4. Wenner, Johansson et al. (2007) and Wenner et al. (2008) used multiple cut-off values (from 1.9% to 4.4%) to determine the optimal value for diagnosis, and Bansal et al. (2009) used two different cut-off values for catheter-free monitoring: 4.4% for pH monitoring more proximal in the oesophagus and 10.6% for more distal pH monitoring (1?cm above the GOJ). Since every study used different cut-off values, they were considered too heterogeneous in their methods to meta-analyse.The study with the largest sample PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZW5uZXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Wenner, Johansson et al. 2007; Wenner et al. 2008) reported sensitivity values between 59% and 88% and specificity values between 75% and 96%, depending on which cut-off value was used. The remaining studies used cut-off values between 4.4% and 5.3% for ‘proximal’ oesophageal pH monitoring, i.e. with the capsule placed approximately 5?cm above the LOS or 6?cm above the SCJ, respectively. The sensitivity and specificity in these studies varied from 67% to 100% and from 66% to 100%, respectively. Whereas most studies use the ‘total time that pH <4 in the oesophagus’ to establish a positive or negative test result, some studies also use a ‘worst day analysis’—they only take the data from the day with the most gastro-oesophageal reflux PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5kb2xmaW5vPC9BdXRob3I+PFllYXI+MjAwMzwvWWVh

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ADDIN EN.CITE.DATA (Pandolfino et al. 2003; Scarpulla et al. 2007; Sweis et al. 2011). This can be either day 1 or day 2 of monitoring, and they then use similar cut-off values. Pandolfino et al. (2003) reported high sensitivity and specificity values with this type of analysis: 83.8% and 84.5%, respectively.Table 28Diagnostic accuracy of catheter-free monitoring compared with catheter-based monitoring for diagnosing GORD in adultsStudyEvidence level and qualityPopulationIndex test & cut-off pointReference standard & cut-off pointSensitivity %[95%CI]Specificity %[95%CI]PPV %[95%CI]NPV %[95%CI]LR+LR–des Varannes et al. (2005)In-subject simultaneous recording studyLevel: II Quality: Patient selection: ?Index test: Reference standard: ?Flow and timing: C1 P236 subjects suspected of GORDBravo pH monitoring (48-hour)Time under pH 4 >2.9%Catheter-based monitoring (24-hour)Time under pH 4 >4.2%78.6% [0.49–0.94]89.5% [0.65–0.98]84.6% [0.54–0.97]85.0% [0.61–0.96]7.490.24Wenner, Johnsson et al. (2007)Randomised crossover trialLevel: IIQuality: Patient selection: Index test: Reference standard: ?Flow and timing: C1 P231 subjects suspected of GORDBravo pH monitoring (48-hour)Time under pH 4 >4.4%Catheter-based monitoring (24-hour)Time under pH 4 >3.4%86.4% [0.64–0.96]77.8% [40.1–0.96]90.5% [0.68–0.98]70.0% [0.35–0.92]3.890.17Hakanson et al. (2009)Case-control study with in-subject simultaneous recordingLevel: III-3 Quality: Patient selection: ?Index test: Reference standard: ?Flow and timing: C1 P292 subjects (45 healthy volunteers and 47 patients)Bravo pH monitoring (48-hour)Time under pH 4 >1.9%Catheter-based monitoring (24-hour)Time under pH 4 >4.0%73.6% [0.59–0.84]92.3% [0.78–0.98]92.9% [0.79–0.98]72.0% [0.57–0.83]9.560.29? = unable to determine / unclear risk; = low risk; = high risk; Table 29Diagnostic accuracy of catheter-free monitoring compared to clinical diagnosis for diagnosing GORD in adultsStudyEvidence level and qualityPopulationIndex test & cut-off pointReference standard & cut-off pointSensitivity % [95%CI]Specificity % [95%CI]PPV %[95%CI]NPV %[95%CI]LR+LR–Accuracy[95%CI]Wenner, Johansson et al. (2007), Wenner et al. (2008)Diagnostic case-control studyLevel: III-3 Quality:Patient selection: Index test: ?Reference standard: Flow and timing: ?CXP3119 subjects (64 patients and 55 controls)Bravo pH monitoring (48-hour)Time under pH 4 >1.9, 2.2, 2.3, 3.2, 3.6 and 4.4 Clinical diagnosis1.9: 88%2.2: 86%2.3: 83%3.2: 68%3.6: 64%4.4: 59%1.9: 75%2.2: 80%2.3: 80%3.2: 85%3.6: 91%4.4: 96%--1.9: 3.522.2: 4.302.3: 4.153.2: 4.533.6: 7.114.4: 14.751.9: 0.162.2: 0.182.3: 0.213.2: 0.383.6: 0.404.4: 0.43-Bansal et al. (2009)Diagnostic case-control study Level: III-3Quality: Patient selection: Index test: ?Reference standard: Flow and timing:?CXP256 subjects (40 patients and 16 controls)Bravo pH monitoring (48-hour) Time under pH 4 >4.4% for the proximal location (6?cm above GOJ), and time under pH 4 >10.6% for the distal location (1?cm above GOJ)Clinical diagnosis (no symptoms of reflux in control population)Proximal: 67%Distal: 60%Proximal: 66%Distal: 88%-----Ayazi et al. (2009) (2)Diagnostic case-control studyLevel: III-3Quality:Patient selection: ?Index test: ?Reference standard: Flow and timing: ?CX P344 subjectsBravo pH monitoring (48-hour)Time under pH 4 >4.2%Clinical diagnosis100% [85–100]95% [76–100] ----98 [88–100]Ayazi et al. (2009) (3)Diagnostic case-control studyLevel: III-3Quality:Patient selection: Index test: ?Reference standard: Flow and timing: CXP338 subjects (28 patients and 10 controls)Bravo pH monitoring (48-hour) Time under pH 4 >4.2%Clinical diagnosis (minimal clinical evidence of GORD in control population)Abnormal combined 48?hours: 82%Abnormal first or second 24?hours:93%Abnormal combined 48?hours: 100%Abnormal first or second 24?hours:100%Abnormal combined 48?hours: 100%Abnormal first or second 24?hours:67%Abnormal combined 48?hours: 67%Abnormal first or second 24?hours:83%--Abnormal combined 48?hours: 87%Abnormal first or second 24?hours:95%Pandolfino et al. (2003)Diagnostic case-control studyLevel: III-3Quality: Patient selection: Index test: ?Reference standard: ?Flow and timing: CX P337 subjectsBravo pH monitoring (48-hour, day 1 (24-hour), worst day (W))Time under pH 4 >5.3%Clinical diagnosis24-h: 67.5%48-h: 64.9%W: 83.8%24-h: 89.7%48-h: 94.8%W: 84.5%24-h: 86.2%48-h: 92.3%W: 83.3%24-h: 74.5%48-h: 74.0%W: 84.6%24-h: 6.5548-h: 12.48W: 5.424-h: 0.3648-h: 0.37W: 0.19-? = unable to determine / unclear risk; = low risk; = high riskConcordance in acid exposure and reflux events in catheter-free monitoring versus catheter-based monitoringThere were nine studies that reported on the oesophageal acid exposure times during catheter-free monitoring compared with catheter-based monitoring in adults ( REF _Ref363115951 \h \* MERGEFORMAT Table 30). Four of these studies were in-subject simultaneous recording studies or randomised crossover trials, which means that both tests were conducted in the same patient population, allowing all confounding factors to be automatically controlled for PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BenphbTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Azzam et al. 2012; des Varannes et al. 2005; Hakanson et al. 2009; Wenner, Johnsson et al. 2007). Results between the two styles of monitoring test are therefore expected to be more similar than when two different patient samples are compared. However, three of these studies reported a significant difference in acid exposure times between catheter-free and catheter-based monitoring. Two studies reported more acid exposure time with the catheter-based system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZXMgVmFyYW5uZXM8L0F1dGhvcj48WWVhcj4yMDA1PC9Z

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ADDIN EN.CITE.DATA (des Varannes et al. 2005; Hakanson et al. 2009), and one study reported more acid exposure with the wireless system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BenphbTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Azzam et al. 2012).The remaining five studies also reported concordance data regarding acid exposure times, but in different patient groups PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bbmc8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Ang et al. 2010; Grigolon et al. 2011; Martinez de Haro et al. 2008; Schneider et al. 2007; Wong et al. 2005). None of the studies reported significant differences in acid exposure times between the two measurement methods. There was one study that reported concordance data on oesophageal acid exposure in children PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9mZmllPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA (Croffie et al. 2007). It reported significantly more reflux detected with wireless monitoring compared with catheter-based monitoring (p=0.0107). The tests were not performed in the same patient population; however, it was an RCT and therefore any baseline differences between the two groups are probably due to chance rather than a form of bias ( REF _Ref379484053 \h \* MERGEFORMAT Table 31).Two level II studies and two level III-2 studies reported not only on acid exposure time concordance, but also on variation in the number of reflux events ( REF _Ref363133126 \h \* MERGEFORMAT Table 32). Three of the four studies—two level II and one level III-2—reported significantly more reflux events with the catheter-based monitoring system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bbmc8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (des Varannes et al. 2005). Therefore, it can be concluded that the difference found in the number of reflux events recorded may be due to differences between the tests themselves and not other confounding factors such as the patient population variability or day-to-day variability in reflux. Table 30Concordance of acid exposure times using both monitoring tests in adultsStudyStudy designN% of total time pH <4 wireless pH monitoring% of total time pH <4 conventional pH catheterp-valueWenner, Johnsson et al. (2007)Randomised crossover trialLevel: IIQuality: 20/2631 patientsMedian: 7.3Median: 6.30.837 ades Varannes et al. (2005)In-subject simultaneous recording studyLevel: II Quality: 20/2633 patientsMedian: 2.4 (10th–90th percentile: 0.4–8.7)Median: 3.6 (10th–90th percentile: 0.7–8.6)0.0001 aAzzam et al. (2012)In-subject simultaneous recording studyLevel: II Quality: 17/26C1 (for accuracy)P225 patientsMedian: 6.1 (range: 0.1–21.4)Median: 4.1 (range: 0.1–13.8)0.001 aHakanson et al. (2009)Case-control study with in-subject simultaneous recordingLevel: IIQuality: 14/261st series: 26 patients, 27 controls2nd series: 21 patients, 18 controlsPatients 1st: median 3.2 (day 1)Patients 2nd: median 2.4 (day 1)Controls 1st: median 0.6 (day 1)Controls 2nd: median 1.3 (day 1)Patients 1st: median 6.8 Patients 2nd: median 7.1 Controls 1st: median 1.9Controls 2nd: median 4.4<0.001 a<0.001 a<0.05 a<0.05 aWong et al. (2007)Randomised controlled trialLevel: IIQuality: 16.5/26Catheter-free monitoring: 25 patientsCatheter-based monitoring: 25 patientsMedian: 1.9 (on PPI)Median: 10.2 (off PPI)Median: 4.8 (on PPI)Median: 7.8 (off PPI)0.70.78 bGrigolon et al. (2011)Matched-pairs retrospective cohort studyLevel: III-2 Quality: 16.5/26Wireless monitoring: 51 patientsCatheter-based monitoring: 51 patientsMedian 24h: 3.5 (1st and 3rd quartile: 1.2–6.6)Median 48h: 4.0 (1st and 3rd quartile: 1.8–7.4)Median 96h: 4.7 (1st and 3rd quartile: 1.9–9.4)Median: 3.5 (1st and 3rd quartile: 1.6–8.8)-Ang et al. (2010)Comparative study of diagnostic yieldLevel: III-2Quality: 14/26Wireless monitoring: 66 patientsCatheter-based monitoring: 55 patientsDay 1: 3.80 ± 6.09Day 2: 3.91 ± 5.32Overall: 3.86 ± 5.364.40 ± 5.34Day 1: 0.57 bDay 2: 0.61 bOverall: 0.57 bMartinez de Haro et al. (2008)Non-randomised controlled trial Level: III-2 Quality: 11/26Control group: 10 (simultaneous recording)No oesophagitis: 10 (5 catheter-based monitoring, 5 catheter-free monitoring)Non-Barrett’s oesophagitis (5 catheter-based monitoring, 5 catheter-free monitoring)Barrett’s oesophagitis (5 catheter-based monitoring, 5 catheter-free monitoring)Controls: mean 1.7No oesophagitis: mean 6.1Non-Barrett’s oesophagitis: mean 8.2Barrett’s oesophagitis: mean 27.3Controls: mean 1.1No oesophagitis: mean 5.8Non-Barrett’s oesophagitis: mean 7.9Barrett’s oesophagitis: mean 22.4-Schneider et al. (2007)Non-randomised controlled trialLevel: III-2Quality: 9/26Control group: 10 Oesophagitis: 68 catheter-free monitoring, 55 catheter-based monitoring After Nissen fundoplication: 43Controls: median 0.8Patients: median 14 Post-surgery: median 0.9Controls: median 1 Patients: median 12Post-surgery: median 1.20.1 b0.8 b0.9 baAnalysis was done using a Wilcoxon signed rank test.bAnalysis was done using the Mann-Whitney U-test.Table 31Concordance of acid exposure times using both monitoring tests in childrenStudyStudy designNReflux index wireless pH monitoringReflux index conventional pH catheterp-valueCroffie et al. (2007)Randomised controlled trialLevel: IIQuality:14.5/2627 patientsMean: 2.5 (range: 0.2–16.6)Mean: 1.6 (range: 0.1–10.8)0.0107aaAnalysis was done using the Mann-Whitney U-test.Table 32Number of reflux events in catheter-free monitoring compared with catheter-based monitoringStudyStudy designNWireless pH monitoringConventional pH catheter Test and p-valueWenner, Johnsson et al. (2007)Randomised crossover trialLevel: IIQuality: 20/2631 patientsMedian: 53 Median: 129<0.0001 ades Varannes et al. (2005)In-subject simultaneous recording studyLevel: II Quality: 20/2636 patientsMedian: 23 (10th– 90th percentile: 4–41) Median: 40 (10th–90th percentile: 7–84) 0.0001 aAng et al. (2010)Comparative study of diagnostic yieldLevel: III-2Quality: 14/26Catheter-free monitoring: 66 patients Catheter-based monitoring: 51 patients(Mean ± SD)Day 1: 27 ± 27Day 2: 31 ± 34(Mean ± SD)99 ± 111 <0.005 b<0.005 bSchneider et al. (2007) Non-randomised controlled trialLevel: III-2Quality: 9/26Control group: 10 Oesophagitis: 68 catheter-free monitoring, 55 catheter-based monitoringAfter Nissen fundoplication: 43 Median in controls: 23 Median in patients: 247Median post-surgery: 24Median in controls: 18Median in patients: 187Median post-surgery: 180.6 b0.09 b0.07 baAnalysis was done using a Wilcoxon signed rank testbAnalysis was done using the Mann-Whitney U-testDiagnostic yield Six studies report diagnostic yield in both wireless and catheter-based monitoring. Two of the studies were in-subject simultaneous recording studies, where both methods of pH monitoring were conducted at the same time in the same subjects. Both these studies reported no significant difference in diagnostic yield between the two tests. Only two comparative diagnostic yield studies of medium quality PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VpczwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Kushnir, Sayuk & Gyawali 2011; Sweis et al. 2009) reported significant differences—more patients were diagnosed with catheter-free monitoring compared with catheter-based monitoring (p-values <0.001) ( REF _Ref363120408 \h Table 33). In the larger of the two comparative diagnostic yield studies, 357/462 (77.2%) patients were diagnosed with the wireless pH test, compared with 849/1605 (52.9%) with the catheter-based test (Kushnir, Sayuk & Gyawali 2011).Table 33Diagnostic yield using catheter-free monitoring compared to catheter-based monitoringStudyEvidence level and qualityNWireless pH monitoring (%)Catheter-based pH monitoring (%)Cut-off value for positive test a p-valueWenner, Johnsson et al. (2007)Randomised crossover trialLevel: IIQuality: 20/2631 patients suspected of GORD21/31 (68)(5 were discordant)22/31 (71)(5 were discordant)CFPM: 4.4%CBPM: 3.4%-Azzam et al. (2012)In-subject simultaneous recording studyLevel: II Quality: 17/2625 patients19/25 (76)16/25 (64)Total: 4.5%Upright: 8.4%Supine: 3.5%0.355 bHakanson et al. (2009)Case-control study with in-subject simultaneous recordingLevel: IIQuality: 14/2692 subjects (45 volunteers and 47 patients)42/92 (45.7)53/92 (57.6)CFPM: 2.0%CBPM: 4.0%-Sweis et al. (2009)Comparative study of diagnostic yieldLevel: III-2 Quality: 15/26129 patients in the wireless group (intolerant of the catheter) 102 patients in the catheter groupCut-off 5.3%: 92/129 (71)Cut-off 4.2%: 98/129 (76)Cut-off 4.2%: 49/102 (48)CFPM: 5.3%CBPM: 4.2%Both: 4.2%<0.001 c<0.001 cAng et al. (2010)Comparative study of diagnostic yieldLevel: III-2 Quality: 14/26Wireless group: 66 patientsCatheter group: 55 patientsOverall: 26/66 (39.4)On day 1 only: 5/66 (7.6)On day 2 only: 8/66 (12.1)Both day 1 and 2: 13/66 (19.7)Overall: 20/55 (36.4)CFPM day 1: 5.8%CFPM day 2: 4.5%CFPM both days: 4.2%CBPM: 4.2%-Kushnir, Sayuk & Gyawali (2011)Comparative study of diagnostic yieldLevel: III-2Quality: 13.5/26462 patients in the wireless group 1,605 patients in the catheter group357/462 (77.2)849/1,605 (52.9)CFPM: 4.0%CBPM: 4.0%<0.001 cCFPM: catheter-free pH monitoringCBPM: catheter-based pH monitoringaCut-off value is presented in the percentage of time the pH <4; the test result is positive when the percentage is higher than the cut-off value.bUnclear which statistical test was used.cAnalysis was done using the Chi square test.As the monitoring period can be lengthened with the wireless pH method (most tests are 48?hours instead of the 24?hours with the traditional catheter-based method), this is likely to increase diagnostic yield. Six studies reported an additional yield on day 2 of monitoring, varying from 2.0% to 15.6% with a median of 7.8% ( REF _Ref362339424 \h \* MERGEFORMAT Table 34). This means that 2.0%–15.6% of patients only get a positive test result above the cut-off value after day 2, and these patients would not have been diagnosed with GORD if they had only had a 24-hour monitoring period.Table 34Yield comparison between 24 hours and 48 hours with catheter-free monitoringStudyStudy designNCut-off value aTotal yield day 1Total yield day 2Overall detection increase (%)Prakash & Clouse (2005)Retrospective case series121 patients5.33%NANA15 (7.5%)Grigolon et al. (2011)Matched pairs cohort study51 patients4.7%24 patients (47.1%)25 patients (49.0%)2.0%Garrean et al. (2008) Prospective case series40 patients5.3%10 patients (25.0%)14 patients (35.0%)10.0%Pandolfino et al. (2003)Diagnostic case-control study37 patients5.33%12 patients (32.4%)15 patients (40.5%)8.1%Scarpulla et al. (2007)Retrospective case series34 patients4.2%12 patients (35.3%)14 patients (41.2%)5.9%Karamanolis et al. (2012)Post-test case series32 patientsDay 1: 5.8%Day 2: 4.5%12 patients (37.5%)17 patients (53.1%)15.6%aCut-off value is presented in the percentage of time the pH <4; the test result is positive when the percentage is higher than the cut-off value.Fourteen studies reported diagnostic yield with the wireless test (and no comparator). Since there is no consensus on what the threshold is for diagnosing GORD, studies used different cut-off points, different scores (composite pH score, acid exposure time, reflux events), different placements in the oesophagus (proximal, distal) and different analysis (an abnormal score on only one day, an abnormal score on both days, worst day analysis) to establish a diagnosis. Therefore, there is a large variation in diagnostic yield, varying from 6.1%—only abnormal on day 2 in patients suspected of GORD (Turner et al. 2007), to 92.9%—abnormal score overall in patients with strong clinical GORD evidence (Ayazi et al. 2009) (see Tables 81 and 82 in REF _Ref364237535 \h \* MERGEFORMAT Appendix H).Does it change patient management?Summary—Does catheter-free (wireless) ambulatory oesophageal pH monitoring change clinical management, compared with no pH monitoring, for patients with symptoms of GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?No studies were available that reported on a change in management based on catheter-free monitoring in the population who would otherwise have had no monitoring, i.e. those who could not tolerate catheter-based monitoring. Five studies reported on change in patient management after catheter-free monitoring in patients who could have potentially tolerated a catheter-based test. One comparative study reported that concordance between the results of the test and management of GORD was higher in the catheter-free monitoring group (78%) than in the catheter-based monitoring group (58%; p<0.05). As with the comparative study, before-and-after case series also reported that the management received did not always correspond to the results of the test. One study reported that 42.2% of patients (38/90) continued to take anti-reflux medication despite a negative pH test result. Only 17 patients recalled being instructed to stop taking PPIs. In another case series, 12/38 patients underwent surgery for GORD even though only 9 of these had a positive diagnosis based on catheter-free monitoring. In a further case series, catheter-free monitoring led to a change in management in 63% of patients referred for monitoring; and in a paediatric study, catheter-free monitoring resulted in a change in management in 88% of patients. Patients with an abnormal study result were more likely to have a change in management than patients with a normal result.From the literature it can be assumed that the results of catheter-free monitoring do influence subsequent management, although not all patients have management consistent with the results of pH monitoring. It is expected that the key changes based on results of catheter-free monitoring are that patients who are found not to have GORD have their (mostly ineffective) PPI treatment suspended, whereas patients who have their GORD confirmed have an additional option of surgical treatment.Studies were included to assess change in management following catheter-free (wireless) oesophageal pH monitoring according to criteria outlined a priori in REF _Ref362247931 \h \* MERGEFORMAT Box 5. No studies were identified that met the population inclusion criteria. Five studies that did not meet the a priori inclusion criteria reported on change in patient management after catheter-free monitoring in patients who were suspected of GORD but who could have potentially tolerated a catheter-based test. Furthermore, none of the studies had ‘no pH monitoring’ as a comparator. However, due to a lack of more relevant data, these studies are discussed below.Box 5Inclusion criteria for identification of studies relevant to an assessment of change in management following catheter-free (wireless) ambulatory oesophageal pH monitoringSelection criteriaInclusion criteriaPopulationPatients with symptoms of GORD in whom a catheter-based test has failed or in whom catheter-based monitoring is anatomically inappropriateInterventionCatheter-free (wireless) ambulatory oesophageal pH monitoring ComparatorsNo pH monitoringOutcomes% change in management plan including surgeries performed and changes in medication plansTime to diagnosisStudy designRandomised or non-randomised controlled trials and cohort studies, case-control studies, case series, or systematic reviews of these study designsSearch periodCatheter-free monitoring was introduced in 2001, so the search period will be 2001 – 5/2013LanguageStudies in languages other than English were excluded unless they represented a higher level of evidence than that available in the English language evidence-baseOne of the studies, a retrospective case series conducted in Chicago, Illinois PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXdyb248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Gawron et al. 2012), reported on the number of patients who continued to take anti-reflux medication despite a negative pH test result. A total of 38 out of 90 patients (42.2%) reported current PPI use despite negative results from a pH study—66 catheter-free and 24 catheter-based monitoring—and 13 of these patients were on twice-daily PPIs. Only 17 patients (18.9%) recalled being instructed to stop taking PPIs after the test. Review data showed documented instructions to stop PPI therapy for only 15 patients (16.7%). In a case series by Sweis et al. (2011), medical therapy or conservative advice was pursued by the physician in 68% (26/38) of the patients, with the outcome assessed at a median of 24?months (range 12–36 months) after a 96-hour wireless test. Anti-reflux surgery was performed in 12/38 (32%) patients, of which 9 had a positive diagnosis based on pathologic acid exposure, 10 had a positive reflux symptom association based on the wireless test, and 2 were operated on despite a negative pH test result. One of these patients had pathological supine reflux and a large hiatal hernia on endoscopy, and the other had ongoing symptoms of non-acid food and fluid regurgitation with normal endoscopy and manometry. Another study, a matched-pairs retrospective cohort PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcmlnb2xvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (Grigolon et al. 2011), compared the change in management after catheter-free monitoring with management changes following catheter-based monitoring. Anti-reflux medication was used in 43/50 (86%) and 38/50 (76%) patients before the wireless and traditional pH monitoring, respectively (baseline rates not significantly different). After the test, concordance between results of the test and treatment for GORD was higher in the wireless than in the traditional group. That is, those with GORD should be treated with medication or surgery, and those without GORD should stop medication—78% versus 58% of the patients (p <0.05). There were 11 discordant cases in the wireless group and 21 in the catheter-based group: that is, 10 and 14 patients, respectively, who were taking PPIs before the test continued treatment despite a negative or indeterminate test; and 1 and 7, respectively, who were not taking PPIs before the test continued to do so despite a positive test result. Treatment for GORD at the time of a follow-up telephone interview 1–2?years after the test was discordant with the treatment recommended after the test in 12 (24%) and 15 (31%) patients in the wireless and traditional groups, respectively (not statistically significant). The majority of discordant cases, 11 in the former and 10 in the latter group, were patients who continued taking PPIs immediately after the test but who had stopped them by the time of the interview. The remaining discordant cases did not undergo GORD treatment after the test but were taking it at the time of the interview ( REF _Ref367188361 \h \* MERGEFORMAT Table 35).Table 35Concordance between results of the test and treatment for GORD Discordant cases and treatment changes Catheter-free monitoring group (n=50)Catheter-based monitoring group (n=50)Discordant cases (between results of test and treatment)11/50 (22%)21/50 (42%) PPIs despite negative or indeterminate test10/50 (20%)14/50 (28%)No treatment despite positive test1/50 (2%)7/50 (14%)Discordant cases (between treatment and recommended treatment after test) 1–2?years after test12/50 (24%)15/50 (31%)Stopped PPIs during follow-up11/50 (22%)10/50 (20%)Started treatment during follow-up1/50 (2%)5/50 (10%)Source: PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcmlnb2xvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (2009, 2011) in paediatric and adult populations, respectively, reported specific management changes after wireless pH monitoring ( REF _Ref362262154 \h \* MERGEFORMAT Table 36). Table 36Specific management changes after wireless oesophageal pH monitoringSpecific management changesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWN5PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA Lacy et al. (2009) n=44 (paediatric)n (%)Referred for surgery69 (41)1 (2.3)Increased dose of medication (PPI or H2RA)32 (19)1 (2.3)Initiated medication (PPI)-24 (54.5)Medication changed (PPI or from H2RA to PPI)19 (11)7 (15.9)Medication stopped (PPI or H2RA)28 (17)9 (20.5)Added medication (hyoscyamine, sucralfate, metoclopramide)21 (13)2 (4.6)Other reason (decreased dose of medication, medication change not otherwise specified)19 (11)-In the larger of two case series by Lacy et al. (2011), conducted in adults, the results of the wireless pH-monitoring capsule directly led to a change in diagnosis in 22% of all patients referred for testing. The diagnosis changed most frequently in those patients undergoing evaluation for chronic cough (50%), followed by ENT symptoms (36%), acid reflux symptoms while off PPIs (29%), and chest pain (26%).The diagnosis was more likely to be changed in patients studied while off PPI therapy compared with being monitored while on PPI therapy. Wireless pH-testing results led to a change in management in 63% of all patients referred for monitoring. Clinical management changes were more likely to occur in patients studied off PPI (77%) compared with once daily (43%) or twice daily (45%) PPI therapy (p<0.001). In the earlier study by Lacy et al. (2009), conducted in children, management changed in 44/50 (88%) patients, and no follow up was available for two patients (4%). Patients with an abnormal study result, i.e. acid exposure time >6%, (n=30) were more likely to get a change in management than those with a normal result (n=14; p<0.0001). Does change in management improve patient outcomes?Summary—Do alterations in clinical management and treatment options have an impact on the health outcomes of patients with symptoms of GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?For people initially suspected of having GORD who are given alternative diagnoses correctly after catheter-free monitoring (true negatives), it is assumed that their clinical management would be optimised as a result of obtaining the correct diagnosis. Patients who receive a false positive would likely continue to receive ineffective PPI treatment and suffer a delay in receiving their correct diagnosis. A false negative would likely result in suspension of PPI treatment and a delay in diagnosis while an alternative diagnosis is sought. No relevant studies were identified regarding the impact of false negatives; however, two studies on false positives were included. These studies reported that infants with infantile spasms with delayed treatment as a result of a false GORD diagnosis had a poorer outcome and worse treatment response than infants without a delay in diagnosis and treatment. Furthermore, two systematic reviews on true positives were included to answer the question of whether anti-reflux surgery for GORD leads to better health outcomes compared with medical treatment in patients with GORD with a positive pH-test result. The first, medium-quality review reported that improved outcomes were more common after surgical than medical treatment, with significant differences in objective outcomes (pH-reflux duration, oesophagitis, LOS pressure etc.) in 5/6 included RCTs and 2/3 cohort studies. Subjective outcomes were also more common among surgical patients in 7/8 studies. The second, more recent, high-quality review compared medical management with laparoscopic fundoplication surgery. Four RCTs were included. Significant improvements in quality of life (QoL) were reported at 3?months and 1?year after surgery, compared with medical treatment. All studies reported significant increases in GORD-specific QoL postoperatively, compared with medical treatment. Post-operative complications were rare. Two of the four RCTs included in the latter review published 5-year follow-up studies after the Cochrane review was conducted. Most patients achieve and remain in remission at 5?years with anti-reflux surgery, and fundoplication continued to give better pain relief than medical management. It should be noted, however, that these trials consisted solely of PPI responders, and their results do not generalise to patients who are refractory to PPI therapy.The expected treatment changes that may result from having a catheter-free monitoring test are likely to benefit QoL.To answer the question of whether a change in management leads to improved patient health outcomes, a second literature search was done based on the PICO criteria outlined a priori in REF _Ref371065728 \h \* MERGEFORMAT Box 6. For people initially suspected of having GORD but eventually given an alternative diagnosis (true negatives) and a subsequent change in management, it was assumed that their management has been optimised as a result of obtaining the correct diagnosis. Box 6Inclusion criteria for identification of studies relevant to an assessment of health outcomes following a change in managementSelection criteriaInclusion criteria true positivesInclusion criteria false positivesInclusion criteria false negativesPopulationPeople with GORDPeople who are wrongly diagnosed with GORDPeople with undiagnosed GORDInterventionOptimal treatment for GORD (PPIs, H2 receptor antagonists, surgery) (Unnecessary) treatment for GORD (PPIs, H2 receptor antagonists, surgery) Possible cessation of PPI therapy and consideration and/or treatment trial for other diagnosesComparatorsAlternative treatment No GORD treatment and/or optimal treatment for true condition Optimal treatment for GORD (PPIs, H2 receptor antagonists, surgery) OutcomesAdverse events from treatment, quality of life, reduction in progression to Barrett’s oesophagus and/or oesophageal cancer, symptom resolution or symptom reductionAdverse events from inappropriate use of GORD treatment, quality of life, adverse events from delay in appropriate treatment for differential diagnosis Quality of life, progression to Barrett’s oesophagus and/or oesophageal cancer, symptom resolution Study designSystematic reviews, meta-analysis, evidence-based clinical practice guidelinesLevel 1 evidence if available, otherwise randomised or non-randomised controlled trials and cohort studies, case-control studies, case series, or systematic reviews of these study designsLevel 1 evidence if available, otherwise randomised or non-randomised controlled trials and cohort studies, case-control studies, case series, or systematic reviews of these study designsSearch periodMost recent studies foundNo limitsNo limitsLanguageStudies in languages other than English were excluded unless they represented a higher level of evidence than that available in the English language evidence-baseTrue positives Patients suspected of GORD are usually given a trial of PPI therapy; where this is not completely successful in managing their symptoms, pH monitoring may be undertaken. If the patient has a (true) positive pH-test result, there may be a change in management in that the patient would have the option to undergo anti-reflux surgery. This is not generally recommended unless acid-reflux has been positively identified as the cause of symptoms. A combination of surgical and medical treatment was therefore included as the intervention (the optimal treatment), and medical treatment was included as the comparator (the alternative treatment). This raises the question of whether anti-reflux surgery for GORD leads to better health outcomes, compared with medical treatment, in patients with GORD with a true positive pH-test result?Out of 5,553 studies (3,708 after duplicates were removed), 114 full-text articles were studied. Three relevant systematic reviews based on these criteria were identified; however, the most recent review PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbCBUYWxhbHdhaDwvQXV0aG9yPjxZZWFyPjIwMTM8L1ll

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ADDIN EN.CITE.DATA (Allgood & Bachmann 2000; Wileman et al. 2010). Allgood and Bachmann (2000) aimed to evaluate and summarise all comparative studies of the effectiveness of surgical and medical management of GORD. Six RCTs and three cohort studies were identified. The review was of medium quality and did not distinguish between the different medical and surgical treatments. Both laparoscopic and open anti-reflux surgical procedures were included, as well as both Nissen-Rossetti (360?) and Toupet (180?) fundoplication. Improved outcomes were more common after surgical than medical treatment, with significant differences in objective outcomes (pH-reflux duration, oesophagitis, LOS pressure etc.) in 5/6 included RCTs and 2/3 cohort studies. Five studies (4 RCTs and 1 cohort study) mentioned changes in oesophageal pH; and three studies (2 RCTs and 1 cohort study) reported a significantly better response to surgery, whereas one RCT only showed a significantly higher response to surgery than to medication for symptoms, and not for continuous medication. Subjective outcomes (symptoms and patients’ satisfaction) were also more common among surgical patients in 7/8 studies. The overall conclusion by the authors was that surgery is consistently more effective across a range of patients and for a range of both short-term and long-term outcomes.The other, more recent included systematic review is a high-quality Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Wileman Samantha</Author><Year>2010</Year><RecNum>613</RecNum><DisplayText>(Wileman Samantha et al. 2010)</DisplayText><record><rec-number>613</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">613</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>Wileman Samantha, M.</author><author>McCann, Sharon</author><author>Grant Adrian, M.</author><author>Krukowski Zygmunt, H.</author><author>Bruce, Julie</author></authors></contributors><titles><title>Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title></periodical><number>3</number><keywords><keyword>Fundoplication [methods]</keyword><keyword>Gastroesophageal Reflux [surgery] [therapy]</keyword><keyword>Health Status</keyword><keyword>Quality of Life</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Adult[checkword]</keyword><keyword>Humans[checkword]</keyword><keyword>Hm-uppergi</keyword></keywords><dates><year>2010</year></dates><publisher>John Wiley &amp; Sons, Ltd</publisher><accession-num>CD003243</accession-num><urls><related-urls><url>;(Wileman et al. 2010). The aim was to compare medical management (either PPIs or H2 receptor antagonists) with laparoscopic fundoplication surgery for the treatment of GORD in adults. Twelve papers were included that reported data on multiple time points of four clinical trials with a total of 1,232 randomised participants, published between 2005 and 2009. All four studies reported health-related QoL, and two studies were combined using fixed effect models. This showed that there were significant improvements in health-related QoL at 3?months and 1?year after surgery, compared with medical therapy (mean difference SF36 general health score: –5.23, 95%CI –6.83 to –3.62, I2 = 0%). One other study reported higher vitality scores compared with medical therapy at 1 and 3?years postoperatively (p<0.001), and the fourth study reported a higher QoL at 3?months and 1?year after surgery, compared with medical therapy (p<0.001). All included studies reported significant increases in GORD-specific QoL postoperatively, compared with medical treatment. The authors reported that symptoms of heartburn, reflux and bloating were improved after surgery, compared with medical therapy, but some patients had persistent postoperative dysphagia. Postoperative complications were rare, but surgery is not without risk and postoperative adverse events did occur. The authors suggest that there is evidence that surgery is more effective than medical management for the treatment of GORD, at least in the short to medium term. Two of the four included RCTs in the Cochrane review (the ‘LOTUS trial’ and the ‘REFLUX trial’) published 5-year follow-up studies after the review was conducted, to give more information on the long-term results of surgery and medication for GORD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxtaWNoZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (Galmiche et al. 2011; Grant, Cotton et al. 2013). The LOTUS randomised trial was conducted in academic hospitals in 11 different European countries between October 2001 and April 2009; it included 554 patients, of which 372 completed the 5-year follow-up PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxtaWNoZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (Grant, Cotton et al. 2013). The aim was to evaluate maintenance therapy with medication vs laparoscopic anti-reflux surgery. In the LOTUS trial, only esomeprazole was used in the medical management group.The LOTUS trial reported that, at 5?years, an estimated 85% (95%CI, 81%–90%) of patients in the surgery group and 92% (95%CI, 89%–96%) in the esomeprazole group remained in remission (log-rank p=0.048). In the REFLUX trial QoL was measured on a disease-specific REFLUX questionnaire; among responders at 5?years the randomised surgery group scored significantly higher compared with the medication group, with a mean difference of 8.5 (95%CI 3.9, 13.1, p<0.001) for intention-to-treat analyses and 11.5 (95%CI 4.2, 18.7, p=0.002) adjusted for treatment received. Short Form-36 scores and mean EuroQol questionnaire 5 dimensions (EQ-5D) scores favoured the surgical group in all domains at all time points, although differences decreased over time. The prevalence of GORD-related symptoms for both treatment groups in both trials can be found in REF _Ref371674608 \h \* MERGEFORMAT Table 37. In the REFLUX trial heartburn, regurgitation and belching were reported less frequently in the group randomised to surgery compared with the medication group, with no significant differences in ‘difficulty swallowing’, ‘wind from the bowel’ and ‘wanting to be sick but being unable’ ( REF _Ref371674608 \h \* MERGEFORMAT Table 37). Galmiche et al. (2011) reported that most patients achieve and remain in remission at 5?years with either medication treatment or laparoscopic surgery. However, the results of both trials are inconsistent, as the majority of the medication group in the REFLUX trial had heartburn at least once a week at the 5-year follow-up. Grant, Cotton et al. (2013; REFLUX trial) concluded that, after 5?years, laparoscopic fundoplication continued to give better relief of GORD symptoms than medical management. It should be noted that these trials consisted solely of (partial or complete) PPI responders, and their results do not generalise to patients who are refractory to PPI therapy. Therefore, these results, especially in the medication groups, need to be interpreted with caution, as the patients who would undergo catheter-free monitoring may be refractory to PPI treatment. Table 37Prevalence of symptoms at 5-year follow-up of LOTUS and REFLUX trials Prevalence of symptomsEsomeprazole group LOTUS (n=192)Surgery group LOTUS (n=180)p-value LOTUSMedication group REFLUX (n) Surgery group REFLUX (n) Heartburn16%8%0.1478 (73.6%)46 (41.4%)Acid regurgitation13%2%<0.00141 (36.6%)29 (24.6%)Dysphagia5%11%<0.00128 (25.5%)27 (22.9%)Bloating28%40%<0.001--Flatulence/wind from bowel40%57%<0.00196 (87.3%)104 (88.1%)Belching---83 (75.5%)71 (60.7%)Nausea but unable to be sick---19 (17.1%)17 (14.4%)Adverse events24.1%28.6%---Sources: PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxtaWNoZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA Galmiche et al. (2011); Grant, Cotton et al. (2013)False positives People in the false positive group would be people who have a positive result on the pH test despite not truly having GORD. This would mean that they would be treated for GORD, either medical treatment or surgery, unnecessarily after their pH-test result. Studies on unnecessary GORD treatment and GORD misdiagnosis were searched and eight were identified PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXZpbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Auvin et al. 2012; Kessing, Bredenoord & Smout 2011; Napuri et al. 2010; Starr 2006, 2007; Susman 2009; Sweetman, Ng & Kerrigan 2007; Taddio et al. 2011). However, six of these studies had to be excluded. Three case reports reported on heart disease patients who were wrongly diagnosed with GORD but one had to be excluded because the patient died before he was able to undergo pH monitoring ADDIN EN.CITE <EndNote><Cite><Author>Susman</Author><Year>2009</Year><RecNum>4281</RecNum><IDText>288</IDText><DisplayText>(Susman 2009)</DisplayText><record><rec-number>4281</rec-number><foreign-keys><key app="EN" db-id="zdzptdeprf9tf0e9xeovwvslddfxtv95te9s">4281</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Susman, J. L.</author></authors></contributors><titles><title>&quot;GERD&quot; turns out to be heart disease</title><secondary-title>The Journal of family practice</secondary-title></titles><periodical><full-title>The Journal of family practice</full-title></periodical><pages>288</pages><volume>58</volume><number>5</number><dates><year>2009</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(Susman 2009), and two patients reported that they responded sufficiently to anti-reflux medication before further investigations (e.g. pH monitoring) were undertaken PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFycjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Starr 2006, 2007). One study reported three case reports where achalasia was initially misdiagnosed as GORD; however, no relevant outcomes were reported ADDIN EN.CITE <EndNote><Cite><Author>Kessing</Author><Year>2011</Year><RecNum>4250</RecNum><IDText>1020-1024</IDText><DisplayText>(Kessing, Bredenoord &amp; Smout 2011)</DisplayText><record><rec-number>4250</rec-number><foreign-keys><key app="EN" db-id="zdzptdeprf9tf0e9xeovwvslddfxtv95te9s">4250</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kessing, B. F.</author><author>Bredenoord, A. J.</author><author>Smout, A. J. P. M.</author></authors></contributors><auth-address>Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, Netherlands</auth-address><titles><title>Erroneous diagnosis of gastroesophageal reflux disease in achalasia</title><secondary-title>Clinical Gastroenterology and Hepatology</secondary-title></titles><periodical><full-title>Clinical Gastroenterology and Hepatology</full-title></periodical><pages>1020-1024</pages><volume>9</volume><number>12</number><keywords><keyword>Achalasia</keyword><keyword>Esophageal Manometry</keyword><keyword>Gastroesophageal Reflux Disease</keyword><keyword>Surgical Fundoplication</keyword></keywords><dates><year>2011</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(Kessing, Bredenoord & Smout 2011). Finally, two studies on GORD misdiagnosis in infants were excluded because they did not report health outcomes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWRkaW88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Auvin et al. 2012; Napuri et al. 2010). Although these infants did not undergo pH monitoring, it gives an indication of the impact of a false positive GORD diagnosis on health outcomes in infants. Auvin et al. (2012) reported that in 83 infants diagnosed with infantile spasms, 7% were initially diagnosed with GORD. This misdiagnosis was an important reason for diagnostic delay, and a diagnostic delay of more than 30?days was associated with a poor outcome (e.g. seizures, mental delay) (RR=12.08 [1.52–96.3]). In the multivariate analysis a poor outcome 2?years after diagnosis was also predicted by diagnostic delay of more than 30?days (RR=31.70 [2.30–437.68]). Napuri et al. (2010) included 156 infants also diagnosed with infantile spasms. Of these patients, 17% were initially diagnosed with GORD. The authors reported that response to treatment was significantly better when treatment lag was less than 6?weeks (40% responders) than when it was longer (20% responders; p=0.021). These results show that infants with infantile spasms benefit from early diagnosis, and a false GORD diagnosis could unnecessarily delay treatment, leading to worse health outcomes.False negativesNo studies were identified that met the criteria for false negatives in REF _Ref371065728 \h \* MERGEFORMAT Box 6.Other relevant considerationsDefining the population and the potential for ‘leakage’It can be difficult to determine whether a person is ‘unable’ to tolerate a catheter. The catheter-free monitoring test is viewed as more convenient and can lead to a higher diagnostic yield due to prolonged monitoring, compared with catheter-based monitoring. Physicians could be inclined to give more patients catheter-free monitoring to avoid discomfort and embarrassment, especially in children. Furthermore, it is shown that catheter-free monitoring has less impact on normal daily activities, which makes the recording more reliable. Therefore, it is possible that the population using catheter-free monitoring may expand beyond those who are currently considered unable to tolerate catheter-based monitoring, when the alternative is no monitoring. That is, the use of the wireless test could start ‘leaking’ into the population currently receiving the catheter-based test. Because of the higher costs of catheter-free monitoring compared with catheter-based monitoring, this ‘leakage’ could lead to extra costs. This scenario is examined in the economics section of the report. Catheter-based monitoring is normally inserted transnasally with manometric guidance, whereas catheter-free monitoring is usually inserted through the mouth using endoscopy, although manometric guidance is possible with catheter-free monitoring. However, as the population eligible for catheter-free monitoring does not tolerate a catheter through the nose, they are unlikely to tolerate manometry, leaving transoral endoscopy as the only option to guide insertion. The costs for endoscopy are higher than for manometry, and this is one of the reasons that the costs for the new MBS item are higher than for MBS item 11810 (catheter-based monitoring). Therefore, if ‘leakage’ takes place and catheter-free monitoring would be performed with manometric guidance through the nose, the fee should be reassessed.What are the economic considerations? Economic evaluationOverviewThe DAP identified two key economic questions. These were:What is the cost-effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring, compared with no pH monitoring, for patients with symptoms of GORD who have previously failed a catheter-based test or where catheter-based monitoring is anatomically inappropriate?What is the cost-effectiveness of catheter-free (wireless) ambulatory oesophageal pH monitoring, compared with catheter-based oesophageal pH monitoring, in patients with symptoms of GORD?To address these questions, two separate economic models are required.Model 1 ScenarioAn evaluation where the population is restricted, as per the proposed listing, to only those patients who cannot tolerate catheter-based monitoring, i.e. who have tried and failed, or are anatomically unsuitable. In this case ‘no alternative pH monitoring’ is the appropriate comparator. Initially, the base-case assumes 100% sensitivity and specificity of catheter-free (wireless) pH monitoring on the grounds that catheter-based pH monitoring is an imperfect reference standard and the true accuracy of either test is unknown. However, the sensitivity and specificity of wireless pH monitoring relative to catheter-based monitoring, based on the results of the systematic review, are also modelled for a sensitivity analysis. This modelled evaluation is intended to answer the first economic question.Model 2 ScenarioAn evaluation where the population accesses wireless pH monitoring as an alternative to catheter-based pH monitoring (the comparator). Within this scenario the assumptions of relative accuracy associated with wireless pH monitoring, referenced to catheter-based monitoring, are also varied and presented as sensitivity analyses. This modelled evaluation is intended to answer the second economic question.In reality, while the proposed listing restricts the population to that in Model 1, given the reported patient preference and convenience associated with wireless monitoring, it may be anticipated that there will be some leakage of wireless pH monitoring beyond the requested listing. Therefore, future MBS-funded clinical practice may include patients who could actually tolerate catheter-based pH monitoring but have a strong preference for wireless monitoring, such as the population in Model 2. It might be expected that the overall population of potential wireless pH-monitoring patients would be made up a combination of patients from each of the model populations. Therefore, results are also presented for various weighted combinations of Models 1 and 2 such that a pragmatic estimate of cost-effectiveness incorporating varying levels of leakage beyond the listing can be made. In both models it is assumed that the monitoring will result in changed health outcomes, and therefore a cost–utility analysis is undertaken that measures incremental differences in quality-adjusted life years (QALYs) and GORD-related resource costs between wireless pH monitoring and the nominated comparator. The analysis is conducted primarily from the Australian health system perspective and, given the lack of long-term clinical data, is assessed over a 15-year time horizon to minimise uncertainty cost-effectiveness. It should be noted that a range of time horizons is explored in sensitivity analyses; however, if longer time horizons are required to demonstrate cost-effectiveness, there will be increasing uncertainty associated with the extended extrapolation and analysis.Economic literature reviewA search to identify existing literature containing economic models relating to pH monitoring and management of GORD symptoms was undertaken (see REF _Ref379440541 \h \* MERGEFORMAT Appendix J). Six citations specifically relating to economic analysis of pH monitoring were identified. Of these, only two related to the relevant clinical pathway (i.e. following endoscopy). PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA Lee et al. (2008) used wireless monitoring but was not restricted to patients who could not tolerate catheter-based monitoring; and the other study (Kleiman et al. 2013) used catheter-based monitoring. Both were cost analyses that did not consider clinical outcomes. None of the existing literature identified was adequate to answer the economic questions posed in the DAP; therefore, further development of economic models was required.In addition, a broader literature search to identify other economic models in the area of gastro-oesophageal reflux was undertaken, with the intent that identified references may provide potential sources of data or validation for various parameters/inputs required in the assessment-developed models. Populations and settingsThe populations modelled are intended to represent Australian patients who would be candidates for wireless pH monitoring funded by Medicare.The clinical pathway describes both the currently available catheter-based pH monitoring and the proposed wireless pH monitoring as being used as a diagnostic tool in patients who, despite a normal endoscopy, have ongoing GORD symptoms that are refractory to PPI use. There is not a single definition in the literature of what it means to be ‘refractory to PPIs’; both the accepted dose range and the acceptability of anything less than a complete response with respect to symptom relief vary.Based on Medicare data, catheter-based pH monitoring is currently undertaken across all ages of the Australian population, from babies to 85+?year olds. The average and median age group is 45–54?year?olds, but the age group with the single largest use is 55–64?year?olds. Of all pH-monitoring patients, 61% are female. To approximate this population, each model assumes that suspected GORD patients receiving pH monitoring are 55?years of age and that there is a male:female ratio of 40%:60%. This assumption is used to estimate background mortality.The setting of the model begins in the outpatient setting with patients in the care of a specialist gastroenterologist. However, on being assigned the proposed intervention, the patient would have the wireless pH-monitoring capsule placed by a gastroenterologist, generally in either an endoscopy suite or day facility, and temporarily become a hospital inpatient for this procedure—93% of endoscopy patients who subsequently receive pH monitoring were inpatients for their initial endoscopy5. In contrast, empirical medical treatment is assumed to be undertaken in the outpatient setting (physician rooms); and only around 4% of MBS claims for catheter-based pH monitoring are for hospital-based patients, as the catheter is generally inserted without sedation.Given the patient definition, it is assumed that patients entering the model will have GORD symptoms and, on average, a QoL commensurate with ongoing symptoms that will be unchanged unless successful treatment is achieved. Likewise, it will be assumed that patients entering the model are, on average, consuming resources equivalent to a standard single daily dose of PPI treatment, although, in reality, pre-existing use and dosing of GORD medication is likely to be heterogeneous. This use is assumed to continue in the first cycle where the intervention (i.e. pH testing/monitoring) is allocated in Model 2, but in the comparator arm of Model 1 (i.e. no pH testing/monitoring plus empirical treatment) it is assumed that there would be a trial of high-dose PPIs immediately.Structure and rationale of the economic evaluationThe structures of the economic models are consistent with the clinical pathway presented in REF _Ref379455005 \h \* MERGEFORMAT Figure 3. A health state diagram showing potential transitions between health states is presented in REF _Ref379458137 \h \* MERGEFORMAT Figure 8. Immediately on entering the model, patients are assumed to be allocated to either receive pH monitoring (Model 1 intervention and Model 2 both arms) or empirical treatment with high-dose PPIs (Model 1 comparator). Figure 8Health state diagram for the economic modelsThe model is constructed in two phases: Phase 1: The first phase represents the first year following the decision to pH monitor or not. In this year patient diagnoses and management strategies are established. Patients are assumed to enter phase 1 of the model with symptoms and be receiving routine daily average-dose GORD medication. Depending on the model scenario, patients are then assigned to receive either:wireless pH monitoring or no monitoring (ongoing medical treatment) [Model 1]orwireless pH monitoring or catheter-based monitoring [Model 2]A summary of the structure of the mechanics of the economic model is presented in REF _Ref379456626 \h Table 38.Table 38Summary of the economic evaluation (applies to both models)Time horizonBase-case analysis of 15 yearsOutcomesQuality-adjusted life yearsMethods used to generate resultsMarkov model (with half-cycle correction)Cycle length1 yearDiscount rate5% for both costs and outcomesSoftware packages usedTreeAge Pro and Excel (hybrid)It is assumed that only patients who have a positive pH test result will be eligible for surgery, and the subsequent uptake of surgery by a percentage of patients following pH monitoring is a key difference between the intervention and the comparator in Model 1. In patients who have a normal pH-test result it is assumed that other diagnoses are investigated and treated. Patients who do not get a pH-test result, due to test failure or allocation to the comparator group, and who do not respond to high-dose PPIs may be investigated for other diagnoses and receive other treatment. However, expert opinion suggests that this would not occur universally in all patients—a number would simply remain as unsuccessfully treated and refractory NERD cases. This assumption is a key driver in the model. The extent to which alternative diagnoses are sought without a negative pH test result is varied and tested in the sensitivity analysis. The specific values associated with all transitions between health states are discussed in the relevant sections under ‘Inputs to the economic evaluation’. The initial phase of each model has six cycles of 2?months, and at the end of the 1-year period it is assumed that diagnoses and treatment paths have been determined.Phase 2: The second phase calculates the long-term costs and outcomes associated with the patient’s diagnosis and treatment as established at the end of the first year of investigation and treatment (phase 1). It is assumed that no new diagnoses or changes in treatment are made in phase 2 and that all patients either remain in the health state in which they ended phase 1, or they die (at the background mortality rate—applied equally across all patients). Costs and outcomes associated with treatment options are calculated in yearly cycles with a 5% annual discount rate. The base-case accrues costs and outcomes for a further 14?years (i.e. total model duration of 15?years); however, timeframes from 1?year to 25?years are tested in the sensitivity analysis. The decision analytic structure for the model pathways is shown in REF _Ref377977732 \h \* MERGEFORMAT Figure 9 .Figure 9 Decision analytic structure of the economic evaluation. Model 1 represents the decision between wireless pH monitoring and non-selective high-dose GORD PPI therapy. Model 2 represents the decision between wireless pH monitoring and catheter-based monitoring.Assumptions incorporated into the model structure:Only one test failure—patients failing a pH-monitoring test obtain a result on a subsequent test.Patients would not tolerate a manometric pH test; therefore, this is not incorporated anywhere in the model as an alternative or subsequent diagnostic tool. Likewise, endoscopic procedures for management of GORD are not included as it is assumed that fundoplication is the standard surgical technique and there is a lack of evidence regarding efficacy of the alternative treatments.Underlying disease is delineated by acid reflux into the oesophagus or not. While this is not a true reflection of the real population, which has mixed/multiple disease aetiologies, it is considered a justifiable simplification for use in the model. Although segregated in the model, the clinical implications of mixed aetiologies are incorporated in the model results because it is assumed that there is an imperfect success rate associated with acid treatments, and the cost of some ongoing acid treatments (PPIs) is incorporated into the expected costs of treatment for alternative diagnoses.Surgery is repeated in 10% of patients and assumed to occur within the same year as the initial surgery. This is consistent with Australian MBS data on surgical revisions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFudDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Grant, Cotton et al. 2013). The diagrammatic structure suggests that only one repeat surgery may be undertaken per patient; however, this strict interpretation is not essential. The final outcome from surgery, either success or failure, is based on overall surgical population outcomes that capture all revisions.Patients that have a diagnosis of acid-related symptoms and who fail to resolve their symptoms with surgery remain on a double dose of PPIs for the remainder of the model. Likewise, patients that have a diagnosis of acid-related symptoms and elect medical management remain on a double dose of PPIs for the remainder of the model, irrespective of whether or not they have successful symptom control. The assumption of a high-dose requirement is consistent with the population initially being considered ‘refractory’ ADDIN EN.CITE <EndNote><Cite><Author>Fass</Author><Year>2009</Year><RecNum>62</RecNum><DisplayText>(Fass 2009)</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fass, Ronnie</author></authors></contributors><titles><title>Proton Pump Inhibitor Failure - What Are the Therapeutic Options?</title><secondary-title>Am J Gastroenterol</secondary-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><pages>S33-S38</pages><volume>104</volume><number>S2</number><dates><year>2009</year><pub-dates><date>//print</date></pub-dates></dates><publisher>American College of Gastroenterology Ltd</publisher><isbn>0002-9270</isbn><urls><related-urls><url>;(Fass 2009).Inputs to the economic evaluationA summary list of all the variables used in the model is presented in REF _Ref379440517 \h Table 85 in REF _Ref379440541 \h Appendix K.Population and test parametersPrevalence, test diagnostic yield and failure rateThere is no direct evidence concerning the true underlying prevalence of acid-related GORD in the symptomatic, endoscopy-negative patient population who would be referred for pH monitoring in the Australian setting. Assuming that the catheter-free pH-monitoring test is accurate, prevalence is estimated based on its diagnostic yield. The clinical report provides a broad range of yields, between 25.7% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWN5PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Domingues, Moraes-Filho & Domingues 2011), although none are in a population that exactly matches that defined in the model. For the purposes of the model, the prevalence of acid-related GORD is estimated to be 40% of the endoscopy-negative population for monitoring. This estimate is broadly consistent (within 10%) with numerous studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BeWF6aTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Ayazi et al. 2009, 2011; Bhat, McGrath & Bielefeldt 2006; Grigolon et al. 2011; Scarpulla et al. 2007) and also with a study in a similarly defined population that used pH manometry as an alternative diagnostic test ADDIN EN.CITE <EndNote><Cite><Author>Broeders</Author><Year>2010</Year><RecNum>51</RecNum><DisplayText>(Broeders et al. 2010)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Broeders, J. A.</author><author>Draaisma, W. A.</author><author>Bredenoord, A. J.</author><author>Smout, A. J.</author><author>Broeders, I. A.</author><author>Gooszen, H. G.</author></authors></contributors><titles><title>Long-term outcome of Nissen fundoplication in non-erosive and erosive gastro-oesophageal reflux disease</title><secondary-title>British Journal of Surgery</secondary-title></titles><periodical><full-title>British Journal of Surgery</full-title></periodical><pages>845-852</pages><volume>97</volume><number>6</number><dates><year>2010</year></dates><publisher>John Wiley &amp; Sons, Ltd.</publisher><isbn>1365-2168</isbn><urls><related-urls><url>;(Broeders et al. 2010). The systematic review results presented earlier identified that where comparative evidence was available between 48-hour wireless monitoring and 24-hour catheter-based monitoring, a (median) additional yield of 7.8% was associated with the longer duration of the wireless test (see REF _Ref362339424 \h \* MERGEFORMAT Table 34). Clinical opinion supports the assumption that the additional yield is accurate and represents true positive patients. However, given that this cannot be verified with an alternative reference standard, it is only incorporated into a supplementary analyses for model 2 (see below). The test is assumed to have a failure rate of 7.5%, based on the median technical failure rate reported in ‘Is it effective – REF _Ref379441632 \h \* MERGEFORMAT Technical efficacy’.Test accuracy The systematic review presents varying results to describe test accuracy, depending on the reference standard, pH cut-off used and duration of monitoring. Given the heterogeneity of the test accuracy studies, a meta-analysis was not considered appropriate. Although the DAP specifies that 24-hour catheter-based monitoring should be considered as the reference standard, the repeated and clinically accepted finding of an increased yield of accurate positive results from the wireless pH-monitoring studies run over 48?hours (see ‘ REF _Ref379442554 \h \* MERGEFORMAT Results of assessment’) does not support the use of catheter-based monitoring as a perfect reference standard.In the economic models the base-case analysis assumes perfect accuracy (i.e. 100% sensitivity and specificity) associated with wireless pH monitoring, given the lack of a reliable reference standard. However, supplementary exploratory analyses were also undertaken:(for models 1 and 2) using test accuracy data where catheter-based monitoring is considered the reference standard. The highest quality study available (level II diagnostic evidence) indicated that, against this reference, the catheter-free test, with a cut-off point of 4.4% of the time that pH <4, had a sensitivity of 86.4% and specificity of 77.8% (see ‘ REF _Ref379442724 \h Is it accurate?’) (for model 2) assuming that catheter-free monitoring is 100% accurate, but the sensitivity of catheter-based monitoring is 80.5% and the specificity 100%. This assumes that catheter-free monitoring has better test performance than catheter-based monitoring, based on the 7.8% increased diagnostic yield (accepted to be true positives) associated with 48-hour catheter-free monitoring over catheter-based monitoring, i.e. subtracting the 7.8% additional yield from the diagnostic yield, to assume that 24-hour catheter-based monitoring would only identify 32.2% (rather than 40%) of patients as pH positive. Implications for true (and false) positive and negative test resultsWhere patients are positively diagnosed with acid-positive NERD, either medical or surgical management options may be appropriate—both strategies are considered to offer an acceptable level of symptom resolution. Numerous clinical comparisons and cost-effectiveness analyses have been published in the literature, from varying perspectives and with varying findings, such that it would be beyond the scope of this report to conclusively determine a single ‘preferred’ treatment route. The model assumes that both treatment options result in an 89% success rate with respect to providing satisfactory symptom management. This effectiveness rate for surgery is supported in the literature ADDIN EN.CITE <EndNote><Cite><Author>Beck</Author><Year>2009</Year><RecNum>57</RecNum><DisplayText>(Beck et al. 2009)</DisplayText><record><rec-number>57</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">57</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Beck, P. E.</author><author>Watson, D. I.</author><author>Devitt, P. G.</author><author>Game, P. A.</author><author>Jamieson, G. G.</author></authors></contributors><auth-address>Department of Surgery, Flinders Medical Centre, Flinders University, Bedford Park, SA, Australia.</auth-address><titles><title>Impact of gender and age on the long-term outcome of laparoscopic fundoplication</title><secondary-title>World J Surg</secondary-title><alt-title>World journal of surgery</alt-title></titles><periodical><full-title>World J Surg</full-title><abbr-1>World journal of surgery</abbr-1></periodical><alt-periodical><full-title>World J Surg</full-title><abbr-1>World journal of surgery</abbr-1></alt-periodical><pages>2620-6</pages><volume>33</volume><number>12</number><edition>2009/09/23</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Female</keyword><keyword>Fundoplication/ methods</keyword><keyword>Gastroesophageal Reflux/ surgery</keyword><keyword>Humans</keyword><keyword>Laparoscopy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Sex Factors</keyword><keyword>Treatment Outcome</keyword><keyword>Young Adult</keyword></keywords><dates><year>2009</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1432-2323 (Electronic)&#xD;0364-2313 (Linking)</isbn><accession-num>19771470</accession-num><urls></urls><electronic-resource-num>10.1007/s00268-009-0216-y</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Beck et al. 2009; ADDIN EN.CITE <EndNote><Cite><Author>Broeders</Author><Year>2010</Year><RecNum>51</RecNum><DisplayText>(Broeders et al. 2010)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Broeders, J. A.</author><author>Draaisma, W. A.</author><author>Bredenoord, A. J.</author><author>Smout, A. J.</author><author>Broeders, I. A.</author><author>Gooszen, H. G.</author></authors></contributors><titles><title>Long-term outcome of Nissen fundoplication in non-erosive and erosive gastro-oesophageal reflux disease</title><secondary-title>British Journal of Surgery</secondary-title></titles><periodical><full-title>British Journal of Surgery</full-title></periodical><pages>845-852</pages><volume>97</volume><number>6</number><dates><year>2010</year></dates><publisher>John Wiley &amp; Sons, Ltd.</publisher><isbn>1365-2168</isbn><urls><related-urls><url> et al. 2010), and it may be considered a conservative assumption that appropriate medical management is equally effective, although of some inconvenience given the requirement for regular medication. This is broadly consistent with the findings of the REFLUX trial, which found similar but marginally higher QoL outcome scores in patients assigned to surgical management over medical management ADDIN EN.CITE <EndNote><Cite><Author>Grant</Author><Year>2013</Year><RecNum>692</RecNum><IDText>1-167</IDText><DisplayText>(Grant, AM, Boachie, et al. 2013)</DisplayText><record><rec-number>692</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">692</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grant, A. M.</author><author>Boachie, C.</author><author>Cotton, S. C.</author><author>Faria, R.</author><author>Bojke, L.</author><author>Epstein, D. M.</author><author>Ramsay, C. R.</author><author>Corbacho, B.</author><author>Sculpher, M.</author><author>Krukowski, Z. H.</author><author>Heading, R. C.</author><author>Campbell, M. K.</author></authors></contributors><auth-address>Health Services Research Unit, Health Sciences Building, University of Aberdeen, Aberdeen, UK. a.grant@abdn.ac.uk</auth-address><titles><title>Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre randomised trial (the REFLUX trial)</title><secondary-title>Health Technol Assess</secondary-title><alt-title>Health technology assessment (Winchester, England)</alt-title></titles><periodical><full-title>Health Technol Assess</full-title><abbr-1>Health technology assessment (Winchester, England)</abbr-1></periodical><alt-periodical><full-title>Health Technol Assess</full-title><abbr-1>Health technology assessment (Winchester, England)</abbr-1></alt-periodical><pages>1-167</pages><volume>17</volume><number>22</number><edition>2013/06/08</edition><dates><year>2013</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>2046-4924 (Electronic)&#xD;1366-5278 (Linking)</isbn><accession-num>23742987</accession-num><urls></urls><electronic-resource-num>10.3310/hta17220</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Grant, Boachie et al. 2013).In the base-case, medical management of confirmed acid reflux (e.g. a positive pH-monitoring test) is assumed to consist of high-dose (twice daily) PPIs and a once-daily H2 antagonist (i.e. ranitidine). The assumption that medical treatment is successful in refractory patients appears contradictory—it is contingent on the assumption that the initial patient population has been selected using a ‘loose’ definition of ‘refractory’. But this is consistent with the literature, which reports that while many GORD patients are labelled ‘refractory’ to standard doses of PPIs, many respond to twice-daily PPIs, and in rare cases (e.g. fast metabolisers) response rates can be achieved with even high doses and/or combinations with additional products (e.g. H2 antagonists, antacids). Nor it is uncommon that medication is not taken in an optimal dosing manner. If this is investigated and addressed, cases previously considered refractory may also have satisfactory medical treatment results PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5hcmF0bmFtPC9BdXRob3I+PFllYXI+MjAwNjwvWWVh

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ADDIN EN.CITE.DATA Scarpignato 2012). Thus, it would appear that many supposedly ‘refractory’ patients can have successful medical treatment following a confirmation of their diagnosis.The implications associated with test results for patients in the model are depicted in REF _Ref371672909 \h \* MERGEFORMAT Table 39 and REF _Ref379458464 \h \* MERGEFORMAT Table 40.Table 39Implications for true positive and true negative test results for patients in the economic evaluation (base-case)True health statepH-monitoring test resultImplicationsNERD due to acidic reflux (positive)Positive(true)Option of medical management (ongoing high-dose PPIs +/– an H2 antagonist) or surgical managementSymptoms not due to acid reflux (e.g. FH, HO, OeO ) (negative)Negative(true)Alternative diagnoses investigated and successfully treated, as specified in the DAP NERD = non-erosive reflux disease; PPIs = proton pump inhibitors, H2 = histamine 2 (receptor); FH = functional heartburn; HO = hypersensitive oesophagus; OeO = oesinophilic oesophagitisTable 40Additional implications for false positive and false negative patients in the supplementary economic evaluationTrue health statepH-monitoring test resultImplicationsNERD due to acidic reflux (positive)Negative(false)Alternative diagnoses investigated and other treatments trialled Alternative treatment is assumed to be 0% effective in patients incorrectly identified to have an alternative diagnosisSymptoms not due to acid reflux (e.g. FH, HO, OeO) (negative)Positive(false)Option of medical management (ongoing high-dose PPIs +/– an H2 antagonist) or surgical managementGORD treatment is assumed to be 0% effective in patients incorrectly identified to be acid-symptom positive patientsNERD = non-erosive reflux disease; PPIs = proton pump inhibitors, H2 = histamine 2 (receptor); FH = functional heartburn; HO = hypersensitive oesophagus; OeO = oesinophilic oesophagitisTest or treatment uptake ratesCatheter-free monitoring uptake The model assumes that patients who do not wish to undertake wireless monitoring will not participate or be charged for it and, as such, they are not relevant or included in the cost-effectiveness model. Therefore, for the purposes of assessing cost-effectiveness, it is assumed that all patients in the intervention arm initially take up wireless monitoring. However, there is a technical failure rate of 7.5% (see ‘ REF _Ref379441632 \h \* MERGEFORMAT Technical efficacy’) and therefore some patients will not get a meaningful test result. The model assumes that half of the patients who experience a technical failure will re-attempt the test and subsequently get a result, and half will not re-attempt the test. This ratio is arbitrary and tested in the sensitivity analyses.Medication uptake The model assumes that where medical management is the selected treatment, patients adhere to recommended treatment regimens and purchase medication accordingly. This applies to situations both where medication is prescribed for suspected or confirmed GORD and where other medications are prescribed for a non-GORD diagnosis (see ‘Healthcare resources’ below for a description of assumed medication regimens). Strictly speaking, this assumption may overestimate medication usage but, given that patients are by definition symptomatic and apparently seeking relief, it would seem reasonable. Surgery uptake Based on the literature regarding fundoplication surgery for reflux, it is considered that this surgery is only appropriate for patients who have a positive pH-monitoring test result. The estimate that 25% of patients who have a positive result have subsequent surgery is based on a calibration of the estimated diagnostic yield (40%), with available Medicare data indicating that in Australia 10% of patients who undergo pH monitoring have subsequent surgeries.Surgery revision (re-operation) Medicare Australia data showed that 10% of fundoplication surgery was revised. This rate is incorporated into the model as the rate of uptake of repeat surgery. This re-operation rate is consistent with many literature reports (PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFudDwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA Beck et al. 2009; Grant et al. 2008: 11.3%; ADDIN EN.CITE <EndNote><Cite><Author>Broeders</Author><Year>2010</Year><RecNum>51</RecNum><DisplayText>(Broeders et al. 2010)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Broeders, J. A.</author><author>Draaisma, W. A.</author><author>Bredenoord, A. J.</author><author>Smout, A. J.</author><author>Broeders, I. A.</author><author>Gooszen, H. G.</author></authors></contributors><titles><title>Long-term outcome of Nissen fundoplication in non-erosive and erosive gastro-oesophageal reflux disease</title><secondary-title>British Journal of Surgery</secondary-title></titles><periodical><full-title>British Journal of Surgery</full-title></periodical><pages>845-852</pages><volume>97</volume><number>6</number><dates><year>2010</year></dates><publisher>John Wiley &amp; Sons, Ltd.</publisher><isbn>1365-2168</isbn><urls><related-urls><url> et al. 2010: 13.6%). Lower rates, as claimed in some publications ( ADDIN EN.CITE <EndNote><Cite><Author>Anvari</Author><Year>2011</Year><RecNum>669</RecNum><IDText>2547-2554</IDText><DisplayText>(Anvari et al. 2011)</DisplayText><record><rec-number>669</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">669</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anvari, Mehran</author><author>Allen, Christopher</author><author>Marshall, John</author><author>Armstrong, David</author><author>Goeree, Ron</author><author>Ungar, Wendy</author><author>Goldsmith, Charles</author></authors></contributors><titles><title>A randomized controlled trial of laparoscopic Nissen fundoplication versus proton pump inhibitors for the treatment of patients with chronic gastroesophageal reflux disease (GERD): 3-year outcomes</title><secondary-title>Surgical Endoscopy</secondary-title><alt-title>Surg Endosc</alt-title></titles><periodical><full-title>Surg Endosc</full-title><abbr-1>Surgical endoscopy</abbr-1></periodical><alt-periodical><full-title>Surg Endosc</full-title><abbr-1>Surgical endoscopy</abbr-1></alt-periodical><pages>2547-2554</pages><volume>25</volume><number>8</number><keywords><keyword>Gastroesophageal reflux disease</keyword><keyword>GERD</keyword><keyword>Laparoscopic antireflux surgery</keyword><keyword>Laparoscopic Nissen fundoplication</keyword><keyword>Medical therapy</keyword><keyword>Proton pump inhibitors</keyword></keywords><dates><year>2011</year><pub-dates><date>2011/08/01</date></pub-dates></dates><publisher>Springer-Verlag</publisher><isbn>0930-2794</isbn><urls><related-urls><url> et al. 2011: 7.8%; ADDIN EN.CITE <EndNote><Cite><Author>Mahon</Author><Year>2005</Year><RecNum>64</RecNum><IDText>695-699</IDText><DisplayText>(Mahon et al. 2005)</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahon, D.</author><author>Rhodes, M.</author><author>Decadt, B.</author><author>Hindmarsh, A.</author><author>Lowndes, R.</author><author>Beckingham, I.</author><author>Koo, B.</author><author>Newcombe, R. G.</author></authors></contributors><titles><title>Randomized clinical trial of laparoscopic Nissen fundoplication compared with proton-pump inhibitors for treatment of chronic gastro-oesophageal reflux</title><secondary-title>British Journal of Surgery</secondary-title></titles><periodical><full-title>British Journal of Surgery</full-title></periodical><pages>695-699</pages><volume>92</volume><number>6</number><dates><year>2005</year></dates><publisher>John Wiley &amp; Sons, Ltd.</publisher><isbn>1365-2168</isbn><urls><related-urls><url> et al. 2005: 3.7%; REFLUX trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFudDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Heidelbaugh, Goldberg & Inadomi 2010; Heidelbaugh et al. 2012). The assumption that many patients remain on PPIs rather than have alternative diagnoses investigated is supported by HESP clinical opinion. There is little evidence to quantify the extent of this occurrence. Considering that the patient group is already those seeking attention for refractory symptoms, and specialists are involved, a conservative estimate that only 10% of patients will not be reassessed and will continue high-dose PPIs indefinitely was applied in the economic models’ base-case for the purposes of the assessment—i.e. 90% of patients that are non-responsive to high-dose PPIs will not continue medication and be prescribed alternative treatments. This assumption is tested in a sensitivity analysis.Clinical outcomesTreatment outcomesTable 41 summarises the treatment outcomes associated with the treatment pathways in the model. For the purpose of modelling QALYs, effectiveness refers to the extent that the different treatments result in patients being free of, or satisfactorily managed for, the GORD or GORD-like symptoms for which they initially sought diagnosis and treatment.Table 41Health outcomes associated with treatment pathways in the modelManagement strategyEffectiveness rateSourceSurgical management (fundoplication) in acid-related NERD89%(range tested:50%–100%)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWNrPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Beck et al. 2009; Broeders et al. 2010; Grant, Cotton et al. 2013)Medical management (high-dose PPIs and H2 antagonists) in acid-related NERD89%(range tested:50%–100%)Conservatively assumed equivalent to surgery and broadly consistent with the REFLUX trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFudDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Grant et al. 2008). Although described as a rate/patient, this rate is assumed to be derived from patient episodes, and therefore the event of an additional revision surgery is assumed to carry additional mortality risk. The same mortality rate is applied to surgery revision (10% of patients), such that the overall surgical mortality risk is 0.055% per patient. Some models do not include a surgical mortality rate at all (implicitly 0% rate), but Epstein et al. (2009) apply a rate of 4/3,397 (0.118%). These alternative estimates are tested as upper and lower limits in the sensitivity analysis.A background mortality rate is applied equally to all patients in each year of the model. This is a time-dependent transition probability, derived from the Australian Bureau of Statistics general Australian population mortality rates, in a 40%:60% male:female ratio, beginning at age 55?years and advancing 1?year of age with each year of the model.Healthcare resourcesHealthcare resources are included at the full MBS or Pharmaceutical Benefits Scheme (PBS) fee, i.e. including standard minimum patient co-payments, on the grounds that the patient and any mandatory co-payment are part of the societal healthcare system and the full fee is the accepted ‘resource cost’. Additional out-of-pocket patient contributions above the published MBS fee are not included in the economic model; these are regarded as privately negotiated arrangements that are external to the healthcare system. Consideration of the impact of the listing of catheter-free pH monitoring on government costs (i.e. excluding patient co-payments) and total costs (i.e. including patient co-payment and gap costs) is considered in the financial analysis (see ‘ REF _Ref379447679 \h \* MERGEFORMAT Financial and costing impact’). The modelled healthcare resource use and costs are presented in REF _Ref371349711 \h \* MERGEFORMAT Table 42.Table 42Testing-related healthcare resources used in the economic model Type of resource itemUnit costComponents/source of unit cost ApplicationWireless pH monitoring (one test)$1,682Proposed fee $913.64PlusAnaesthesia: (MBS items 17610; $43, 20740; $99, 23010; $19.80)Facility fee: (AR-DRG Z40Z) same day: $607All patients receiving test, plus repeated cost in % of patients with initial test failure who elect to repeat test.Regular-dose PPIs(per monthly prescription)$27.66Weighted average DPMQ of omeprazole 20mg, esomeprazole 20mg, esomeprazole 40mg and pantoprazole 40mg (based on Medicare usage data 2012–13)Assumed regimen of patients entering the model. In the intervention arm, this regimen is maintained during the first 2?months while pH monitoring is carried out and before future treatment decisions are made on the basis of the test resultsHigh-dose PPIs(per monthly prescription)$48.69Twice the DPMQ of the average normal dose (weighted combination of omeprazole, esomeprazole and pantoprazole—as above—less 1x pharmacist dispensing fee)Assumed to be used as medical management strategy: (i) as empirical treatment in comparator arm, and(ii) in all patients diagnosed after pH monitoring as having an acid-related conditionLow-dose or intermittent-use PPIs(per monthly prescription)$9.22One-third of the cost of daily PPIs, on the basis that only one-third of patients require daily medication after surgery.Following successful fundoplication surgery (no ongoing symptoms), an ongoing medication cost is still assumedTreatment of alternative diagnosis(per monthly prescription(s))$47.27Average (unweighted) DPMQ cost of treatments reported as potentially used for alternative diagnoses (baclofen, TCA, SSRI, metoclopramide, domperidone etc.): $19.61, plus assumed to be taken with low-dose PPI: $27.66 = monthly drug costs: $47.27Assumed to be used as management strategy in all patients considered to have a condition that is not acid-related (i.e. after negative pH monitoring and in a proportion of patients who fail high-dose PPIs and have reassessment.)Fundoplication surgery(total costs per episode of surgery)$6,583$7,106(in 10% patients)Initial:Surgery MBS items – 119: $43, 31464: $871, 51303: $174Anaesthesia (~2?h?30?min) MBS items – 17610: $43, 20706: $138.60, 23111: $218Facility fee (AR-DRG G03C) ALOS 2.7?days: $5,138Revision:Surgery MBS items – 119: $43, 31466: $1,307, 51303: $261Anaesthesia (~2?h?30?min) MBS items – 17610: $43, 20706: $138.60, 23111: $218Facility fee (AR-DRG G03C) ALOS 2.7?days: $5,138Assumed to be used as the surgical management strategy in patients who choose this management strategy after they have been diagnosed as having an acid-related condition, confirmed with pH monitoring.Catheter-based monitoring(one test)$174.45MBS item 11810 (includes results)All patients receiving test, plus repeated cost in % of patients with initial test failure who elect to repeat test.DPMQ = Dispensed price maximum quantity (for PBS prescription); PBS = Pharmaceutical Benefits Scheme; PPI = proton pump inhibitor; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor; ALOS = average length of stayUtility valuesAt all times, regardless of the specific management, the economic model assumes that patients are in one of three health utility states:experiencing GORD or GORD-like symptoms, i.e. unsuccessfully treated;free of GORD or GORD-like symptoms, i.e. successfully treated; ordead.The utility weights associated with the health states and the sources of these utilities are presented in REF _Ref379456865 \h \* MERGEFORMAT Table 43.Table 43Health state utilities used in the economic evaluationHealth stateUtility weightSourceUnsatisfactorily managed (normal medication refractory) NERD (or apparent NERD)0.56Baseline in REFLUX trial (0.72) less decrement for symptoms in Heudebert et al. ADDIN EN.CITE <EndNote><Cite><Author>Heudebert</Author><Year>1997</Year><RecNum>694</RecNum><IDText>1078-86</IDText><DisplayText>(Heudebert et al. 1997)</DisplayText><record><rec-number>694</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">694</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heudebert, G. R.</author><author>Marks, R.</author><author>Wilcox, C. M.</author><author>Centor, R. M.</author></authors></contributors><auth-address>Department of Medicine, Birmingham Veterans Administration Medical Center, and University of Alabama at Birmingham, 35294-3296, USA. gheudebert@gim.dom.uab.edu</auth-address><titles><title>Choice of long-term strategy for the management of patients with severe esophagitis: a cost-utility analysis</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><alt-periodical><full-title>Gastroenterology</full-title></alt-periodical><pages>1078-86</pages><volume>112</volume><number>4</number><edition>1997/04/01</edition><keywords><keyword>Adult</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Esophagitis/ drug therapy/ surgery</keyword><keyword>Fundoplication</keyword><keyword>Health Care Costs</keyword><keyword>Humans</keyword><keyword>Markov Chains</keyword><keyword>Middle Aged</keyword><keyword>Monte Carlo Method</keyword><keyword>Omeprazole/ therapeutic use</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1997</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>9097989</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(1997) (0.18) Approach as per ADDIN EN.CITE <EndNote><Cite><Author>Bojke</Author><Year>2007</Year><RecNum>674</RecNum><IDText>829-41</IDText><DisplayText>(Bojke, Hornby &amp; Sculpher 2007)</DisplayText><record><rec-number>674</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">674</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bojke, L.</author><author>Hornby, E.</author><author>Sculpher, M.</author></authors></contributors><auth-address>Centre for Health Economics, University of York, York, UK. lg116@york.ac.uk</auth-address><titles><title>A comparison of the cost effectiveness of pharmacotherapy or surgery (laparoscopic fundoplication) in the treatment of GORD</title><secondary-title>Pharmacoeconomics</secondary-title><alt-title>PharmacoEconomics</alt-title></titles><periodical><full-title>Pharmacoeconomics</full-title><abbr-1>PharmacoEconomics</abbr-1></periodical><alt-periodical><full-title>Pharmacoeconomics</full-title><abbr-1>PharmacoEconomics</abbr-1></alt-periodical><pages>829-41</pages><volume>25</volume><number>10</number><edition>2007/09/25</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Drug Therapy/ economics</keyword><keyword>Fundoplication/ economics</keyword><keyword>Gastroesophageal Reflux/ drug therapy/economics/ surgery</keyword><keyword>Great Britain</keyword><keyword>Health Care Costs/statistics &amp; numerical data</keyword><keyword>Humans</keyword><keyword>Laparoscopy/economics</keyword><keyword>Markov Chains</keyword><keyword>Middle Aged</keyword><keyword>Models, Statistical</keyword><keyword>Quality-Adjusted Life Years</keyword><keyword>Software</keyword></keywords><dates><year>2007</year></dates><isbn>1170-7690 (Print)&#xD;1170-7690 (Linking)</isbn><accession-num>17887805</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>Bojke, Hornby & Sculpher (2007)Satisfactorily managed NERD (or apparent NERD)0.78 (2)REFLUX trial post-surgery (average 2–5?years) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFudDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA Comay et al. (2008; Heudebert et al. (1997)Given that each patient is assigned 1.1 episodes of surgery, to account for the 10% revision rate, each patient undergoing surgery acquires a decrement of –0.022 QALYs to account for the decreased utility associated with revision surgeriesDaily medication decrement–0.01 (decrement each year on medication)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bcmd1ZWRhczwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+

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ADDIN EN.CITE.DATA Arguedas et al. (2004; Comay et al. (2008)Applied to all patients without GORD symptoms but requiring ongoing medication to maintain symptom relief, to account for inconvenience of regular medication requirement It is noted that this value is less than the difference between post-surgery and medical management groups in REFLUX (Grant, Cotton et al. 2013); therefore, this may be considered a conservative estimate.QALY = quality-adjusted life yearsIt is assumed that:all patients with refractory NERD and refractory NERD-like symptoms have the same utility weight while symptomatic, i.e. when entering the model or during the model if they are unsuccessfully treated. Likewise, all successfully treated patients, either true NERD or those with an alternative diagnosis, have the same symptom-free utility weightall symptomatic patients are taking medication, although without adequate effect, and that the disutility of medication is incorporated into the disutility associated with being symptomaticall patients with a negative pH-test result and/or diagnosis other than NERD will require other ongoing treatment for their alternative diagnosis. Outputs from the economic evaluationIncremental costs and effectivenessThe overall costs and outcomes, and incremental costs and outcomes, as calculated for the intervention and comparator in each model, with the base-case assumptions, are shown in Table 45 and Table 46.Table 45 Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERDCostIncremental costEffectiveness (QALYs)Incremental effectivenessICERIntervention$8,7057.874Comparator$6,927$1,7787.7510.123$14,457QALY = quality-adjusted life years; ICER = incremental cost-effectiveness ratioTable 46 Model 2: Cost-effectiveness of wireless pH monitoring vs catheter-based pH monitoring in patients with refractory NERDCostIncremental costEffectiveness (QALYs)Incremental effectivenessICERIntervention$8,7057.874Comparator$7,136$1,5697.878–0.004DominatedQALY = quality-adjusted life years; ICER = incremental cost-effectiveness ratioAlthough the base-case comparison of catheter-free (wireless) pH monitoring and catheter-based pH monitoring assumes equivalent efficacy, accuracy and subsequent treatment decisions following positive or negative test results, wireless pH monitoring results in fewer gains in health outcomes. This is due to the increased technical failure rate associated with wireless monitoring (7.5% vs 0.89%), and the subsequent increased number of ‘no result’ patients (50% of test failures) who revert to empirical treatment, i.e. the comparator in Model 1.Weighted combinations of models 1 and 2As neither Model 1 nor Model 2 are predicted to represent the actual patient market, the following analysis considers combinations of these models, which include all patients in the proposed listing combined with various extents of leakage into the existing catheter-based monitoring market. The relative sizes of these markets are discussed under ‘Background’ and ‘Financial and costing impact’, where it is estimated that the existing catheter-based market is approximately 10 times the proposed catheter-free market. Therefore, a 10% leakage of catheter-based-monitoring patients to catheter-free monitoring will result in a 50%:50% ratio of catheter-free patients representing Model 1 and 2. A summary of the cost-effectiveness of the intervention where this leakage occurs, and of further leakage scenarios is presented in REF _Ref379457712 \h \* MERGEFORMAT Table 47.Table 47 Societal ICERs following the proposed listing, allowing for various levels of leakage to include patients tolerant of catheter-based pH monitoring accessing wireless monitoringExtent of catheter-based monitoring leakage(% of catheter market) aWeighting of catheter-based aWeighting of ‘no test’Weighted costs bWeighted QALYs cICER d0%0%100%$6,9277.751$14,45710%50%50%$7,0327.815$28,12920%67%33%$7,0667.836$42,69430%75%25%$7,0847.846$58,42940%80%20%$7,0947.853$75,27850%83%17%$7,1017.857$93,43660%86%14%$7,1067.860$113,06170%88%13%$7,1107.862$134,33980%89%11%$7,1137.864$157,48790%90%10%$7,1157.865$182,764100%91%9%$7,1177.866$210,478aThe catheter-suitable market is estimated at 10x the size of the catheter-intolerant market; therefore, a 10% leakage in this market represents an equal number of patients to the intolerant market etc.bWeighted combination of comparator, catheter-based: 7.878 QALYs; and no pH monitoring: 7.751 QALYs cWeighted combination of comparator, catheter-based: $7,136; and no pH monitoring: $6,927 dIn all cases the ICER is calculated against the proposed intervention of 100% wireless monitoring, which, on average, has a cost of $8,705 and accrues 7.874 QALYs (per patient). The combination analysis above suggests that the cost-effectiveness of the proposed listing is highly dependent on limiting the leakage of use in patients who could otherwise tolerate catheter-based monitoring. If this leakage is relatively small (e.g. under 20%), the proposed listing is more likely to be considered cost-effective in typical Australian ICER interpretation, whereas if there is extensive leakage (e.g. greater than 50%), the proposed listing is unlikely to be considered cost-effective in broadly accepted terms.Scenario and sensitivity analysesMany variables in the models are uncertain, with estimates derived from mixed sources other than local Australian data, i.e. literature reports, expert opinion and arbitrary estimates; therefore, the impacts of these variables are examined in sensitivity analyses. The key sensitivity analyses relate to the accuracy of the wireless pH test, the extent that doctors will look for other diagnoses and discontinue high-dose PPIs in non-responders and the timeframe of the cost–utility analysis. Other variables and inputs are also tested.Sensitivity analyses in Model 1: Wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERDThe cost-effectiveness of wireless monitoring vs no monitoring is dependent on the accuracy, particularly the specificity, of the test ( REF _Ref379457727 \h \* MERGEFORMAT Table 48). Using the accuracy data estimated in the report, which is known to be imperfect given the imperfect reference standard (catheter-based monitoring) and inconsistent test result interpretation criteria, wireless monitoring is dominated by the comparator in the sensitivity analysis, thus producing fewer health outcomes at a higher cost. This is found in all analyses conducted where the test specificity of catheter-free monitoring is less than 95%. However, the cost-effectiveness of the wireless test hardly changes, relative to the base-case, when the sensitivity of the test is reduced to 86% as long as 100% specificity is maintained.Table 48Sensitivity analyses around wireless pH-test accuracy for Model 1Catheter-free test:Cost ($)Catheter-free test:Outcomes (QALYs)No pH test:Cost ($)No pH test:Outcomes (QALYs)ICERBase-case (100% accurate)$8,7057.874$6,927 7.751$14,457With sensitivity of 86% and specificity of 77%$9,0607.577$6,927 7.751DominatedWith sensitivity of 100% and specificity of 77%$9,1687.587$6,9277.751DominatedWith sensitivity of 86% and specificity of 100%$8,5977.863$6,9277.751$14,912With sensitivity of 90% and specificity of 90%$8,8297.742$6,9277.751DominatedWith sensitivity of 95% and specificity of 95%$8,7677.803$6,9277.751$35,388QALY = quality-adjusted life years (gained); ICER = incremental cost-effectiveness ratioThere are no data available to estimate the extent to which untested patients in this symptomatic population remain on PPIs despite the lack of efficacy and potentially an alternative diagnosis and treatment being more appropriate. It is suggested that the base-case estimate, where only 10% of patients remain inappropriately followed up, is conservative. Alternative assumptions are shown in REF _Ref379457753 \h \* MERGEFORMAT Table 49. The cost-effectiveness of wireless monitoring increases substantially if it is assumed that more than 10% of patients remain on inappropriate treatment, although at no time does it become less expensive. However, if active follow-up of alternative diagnoses and discontinuation of inappropriate PPIs occurred in 99% of patients, pH monitoring would be unlikely to be considered cost-effective. If 100% of patients were followed up, the wireless pH test would be dominated, as empirical medication treatment would achieve greater outcomes at less cost.Table 49Sensitivity analyses around the assumption of PPI discontinuation for Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERD% of non-responders to high-dose PPIs that remain on inappropriate treatmentCatheter-free test:Cost ($)Catheter-free test:Outcomes (QALYs)No pH test:Cost ($)No pH test:Outcomes (QALYs)ICER100% (all non-responders remain on high-dose PPI treatment)$8,7417.83$7,9826.593$61375% $8,7317.842$7,6246.915$1,19450% $8,7217.855$7,3567.237$2,20925% $8,7117.867$7,0887.558$5,253Base-case: 10% of non-responders remain on high-dose PPIs and 90% discontinue$8,7057.874$6,9277.751$14,4575%$8,7037.876$6,8747.816$30,4862.5%$8,7027.877$6,8477.848$63,9711%$8,7017.878$6,8317.867$170,0140% (all non-responders to high-dose PPIs investigated/treated for alternative diagnoses)$8,7017.879$6,8207.880DominatedNERD = non-erosive reflux disease; ICER = incremental cost-effectiveness ratio, PPI = proton pump inhibitors; QALY = quality-adjusted life years (gained)An analysis of cost-effectiveness when considered across different time horizons was also undertaken ( REF _Ref379457782 \h \* MERGEFORMAT Table 50). The cost-effectiveness of pH monitoring is substantially improved as time horizons of a longer duration are considered. This is driven by the fact that the most significant costs are incurred in the first year (i.e. costs of the test and of subsequent surgery), as is the QALY decrement associated with surgery; however, both cost savings due to reduced expenditure on high-dose PPIs, and QALY benefits associated with discontinued use of medication, accrue every year thereafter. The ICER does not change substantially after 20?years, given that discounting and background mortality reduce the overall impact of distant years. Table 50Sensitivity analyses around the time horizon measured in Model 1: Cost-effectiveness of wireless pH monitoring vs no monitoring (empirical treatment) in patients with refractory NERDCatheter-free test:Cost ($)Catheter-free test:Outcomes (QALYs)No pH test:Cost ($)No pH test:Outcomes (QALYs)ICER1 year $3,0110.73$6810.729$2,330,1505 years$5,1253.382$3,0003.336$46,19910 years$7,1785.957$5,2525.868$21,642Base-case: timeframe 15?years$8,7057.874$6,927 7.751$14,45720 years$9,8149.265$8,1439.119$11,44625 years$10,58210.229$8,98710.067$9,847QALY = quality-adjusted life years (gained); ICER = incremental cost-effectiveness ratioAdditional sensitivity analyses undertaken on Model 1 showed that the model was not particularly sensitive to discounting, surgical mortality rates, technical failure rates, re-test uptake rate after technical failure, fundoplication surgery costs, or the cost of investigation and treatment of alternative diagnoses. The results of these analyses are presented in REF _Ref378948439 \h \* MERGEFORMAT Table 86 in Appendix K.Sensitivity analyses in Model 2: Wireless pH monitoring vs catheter-based monitoringSensitivity analyses around test accuracy were also undertaken for Model 2 ( REF _Ref379457802 \h \* MERGEFORMAT Table 51). The wireless test is dominated by the less expensive and more technically reliable catheter-based test, even when assuming perfect accuracy of the wireless test (compared with catheter-based monitoring); predictably, for all analyses where the wireless test has less-accurate test parameters, it remains dominated. Where the catheter-based test is assumed to be imperfect, with a sensitivity of 0.805, but other (including all wireless) test accuracy parameters are assumed perfect, the wireless test has a positive but relatively high ICER. This suggests that the transfer of patients from catheter-based to wireless monitoring when it is not needed is unlikely to be cost-effective, irrespective of whether or not the clinical yield and sensitivity of wireless pH monitoring is higher than catheter-based monitoring. This is consistent with the wording of the proposed listing to restrict funding to patients who are unable to tolerate catheter-based monitoring.Table 51Sensitivity analyses around the accuracy of wireless pH monitoring and catheter-based monitoring in Model 2Catheter-free test:Cost ($)Catheter-free test:Outcomes (QALYs)Catheter-based test:Cost ($)Catheter-based test:Outcomes (QALYs)ICERBase-case (100% accurate)$8,7057.874$7,1367.878DominatedWith wireless test sensitivity of 86% and specificity of 77% (catheter-based test reference standard, assumed 100% accurate)$9,0607.577$7,1367.878DominatedWhere catheter-based monitoring is assumed to have a sensitivity of 80.5% and all other accuracy parameters are 100%$8,7057.874$6,9807.863$156,818With wireless sensitivity of 100% and specificity of 77%$9,1687.587$7,1367.878DominatedWith wireless sensitivity of 86% and specificity of 100%$8,5977.863$7,1367.878DominatedWith wireless sensitivity of 95% and specificity of 95%$8,7677.803$7,1367.878DominatedQALY = quality-adjusted life years (gained); ICER = incremental cost-effectiveness ratioFinancial and costing impactThe estimated financial costs associated with wireless pH monitoring have been determined using a combined market share and epidemiological approach. This involves consideration of the existing catheter-based pH-monitoring market, and also epidemiological estimates with regard to the extent of catheter intolerance (i.e. failure of catheter-based monitoring or anatomically inappropriate).Data sources used in the financial analysisExisting usage and costing data relating to existing catheter-based pH monitoring (item 11810) and endoscopy was provided by Medicare Australia, on request.The estimated percentage of patients <1 or >70?years of age (5–10%) is based on Medicare Local data concerning item 11810. The estimate of placement error is based on the analysis presented under ‘ REF _Ref379441632 \h \* MERGEFORMAT Technical efficacy’ on page PAGEREF _Ref379441632 \h 75.Estimates of patient catheter intolerance (~10%) are based on expert opinion and are supported by the literature PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VpczwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Sweis et al. 2009).Use and costs of the proposed wireless pH-monitoring strategyProposed feeThe proposed fee per occasion of wireless pH monitoring, as requested in the application, is $913.64. This fee has been calculated by the applicant on the basis that it includes:professional time (estimated at 50?minutes with a value of $350):performing the procedure (~27 minutes)downloading and reading of data (~20 minutes)equipment costs (estimated at $563.64):consumable pH transmitter capsule (Bravo) $430.30depreciation of capital—wireless receiver and recording system, including software (Bravo) $19,990, depreciated fully over 3?years/150 patients at $133.34/occasion.A significant proportion (62%) of the proposed fee is for equipment. It is noted that even after adjustment for currency exchange, the quoted equipment prices remain considerably higher than the 2006 prices published by the American Society for Gastrointestinal Endoscopy Technology Committee ADDIN EN.CITE <EndNote><Cite><Author>Chotiprashidi</Author><Year>2005</Year><RecNum>11</RecNum><IDText>485-7</IDText><DisplayText>(Chotiprashidi et al. 2005)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="wzxrta50d9xespexfa6vr9smxrfdvs20ft99">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chotiprashidi, P.</author><author>Liu, J.</author><author>Carpenter, S.</author><author>Chuttani, R.</author><author>DiSario, J.</author><author>Hussain, N.</author><author>Somogyi, L.</author><author>Petersen, B. T.</author></authors></contributors><titles><title>ASGE Technology Status Evaluation Report: wireless esophageal pH monitoring system</title><secondary-title>Gastrointest Endosc</secondary-title><alt-title>Gastrointestinal endoscopy</alt-title></titles><periodical><full-title>Gastrointest Endosc</full-title><abbr-1>Gastrointestinal endoscopy</abbr-1></periodical><alt-periodical><full-title>Gastrointest Endosc</full-title><abbr-1>Gastrointestinal endoscopy</abbr-1></alt-periodical><pages>485-7</pages><volume>62</volume><number>4</number><edition>2005/09/28</edition><keywords><keyword>Cost-Benefit Analysis</keyword><keyword>Equipment Design</keyword><keyword>Esophagus/ physiopathology</keyword><keyword>Gastric Acidity Determination/instrumentation</keyword><keyword>Gastroesophageal Reflux/physiopathology</keyword><keyword>Humans</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Monitoring, Ambulatory/economics/ instrumentation</keyword><keyword>Telemetry/economics/ instrumentation</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0016-5107 (Print)&#xD;0016-5107 (Linking)</isbn><accession-num>16185957</accession-num><urls></urls><electronic-resource-num>10.1016/j.gie.2005.07.007</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Chotiprashidi et al. 2005) presented in REF _Ref379470882 \h \* MERGEFORMAT Table 87 in REF _Ref379470901 \h \* MERGEFORMAT Appendix L, despite a general trend in other medical technology prices to have decreased over this time.Of concern is that the calculated depreciation of capital requires each doctor providing the service to perform 50 services each year to break even with respect to equipment costs. The predicted current patient demand for services, based on the restricted listing, estimates that less than 400 tests should be required per year. This would suggest that the market would only support 8 practitioners around Australia to purchase the equipment and provide the service whereas, currently, catheter-based pH monitoring is undertaken by at least 56 practitioners (Medicare Australia 2013). Reduced numbers of practitioners may either result in access difficulties or, if most practitioners who currently undertake catheter-based monitoring were to invest in a wireless pH-monitoring system, there would be economic pressure to either increase the patient cost beyond the schedule fee (i.e. have a large gap payment) or to over-service (‘leakage’).In addition, a technical failure rate of approximately 7.5% is associated with the wireless pH-monitoring procedure, most commonly involving placement failure of the wireless capsule without results, such that an additional capsule is required. Clarification is needed as to who (e.g. doctor, patient, private insurer, manufacturer) bears this cost—capsule (~$430) or procedure ($914).Other issues of note that relate to the proposed fee include the following: Automatic annual indexation may not be appropriate given the equipment component.If the Bravo capsule component funding were to be obtained through an alternative source (e.g. the Department of Health’s Prostheses List), revision of the fee would be required. It is anticipated that the service would be typically undertaken in the inpatient setting, such that the MBS would rebate 75% of the fee ($685.23) and the patient contribution would be $228.32.Associated resourcesIn addition, with each occasion of wireless pH monitoring, additional resources, from both MBS and healthcare facility providers, beyond the procedure item will be incurred. These relate to the requirement for anaesthesia while the capsule insertion takes place, and are listed in REF _Ref377978110 \h \* MERGEFORMAT Table 52 and REF _Ref379467457 \h \* MERGEFORMAT Table 53. Both the placement of the capsule by endoscopy, and the later interpretation of results, are included in the proposed fee; therefore, neither an endoscopy nor follow-up consultation for interpretation of results can be claimed with the proposed item.Table 52Additional MBS item resources expected to be used concurrently with all occasions of the proposed interventionMBS itemDescriptionFull MBS cost (fee)MBS benefit a17610ANAESTHETIST, PRE-ANAESTHESIA CONSULTATION (Professional attendance by a medical practitioner in the practice of ANAESTHESIA) A BRIEF consultation involving a targeted history and limited examination (including the cardio-respiratory system). (etc)$43.00$32.2520740INITIATION OF MANAGEMENT OF ANAESTHESIA for upper gastrointestinal endoscopic procedures$99.00$74.2523010ANAESTHESIA, PERFUSION OR ASSISTANCE AT ANAESTHESIA (a) administration of anaesthesia performed in association with an item in the range 20100 to 21997… (etc)For a period of: FIFTEEN MINUTES OR LESS$19.80$14.85Total MBS resources$161.80$121.35a75% benefit applied, assuming most claims are in the inpatient settingTable 53 Other resources expected to be used concurrently with all occasions of the proposed interventionType of resourceDescriptionAverage costHealthcare facility costEndoscopy and follow-up care (AR-DRG Z40Z)$607Furthermore, at least 5% of patients currently obtaining pH monitoring are 75?years or older (Medicare data), and it might be estimated that another 5% are infants or between the ages of 70 and 74?years, such that up to 10% of patients would be eligible for the anaesthesia age-modifier fee. Also, in cases where insertion is difficult or a technical failure occurs during insertion but can be rectified without abandoning the procedure, increased fees associated with an increased duration of anaesthesia might be expected. The relevant item numbers associated with these occasional additional resources are shown below in REF _Ref379466968 \h \* MERGEFORMAT Table 54.Table 54 Additional MBS item resources expected to be used concurrently in approximately 5%–10% of the proposed interventionsMBS itemDescriptionFull cost (fee)MBS benefit a25015ANAESTHESIA, PERFUSION OR ASSISTANCE AT ANAESTHESIA - where the patient is less than 12 months of age or 70 years or greater $19.80$14.8523021[From 23010: ANAESTHESIA….(a) administration of anaesthesia performed in association with an item in the range 20100 to 21997… (etc)]For a period of: 16 MINUTES TO 20 MINUTES$39.60$29.70Total MBS resources$59.40$44.55Average additional MBS expenditure/patient (5–10%)$2.97–$5.94$2.23–$4.46a75% benefit applied, assuming most claims are in the inpatient settingIt is plausible that on very rare occasions serious complications or side effects associated with endoscopy and sedation may occur (e.g. oesophageal tear, haemorrhage). However, there is no quantitative report of the occurrence of these complications associated with wireless pH monitoring and, due to their unknown but expected very low incidence, they are not included in the costing assessment. Likewise, the MBS costs associated with potential downstream treatment decisions (e.g. fundoplication surgery), although included in the economic model, are not included in the costing analysis, given that they are not directly or routinely associated with the proposed intervention.For the remainder of the costing analysis, an associated MBS expenditure of $166 per patient in addition to the proposed fee will be assumed, equal to the sum of $161?+?$5—rounded values from REF _Ref377978110 \h \* MERGEFORMAT Table 52 and REF _Ref379466968 \h Table 54. Of this, $125 is assumed to be paid as benefits and $41 as a patient co-payment.A summary of the total costs and funding sources directly associated with the proposed intervention are presented in REF _Ref379467006 \h \* MERGEFORMAT Table 55. Without knowledge of the actual fees that doctors intend to charge for the proposed listing, it is not possible to calculate the additional patient out-of-pocket payments. Table 55 Total costs directly associated with a service of wireless pH monitoring under the proposed MBS listingDescriptionMBS rebate (benefits paid)Patient MBS co-paymentPrivate insurance or patient costTotalProposed listing$685.32$228.32$0$913.64Associated MBS items$125$41$0$166Facility fee$0$0$607$607Total contributions$810.32$269.32$607$1,686.64Estimated volume per yearThe proposed listing is restricted to use in patients who are indicated for but cannot tolerate a catheter-based pH test. 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ADDIN EN.CITE.DATA (Sweis et al. 2009). To estimate the number of patients eligible for wireless monitoring under the proposed listing, the upper end of the estimate (10%) is applied to the number of catheter-based patients from existing Medicare data. The number of claims for catheter-based monitoring has increased by an average of approximately 4% each year over the past 4?years (2009–13), and therefore in the base-case it is assumed that an ongoing annual growth rate of 4% will apply to all pH monitoring. An estimate of the number of pH tests expected to be undertaken using this calculation is presented in REF _Ref379467518 \h \* MERGEFORMAT Table 56.Table 56Projected number of wireless pH tests annually under the proposed listing (base-case estimates)2012–132013–14 a 2014–15 a 2015–16 a 2016–17 aBase-caseNumber of catheter-based tests 3,5903,7343,8834,0384,200Estimated number of wireless tests(10% of catheter-based pH tests)359373388404420Total pH tests3,9494,1074,2714,4424,620aprojected to increase annually at 4%There is uncertainty around the estimated growth rate; if only the most recent data is considered (2011–13), catheter-based monitoring has increased annually by 8%. If this annual growth rate is maintained, costs associated with listing will increase more rapidly. The impact of an increased growth rate on the number of tests is tested in a sensitivity analysis in REF _Ref379467545 \h \* MERGEFORMAT Table 57. There is also considerable uncertainty with respect to whether ‘leakage’ beyond the eligibility criteria for wireless monitoring will occur. The incentives for use include:Patient preference: there are reports that some patients feel considerable embarrassment and discomfort with the transnasal catheter in situ, and they may avoid attending work or leaving their home. The wireless monitoring system, on the other hand, is relatively discreet, with most patients reporting that they can maintain normal daily activities during the monitoring interval. Therefore, this may result in some patients requesting wireless monitoring and claiming unsuitability for catheter-based monitoring. This ‘unsuitability’ would be based on patient preference rather than an ‘absolute’ intolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaXJhbm88L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Hirano 2006; Mearin et al. 1998).Clinical claim: despite the uncertain conclusion with respect to comparative accuracy and effectiveness, if doctors or patients are convinced that the wireless system reports an additional 10% accurate positive yield with respect to providing a diagnostic result, there is a clinical incentive to opt for wireless monitoring. Financial incentive for doctors: the proposed fee structure includes a component to cover capital depreciation of the pH-monitoring system, assuming that doctors have invested a significant capital outlay. This inherently results in an economic incentive for the doctor to favour this service rather than a strictly time-funded one, as a means to recoup their equipment costs (see earlier discussion under ‘Proposed fee’)Countering these incentives is the fact that wireless pH monitoring requires an endoscopy procedure with sedation. The need for sedation, and therefore admittance to a hospital and third-party observation plus transport home afterward, involves considerable additional risk, money and inconvenience for the patient, such that it will not always be the preferred alternative. There are no data available to make a quantitative estimate as to the extent that leakage to wireless monitoring in place of catheter-based monitoring is likely to occur in practice. For the purposes of a sensitivity analysis, the financial analysis presents cost estimates where the respective ratio of wireless:catheter-based pH monitoring is reversed, arbitrarily making a 91%:9% ratio, with the intention that this be considered the upper estimate of plausible leakage. Estimated numbers of wireless tests under this scenario are also calculated in REF _Ref379467545 \h \* MERGEFORMAT Table 57.Table 57Sensitivity analyses for the projected number of wireless pH tests under the proposed listing2012–132013–14 a2014–15 a2015–16 a2016–17 a1: Increased annual growth rate of 8%Number of catheter-based test a3,5903,8774,1874,5224,884Estimated number of wireless tests(10% of catheter-based pH tests)3593884194524882: Assuming extensive leakage beyond the restrictionNumber of catheter-based tests 388404420Number of wireless tests (upper limit)3,8834,0384,200Total pH tests 4,2714,4424,620aprojected to increase annually at 8%In the majority of patients it is anticipated that pH monitoring would only occur once in their lifetime. However, in a minority of patients who continue to have symptoms despite different medication regimens or surgery, repeat monitoring (e.g. on/off treatment) may be indicated. The MBS claims data does not differentiate between individual one-off patient tests and repeat tests in the same patient; therefore, assuming that repeat monitoring would occur similarly across both pH-monitoring technologies, the extent of repeat monitoring will not affect the costing estimates. There is a significant technical failure rate with wireless pH monitoring that is generally associated with capsule placement. It is assumed that where a capsule has not been placed successfully, an MBS claim would not be submitted. Estimated MBS costs per yearThe direct costs to the MBS per year associated with the proposed listing—specifically for the new item—for directly associated items and in total are calculated in REF _Ref379467593 \h \* MERGEFORMAT Table 58. The government benefits paid and patient contributions are also estimated.Table 58 Total cost of the proposed intervention to the MBS (base-case)2013–14 a2014–15 a2015–16 a2016–17 aNumber of patients eligible for wireless test( REF _Ref379467518 \h \* MERGEFORMAT Table 56)373388404420Fees of the proposed item number ($913.64) b$341,117$354,761$368,952$383,710MBS benefits (75%)$255,871$266,106$276,750$287,820Patient co-payments $85,246$88,655$92,202$95,890MBS fees of associated items ($166)$61,978$64,457$67,035$69,717MBS benefits (75%)$46,670$48,537$50,478$52,497Patient co-payments$15,308$15,920$16,557$17,219Total MBS fees associated with listing$403,094$419,218$435,987$453,426MBS benefits payable (75%)$302,541$314,643$327,228$340,318Patient co-payments $100,553$104,575$108,758$113,109aestimated projectionsbMBS benefits payable per patient round up to $810.32, which results in a total benefits calculation slightly higher than 75% of the total fees.MBS = Medicare Benefits ScheduleSensitivity analyses around the MBS costs allowing for (i) increased growth and (ii) an estimate of the upper limit of plausible leakage are presented in REF _Ref379467873 \h \* MERGEFORMAT Table 59 and REF _Ref379467880 \h \* MERGEFORMAT Table 60, respectively.Table SEQ Table \* ARABIC 59 Sensitivity analysis: Projected MBS costs associated with wireless pH monitoring if patient numbers grow at increased annual rate of 8% 2014–152015–162016–17Estimated number of patients receiving wireless test with 8% annual growth rate419452488Fees of the proposed item number ($913.64) a$382,575$413,181$446,236MBS benefits (75%)$286,969$309,927$334,721Patient co-payments $95,606$103,255$111,515MBS fees of associated items ($166)$69,510$75,071$81,077MBS benefits (75%)$52,342$56,530$61,052Patient co-payments $17,168$18,542$20,025Total MBS fees associated with listing$452,086$488,253$527,313MBS benefits payable (75%)$339,311$366,456$395,773Patient co-payments $112,774$121,796$131,540a MBS benefits payable per patient round up to $810.32, which results in a total benefits calculation slightly higher than 75% of the total fees.MBS = Medicare Benefits ScheduleTable 60 Sensitivity analysis: Projected MBS costs associated with potential leakage (upper plausible extent) of wireless pH monitoring beyond the restriction (i.e. use in 90% of patients who are tolerant to catheter-based monitoring)2014–152015–162016–17Estimated number of patients receiving wireless test, including upper limit of plausible leakage3,8834,0384,200Fees of the proposed item number ($913.64) a$3,547,664$3,689,278$3,836,849MBS benefits (75%)$2,661,098$2,767,322$2,878,015Patient co-payments $886,567$921,956$958,834MBS fees of associated items ($166)$644,578$670,308$697,120MBS benefits (75%)$485,375$504,750$524,940Patient co-payments $159,203$165,558$172,180Total MBS fees associated with listing$4,192,242$4,359,586$4,533,970MBS benefits (75%)$3,146,473$3,272,072$3,402,955Patient co-payments $1,045,770$1,087,514$1,131,015a MBS benefits payable per patient round up to $810.32, which results in a total benefits calculation slightly higher than 75% of the total fees.MBS = Medicare Benefits ScheduleChanges in use and cost of current monitoring strategyTechnically, given that the listing is restricted to patients who cannot tolerate catheter-based monitoring, the comparator is ‘ongoing medical care without a diagnostic test and empirical treatment’. However, given the diversity of medical care and treatments that may be afforded (briefly described in ‘Economic evaluation’) and the lack of any evidence or suggestion that the proposed test will directly alter the actual number of consultations, the base-case comparator for the purposes of the financial analysis is simply ‘no pH test’.Therefore, in the base-case assumption for the proposed listing of wireless monitoring, public funding would be in addition to existing levels of catheter-based pH monitoring, and the extent of catheter-based monitoring would remain unchanged, i.e. there would be no cost offsets associated with the new test listing. Similarly, market growth is independent and the rate of market growth is not relevant.However, if wireless pH monitoring was to be undertaken in place of catheter-based monitoring, i.e. ‘leakage’ beyond the listing (as described under ‘Use and costs of the proposed wireless pH-monitoring strategy’), the extent of use of catheter-based monitoring would be expected to decrease 1:1 with the extent of increased ‘leaked’ use of wireless monitoring. In this sensitivity analysis scenario, an upper plausible limit of leakage to wireless monitoring, the estimated change in use and associated costs of catheter-based monitoring are calculated in REF _Ref379468075 \h \* MERGEFORMAT Table 61. The listed MBS fee for catheter-based monitoring (item 11810) is $174.75 (benefit: 75% = $130.85, 85% = $148.30). However, Medicare data from 2012–13 report that the average fee per service is $190.80, and the average benefit paid per service is $154.81, 96% being for out-of-hospital services and a significant quantity attracting additional Medicare Safety Net benefits; therefore, these values are used in the calculations.Table SEQ Table \* ARABIC 61 Sensitivity analysis: Changes in MBS costs of catheter-based monitoring associated with upper plausible limit of potential leakage to wireless pH monitoring beyond the restriction2013–14a 2014–15a 2015–16a 2016–17aExtent of current monitoring without proposed listing, or with proposed listing and no leakageProjected use of catheter-based pH monitoring (number of claims)3,7343,8834,0384,200Total projected fees: $712,371$740,876$770,450$801,268Estimated Medicare benefits payable (based on existing benefit paid/test$577,999$601,127$625,123$650,128Estimated patient contributions (based on existing contributions/test)$134,372$139,749$145,328$151,141With wireless test MBS-listed and significant leakageProjected use of catheter-based pH monitoring (number of claims)373388404420Total projected fees: $71,237$74,030$77,083$80,167Estimated Medicare benefits payable$57,800$60,066$62,543$65,045Estimated patient contributions$13,437$13,964$14,540$15,122Estimated difference (decrease) in number of claims for catheter-based monitoring if listing and leakage occurs–3,360–3,495–3,634–3,779Estimated difference (saving) in fees for catheter-based monitoring $641,134$666,846$693,367$721,102Difference (saving) in Medicare benefits payable$520,199$541,061$562,580$585,083Difference (saving) in patient contributions$120,935$125,785$130,788$136,019aestimated projectionsMBS = Medicare Benefits ScheduleFinancial implications to the Medical Benefits Schedule (MBS) In the base-case there is no evidence of direct or quantifiable cost offsets associated with the proposed wireless pH test. Therefore, assuming no leakage beyond the proposed restriction, the overall costs to the MBS remain those associated with the listing, as calculated in REF _Ref379467593 \h \* MERGEFORMAT Table 58. The total value of the MBS fees charged in the restricted population is estimated to grow annually, from approximately $420,000 (in 2014–15) to $455,000 (in 2016–17), and would be expected to exceed $500,000 by 2020. In 2014–15 the MBS would be expected to fund approximately $323,000 of this amount, with patient contributions of $97,000, increasing by 2016–17 to MBS funding of approximately $350,000 and patient contributions of approximately $105,000.Uncertainty scenariosIf the market growth rate increases annually by 8%, the overall MBS costs are as presented in REF _Ref379467873 \h \* MERGEFORMAT Table 59, with annual MBS costs increasing by an additional approximately $50,000 (2014–15) to $75,000 (2016–17).For the scenario analysis allowing for leakage beyond the restriction (i.e. from catheter-based monitoring) to an upper plausible extent, the overall MBS costs will increase substantially. These costs are calculated in REF _Ref379468344 \h \* MERGEFORMAT Table 62 and indicate that if substantial leakage occurs, total MBS fees could be increased by over $3.5?million in the 2014–15 financial year, with further increases annually. Government-funded benefits would increase to approximately $2.7?million and patients would additionally contribute approximately $850,000, annually, with ongoing growth expected.Table SEQ Table \* ARABIC 62 Sensitivity analysis: Net change in MBS costs associated with the proposed listing of wireless pH monitoring, assuming the upper plausible extent of leakage beyond the restriction2014–15 a 2015–16 a 2016–17 a MBS costs associated with proposed listing$4,192,242$4,359,586$4,533,970MBS benefits (75%) b $3,146,473$3,272,072$3,402,955Patient co-payments $1,045,770$1,087,514$1,131,015Savings in fees for substituted catheter-based monitoring (calculated in REF _Ref379468075 \h \* MERGEFORMAT Table 61)–$666,846–$693,367–$721,102Difference (saving) in Medicare benefits payable–$541,061–$562,580–$585,083Difference (saving) in patient contributions–$125,785–$130,788–$136,019Net change in total MBS costs$3,525,396$3,666,219$3,812,868Net change in MBS benefits $2,605,412$2,709,492$2,817,872Net change in patient contributions$919,985$956,726$994,996 a estimated projections; b MBS benefits payable per patient round up to $810.32, which results in a total benefits calculation slightly higher than 75% of the total fees.MBS = Medicare Benefits ScheduleClearly, the potential for leakage is significant, and the financial ramifications to the MBS are high should such leakage occur.Other Australian healthcare system costsCosts to the state and territory health systemsAlthough the proposed listing will occur in the hospital setting, it is assumed that MBS claims will only be made for patients admitted in private hospitals, and no additional public hospital funding is envisaged. It is currently unknown whether this technology is available to public hospital patients, and therefore accessibility may present an equity issue.Costs to the private health insurer and/or patientAs identified in REF _Ref379467457 \h \* MERGEFORMAT Table 53, the proposed listing does require utilisation of a hospital facility, at cost to either a private health insurer or the patient. The additional costs to the insurer or patient associated with hospitalisation are calculated in REF _Ref379468581 \h \* MERGEFORMAT Table 63.Table 63Costs of hospitalisation incurred by private insurer or patient (base-case)2014–15a 2015–16a 2016–17a Number of patients eligible for wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)388404420Hospital costs associated with test ($607/patient)$235,695$245,122$254,927aestimated projectionsSensitivity analysisThe additional hospitalisation costs that would be borne by private health insurers and/or patients according to (i) the alternative annual market growth rate (8%) and (ii) significant leakage beyond the restriction (i.e. replacing catheter-based tests) are estimated in Table 64.Table 64 Costs of hospitalisation incurred by private insurer or patient—alternative scenarios2014–15a2015–16a2016–17aIncreased market growth rateNumber of patients eligible for wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)419452488Hospital costs associated with test ($607/patient)$254,174$274,508$296,468Significant market leakageNumber of patients having wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)3,8834,0384,200Hospital costs associated with test ($607/patient))$2,356,981$2,451,066$2,549,109MBS = Medicare Benefits ScheduleTotal Australian healthcare system costsThe total costs to the Australian healthcare system are presented in REF _Ref379470177 \h Table 65.Table 65 Total Australian healthcare system costs (base-case)2014–15a2015–16a2016–17aNumber of patients eligible for wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)388404420MBS costs (Table 58)$419,218$435,987$453,426Private insurer/patient costs ( REF _Ref379468581 \h \* MERGEFORMAT Table 63) $235,695$245,122$254,927Total$654,913$681,109$708,353MBS = Medicare Benefits Schedule REF _Ref379470276 \h \* MERGEFORMAT Table 66 also calculates the total healthcare system costs (i) assuming an increased annual market growth rate of 8% (vs base-case of 4%) and (ii) assuming significant market leakage.Table 66Total Australian healthcare system costs—alternative scenarios2014–15a 2015–16a 2016–17a Increased market growth rateNumber of patients eligible for wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)419452488Net MBS costs ( REF _Ref379467593 \h \* MERGEFORMAT Table 58)$452,086$488,253$527,313Private insurer/patient costs ( REF _Ref379470336 \h \* MERGEFORMAT Table 64) $254,174$274,508$296,468Total healthcare costs$706,260$762,760$823,781Significant market leakageNumber of patients having wireless test ( REF _Ref379467518 \h \* MERGEFORMAT Table 56)3,8834,0384,200Net MBS costs ( REF _Ref379468344 \h \* MERGEFORMAT Table 62)$3,525,396$3,666,219$3,812,868Private insurer/patient costs ( REF _Ref379470336 \h \* MERGEFORMAT Table 64) $2,356,981$2,451,066$2,549,109Total healthcare costs$5,882,377$6,117,285$6,361,977MBS = Medicare Benefits ScheduleDiscussion Safety The population that would normally receive catheter-free monitoring in Australia comprises patients who cannot tolerate a transnasal catheter or in whom a catheter is anatomically inappropriate. Therefore, the appropriate comparator would be ‘no pH monitoring’, since this patient group does not receive pH monitoring in current practice. However, due to the absence of evidence on catheter-free monitoring in the right patient population and with the specified comparator, the selection criteria were amended to include patients suspected of GORD but who can possibly tolerate a transnasal catheter, which allowed the inclusion of catheter-based monitoring as a comparator. Of the 47 comparative and non-comparative studies identified in the literature, only one compared catheter-free monitoring with no monitoring; and only one included patients who were unable to tolerate catheter-based monitoring, with a group undergoing catheter-based monitoring as a comparator. Francis et al. (2012) used ‘no monitoring’ as a comparator when investigating safety issues on catheter-free monitoring 16?cm above the gastro-oesophageal junction (GOJ); however, 48?hours before proximal capsule placement a more distal capsule was placed approximately 6?cm above the GOJ. This means that there is a large probability that the distal capsule was still in the oesophagus at the time of placement of the proximal capsule, possibly causing additional discomfort since most capsules stay in place for more than 48?hours. One conclusion from this study is that a proximal capsule placement in addition to a ‘normal’ capsule placement can cause additional discomfort. Sweis et al. (2009) compared a group of patients who could not tolerate catheter-based monitoring and underwent catheter-free monitoring with patients suspected of GORD undergoing catheter-based monitoring. The catheter-free monitoring patients were significantly more satisfied with the test than the group undergoing catheter-based monitoring. This shows that patients who cannot tolerate a catheter are still capable of tolerating catheter-free monitoring. Therefore, even though there was only limited evidence on the population of interest that was outlined a priori, we can assume that this population is able to undergo catheter-free monitoring.Most adverse events reported in the included studies were related to discomfort caused either by the catheter or by the capsule attaching to the oesophageal mucosa. More-severe complications from catheter-free monitoring, such as a rupture in the oesophageal mucosa, are often caused by a technical failure or human error where the capsule fails to detach from the catheter while inserting the device. Capsule aspirations or dislodgements were reported in case reports and can be dangerous if they dislodge in the lung. This highlights the usefulness of case reports in describing safety outcomes; rare complications are unlikely to be reported by controlled studies or case series. Therefore, case reports can play an essential role in identifying complications from catheter-free monitoring, but caution should be exercised while commenting on rare complications based on case reports that have been presented for catheter-free monitoring but not for its comparator(s).There was limited data on adverse events of catheter-free monitoring in children. It is not clear if children are less likely to tolerate the transnasal catheter but, if this is the case, data on the safety of catheter-free monitoring in children is essential since they will constitute a considerable share of the catheter-free monitoring users. Croffie et al. (2007) reported more chest discomfort with the new test but less overall discomfort in children, compared with the catheter-based test. However, in four case series with a total of 410 children, two mucosal tears were reported using catheter-free monitoring, so severe adverse events do occur in children when using catheter-free monitoring. The percentage of patients who reported pain and discomfort attributable to catheter-free monitoring varied greatly between studies. In the non-comparative studies that reported chest pain or discomfort as an adverse event, rates varied between 0.27% and 45%. Some comparative studies reported a median discomfort score on a VAS, some used a different scale and others listed percentages of patients with adverse events. It is possible that patients would report some chest pain on a VAS, but would not report chest pain when the question ‘Do you have any side effects from monitoring?’ was asked. Results may be biased owing to different methods of reporting adverse events, variation in the physician’s experience in performing the procedure, and small sample sizes within the studies included in this assessment.EffectivenessTwo studies were identified that reported on the effectiveness of catheter-free (wireless) pH monitoring in terms of health outcomes. However, these studies did not meet the specific inclusion criteria a priori, as patients were those who could have potentially tolerated catheter-based monitoring. Health outcomes were similar between those monitored by the catheter-based test and those by the catheter-free test. Given the assumption that catheter-based monitoring is considered superior to no monitoring in those who can tolerate catheter-based monitoring, and the finding that the catheter-free system appears as good as the catheter-based system, it is expected that catheter-free monitoring improves health outcomes compared with no monitoring. However, the available direct evidence was limited and of low quality, so this justified the use of a supportive linked evidence approach, i.e. assessing the diagnostic accuracy of catheter-free monitoring and its impact on patient management. Nine studies compared technical failures in catheter-free monitoring with catheter-based monitoring failure rates. Even though only one study identified catheter-free monitoring as being at higher risk for technical failures, when a meta-analysis was conducted the relative risk was 3.3 (95%CI 1.63, 6.81; I2 = 0%, p=0.906; k = 8 studies) for the occurrence of technical failures while using catheter-free monitoring compared with catheter-based monitoring. The most commonly reported technical failures that caused problems in catheter-free monitoring were early capsule detachments (i.e. in the wrong place in the oesophagus or where the capsule fails to attach to the oesophageal mucosa), causing incomplete data capture and errors in placement of the system. A concern was raised that oesophageal acid exposure exhibited day-to-day variability. If this is the case, monitoring for 48?hours instead of 24?hours, as with traditional catheter-based monitoring, would give truer and more-accurate results. However, even though there were 20 studies reporting on day-to-day variability in adults, there was no consistency in their results. Fourteen studies reported no significant difference in oesophageal acid exposure when comparing the first day with the second day of monitoring, and three and two studies reported more acid exposure on day 1 and day 2, respectively. But there is evidence that increasing the monitoring period leads to an increased diagnostic yield: the incremental diagnostic yield when increasing the monitoring time from 24?hours to 48?hours varied from 2% to 15.6%, as reported by six studies. Because catheter-free monitoring has a standard monitoring period of 48?hours, it should be able to correctly diagnose more people than the standard catheter-based method, where a 24-hour monitoring period is used. Catheter-based monitoring was used as a reference standard for diagnostic accuracy in the current assessment; however, as there is an incremental diagnostic yield with catheter-free monitoring, the validity of this reference standard should be questioned. Sensitivity, specificity, PPV, NPV, LR+ and LR– were used in some studies to determine how well catheter-free monitoring classifies patients in having or not having GORD based on an arbitrary cut-off point, and for some studies the sensitivity and specificity could be calculated based on the available data. Catheter-based monitoring and clinical diagnosis were used as reference standards in three and five studies, respectively. A diagnostic test is ideal if its sensitivity, specificity, NPV and PPV all reach 100%, although this assumes a perfect reference standard and perfect concordance. Diagnostic tests in practice vary in this regard. For those compared against the potentially imperfect reference standard of catheter-based monitoring, lower sensitivity and specificity could be due to catheter-free monitoring being more accurate. Furthermore, the threshold for a positive/negative test result changes the characteristics of the index test. When the threshold for GORD diagnosis in a specific test is set lower, the sensitivity and NPV will be higher and the specificity and PPV will be lower. Decisions on determining the optimal balance of sensitivity and specificity require compromise. Currently, there is a lack of consensus as to the optimal cut-off value for diagnosis in catheter-free and catheter-based monitoring, and therefore the eight studies reporting sensitivity and specificity vary greatly in thresholds for diagnosis, which in turn leads to differences in specificity, sensitivity, NPV and PPV. With no consistency in cut-off values, a meta-analysis on diagnostic accuracy was not conducted. The majority of patients are already being treated with PPIs prior to the test, so a high sensitivity and NPV are important: the true value of the test may be ruling out those who don’t have the disease to reduce the number of patients with false negative results. Consensus on an appropriate cut-off value is therefore necessary to diagnose GORD consistently across different settings when using either catheter-free or catheter-based monitoring.When establishing a GORD diagnosis, not only does a cut-off value in acid exposure have to be determined, but people also have to agree on how the cut-off value will be used. For instance, a positive diagnosis can be based on one positive day (day 1 or day 2), two positive days (having a score above the threshold during both days), a positive score on the ‘worst day’ of monitoring, or a reflux symptom correlation (symptom index, sensitivity index or associated probability). In addition, whatever is decided as the cut-off value, the result should be used to guide management, and there was evidence that this is not always done. Furthermore, there should be one standard location of the capsule in the oesophagus. 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ADDIN EN.CITE.DATA (Pandolfino et al. 2006). Often, reflux-related mucosal injuries, such as oesophagitis and Barrett’s metaplasia, are localised closer to the SCJ. With catheter-free monitoring the capsule can be attached to the oesophageal mucosa at any desired level that maintains a consistent position, so further discussion could be had regarding whether a more distal capsule placement would have a greater relevance to GORD diagnosis. A study by Wenner et al. (2008) showed improved diagnostic accuracy for pH monitoring at 1?cm, compared with 6?cm, above the GOJ in patients with typical reflux symptoms.Nine studies reported on concordance of oesophageal acid exposure times comparing catheter-free monitoring with catheter-based monitoring. There was no clear consistency in acid exposure time concordance, and discrepancy between the two monitoring methods was particularly clear in studies that used in-subject simultaneous recording. This was unexpected because the acid exposure times should closely match when measured in the same subject and at the same time, adjusting for all confounders. Pandolfino et al. (2005) investigated the differences in acid exposure and concluded that there was a consistent offset in pH measurement between the two tests in healthy volunteers. This offset was confirmed further by an in-vivo reference measurement using orange juice with a known pH. The dominant source of discrepancy between the two monitoring systems was an inaccuracy in catheter-free monitoring electrode calibration; after adjustment, the discrepancy improved by 40%. However, some differences still existed and were most pronounced during short reflux events. This corresponds to the results of this assessment, where three out of four studies on concordance in reflux events reported more reflux events in the catheter-based system. One possible explanation is that short drops in pH can be caused by factors unrelated to acid reflux ADDIN EN.CITE <EndNote><Cite><Author>Fox</Author><Year>2006</Year><RecNum>590</RecNum><DisplayText>(Fox 2006)</DisplayText><record><rec-number>590</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">590</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fox, M.</author></authors></contributors><titles><title>Bravo wireless versus catheter pH monitoring systems</title><secondary-title>Gut</secondary-title><alt-title>Gut</alt-title></titles><periodical><full-title>Gut</full-title></periodical><alt-periodical><full-title>Gut</full-title></alt-periodical><pages>434-5</pages><volume>55</volume><number>3</number><keywords><keyword>Capsules</keyword><keyword>Gastric Acidity Determination</keyword><keyword>Gastroesophageal Reflux/*diagnosis</keyword><keyword>Humans</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Monitoring, Ambulatory/methods</keyword><keyword>Reproducibility of Results</keyword><keyword>*Telemetry</keyword></keywords><dates><year>2006</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0017-5749 (Print)&#xD;0017-5749 (Linking)</isbn><accession-num>16474112</accession-num><urls><related-urls><url>;(Fox 2006); for example, due to the ingestion of mildly acidic fluids, movement of the catheter relative to the mucosa in catheter-based monitoring, and movement of the catheter relative to the GOJ during swallowing. On swallowing, the oesophagus shortens by a couple of centimetres due to muscle contractions. As it shortens, the catheter electrode in catheter-based monitoring moves towards the GOJ and may pass into the stomach where the pH is low. The catheter electrode can dip into the ‘acid pocket’ before the catheter returns to its original position. Other short pH drops can occur with peristaltic contractions or during transient LOS relaxation, and resolve without swallowing. Therefore, many of the short reflux events measured by catheter-based monitoring and not catheter-free monitoring could be artefacts that are not related to GORD. When pH monitoring indicates that there is pathological acid reflux, patients could undergo anti-reflux surgery. Two systematic reviews were identified to answer the question whether anti-reflux surgery for GORD leads to better health outcomes than medical treatment. Improved health outcomes were more common after surgical treatment compared with medical treatment in the short to medium term according to both systematic reviews. Two trials reported 5-year follow-up results and concluded that most patients remain in remission for 5?years after anti-reflux surgery, and this group continued to have better pain relief than the medication group. However, these trials consisted solely of patients who responded to PPI therapy, and it is not known if the results generalise to patients who do not respond to medical therapy.There were no studies identified that provided relevant information on the implications of non-treatment on false negative results. False negative patients would probably go off PPI therapy, and would either not undergo surgery or would delay surgical treatment, even though they have GORD. They would likely undergo investigations for alternative diagnoses. It was assumed that the management of false positive patients is not likely to change, although two studies mentioned a patient receiving anti-reflux surgery after a false GORD diagnosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VldG1hbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

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ADDIN EN.CITE.DATA (Sweetman, Ng & Kerrigan 2007; Taddio et al. 2011). Furthermore, patients with a false positive result would probably have a delay in treatment for their ‘real’ diagnosis, as they are misdiagnosed with GORD. Two studies on infants have been identified regarding delayed treatment after GORD misdiagnosis that confirmed the assumptions: infants with infantile spasms and a delayed diagnosis/treatment had a poorer outcome and a worse treatment response. Although these children never underwent pH monitoring and it is not known if they were eligible for the procedure, it shows that early diagnosis in children suspected of GORD can lead to better health outcomes.The body of evidence included in this assessment report was appraised according to the NHMRC’s methodological guidelines ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2008</Year><RecNum>132</RecNum><DisplayText>(NHMRC 2008)</DisplayText><record><rec-number>132</rec-number><ref-type name="Electronic Source">12</ref-type><contributors><authors><author>NHMRC</author></authors></contributors><titles><title>NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Stage 2 consultation.</title></titles><number>11/03/08</number><dates><year>2008</year></dates><publisher>National Health and Medical Research Council, Australian Government</publisher><work-type>Internet</work-type><urls><related-urls><url>.au/consult/index.htm</url></related-urls></urls></record></Cite></EndNote>(NHMRC 2008). This appraisal considered the evidence-base, consistency of the studies’ results, clinical relevance of the safety and effectiveness data, generalisability of the evidence to the population of interest, and applicability to the Australian healthcare system. REF _Ref363634333 \h \* MERGEFORMAT Table 67 presents the results of the assessment of the body of evidence for catheter-free monitoring in GORD.Table 67Body of evidence matrix ComponentABCDExcellentGoodSatisfactoryPoorEvidence-base aOne or two level III studies with a low risk of bias, or level I or II studies with a moderate risk of biasConsistency bMost studies consistent and inconsistency may be explainedClinical impactModerate (with regard to safety) Slight or restricted (with regard to change in management)GeneralisabilityPopulation(s) studied in body of evidence differ from target population for guideline but it is clinically sensible to apply this evidence to target population cApplicabilityApplicable to Australian healthcare context with few caveats Source: adapted from ADDIN EN.CITE <EndNote><Cite><Author>NHMRC</Author><Year>2008</Year><RecNum>132</RecNum><DisplayText>(NHMRC 2008)</DisplayText><record><rec-number>132</rec-number><ref-type name="Electronic Source">12</ref-type><contributors><authors><author>NHMRC</author></authors></contributors><titles><title>NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Stage 2 consultation.</title></titles><number>11/03/08</number><dates><year>2008</year></dates><publisher>National Health and Medical Research Council, Australian Government</publisher><work-type>Internet</work-type><urls><related-urls><url>.au/consult/index.htm</url></related-urls></urls></record></Cite></EndNote>NHMRC (2008)aLevel of evidence determined from the NHMRC evidence hierarchy (Table 9)bIf there is only one study, rank this component as ‘not applicable’. cFor example, results in adults that are clinically sensible to apply to children OR psychosocial outcomes for one cancer that may be applicable to patients with another cancer.Economic considerationsEstimated cost-effectivenessThe economic evaluation suggested that catheter-free (wireless) pH monitoring, while not cost-saving, was reasonably cost-effective vs no monitoring in patients who could not tolerate catheter-based monitoring (base-case ICER: $14,457/QALY). However, it was not cost-effective if patients could have used catheter-based monitoring as an alternative (ICER: Dominated—more costly and less effective). The economic evaluations required numerous assumptions and uncertain inputs. Where inputs could not be derived from the systematic review or published literature, expert opinion or plausible estimates were required, and a conservative approach, not favourable to a finding of cost-effectiveness, was employed. Most inputs, although uncertain, were not found to be drivers with respect to cost-effectiveness, but two key determinants of the cost-effectiveness were identified:The accuracy of the pH test in detecting acid-related conditions. If wireless monitoring is assumed to be of equivalent accuracy to a clinical trial of high-dose PPI treatment, and both are equivalent to catheter-based monitoring, the accuracy does not limit cost-effectiveness. However, where catheter-based pH monitoring is used as a perfect reference standard and the accuracy of wireless monitoring relative to this standard is considerably lower, wireless pH monitoring is dominated in all cost–utility analyses. Although catheter-based monitoring was the DAP-specified reference, the concerns with this approach are detailed in ‘Discussion – Effectiveness’.The extent to which patients who do not receive pH monitoring to ascertain a refinement of their diagnosis would remain on high-dose PPIs, even in cases where they are not effective. If 100% of patients who do not obtain pH monitoring received active follow-up and review of their treatment and empirical investigations for alternative diagnoses, the economic analysis suggests that wireless monitoring would not be cost-effective; however, if even as few as 1 in 10 patients do not receive follow-up and inappropriately remain on high-dose PPI treatment, as assumed in the base-case, the option of wireless monitoring to assist in diagnosis becomes relatively cost-effective.The proposed listing is for use of wireless pH monitoring only in patients that cannot tolerate or that fail catheter-based pH monitoring; however, the classification of patients as such may be subjective, and some patients may have a preference toward wireless monitoring. There is then a risk that, following a listing, some patients would receive wireless monitoring when they would otherwise have had a catheter-based pH test. This economic analysis suggests that this is not cost-effective, and were it to occur in any more than one in five patients who could otherwise undergo catheter-based monitoring, the overall cost-effectiveness of the proposed listing may be compromised. The extent to which leakage would occur in practice is highly uncertain. Estimated financial impactShould the listing proceed, it is estimated that, over the next few years, approximately 400–500 patients would be eligible for the procedure each year. This represents 10% of the number of patients who receive catheter-based monitoring, as this is the estimated catheter-intolerance rate. An annual growth rate in eligibility of 4%–8% is estimated, which is consistent with recent growth rates of catheter-based monitoring.It is assumed that each episode represents a single patient; however, it is possible that some degree of repeat monitoring is undertaken such that the number of patients receiving monitoring in a year may be fewer than the number of tests, e.g. if on-medication and off-medication tests are required. The extent of this is not explored as it is not expected to change the overall financial impacts significantly.If the estimate of intolerance to catheter-based monitoring is an underestimate, or if patients who could tolerate catheter-based monitoring ‘leak’ into the market for wireless monitoring, the number of patients could increase by approximately 10-fold. It is noted that some patients will have a preference for wireless monitoring PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaXJhbm88L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Hirano 2006; Mearin et al. 1998), and the proposed fee structure incentivises doctors to provide the wireless service rather than the catheter-based one. Therefore, a degree of leakage is anticipated, although a realistic estimate of the extent to which this may occur is difficult to predict.In addition to the cost directly associated with the MBS item listing, each wireless pH-test episode is associated with:anaesthesia (MBS items 17610, 20740, 23010) to the value of $161.80, plus an average of $5.94/patient (1 in 10 patients) to allow for additional anaesthesia costs associated with age and complication (MBS Items 25015, 23021)admission to a hospital/day-centre (AR-DRG Z40Z; average cost $607).While the standard patient MBS co-contribution of 25% (for in-patients) of the MBS fees—the proposed listing and MBS anaesthetic fees—can be estimated, the extent to which doctors’ bills will include an additional ‘gap’ charge payable by the patient is unknown. It is expected that hospital/day-facility fees will generally be paid for by private insurance companies but in some cases this may represent an additional out-of-pocket expense for the patient. Where wireless monitoring is undertaken in patients who would not have tolerated catheter-based monitoring, there are no cost offsets to be considered. Where wireless monitoring leaks into the market for patients who would have otherwise undergone catheter-based monitoring, the cost of catheter-based monitoring (MBS item 11810; $174.75) is offset from the cost implications of the wireless test.A summary of the overall financial impacts associated with the listing, in the scenarios of restricted use in the proposed population and allowing for a high level of leakage in patients who would have undergone catheter-based monitoring, are presented in Table 68 and Table 69.Table SEQ Table \* ARABIC 68Financial impact on the MBS, patients and private health insurers, assuming use is strictly limited to patients who cannot tolerate catheter-based monitoring2014–152015–162016–17Number of patients eligible for wireless test (restricted) ( REF _Ref379468075 \h \* MERGEFORMAT Table 61)388404420MBS cost of the proposed item number ($913.64/patient) a$354,761$368,952$383,710Total MBS costs associated with listing (no leakage)$419,218$435,987$453,426MBS benefits payable (75%)$314,643$327,228$340,318Patient co-payments $104,575$108,758$113,109Hospital costs associated with test ($607/patient) (Table 63)$235,695$245,122$254,927Total healthcare costs (no leakage)$654,913$681,109$708,353aMBS Benefits payable per patient round up to $810.32, which results in a total benefits calculation slightly higher than 75% of the total fee. MBS = Medicare Benefits ScheduleTable SEQ Table \* ARABIC 69Financial impact on the MBS, patients and private health insurers, assuming extensive use of wireless monitoring in patients who would otherwise have a catheter-based pH test2014–152015–162016–17Number of patients taking up wireless test including upper limit of plausible leakage (Table 60)3,8834,0384,200Total MBS costs associated with listing (with leakage)$4,192,242$4,359,586$4,533,970Cost-offset associated with replaced catheter-based test (Table 61)–$666,846–$693,367–$721,102Net change in total MBS costs (Table 62)$3,525,396$3,666,219$3,812,868Net change in MBS benefits $2,605,412$2,709,492$2,817,872Net change in patient contributions$919,985$956,726$994,996Hospital costs associated with test ($607/patient) (Table 64)$2,356,981$2,451,066$2,549,109Total healthcare costs with high level of leakage$5,882,377$6,117,285$6,361,977MBS = Medicare Benefits ScheduleWhile the leakage of wireless monitoring beyond the proposed population as presented in Table 69 is extreme and unlikely to occur to such an extent, it is clear that the level of leakage that may occur would have a very significant impact on the overall financial impacts of the proposed listing. While a strictly observed restriction would have a relatively low healthcare system cost (less than $1?million/year), even a modest amount of leakage is likely to increase this impact substantially. Conclusions Is catheter-free monitoring safe? Adverse effects may occur from catheter-free monitoring as a result of the capsule being attached to the oesophageal wall. One study reported that chest pain was significantly more likely to occur in those undergoing catheter-free monitoring than in those undergoing no pH monitoring. Rare reported complications regarding the capsule include dislodgement and/or aspiration, retention somewhere in the gastrointestinal tract, and oesophageal perforation or tearing caused by capsule placement. Twelve comparative studies reported complications of catheter-free monitoring compared with catheter-based monitoring. No deaths or life-threatening events were reported. In general, catheter-free monitoring causes less overall discomfort than catheter-based monitoring and has less impact on normal daily activities and work attendance. Nose and throat pain, dysphagia, eating and drinking difficulties, and headache were more prevalent in catheter-based monitoring. However, chest pain and foreign-body sensation were more likely to occur with catheter-free monitoring, compared with catheter-based monitoring. In conclusion, catheter-free monitoring is usually better tolerated than catheter-based monitoring. Most reported complications are mild and do not require medical therapy but some (rare) complications could become severe when they are left untreated (e.g. mucosal tears).Is catheter-free monitoring effective?Direct evidence on the health impact of catheter-free monitoring versus no monitoring in the selected study population was not available. However, there was limited evidence that the health effects of catheter-free monitoring are similar to catheter-based monitoring: one study reported disappearance of the principal symptom in 73% of patients in the catheter-free monitoring group and 69% in the catheter-based monitoring group. On the other hand, catheter-free monitoring faced more technical problems compared with catheter-based monitoring according to a meta-analysis based on eight studies (RR=3.3, 95%CI 1.47 – 5.62). The most commonly reported technical failures that caused problems in catheter-free monitoring were early capsule detachments (i.e. in the wrong place in the oesophagus or where the capsule fails to attach to the oesophageal mucosa), causing incomplete data capture and errors in placement of the system.Sensitivity and specificity could be calculated from eight studies—three used catheter-based monitoring as a reference standard, and in five the reference standard was clinical diagnosis. Sensitivity and specificity in the latter five studies varied from 67% to 100% and from 66% to 100%, respectively, versus around 86.4% and 77.8%, respectively, in the first three studies. However, these accuracy values are likely to be biased. First, as arbitrary cut-off points were used in these studies, the threshold for a positive/negative test result changes the characteristics of the index test. It has to be determined which cut-off value leads to optimal accuracy. Second, there is currently no consensus on how the cut-off values lead to a positive test result (i.e. worst day analysis, positive value on both days or reflux symptom correlations). Third, the optimal position of the capsule in the oesophagus should be determined to maximise accuracy results. Finally, the catheter-free monitoring period is 48?hours instead of only 24?hours, as with catheter-based monitoring. This increased monitoring period leads to an incremental diagnostic yield of 2.0%–15.6%, as reported in six studies. Catheter-based monitoring was used as a reference standard for diagnostic accuracy in the assessment; however, as there is an incremental diagnostic yield with catheter-free monitoring, the validity of this reference standard should be questioned. As a result of these uncertainties, no conclusion can be drawn regarding the accuracy of catheter-free monitoring compared with catheter-based monitoring. Consensus has first to be reached on a cut-off value, the use of a cut-off value, the position of the capsule and an appropriate reference standard.There was no available evidence that met the population inclusion criteria on change in management; however, change occurred in around 60% of patients who could potentially tolerate catheter-based monitoring, and management changed in 88% of child patients after a pH test. Patients with an abnormal study result were more likely to get a change in management than patients with a normal result.The evidence on whether a change in management leads to improved health outcomes was limited. Two systematic reviews and two RCTs on true positives were included to answer the question whether anti-reflux surgery for GORD leads to better health outcomes compared with medical treatment in patients with GORD (and a positive pH-test result). Anti-reflux surgery led to better health outcomes and had a higher decrease in symptoms, compared with medical management. Two RCTs published 5-year follow-up results; most patients achieved and remained in remission at 5?years with anti-reflux surgery, and fundoplication continued to give better pain relief than medical management. However, these results cannot be generalised to patients who are refractory to PPI therapy, as these trials were conducted in patients who responded to PPI therapy. Furthermore, two studies on GORD misdiagnosis in small infants were included, to provide evidence on false positive results. A small percentage (7% and 17%) of infants with infantile spasms initially received a GORD diagnosis, which led to a delay in (true) diagnosis and treatment. Treatment delay was associated with a poor outcome 2?years after diagnosis and low treatment response. In conclusion, false GORD diagnosis could lead to a delay in correct treatment and suboptimal health outcomes. However, it is not known whether this patient population is eligible for oesophageal pH monitoring. In summary, using catheter-free monitoring for GORD appears likely to be effective at benefiting the health of patients, compared with no monitoring; however, due to applicability concerns regarding the patient populations used in the studies, there is a large amount of uncertainty surrounding this conclusion. Is catheter-free monitoring cost-effective?Economic modelling suggests that catheter-free pH monitoring appears to be reasonably cost-effective in a patient population who have PPI-refractory, endoscopic negative GORD symptoms who cannot tolerate catheter-based pH monitoring, as it may result in improved diagnosis and management of symptoms, albeit at some additional cost—a base-case ICER of $14,457/QALY.However, this conclusion only holds if the accuracy of catheter-free monitoring is assumed to be close to equivalent or better than catheter-based pH monitoring, and this assumption is uncertain given the lack of evidence in using an appropriate alternative reference standard.Furthermore, the proposed listing may be used beyond the intended population in patients who would otherwise have had catheter-based monitoring; where this occurs, cost-effectiveness is substantially reduced.CostingThe expected uptake of catheter-free pH monitoring in the intended catheter-intolerant population is estimated at approximately 400 tests annually. However, if monitoring occurs in a broader population, as many as 4,000 tests could be undertaken annually. The total cost to the MBS for catheter-free pH monitoring in the intended catheter-intolerant population is estimated to be approximately $500,000 annually. This would increase to $3.6?million if the test is used in the broader population requiring pH monitoring.The total cost to the Australian healthcare system including the MBS for catheter-free pH monitoring in the intended catheter-intolerant population is estimated to be $700,000 annually, increasing to over $6?million if the test is used in the broader population requiring pH monitoring.Appendix AHealth Expert Standing Panel and Assessment GroupHealth Expert Standing Panel (HESP)MemberExpertise or affiliationProf. Robert FraserGastroenterologist, Flinders University Department of Gastroenterology, Adelaide, AustraliaProf. Robert BateyGastroenterologist, Addiction Medicine, Central Clinical School, Royal Prince Alfred Hospital, the University of Sydney, Sydney, AustraliaAssessment groupAHTA, University of Adelaide, South AustraliaNamePositionMs Sharon KesselsResearch Officer Ms Camille SchubertSenior Health EconomistMs Skye NewtonTeam leader (Medical HTA)Assoc. Prof. Tracy MerlinManaging DirectorNoted conflicts of interestThere were no conflicts of interest.Appendix BSearch strategiesAUSTRALIAAustralian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S) for Clinical Effectiveness, Monash University for Health Economics, Monash University of Technology Assessment / HTA unit d’Evaluation des Technologies et des Modes d’Intervention en Santé (AETMIS) Heritage Foundation for Medical Research (AHFMR) Institute of Health Economics Canadian Agency for Drugs And Technologies in Health (CADTH) Health Economics Research Association (CHERA/ACRES) – Cabot database Centre for Health Economics and Policy Analysis (CHEPA), McMaster University for Health Services and Policy Research (CHSPR), University of British Columbia Utilities Index (HUI) for Clinical and Evaluative Studies (ICES) Health Quality Council (Canada) Centre for Evaluation and Health Technology Assessment (DACEHTA) Institute for Health Services Research (DSI) Office for Health Technology Assessment (FINOHTA) ’Agence Nationale d’Accréditation et d’Evaluation en Santé (ANAES) Institute for Medical Documentation and Information (DIMDI) / HTA for Quality and Efficiency in Health Care (IQWiG) NETHERLANDSHealth Council of the Netherlands Gezondheidsraad for Medical Technology Assessment (Netherlands) ZEALANDNew Zealand Health Technology Assessment (NZHTA) Knowledge Centre for the Health Services de Evaluación de Tecnologias Sanitarias, Instituto de Salud “Carlos III”I/Health Technology Assessment Agency (AETS) Agency for Health Technology Assessment (Spain) Agency for Health Technology Assessment (CAHTA) for Medical Health Technology Assessment Council on Technology Assessment in Health Care (SBU) Network on Health Technology Assessment (SNHTA) KINGDOMNational Health Service Health Technology Assessment (UK) / National Coordinating Centre for Health Technology Assessment (NCCHTA) Quality Improvement Scotland Institute for Clinical Excellence (NICE) European Information Network on New and Changing Health Technologies of York NHS Centre for Reviews and Dissemination (NHS CRD) STATESAgency for Healthcare Research and Quality (AHRQ) School of Public Health for Clinical and Economic Review (ICER) for Clinical Systems Improvement (ICSI) Department of Health (US) Information Centre of Health Services Research and Health Care Technology (US) Health Resources Commission (US) of Health Technology Assessment Archive (US). Blue Cross/ Blue Shield Association Technology Evaluation Center (Tec)’s Affairs Research and Development Technology Assessment Program (US) databasesElectronic databaseTime periodCochrane Library – including, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials (CENTRAL), the Health Technology Assessment Database, the NHS Economic Evaluation Database2001 – 9/2013Current Contents 2001 – 9/2013Embase 2001 – 9/2013PubMed2001 – 9/2013Web of Science – Science Citation Index Expanded2001 – 9/2013Cinahl2001 – 9/2013Econlit2001 – 9/2013Scopus2001 – 9/2013Additional sources of literatureSourceLocation InternetNHMRC- National Health and Medical Research Council (Australia) Department of Health and Human Services (reports and publications) York Academy of Medicine Grey Literature Report database Controlled Trials metaRegister Library of Medicine Health Services/Technology Assessment Text. National Research Register Scholar and New Zealand Clinical Trials Registry included articles will have their reference lists searched for additional relevant source materialGuidelines search (last step linked evidence)Guidelines International Network (G-I-N) Clinical Guidelines Portal databases searched for economic evaluationsElectronic databaseCost-effectiveness Analysis (CEA) RegistryDatabase of Abstracts of Reviews of Effects or Reviews of Effects (DARE)Health Technology Assessment databaseNHS Economic Evaluation Database (NHS EED)European Network of Health Economics Evaluation Databases (EURONHEED)Specialty websitesInternational Foundation for Functional Gastrointestinal Disorders Gastroenterological Association college of Gastroenterology Society of Australia CStudies included in the review Study profiles of included studies on safetyStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / Exclusion criteriaDiagnostic testsSafety outcomes assessedAgrawal, Akerman & Rich PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QWdyYXdhbDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2009)Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USACase reportLevel: NA1 patient45 year old femaleIndication:Persistent heartburn despite maximal acid-suppressive therapyInclusion:NAExclusion:NAIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the SCJDuration: not statedMild epigastric painSevere retrosternal chest discomfortAhlawat et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QWhsYXdhdDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Department of Medicine, Georgetown University Hospital, Washington, DC, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P290 patients 48 males and 42 femalesAge range: 18–80 yearsIndications:Being intolerant to the conventional naso-oesophageal pH catheter placement or had normal 24-hour oesophageal pH monitoring despite symptomsInclusion:Not statedExclusion:Patients with bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers, implantable cardiac defibrillators, and surgical manipulations of the upper GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursComparator: NAChest painForeign-body sensationAndrews et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QW5kcmV3czwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2012)Division of Gastroenterology, University of Calgary, CanadaDual centre, randomised, non-blinded trialLevel: IIQuality: 19/26CX P286 patients(40 in Calgary and 46 in Edmonton)61 females, 25 malesAge range 18–75 yearsIndications:Reflux symptomsChest painDysphagiaInclusion:Patients aged 18–75?years referred for ambulatory pH monitoring between August 2008 and August 2009Exclusion:Patients with previous oesophageal surgery or achalasiaIndex test:System: activated and calibrated Bravo? wireless capsule system, Medtronic Inc., Minneapolis, MNInsertion: transorally Placement: 5 cm above the proximal border of the LOSDuration: 24 (Calgary) or 48 (Edmonton) hoursComparator:Catheter: calibrated standard antimony-based pH catheter (Comfortec Plus catheter and ZepHR Sleuth recorder, Sandhill Scientific Inc., Highlands Ranch, CO)Insertion: transnasallyPlacement: 5 cm above the proximal border of the LOSDuration: 24 hoursManometry discomfort (nasal, throat, chest, overall) pH placement discomfort (nasal, throat, chest, overall) pH-test discomfort (nasal, throat, chest, overall)Eating and drinkingAbility to do usual daily activitiesAzzam et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXp6YW08L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2012)Sao Paulo University Medical School, Sao Paulo, BrazilCase seriesLevel: IV Quality: Q1CX (no comparator)P225 patients21 females, 4 malesMean age: 52.4 years (range 34–73)Indications:All patients had as predominant symptom the typical GORD complaints; 64% also had atypical complaints and 76% had associated extra oesophageal complaintsInclusion:Heartburn and/or regurgitation as the main clinical complaint; at least 18?years of age; recent upper GI endoscopy (within the past 2?months); interruption in the administration of PPIs for 7 days; and signature on the free and informed consent formExclusion:Oesophageal diverticula; strictures and varices; hiatal hernia greater than or equal to 3?cm; erosive oesophagitis Los Angeles grades C or D; Barrett’s oesophagus; neoplasms; obstructive diseases; previous surgery of the GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 3 cm above the superior border of the LOSDuration: 48 hoursComparator: NAChest pain (none)Belafsky et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmVsYWZza3k8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2004)Scripps Center for Voice and Swallowing, La Jolla, California, USAProspective case seriesLevel: IVQuality: Q2CX (no comparator)P246 patients23 males and 23 femalesMean age: 52 yearsIndications: GORD, chronic cough, laryngopharyngeal reflux Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the manometric lower oesophageal high-pressure zone or 6?cm above the endoscopic SCJDuration: >36 hoursComparator: NASelf-limited epistaxisLaryngospasmVasovagal reactionBhat, McGrath & Bielefeldt PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmhhdDwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2006)Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAProspective case seriesLevel: IVQuality: Q2CX (no comparator)P2217 patients140 females, 77 malesMean age: 51 years (range 42–58)Indications:Preoperative workup for fundoplication, possible extra oesophageal manifestations of reflux disease, symptoms after fundoplication, refractory symptoms on medication, atypical symptomsInclusion:Adult patients undergoing endoscopy with wireless pH studies at the University of Pittsburgh Medical Center between 9 April 2004 and 31 March 2005Exclusion:Individuals unable to give informed consent, pregnant women, prisoners, patients with oesophageal varices, patients requiring continuing anticoagulation, patients with cardiac defibrillatorsIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NAChest discomfortRashBothwell, Phillips & Bauer PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Qm90aHdlbGw8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2004)Department of Otolaryngology, University of Missouri-Columbia, Columbia, Missouri, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P225 patientsMean age: 3 years (range 3 months – 11 years)Indications: Vomiting and dysphagia, ‘noisy breathing’, chronic cough, aspiration pneumonia, reactive airway disease, recurrent croup, known subglottic stenosis, nasal airway obstruction with rhinosinusitis, sleep apnoea, restrictive lung diseaseInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: just below the closed cricopharyngeal muscle in the upper oesophagusDuration: 48 hoursComparator: NAMucosal tearBradley et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QnJhZGxleTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USACohort studyLevel: III-2Quality: 15/26CXP2341 patients (248 patients underwent Bravo monitoring)62% females in the wireless group, 72% females in the catheter groupMean age: 58 years in wireless group, 57?years in catheter groupInclusion:Outpatients undergoing ambulatory pH-metry between October 2006 and October 2008Exclusion:Known history of oesophageal strictures, obstructions or surgical manipulations of the upper GI tract (e.g. anti-reflux surgery or oesophagectomy)Index test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJ or 5 cm above the upper border of the LOSDuration: 48 hoursComparator (MII-pH):System: Sandhill Scientific Inc., Highland Ranch, USAInsertion: transnasallyPlacement: proximal channel 5 cm above upper border of the LOSDuration: 24 hoursComparator (pH-metry):System: Alpine Biomed, Corp, Fountain Valley, USA Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursChest discomfortForeign-body sensationChest and abdominal painDifficulty swallowingPainful swallowingEating and drinkingNausea and vomitingCabrera et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2FicmVyYTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana, USAProspective case seriesLevel: IVQuality: Q1CX (no comparator)P2289 patients (At least 1?day of data was obtained in 278 patients; 2 days were obtained in 274 patients)144 females, 145 malesAge: range 4–22 yearsIndications:Epigastric abdominal pain (59.9%), vomiting (33.9%), regurgitation (23.9%), heartburn (18.3%)Inclusion:Children who are at least 4?years of age and weigh at least 30?lbExclusion:Children with a history of oesophageal surgery, a documented anatomic abnormality, or a history of coagulopathy or a bleeding diathesisIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: at 87% of the distance from the incisors to the Z lineDuration: 48 hoursComparator: NAOesophageal mucosa tearCalabrese et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2FsYWJyZXNlPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2008)Department of Clinical Medicine, University of Bologna, Bologna, ItalyCase seriesLevel: IVQuality: Q2CX (no comparator)P324 patients (12 males, 12 females)Mean age: 37.7 ± 11.9?yearsIndications: Typical symptoms of GORD (heartburn and/or regurgitation)Inclusion:The presence of clinical symptoms such as heartburn and/or regurgitation without erosive oesophagitis, symptoms occurred more than twice weekly for at least 6?months, treatment with acid suppression had results in complete symptom relief or in reduction of the symptoms by more than 50%Exclusion:Coagulopathy, severe oeosphagitis/strictures, erosive oesophagitis, portal hypertension, a history of upper Gl surgery, Helicobacter pylori infection, age <20 or >70?years, pacemakerIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 96 hoursComparator: NAOccasional retrosternal discomfort on swallowingCroffie et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q3JvZmZpZTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2007)Section of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana, USARandomised controlled trialLevel: IIQuality:14.5/26CXP266 patients (children)(but 5 patients were excluded due to operative failure, failed recording etc.)32 males, 34 femalesMean age: 9.4 years (range 4–16.5)Indications:Persistent epigastric or substernal pain, persistent vomiting, heartburn, chronic nocturnal cough or wheezing, persistent throat clearance, dental abnormalities suspected to be caused by refluxInclusion:Children between the ages of 4 and 18?years and weighing at least 30?lb who were undergoing oesophagogastroduodenoscopy and oesophageal pH monitoring for symptoms suggestive of gastro-oesophageal reflux.Exclusion:Children younger than 4?years of age or weighing <30?lb, having anatomic abnormalities of the oesophagus, a history of surgical procedure of the oesophagus, stomach or duodenum, a history of coagulopathy or bleeding diathesis, presence of oesophageal varices, significant medical illnessIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: at 87% of the distance from the incisors to the Z lineDuration: 48 hoursComparator:System: not stated (catheter-based)Insertion: transnasallyPlacement: tip at 87% of the distance from the nostril to the GOJDuration: 24 hoursVomitingChest painThroat painOesophageal discomfortEating and drinkingActivitySatisfaction Crowell et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q3Jvd2VsbDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2009)Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USACase seriesLevel: IVQuality: Q1CX (no comparator)P2157 patients, predominantly (>95%) Caucasian Indications: heartburn/regurgitation symptoms, chest pain, abdominal pain/discomfort Inclusion:Patients with GORD symptomsExclusion:History of bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers or implantable cardiac defibrillatorsIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the endoscopically determined GOJ or 5?cm above the manometrically determined upper margin of the LOS Duration: 48 hoursComparator: NAForeign-body sensationChest discomfortChest painDiminished appetitede Hoyos & Esparza (2010); de Hoyos, Esparza & Loredo (2009)Department of Gastroenterology, Angeles del Pedregal Hospital, Mexico City, MexicoProspective case seriesLevel: IVQuality: Q2CX (no comparator)P266 patients27 males, 39 femalesMean age: 41.7 years (range 11–73)Indications:Typical oesophageal reflux symptoms, atypical manifestations or a mixed symptomatologyInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm from the SCJDuration: 48 hoursComparator: NAIntolerable chest painDetachment failuredes Varannes et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+ZGVzIFZhcmFubmVzPC9BdXRo

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology and Hepatology, Hopital Hotel Dieu, Nantes, FranceCase seriesLevel: IV Quality: Q1CX (no comparison)P240 patients(probe successfully attached in 36 patients)21 males, 19 femalesMean age: 50 yearsIndications:Heartburn (n=7), regurgitation (n=6) or both symptoms (n=26)Inclusion:Patients suggestive of GORD and referred to the functional laboratory of four French academic centres for pH monitoringExclusion:Severe oesophageal motility disorders, severe oesophagitis (Los Angeles grade C or above), pregnancy, women who were not using reliable contraceptionIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the Z lineDuration: 48 hoursComparator: NAEpistaxisDizzy spellsSleep disordersDysphagia for liquidsSwallowing discomfortThoracic discomfortDomingues, Moraes-Filho & Domingues PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RG9taW5ndWVzPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USACase reportLevel: NA1 patient76 year old womanIndication:Recurrent GORD, failing to respond to medical therapyInclusion:NAExclusion:NAIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: not statedDuration: NAComparator: NAMucosal tear with oesophageal perforationFrancis, DL ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Francis</Author><Year>2008</Year><RecNum>235</RecNum><IDText>2663</IDText><DisplayText>(2008)</DisplayText><record><rec-number>235</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">235</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, D. L.</author></authors></contributors><titles><title>Attachment disorder: a decline in the performance of the Bravo pH system</title><secondary-title>Am J Gastroenterol</secondary-title><alt-title>The American journal of gastroenterology</alt-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><alt-periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></alt-periodical><pages>2663</pages><volume>103</volume><number>10</number><edition>2008/10/16</edition><keywords><keyword>Endoscopes, Gastrointestinal</keyword><keyword>Equipment Failure</keyword><keyword>Esophageal pH Monitoring/ instrumentation</keyword><keyword>Esophagus/ physiopathology</keyword><keyword>Gastroesophageal Reflux/ diagnosis/physiopathology</keyword><keyword>Humans</keyword><keyword>Peristalsis/ physiology</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>18855870</accession-num><urls><related-urls><url>;(2008)Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P276 patientsInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NASevere chest painCapsule dislodgement in the pyriform sinusFrancis, DO et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Francis</Author><Year>2012</Year><RecNum>236</RecNum><IDText>91-97</IDText><DisplayText>(2012)</DisplayText><record><rec-number>236</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">236</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, D. O.</author><author>Sumner, E.</author><author>Goutte, M.</author><author>Slaughter, J. C.</author><author>Garrett, C. G.</author><author>Hagaman, D.</author><author>Vaezi, M. F.</author></authors></contributors><titles><title>Feasibility of Dual Wireless Esophageal pH Monitoring: Randomized Blinded Sham-Controlled Trial</title><secondary-title>Otolaryngology-Head and Neck Surgery</secondary-title></titles><periodical><full-title>Otolaryngology-Head and Neck Surgery</full-title></periodical><pages>91-97</pages><volume>147</volume><number>1</number><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0194-5998</isbn><accession-num>CCC:000314267600016</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000314267600016</url><url>;(2012)Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USARandomised, blinded controlled trialLevel: II Quality: 16/26C1P222 patients were included (13 males, 9 females)Indications:Cough, hoarseness, globus, heartburn, regurgitationInclusion:Patients >18 years of age, scheduled for planned oesophagogastroduodenoscopy and wireless pH monitoring for physiologic assessment of oesophageal acid exposure for typical GORD symptoms or for extraoesophageal reflux (EER) symptomsExclusion:History of upper oesophageal surgery, bleeding dyscrasia, recent cerebrovascular accident or transient ischemic attack, recent (<6?months) GI haemorrhage, oesophageal varices or significant medical illness, current pregnancyIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 16 cm above the SCJDuration: 48 hoursComparator:No monitoring (a sham capsule placement)Chest pain (adj OR)Odynophagia (adj OR)Dysphagia (adj OR)Garrean et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FycmVhbjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2008)Division of Gastroenterology, Northwestern University Freiberg School of Medicine, Chicago, Illinois, USACase series (prospective?)Level: IVQuality: Q2CX (no comparator)P260 patients (22 males and 38 females) Age: 19–80?years40 patients had complete 4-day data acquisitionIndications: acid reflux symptoms, chest pain, laryngeal symptoms that were poorly responsive to twice-daily PPI therapy for a minimum of 6?weeksInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJComparator: NABack painGlobus sensationChest painGillies et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2lsbGllczwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2007)Departments of Upper Gastrointestinal Surgery and Gastrointestinal Physiology, Royal Berkshire hospital, Reading, UKNon-randomised controlled trialLevel: III-2 Quality: 13.5/26CXP2185 patients, but 200 oesophageal pH studies104 males, 81 femalesMean age: Catheter group: 46?years (range 16–71)Bravo group: 45?years (range 13–75)Indication: Symptoms suggestive of GORD or documenting the outcome of laparoscopic anti-reflux surgeryInclusion:See indicationExclusion:No specific exclusion criteria existIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursComparator:System: MedtronicInsertion: transnasallyPlacement: 5 cm above the proximal border of the LOSDuration: 24 hoursOverall discomfort (during insertion and monitoring)Nasal discomfortThroat discomfortOesophageal discomfortInterference with daily activitiesEatingSleepingWork attendanceGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2007)Gastroenterology, Department of Medical Sciences, University of Milan, Milan, ItalyPseudo-randomised controlled trialLevel: III-1Quality: 13.5/26CXP2133 patientsCatheter group: 78 patients, 46% males, aged 53 ± 2?yearsBravo group: 55 patients, 45% males, aged 44 ± 3?years)Indication: Suspected GORD, consecutively referred for oesophageal pH monitoringInclusion:See indicationExclusion:Previous GI surgery (excluding cholecystectomy and appendectomy) and known or suspected stricture of the GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach, or 5?cm above the upper margin of the LOS Duration: 24 hoursDiscomfort at placementOverall discomfortChest discomfortEating and drinkingInterference with daily activitiesGunnarsdottir, Stenstrom & Arnbjornsson PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3VubmFyc2RvdHRpcjwvQXV0

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ADDIN EN.CITE.DATA (2007, 2008)Department of Paediatric Surgery, Lund University Hospital, Lund, SwedenCase seriesLevel: IVQuality: Q1CX (no comparator)P258 children37 males, 21 females Mean age: 8 ± 4?yearsIndications:Vomiting, abdominal and chest pain, GORD control, GI bleeding, respiratory symptomsInclusion:Not statedExclusion: Oesophageal strictures, coagulopathy, any suspicion of intestinal stricturesIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: above the diaphragm valve at the width of two of the individual patient’s vertebral bodies as visualised on a perioperative X-rayDuration: 24 or 48?hours (23 children had 48-hour measurement)Comparator: NA Chest discomfortCoughingDysphagiaHakanson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SGFrYW5zb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2009)Department of Surgery, Center of Gastrointestinal Disease, Ersta Hospital, Stockholm, SwedenCase-control study with in-subject simultaneous recordingLevel: III-2Quality: 14/26CXP253 volunteers and 55 patients (45 volunteers and 47 patients had enough data to be included)30 females and 15 males in volunteer group27 females and 20 males in patient groupMean age: Volunteers: 47?years (range 21–68)Patients: 50?years (range 23–69)Indication: Patients had symptoms including mainly heartburn, acid regurgitation, and chest or epigastric painInclusion:Patients: referred to the clinic for investigation of GORDExclusion:Volunteers: history of GORD or any other pathology of the upper GI tract, taking acid-suppressing agents or medication known to affect GI motilityIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJ Duration: 48 hoursComparator:System: Slimline, Medtronic, Skovlunde, DenmarkInsertion: transnasallyPlacement: 5 cm proximal to the upper border of the LOSDuration: 24 hoursComplications (none)Premature removal of the capsule (none)Hirano et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Hirano</Author><Year>2005</Year><RecNum>511</RecNum><IDText>1083-1088</IDText><DisplayText>(2005)</DisplayText><record><rec-number>511</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">511</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hirano, I.</author><author>Zhang, Q.</author><author>Pandolfino, J. E.</author><author>Kahrilas, P. J.</author></authors></contributors><titles><title>Four-day Bravo pH capsule monitoring with and without proton pump inhibitor therapy</title><secondary-title>Clinical Gastroenterology and Hepatology</secondary-title></titles><periodical><full-title>Clinical Gastroenterology and Hepatology</full-title></periodical><pages>1083-1088</pages><volume>3</volume><number>11</number><dates><year>2005</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1542-3565</isbn><accession-num>CCC:000234106100009</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000234106100009</url></related-urls></urls><electronic-resource-num>10.1016/s1542-3565(05)00529-x</electronic-resource-num></record></Cite></EndNote>(2005)Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USACase series (prospective)Level: IVQuality: Q2CX (no comparator)P218 patients (17 patients had enough data to be included)6 males, 12 femalesMedian age: 52 yearsIndications:Chest pain, refractory heartburn, laryngeal symptomsInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the endoscopically determined SCJDuration: 4 days Comparator: NAChest pain (none)Dysphagia (none)Bleeding (none)Hochman and Favaloro-Sabatier PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SG9jaG1hbjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2009)Gastrointestinal Associates, Jackson, Mississippi, USACase report (letter to the editor)Level: NA1 patient72 year old maleIndication: Symptoms of gastro-oesophageal refluxInclusion:NAExclusion:NAIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: not statedDuration: not stated2-year retention of the capsule in a giant colonic diverticulumKaramanolis et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Karamanolis</Author><Year>2012</Year><RecNum>268</RecNum><IDText>169-73</IDText><DisplayText>(2012)</DisplayText><record><rec-number>268</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karamanolis, G.</author><author>Triantafyllou, K.</author><author>Psatha, P.</author><author>Vlachogiannakos, I.</author><author>Gaglia, A.</author><author>Polymeros, D.</author><author>Fessatou, S.</author><author>Triantafyllou, M.</author><author>Papanikolaou, I. S.</author><author>Ladas, S. D.</author></authors></contributors><auth-address>Hepatogastroenterology Unit, 2nd Department of Internal Medicine - Propaedeutic, Attikon University General Hospital, Athens Medical School, Athens, Greece.</auth-address><titles><title>Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors</title><secondary-title>J Neurogastroenterol Motil</secondary-title><alt-title>Journal of neurogastroenterology and motility</alt-title></titles><periodical><full-title>J Neurogastroenterol Motil</full-title><abbr-1>Journal of neurogastroenterology and motility</abbr-1></periodical><alt-periodical><full-title>Journal of Neurogastroenterology and Motility</full-title></alt-periodical><pages>169-73</pages><volume>18</volume><number>2</number><edition>2012/04/24</edition><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2093-0887 (Electronic)&#xD;2093-0879 (Linking)</isbn><accession-num>22523725</accession-num><urls><related-urls><url>;(2012)2nd Department of Internal Medicine, Propaedeutic Attikon University General Hospital, Athens, GreeceCase series (prospective?)Level: IVQuality: Q1CX (no comparator)P232 patients18 males, 14 femalesMean age: 45.3 ± 12.5?yearsIndications:Three episodes of non-cardiac chest pain per weekInclusion:Patients with at least three episodes of chest pain per week and normal oesophageal manometry (in order to exclude the presence of any oesophageal motility disorder)Exclusion:Patients that were using aspirin or NSAIDs, a history of upper GI surgery, gastric or duodenal ulcer, connective tissue disease, or severe liver, lung, renal or haematological diseaseIndex test:System: Bravo? wireless capsule systemInsertion: transorally Placement: 6 cm proximal to the SCJDuration: 48 hoursComparator: NAThroat painBack painGlobus sensationKramer & Chokhavatia PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+S3JhbWVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2012)Department of Medicine, the Mount Sinai Medical Center, New York, New York, USACase reportLevel: NA1 patient44 year old maleIndication:History of GORD symptoms, non-adherent to anti-reflux therapyInclusion:NAExclusion:NAIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the GOJComparator: NACapsule dislodging into the pyriform sinusLacy, Chehade & Crowell PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2011)Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USACase seriesLevel: IVQuality: Q1CX (no comparator)P2358 patients (257 females, 101 males)Mean age: 51 ±14?yearsPredominantly (97%) Caucasian Indications: Symptoms thought secondary to GORDInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the GOJ or 5?cm above the upper border of the LOSDuration: 48 hoursComparator: NAChest discomfortLee et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGVlPC9BdXRob3I+PFllYXI+

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ADDIN EN.CITE.DATA (2005)Department of Internal Medicine, Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, TaiwanProspective case seriesLevel: IVQuality: Q3CX (no comparator)P240 patients (27 males and 13 females)Age: range 28–83 yearsIndications:Typical heartburn with unsatisfactory response to therapy (15), erosive oesophagitis and undergoing preoperative evaluation (25)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NARetrosternal discomfortMucosal lesionForeign-body sensationMarchese et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Marchese</Author><Year>2006</Year><RecNum>516</RecNum><IDText>813-818</IDText><DisplayText>(2006)</DisplayText><record><rec-number>516</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">516</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchese, M.</author><author>Spada, C.</author><author>Iacopini, F.</author><author>Familiari, P.</author><author>Shah, S. G.</author><author>Tringali, A.</author><author>Costamagna, G.</author></authors></contributors><titles><title>Nonendoscopic transnasal placement of a wireless capsule for esophageal pH monitoring: feasibility, safety, and efficacy of a manometry-guided procedure</title><secondary-title>Endoscopy</secondary-title></titles><periodical><full-title>Endoscopy</full-title><abbr-1>Endoscopy</abbr-1></periodical><pages>813-818</pages><volume>38</volume><number>8</number><dates><year>2006</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0013-726X</isbn><accession-num>CCC:000240368800009</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000240368800009</url></related-urls></urls><electronic-resource-num>10.1055/s-2006-944526</electronic-resource-num></record></Cite></EndNote>(2006)Digestive Endoscopy Unit, Agostino Gemelli University Hospital, Catholic University of Rome, Rome, ItalyProspective case seriesLevel: IVQuality: Q1CX (no comparator)P240 patients (36 patients had successful oesophageal placement of the capsule)23 males, 17 femalesMean age: 42.5 yearsIndications:Reflux symptoms that were refractory to PPI therapy Inclusion:Patients with reflux symptoms refractory to PPI therapy who had normal or equivocal endoscopic findingsExclusion:Patients with oesophageal varices, previous GI surgery, known coagulopathy or bleeding diathesis, cardiac pacemakers, defibrillators or other electromedical devices, significant comorbidity, pregnant women and patients <18?years of ageIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the upper margin of the LOSDuration: 24 or 48 hoursComparator: NAMild discomfortSevere chest pain(Endoscopic removal of the capsule)EpistaxisPharyngeal irritationNusrat, Roy & Bielefeldt PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TnVzcmF0PC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2012)University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2356 patients (65% females)Mean age: 49.9 ± 0.8?yearsIndications:Evaluations of GORD, recurrent or persistent symptoms after fundoplication, chest pain, unexplained cough or other atypical symptomsInclusion:Not statedExclusion:Patients with pacemakers, implanted cardiac defibrillators, known oesophageal varices, bleeding disorders or ongoing anticoagulationIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the endoscopically localised SCJ or 5?cm above the manometrically determined upper border of the LOSDuration: 48 hoursComparator: NANo significant adverse effects during the studyPandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2003)Northwestern University Feinberg School of Medicine, Chicago, Illinois, USACohort studyLevel: III-2 Quality: 11.5/26CX P344 controls (13 males, 31 females, aged 23–53?years) 41 patients (26 males, 15 females, aged 32–72?years)Inclusion:Not statedExclusion:Controls: abdominal symptoms, use of antacids or antisecretory medication, abnormal endoscopyPatients: history of surgical manipulation of the upper GI tract, history of bleeding diathesis or coagulopathy, stroke or transient ischemic attack in the past 6?months, significant medical illness, oesophageal varicesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJComparator:System: not stated (catheter-based)Insertion: transnasallyPlacement: not statedDuration: 24 hoursForeign-body sensationChest painThroat discomfortLate detachmentOesophageal discomfortEating and drinkingActivitySleep patternsPandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USACase seriesLevel: IVQuality: Q2CX (no comparator)P310 normal control subjects (7 males and 3 females, aged 21–53?years) 10 patients with GORD (6 males and 4 females, aged 20–54?years)Inclusion:Controls: no history of heartburn, reflux, chest pain or atypical symptomsPatients: oesophagitis (3) or an abnormal 24-hour oesophageal pH study prior to this studyExclusion:History of surgical manipulation of the upper GI tract, anticoagulation therapy, significant medical diseaseControls: abdominal symptoms, use of antacids, abnormal upper endoscopyIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 1 cm proximal to SCJDuration: 24 hoursComparator: NAChest discomfortForeign-body sensationPrakash et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UHJha2FzaDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P28 patients (who required endoscopic dislodgement because of severe discomfort) out of 452 patients6 females, 2 malesMean age: 44.5 years (range 29–67)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: not statedDuration: not statedComparator: NASevere discomfortSevere chest pain and/or odynophagiaForeign-body sensationRemes-Troche et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UmVtZXMtVHJvY2hlPC9BdXRo

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran, Mexico City, MexicoProspective case seriesLevel: IVQuality: Q1CX (no comparator)P284 patients (77 patients had enough data to be included)49 females, 35 malesMean age: 44 ± 12?years (range 19–73)Indications:Persistent GORD symptoms on PPI, preoperative evaluation before surgery, previous failed transnasal pH monitoring, extraoesophageal GORDInclusion:Consecutive patients with GORD symptoms with an indication for 24-hour pH monitoringExclusion:Patients with surgical manipulation of the upper GI tract, bleeding diathesis or coagulopathy, severe GI bleeding in the past 6?months, oesophageal varices, significant comorbiditiesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NAChest painForeign-body sensationNauseaRenteln et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UmVudGVsbjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2008)Department of Gastroenterology, Hepatology and Oncology, Klinikum Ludwigsburg, Ludwigsburg, GermanyCase reportLevel: NA One 44 year old patientIndication: Evaluation of atypical GORD symptomsInclusion:NAExclusion:NAIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the upper margin of the LOSDuration: NAComparator: NARetchHeavy coughDropped oxygen saturationCapsule aspirationScarpulla et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U2NhcnB1bGxhPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2007)Department of General, Visceral, and Transplant Surgery, University Hospital of Tubingen, Tubingen, GermanyNon-randomised controlled trialLevel: III-2Quality: 9/26CXP3123 patientsBravo group: 36 males and 32 females, mean age: 51?years (range 34–67)Catheter group: 29 males and 26 females, mean age 43?years (range 32–59)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 5 cm above the upper border of the LOSDuration: 48 hoursComparator:System: not statedInsertion: transnasallyPlacement: not statedDuration: 24 hoursThroat discomfortOesophageal discomfortLimitation in daily activitiesShahid & Fisher ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Shahid</Author><Year>2011</Year><RecNum>542</RecNum><IDText>S378-S379</IDText><DisplayText>(2011)</DisplayText><record><rec-number>542</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">542</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shahid, S.</author><author>Fisher, R.</author></authors></contributors><auth-address>Shahid, S., Gastroenterology, Temple University Hospital, PhiladelphiaUnited States</auth-address><titles><title>Left, right and out: Esophageal probe aspiration</title><secondary-title>American Journal of Gastroenterology</secondary-title></titles><periodical><full-title>American Journal of Gastroenterology</full-title></periodical><pages>S378-S379</pages><volume>106</volume><keywords><keyword>proton pump inhibitor</keyword><keyword>aspiration</keyword><keyword>gastroenterology</keyword><keyword>college</keyword><keyword>human</keyword><keyword>patient</keyword><keyword>pH</keyword><keyword>coughing</keyword><keyword>esophagus pH</keyword><keyword>bronchus</keyword><keyword>endoscopy</keyword><keyword>bronchoscopy</keyword><keyword>endoscope</keyword><keyword>esophagus mucosa</keyword><keyword>esophagus</keyword><keyword>stomach</keyword><keyword>dental anesthesia</keyword><keyword>vital sign</keyword><keyword>thorax</keyword><keyword>intensive care unit</keyword><keyword>thorax radiography</keyword><keyword>anesthesiology</keyword><keyword>heartburn</keyword><keyword>female</keyword><keyword>thorax pain</keyword><keyword>conscious sedation</keyword><keyword>duodenum</keyword></keywords><dates><year>2011</year></dates><isbn>0002-9270</isbn><urls><related-urls><url>;(2011)Gastroenterology, Section, Temple University Hospital, Philadelphia, Pennsylvania, USACase report1 patient 61 year old femaleIndication: History of heartburn, regurgitation and intermittent chest pain, unresponsive to PPI therapyInclusion:NAExclusion:NAIndex testSystem: Bravo? wireless capsule systemInsertion: transorallyPlacement: not statedComparator: NACapsule dislodgement in the left mainstem bronchusSofi et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Sofi</Author><Year>2011</Year><RecNum>540</RecNum><IDText>243-248</IDText><DisplayText>(2011)</DisplayText><record><rec-number>540</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">540</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sofi, A.</author><author>Filipiak, C.</author><author>Sodeman, T.</author><author>Ahmad, U.</author><author>Bawany, M.</author><author>Daboul, I.</author></authors></contributors><auth-address>Department of Gastroenterology, University of Toledo Medical Center, Toledo, OH, United States</auth-address><titles><title>Comparison of esophageal placement of Bravo capsule system under direct endoscopic guidance with conventional placement method</title><secondary-title>Turkish Journal of Gastroenterology</secondary-title></titles><periodical><full-title>Turkish Journal of Gastroenterology</full-title></periodical><pages>243-248</pages><volume>22</volume><number>3</number><keywords><keyword>Bravo capsule</keyword><keyword>Direct/indirect</keyword><keyword>Technique</keyword></keywords><dates><year>2011</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(2011)Department of Gastroenterology, University of Toledo Medical Center, Toledo, Ohio, USARetrospective case series58 patientsAge range: 26– 87?years17 males, 41 femalesInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the GOJComparator: NASevere chest painThroat painDysphagiaCoughWork attendanceSweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2009)Functional GI Disease Unit, Clinic for Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland Cohort study Level: III-2 Quality: 15/26CXP1134 patients Mean age: 60?years (range 18–76) 58 males, 76 females Compared with 110 consecutive catheter pH controlsMean age: 57?years (range 16–85) 44 males, 66 femalesIndications:Intolerance of catheter insertion, intolerance of catheter after intubation, or vomiting of catheter within 24?hours of the monitoring periodInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursComparator:System: Slimline, MedtronicInsertion: transnasallyPlacement: 5 cm above the lower oesophageal high-pressure zoneDuration: 24 hoursOverall satisfactionSweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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Tm90ZT4A

ADDIN EN.CITE.DATA (2011)Guy’s and St Thomas Hospitals, London, UKCase series Level: IVQuality: Q2CX P238 patients13 males, 25 femalesMedian age: 41.6?years (range 17–75)Indication: Reflux symptoms and no diagnosis of GORD on catheter-based pH monitoringInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 96 hoursComparator: NANo patient complained of severe symptomsTankurt et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VGFua3VydDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Kent Hospital, Department of Gastroenterology, Izmir, TurkeyCase seriesLevel: IVQuality: Q2CX (no comparator)P264 patients (37 males, 27 females)Mean age: 37.9?years (range 25–58)Indications: Preoperative evaluation (17), evaluation of atypical reflux symptoms (40) and ‘other’ (7)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NARetrosternal pain or discomfortTharavej et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VGhhcmF2ZWo8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2006)Division of Thoracic and Foregut Surgery, Department of Surgery, University of Southern California, Los Angeles, California, USACase seriesLevel: IVQuality:Q1CX (no comparator)P280 patients (40 in control group and 40 in study group)Study group:15 males and 25 females; mean age 45.5?years (range 40–53) Control group: 15 males and 25 females; mean age 49?years (range 44–63) Inclusion:Consecutive patients with gastro-oesophageal reflux symptomsExclusion:Patients with a history of achalasia, benign or malignant stricture, or a previous oesophageal or gastric surgeryIndex test:System: Bravo? wireless capsule systemInsertion: transorally (study group) or transnasally (control group)Placement: 6 cm above the upper limit of the rugal folds (study group) or 5?cm above the upper border of the LOSDuration: 48 hoursComparator: NAHigh distal oesophageal contraction amplitudeChest painHypertensive oesophageal contractionsTriester et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VHJpZXN0ZXI8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2005)Digestive Health Center, Department of Surgery and Division of Gastroenterology, Oregon Health and Science University, Portland, Oregon, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2190 procedures and 186 patients (some patients had the test performed twice) 72 males and 114 femalesMean age: 51 yearsIndications: Being evaluated for GORDInclusion:Patients older than 18?years of ageExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5– 6 cm above the LOS or 5–6?cm above the SCJ Duration: 48 hoursComparator:24-hour Bravo monitoringSevere gagging during placementForeign-body sensationChest painTu et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Tu</Author><Year>2004</Year><RecNum>527</RecNum><IDText>1586-1589</IDText><DisplayText>(2004)</DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tu, C. H.</author><author>Lee, Y. C.</author><author>Wang, H. P.</author><author>Wu, M. S.</author><author>Chiu, H. M.</author><author>Lin, J. T.</author></authors></contributors><titles><title>Ambulatory esophageal pH monitoring by using a wireless system: A pilot study in Taiwan</title><secondary-title>Hepato-Gastroenterology</secondary-title></titles><periodical><full-title>Hepatogastroenterology</full-title><abbr-1>Hepato-gastroenterology</abbr-1></periodical><pages>1586-1589</pages><volume>51</volume><number>60</number><dates><year>2004</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><isbn>0172-6390</isbn><accession-num>CCC:000224607400004</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000224607400004</url></related-urls></urls></record></Cite></EndNote>(2004)Department of Internal Medicine and Department of Emergency Medicine, National Taiwan University Hospital, Taipei, TaiwanProspective case seriesLevel: IVQuality: Q1CX (no comparator)P230 patients20 males, 10 femalesMean age: 57.6 ± 14.3?years (range 29–83)Indications: 24 patients with GORD were evaluated for drug effectiveness before surgery, 6 patients showed typical heartburn but their endoscopic findings were normal.Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the GOJDuration: 48 hoursComparator: NAMucosal abrasion and minor haemorrhageTurner et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Turner</Author><Year>2007</Year><RecNum>536</RecNum><IDText>737-741</IDText><DisplayText>(2007)</DisplayText><record><rec-number>536</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">536</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turner, B. G.</author><author>Saltzman, J. R.</author><author>Hua, L.</author><author>Maurer, R.</author><author>Feldman, N.</author><author>Carr-Locke, D. L.</author><author>Burakoff, R.</author><author>Liu, J. J.</author></authors></contributors><titles><title>Endoscopic pH monitoring for patients with suspected or refractory gastroesophageal reflux disease</title><secondary-title>Canadian Journal of Gastroenterology</secondary-title></titles><periodical><full-title>Canadian Journal of Gastroenterology</full-title></periodical><pages>737-741</pages><volume>21</volume><number>11</number><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0835-7900</isbn><accession-num>CCC:000251481000008</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000251481000008</url><url>;(2007)Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, USACase seriesLevel: IVQuality: Q2CX (no comparator)P2198 pH studies (148 studies had enough data to be included)Off medical therapy: 115 patients, 76 females, 39 males; mean age: 50 ± 13?yearsOn medical therapy: 33 patients, 26 females, 7 males; mean age: 52 ± 14?yearsIndications: Typical and atypical symptoms of GORD or persistent GORD-related symptoms despite medical therapy. Patients with planned anti-reflux surgery were also evaluatedInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: (during endoscopy)Placement: 6 cm above the SCJDuration: 48 hoursComparator: NAChest pain requiring capsule removalWenner, Johnsson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2007)Department of Surgery, Lund University Hospital, Lund, SwedenRandomised crossover trialLevel: IIQuality: 20/26CXP235 patients (31 patients had enough data to be included)15 males, 16 femalesMedian age: 52 yearsMedian BMI: 27 (range 24–28)Indications: Typical reflux symptoms (55%) and atypical reflux symptoms (45%)Inclusion:Patients referred for oesophageal pH monitoring Exclusion:Patients with coagulopathy, severe oesophagitis/stricture, portal hypertension, a pacemaker, age <20 or >70?years, previous gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline (Medtronic) Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursNose and/or throat symptomsSwallow-induced symptomsChest symptomsAll adverse symptomsNormal work activitiesPhysical activitiesEating and drinkingNormal daily lifeWong et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V29uZzwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2005)The Neuro-Enteric Clinical Research Group, Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System and University of Arizona Health Sciences Center, Tucson, Arizona, USARandomised controlled trialLevel: IIQuality: 16.5/26CXP250 patients Mean age: 50.2?years (range 21–79)26 males and 24 femalesIndication: Failure in controlling symptoms while on PPI therapy or for evaluation before anti-reflux surgeryInclusion:Not statedExclusion:Patients with a history of bleeding tendency or coagulopathy, significant concomitant medical co-morbidity, severe GI bleeding within the past 6?months, a history of upper GI surgery, oesophageal varices, pacemaker, implantable cardiac defibrillator, being unable to complete the 24-hour pH monitoring, unable to report daily activityIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursComparator:System: Digitrapper Mark III (Medtronic)Insertion: transnasallyPlacement: 5 cm above the proximal margin of the LOS Duration: 24 hoursNose painRunny noseThroat painThroat discomfortCoughChest discomfortHeadacheNose bleedingWorkEating and drinkingDaily activitiesOverall experience with the testSatisfaction with the testStudy profiles of included studies on direct effectivenessDirect evidenceStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / Exclusion criteriaDiagnostic testsHealth outcomes assessedGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2011)Department of Gastroenterology, Universita Degli Studi and Fondazione IRCCS Ca Granada, Ospedale Maggiore Policlinico, Milan, ItalyMatched-pairs retrospective cohort studyLevel: III-2 Quality: 16.5/26CXP2102 patientsCatheter group: 51 patients, 20 males, mean age 48?years (range 22–78) Bravo group: 51 patients, 22 males, mean age 48?years (range 23–82)Inclusion:All consecutive patients who underwent wireless 96-hour pH monitoring between January and December 2007 off PPI therapy, and patients undergoing traditional 24-hour pH monitoring in the same period, after matching for the most troublesome symptom potentially related to GORD, sex and ageExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJDuration: 48–96 hoursComparator:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach or 5?cm above the upper margin of the LOS Duration: 24 hoursOutcome of the principal symptom Sweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2011)Guy’s and St Thomas Hospitals, London, UKCase series Level: IVQuality: Q2CX P238 patients13 males, 25 femalesMedian age: 41.6?years (range 17–75)Indication: Reflux symptoms and no diagnosis of GORD on catheter-based pH monitoringInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 96 hoursComparator:(24-, 48-, 72-hour Bravo pH monitoring)Improvement in symptoms / poor outcome (with 24-, 48-, 72-hour Bravo as a comparator)Technical efficacyStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / Exclusion criteriaDiagnostic testsTechnical efficacy outcomes assessedAhlawat et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QWhsYXdhdDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Department of Medicine, Georgetown University Hospital, Washington, DC, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P290 patients (82 patients had enough data to be included)48 males and 42 femalesAge range: 18–80 yearsIndications:Being intolerant to the conventional naso-oesophageal pH catheter placement or had normal 24-hour oesophageal pH monitoring despite symptomsInclusion:Not statedExclusion:Patients with bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers, implantable cardiac defibrillators, and surgical manipulations of the upper Gl tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursComparator: NATechnical efficacy:Technical failureDay-to-day variability (% time pH <4)Andrews et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QW5kcmV3czwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2012)Division of Gastroenterology, University of Calgary, CanadaDual centre, randomised non-blinded trialLevel: IIQuality: 19/26CX P286 patients(40 in Calgary and 46 in Edmonton)61 females, 25 malesAged 18–75 yearsIndications:Reflux symptomsChest painDysphagia Inclusion:Patients aged 18–75 years referred for ambulatory pH monitoring between August 2008 and August 2009Exclusion:Patients with previous oesophageal surgery or achalasiaIndex test:System: activated and calibrated Bravo? wireless capsule system, Medtronic Inc., Minneapolis, MNInsertion: transorally Placement: 5 cm above the proximal border of the LESDuration: 24 (Calgary) or 48 (Edmonton) hoursComparator:Catheter: calibrated standard antimony-based pH catheter (Comfortec Plus catheter and ZepHR Sleuth recorder, Sandhill Scientific Inc., Highlands Ranch, CO)Insertion: transnasallyPlacement: 5 cm above the proximal border of the LOSDuration: 24 hoursTechnical efficacy:Equipment malfunctionCalibration failureEarly detachmentInsertion intolerance Ayazi et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXlhemk8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2011)Division of Thoracic Foregut Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, California, USACase seriesLevel: IVQuality: Q1CX (no comparator)P2310 patients (158 males and 152 females)Median age: 52?years (IQR=42–63)Inclusion:Patients with no history of foregut surgery who had the Bravo capsule placed transnasally without sedation and who were monitored while off acid-suppression therapyExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the manometrically determined border of the LOSDuration: 48 hoursComparator: NATechnical efficacy:Day-to-day variability (% time pH <4 and reflux events)Azzam et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXp6YW08L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2012)Sao Paulo University Medical School, Sao Paulo, BrazilIn-subject simultaneous recording studyLevel: II Quality: 17/26CX P225 patients21 females, 4 malesMean age: 52.4 years (range 34–73)Indications:All patients had as predominant symptom the typical GORD complaints; 64% also had atypical complaints and 76% had associated extra oesophageal complaintsInclusion:Heartburn and/or regurgitation as the main clinical complaint; at least 18?years of age; recent upper GI endoscopy (within the past 2?months); interruption in the administration of PPIs for 7?days; and signature on the free and informed consent formExclusion:Oesophageal diverticula; strictures and varices; hiatal hernia greater than or equal to 3?cm; erosive oesophagitis Los Angeles grades C or D; Barrett’s oesophagus; neoplasms; obstructive diseases; previous surgery of the GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 3 cm above the superior border of the LOSDuration: 48 hoursComparator:System: Alacer (Brazil) pH-monitor catheter with Medtronic/Synetics (USA) recording deviceInsertion: transnasallyPlacement: distal sensor was placed 3?cm above the superior border of the LOS, proximal sensor was positioned 5?cm above the superior border of the LOSDuration: 24 hoursTechnical efficacy:Early detachment Bansal et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmFuc2FsPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2009)Divisions of Gastroenterology and Hepatology, University of Kansas School of Medicine and Veterans Affairs Medical Center, Kansas City, Missouri, USACase seriesLevel: IVQuality: Q1 CXP248 patients (43 males, 5 females) and 22 controls (22 males)Mean age:Patients: 57 ± 13?yearsControls: 59 ± 9?yearsIndication: Patients: reflux symptomsInclusion:Patients: answering ‘yes’ to either heartburn or regurgitation, having a score of >2 on the RDQControls: answering ‘no’ to heartburn and regurgitation, having a score of 0 on the RDQExclusion:Patients: cancer or mass lesion in the oesophagus, advanced chronic liver disease, severe uncontrolled coagulopathy, history of oesophageal or gastric surgeryControls: use of acid suppression, evidence of erosive oesophagitisIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 1 cm above the GOJDuration: 24 hoursIndex test 2:System: Bravo? wireless capsule systemInsertion: NS Placement: 6 cm above the GOJ Duration: 24 hoursComparator: NATechnical efficacy:Early detachmentCardia placementLoss of dataBechtold et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmVjaHRvbGQ8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2007)Division of Gastroenterology, University of Missouri Hospital and Clinics, Columbia, Missouri, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P227 patients (26 patients had enough data to be included)6 males and 20 femalesMean age: 47.6 ± 12.2?years (range 15–67)Inclusion:Patients who underwent 48-hour Bravo ambulatory oesophageal pH monitoring for suspected GORD off any anti-reflux medicationsExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the GOJComparator: NATechnical efficacy:Early detachmentDay-to-day variability (time pH <4 (upright, supine, total), number of reflux episodes, long refluxes etc.)Belafsky et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmVsYWZza3k8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2004)Scripps Center for Voice and Swallowing, La Jolla, California, USAProspective case seriesLevel: IVQuality: Q2CX (no comparator)P246 patients23 males and 23 femalesMean age: 52 yearsIndications: GORD, chronic cough, laryngopharyngeal reflux Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the manometric lower oesophageal high-pressure zone or 6?cm above the endoscopic SCJDuration: >36 hoursComparator: NATechnical efficacy:Failures due to tight nasal vaultEarly detachment rateDelivery system failure rateLost recorder rateBhat, McGrath & Bielefeldt PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmhhdDwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2006)Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAProspective case seriesLevel: IVQuality: Q2CX (no comparator)P2217 patients(203 patients had enough data to be included)140 females, 77 malesMean age: 51?years (range 42–58)Indications:Preoperative workup for fundoplication, possible extra oesophageal manifestations of reflux disease, symptoms after fundoplication, refractory symptoms on medication, atypical symptomsInclusion:Adult patients undergoing endoscopy with wireless pH studies at the University of Pittsburgh Medical Center between 9 April 2004 and 31 March 2005Exclusion:Individuals unable to give informed consent, pregnant women, prisoners, patients with oesophageal varices, patients requiring continuing anticoagulation, patients with cardiac defibrillatorsIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Operative failure ratesEarly detachment rateDay-to-day variabilityBradley et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QnJhZGxleTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USACohort studyLevel: III-2Quality: 15/26CXP2341 patients (338 patients had enough data to be included, 248 patients underwent Bravo monitoring)62% females in the wireless group, 72% females in the catheter groupMean age: 58?years in wireless group, 57?years in catheter groupInclusion:Outpatients undergoing ambulatory pH-metry between October 2006 and October 2008Exclusion:Known history of oesophageal strictures, obstructions or surgical manipulations of the upper GI tract (e.g. anti-reflux surgery or oesophagectomy)Index test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJ or 5?cm above the upper border of the LOSDuration: 48 hoursComparator (MII-pH):System: Sandhill Scientific, Inc., Highland Ranch, USAInsertion: transnasallyPlacement: proximal channel 5?cm above upper border of the LOSDuration: 24 hoursComparator (pH-metry):System: Alpine Biomed, Corp, Fountain Valley, US Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursTechnical efficacy:Early detachmentInsertion intolerance Endoscopic removalCabrera et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2FicmVyYTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana, USAProspective case seriesLevel: IVQuality: Q1CX (no comparator)P2289 children (At least 1?day of data was obtained in 278 patients, 2?days were obtained in 274 patients)144 females, 145 males,Age: range 4–22 yearsMain indications:Epigastric abdominal pain (59.9%), vomiting (33.9%), regurgitation (23.9%), heartburn (18.3%)Inclusion:Children who are at least 4?years of age and weigh at least 30?lbExclusion:Children with a history of oesophageal surgery, a documented anatomic abnormality, or a history of coagulopathy or a bleeding diathesisIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: at 87% of the distance from the incisors to the Z lineDuration: 48 hoursComparator: NATechnical efficacy:Early detachmentOperative success/failureRecording failuresChander et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhbmRlcjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2012)Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2124 patients 87 females, 37 malesAge range: 24–68?yearsIndications: Heartburn, regurgitation, chest pain, belching or cough. And a previous negative EGD and symptoms despite PPI treatmentInclusion:See indicationsExclusion:Patients with a history of pacemakers, implantable defibrillators, oesophageal varices, severe oesophagitis, bleeding disorders, intestinal obstructionIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the GOJDuration: 48 hoursComparator: NA Technical efficacy:Day-to-day variability in acid exposure Croffie et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q3JvZmZpZTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2007)Section of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana, USARandomised controlled trialLevel: IIQuality:14.5/26CXP266 children(but 5 patients were excluded due to operative failure, failed recording etc.)32 males, 34 femalesMean age: 9.4 years (range 4–16.5)Indications:Persistent epigastric or substernal pain, persistent vomiting, heartburn, chronic nocturnal cough or wheezing, persistent throat clearance, dental abnormalities suspected to be caused by refluxInclusion:Children between the ages of 4 and 18?years and weighing at least 30?lb who were undergoing oesophagogastroduodenoscopy and oesophageal pH monitoring for symptoms suggestive of gastro-oesophageal refluxExclusion:Children younger than 4?years of age or weighing <30?lb, having anatomic abnormalities of the oesophagus, a history of a surgical procedure of the oesophagus, stomach or duodenum, a history of coagulopathy or bleeding diathesis, presence of oesophageal varices, significant medical illnessIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: at 87% of the distance from the incisors to the Z lineDuration: 48 hoursComparator:System: not stated (catheter-based)Insertion: transnasallyPlacement: tip at 87% of the distance from the nostril to the GOJDuration: 24 hoursTechnical efficacy:Operative successRecording failuresEarly detachmentDay-to-day variability in acid exposureCrowell et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q3Jvd2VsbDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2009)Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USACase seriesLevel: IVQuality: Q1CX (no comparator)P2157 (>95%) patients, predominantly Caucasian Indications: Heartburn/regurgitation symptoms, chest pain, abdominal pain/discomfort Inclusion:Patients with GORD symptomsExclusion:History of bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers or implantable cardiac defibrillatorsIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the endoscopically determined GOJ or 5?cm above the manometrically determined upper margin of the LOS Duration: 48 hoursComparator: NATechnical efficacy:Day-to-day variabilityEarly detachmentde Hoyos & Esparza (2010); de Hoyos, Esparza & Loredo (2009) Department of Gastroenterology, Angeles del Pedregal Hospital, Mexico City, MexicoProspective case seriesLevel: IVQuality: Q2CX (no comparator)P266 patients27 males, 39 femalesMean age: 41.7 years (range 11–73)Indications:Typical oesophageal reflux symptoms, atypical manifestations or a mixed symptomatologyInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm from the SCJDuration: 48 hoursComparator: NATechnical efficacy:Poor data receptionEarly detachmentTransmission failuredes Varannes et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+ZGVzIFZhcmFubmVzPC9BdXRo

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology and Hepatology, Hopital Hotel Dieu, Nantes, FranceIn-subject simultaneous recording studyLevel: II Quality: 20/26CXP240 patients(probe successfully attached in 36 patients)21 males, 19 femalesMean age: 50 yearsIndications:Heartburn (n=7), regurgitation (n=6) or both symptoms (n=26)Inclusion:Patients suggestive of GORD and referred to the functional laboratory of four French academic centres for pH monitoringExclusion:Severe oesophageal motility disorders, severe oesophagitis (Los Angeles grade C or above), pregnancy, women who were not using reliable contraceptionIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the Z lineDuration: 48 hoursComparator:System: Mark III or Digitrapper pH, Medtronic, Stockholm, SwedenInsertion: transnasallyPlacement: adjusted to the same level as the index testDuration: 24 hoursTechnical efficacy:Insertion intoleranceOperative failureEarly detachmentDay-to-day variabilityDoma et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Doma</Author><Year>2010</Year><RecNum>225</RecNum><DisplayText>(2010)</DisplayText><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Doma, S.</author><author>Paladugu, S.</author><author>Parkman, H. P.</author><author>Friedenberg, F. K.</author></authors></contributors><auth-address>Gastroenterology Section, Temple University School of Medicine, Philadelphia, PA 19140, USA.</auth-address><titles><title>Wireless capsules for esophageal pH monitoring: are we placing them correctly?</title><secondary-title>Digestion</secondary-title><alt-title>Digestion</alt-title></titles><periodical><full-title>Digestion</full-title></periodical><alt-periodical><full-title>Digestion</full-title></alt-periodical><pages>54-9</pages><volume>82</volume><number>1</number><edition>2010/03/11</edition><keywords><keyword>Analysis of Variance</keyword><keyword>Capsule Endoscopy</keyword><keyword>Chi-Square Distribution</keyword><keyword>Esophageal pH Monitoring/ instrumentation</keyword><keyword>Esophagus/ anatomy &amp; histology</keyword><keyword>Female</keyword><keyword>Gastroesophageal Reflux/ physiopathology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Manometry</keyword><keyword>Medical Errors/ statistics &amp; numerical data</keyword><keyword>Middle Aged</keyword><keyword>Monitoring, Ambulatory/ instrumentation</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2010</year></dates><isbn>1421-9867 (Electronic)&#xD;0012-2823 (Linking)</isbn><accession-num>20215751</accession-num><urls><related-urls><url>;(2010)Gastroenterology Section, Temple University School of Medicine, Philadelphia, Pennsylvania, USACase series (prospective?)Level: IVQuality: Q1CX (no comparator)P2161 patients, but 147 patients had enough data to be included (44 males, 103 females)Age: 45.6 ± 16?yearsMost common indications: Heartburn (44.2%), chest pain (19.7%), cough (4.1%), regurgitation (8.8%) Inclusion:Not statedExclusion: Prior upper GI tract surgeryIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 6 cm above the SCJComparator: NATechnical efficacy:Inaccurate placement of the capsuleDomingues, Moraes-Filho & Domingues PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RG9taW5ndWVzPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2011)Motility laboratory (Gastro Resolucao Diagnostico Laboratorio de Motilidade Digestive), Rio de Janeiro, BrazilRetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P2100 patients(probe successfully attached in 95 patients)39 female, 61 maleMean age: 53 years (range 18– 81)Indications:82% of patients referred to diagnose GORD, 18% referred due to persistent symptoms despite PPI useInclusion:Patients referred to a GI motility laboratory to investigate GORD with typical or atypical symptoms, persistent GORD symptoms on medical therapy or recurrent GORD symptoms after surgical fundoplication, between 2004 and 2009Exclusion:<18 years of age, a history of bleeding tendency or coagulopathy, significant concomitant medical co-morbidities, severe GI bleeding in the past 6?months, a history of upper GI surgery, medication with PPIs, presence of oesophageal varices, Barrett’s oesophagus, oesophageal stenosis, erosive oesophagitis, pacemaker or implantable cardiac defibrillator in situIndex test:System: Bravo? wireless capsule systemInsertion: 5 cm above the upper border of the LOS (manometry) or 6?cm above the LOS (endoscopy)Placement: transorallyDuration: 48 hoursComparator: NATechnical efficacy:Attachment failureTechnical flaws (recording failure, downloaded data lost etc.)Early detachmentDay-to-day variability in oesophageal acid exposureFrancis, DL ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Francis</Author><Year>2008</Year><RecNum>235</RecNum><IDText>2663</IDText><DisplayText>(2008)</DisplayText><record><rec-number>235</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">235</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, D. L.</author></authors></contributors><titles><title>Attachment disorder: a decline in the performance of the Bravo pH system</title><secondary-title>Am J Gastroenterol</secondary-title><alt-title>The American journal of gastroenterology</alt-title></titles><periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></periodical><alt-periodical><full-title>Am J Gastroenterol</full-title><abbr-1>The American journal of gastroenterology</abbr-1></alt-periodical><pages>2663</pages><volume>103</volume><number>10</number><edition>2008/10/16</edition><keywords><keyword>Endoscopes, Gastrointestinal</keyword><keyword>Equipment Failure</keyword><keyword>Esophageal pH Monitoring/ instrumentation</keyword><keyword>Esophagus/ physiopathology</keyword><keyword>Gastroesophageal Reflux/ diagnosis/physiopathology</keyword><keyword>Humans</keyword><keyword>Peristalsis/ physiology</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>18855870</accession-num><urls><related-urls><url>;(2008)Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P276 patientsInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Technical failure to capture all dataEarly detachmentAttachment failureFrancis, DO et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Francis</Author><Year>2012</Year><RecNum>236</RecNum><IDText>91-97</IDText><DisplayText>(2012)</DisplayText><record><rec-number>236</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">236</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, D. O.</author><author>Sumner, E.</author><author>Goutte, M.</author><author>Slaughter, J. C.</author><author>Garrett, C. G.</author><author>Hagaman, D.</author><author>Vaezi, M. F.</author></authors></contributors><titles><title>Feasibility of Dual Wireless Esophageal pH Monitoring: Randomized Blinded Sham-Controlled Trial</title><secondary-title>Otolaryngology-Head and Neck Surgery</secondary-title></titles><periodical><full-title>Otolaryngology-Head and Neck Surgery</full-title></periodical><pages>91-97</pages><volume>147</volume><number>1</number><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0194-5998</isbn><accession-num>CCC:000314267600016</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000314267600016</url><url>;(2012)Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USARandomised blinded controlled trialLevel: II Quality: 16/26C1P222 patients were included (13 males, 9 females)Indications:Cough, hoarseness, globus, heartburn, regurgitationInclusion:Patients >18 years of age, scheduled for planned oesophagogastroduodenoscopy and wireless pH monitoring for physiologic assessment of oesophageal acid exposure for typical GORD symptoms or for extraoesophageal reflux (EER) symptomsExclusion:History of upper oesophageal surgery, bleeding dyscrasia, recent cerebrovascular accident or transient ischemic attack, recent GI haemorrhage <6?months, oesophageal varices or significant medical illness, current pregnancyIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 16 cm above the SCJDuration: 48 hoursComparator (other half of randomisation):No monitoring (a sham capsule placement)Comparator 2: Initial test (whole population):System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJDuration: 48 hoursTechnical efficacy:Operative successGarrean et al. 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ADDIN EN.CITE.DATA (2007)Departments of Upper Gastrointestinal Surgery and Gastrointestinal Physiology, Royal Berkshire hospital, Reading, UKNon-randomised Controlled trialLevel: III-2 Quality: 13.5/26CXP2185 patients, but 200 oesophageal pH studies104 males, 81 femalesMean age: Catheter group: 46?years (range 16–71)Bravo group: 45?years (range 13–75)Indication: Symptoms suggestive of GORD or documenting the outcome of laparoscopic anti-reflux surgeryInclusion:See indicationExclusion:No specific exclusion criteria existIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursComparator:System: MedtronicInsertion: transnasallyPlacement: 5 cm above the proximal border of the LOSDuration: 24 hoursTechnical efficacy:Attachment failuresTechnical failures (recording failures etc.)Early detachmentDay-to-day variabilityGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2007)Gastroenterology, Department of Medical Sciences, University of Milan, Milan, ItalyPseudo-randomised controlled trialLevel: III-1Quality: 13.5/26CXP2133 patientsCatheter group: 78 patients, 46% males, aged 53 ± 2?yearsBravo group: 55 patients, 45% males, aged 44 ± 3?years)Indication: Suspected GORD, consecutively referred for oesophageal pH monitoringInclusion:See indicationExclusion:Previous GI surgery (excluding cholecystectomy and appendectomy) and known or suspected stricture of the GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach, or 5?cm above the upper margin of the LOS Duration: 24 hoursTechnical efficacy:Early detachmentTechnical failureRecording timeDay-to-day variabilityGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2011)Department of Gastroenterology, Universita Degli Studi and Fondazione IRCCS Ca Granada, Ospedale Maggiore Policlinico, Milan, ItalyOne arm of matched pairs retrospective cohort studyLevel: IV Quality: Q2CX (no comparator)P2Bravo group: 57 patients, of which 51 had enough data to be included 22 males, mean age 48?years (range 23–82)Inclusion:All consecutive patients who underwent wireless 96-hour pH monitoring between January and December 2007 off PPI therapy, and patients undergoing traditional 24-hour pH monitoring in the same period, after matching for the most troublesome symptom potentially related to GORD, sex and ageExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJDuration: 48–96 hoursComparator:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach, or 5?cm above the upper margin of the LOS Duration: 24 hoursTechnical efficacy:Early detachmentIncomplete data capture Gunnarsdottir, Stenstrom & Arnbjornsson PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3VubmFyc2RvdHRpcjwvQXV0

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ADDIN EN.CITE.DATA (2007, 2008)Department of Paediatric Surgery, Lund University Hospital, Lund, SwedenCase seriesLevel: IVQuality: Q1CX (no comparator)P258 children37 males, 21 females Mean age: 8 ± 4?yearsIndications:Vomiting, abdominal and chest pain, GORD control, GI bleeding, respiratory symptomsInclusion:Not statedExclusion: Oesophageal strictures, coagulopathy, any suspicion of intestinal stricturesIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: above the diaphragm valve at the width of two of the individual patient’s vertebral bodies as visualised on a perioperative X-rayDuration: 24 or 48 hours (23 children had 48-hour measurement)Comparator: NA Technical efficacy:Attachment failureTechnical failureDay-to-day variability in oesophageal acid exposureHakanson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SGFrYW5zb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2009)Department of Surgery, Center of Gastrointestinal Disease, Ersta Hospital, Stockholm, SwedenCase-control study with in-subject simultaneous recordingLevel: III-2Quality: 14/26CXP253 volunteers and 55 patients (45 volunteers and 47 patients had enough data to be included)30 females and 15 males in volunteer group27 females and 20 males in patient groupMean age: Volunteers: 47?years (range 21–68)Patients: 50?years (range 23–69)Indication: Patients had symptoms including mainly heartburn, acid regurgitation, and chest or epigastric painInclusion:Patients: referred to the clinic for investigation of GORDExclusion:Volunteers: history of GORD or any other pathology of the upper GI tract, taking acid-suppressing agents or medication known to affect GI motilityIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJ Duration: 48 hoursComparator:System: Slimline, Medtronic, Skovlunde, DenmarkInsertion: transnasallyPlacement: 5 cm proximal to the upper border of the LOSDuration: 24 hoursTechnical efficacy:Attachment failureEarly detachmentTechnical failure (recording failures etc.)Day-to-day variability in oesophageal acid exposureHochman and Favaloro-Sabatier PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SG9jaG1hbjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2005)Children’s Center for Digestive Health Care, Atlanta, Georgia, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P250 patients (44 patients had enough data to be included)27 males, 17 femalesMean age: 11.8?years (range 6–19)Inclusion: Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the proximal border of the LOSDuration: 48 hoursComparator: NATechnical efficacy:Early detachmentAttachment failureDay-to-day variability in oesophageal acid exposureIqbal et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SXFiYWw8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2007)Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2100 patients58 females, 42 malesMean age:Women: 40 ± 14 yearsMen: 42 ± 16 yearsInclusion:Consecutive patients with GORD symptoms and undergoing Bravo pH monitoring over a 1-year periodExclusion:Patients with surgical history of the upper GI tract, bleeding diathesis or coagulopathy, oesophageal strictures, severe GI bleeding in the past 3?months, advanced cirrhosis or significant comorbiditiesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJComparator: NATechnical efficacy:Early detachmentKorrapati et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+S29ycmFwYXRpPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2011)Department of Gastroenterology and Hepatology, Winthrop University Hospital, Mineola, New York, USARetrospective case seriesLevel: IVQuality: Q2CX (no comparator)P2108 patients (47 male, 61 female)Mean age: 54.74 ± 14.67?yearsIndications: Heartburn (58%), chest pain (30%), chronic cough (8%), laryngitis (21%), bloating (35%)Inclusion:Not statedExclusion: Patients on anti-reflux medicationIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the GOJDuration: 48 hoursComparator: NATechnical efficacy:Day-to-day variability (% time pH <4)Lacy et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2009)Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USAProspective case seriesLevel: IVQuality: Q1CX (no comparator)P251 patients (50 patients had enough data to be included)24 males, 26 femalesMean age: 13 years (range: 5–17)Indications: Heartburn, regurgitation, abdominal pain, nausea and/or vomiting, chest painInclusion:Not statedExclusion:Prior surgery to the oesophagus or stomach, known intestinal obstruction or oesophageal varices, achalasia, inability to understand the procedure, inability to undergo oesophageal manometry or sedationIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Day-to-day variability in oesophageal acid exposureLacy, Chehade & Crowell PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2011)Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USACase seriesLevel: IVQuality: Q1CX (no comparator)P2358 patients (257 females, 101 males)Mean age: 51 ± 14?yearsPredominantly (97%) Caucasian Indications: Symptoms thought secondary to GORDInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the GOJ or 5 cm above the upper border of the LOSDuration: 48 hoursComparator: NATechnical efficacy:Early detachmentLoss of signalLee et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGVlPC9BdXRob3I+PFllYXI+

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ADDIN EN.CITE.DATA (2005)Department of Internal Medicine, Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, TaiwanProspective case seriesLevel: IVQuality: Q3CX (no comparator)P240 patients (27 males and 13 females)Age: range 28–83 yearsIndications:Typical heartburn with unsatisfactory response to therapy (15), erosive oesophagitis and undergoing preoperative evaluation (25)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Attachment failureEarly detachmentMarchese et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Marchese</Author><Year>2006</Year><RecNum>516</RecNum><IDText>813-818</IDText><DisplayText>(2006)</DisplayText><record><rec-number>516</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">516</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchese, M.</author><author>Spada, C.</author><author>Iacopini, F.</author><author>Familiari, P.</author><author>Shah, S. G.</author><author>Tringali, A.</author><author>Costamagna, G.</author></authors></contributors><titles><title>Nonendoscopic transnasal placement of a wireless capsule for esophageal pH monitoring: feasibility, safety, and efficacy of a manometry-guided procedure</title><secondary-title>Endoscopy</secondary-title></titles><periodical><full-title>Endoscopy</full-title><abbr-1>Endoscopy</abbr-1></periodical><pages>813-818</pages><volume>38</volume><number>8</number><dates><year>2006</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0013-726X</isbn><accession-num>CCC:000240368800009</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000240368800009</url></related-urls></urls><electronic-resource-num>10.1055/s-2006-944526</electronic-resource-num></record></Cite></EndNote>(2006)Digestive Endoscopy Unit, Agostino Gemelli University Hospital, Catholic University of Rome, Rome, ItalyProspective case seriesLevel: IVQuality: Q1CX (no comparator)P240 patients (36 patients had successful oesophageal placement of the capsule)23 males, 17 femalesMean age: 42.5?yearsIndications:Reflux symptoms that were refractory to PPI therapy Inclusion:Patients with reflux symptoms refractory to PPI therapy who had normal or equivocal endoscopic findingsExclusion:Patients with oesophageal varices, previous GI surgery, known coagulopathy or bleeding diathesis, cardiac pacemakers, defibrillators or other electromedical devices, significant comorbidity, pregnant women and patients <18?years of ageIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the upper margin of the LOSDuration: 24 or 48 hoursComparator: NATechnical efficacy:Technical failure Capsule displacementMartinez de Haro et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TWFydGluZXogZGUgSGFybzwv

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ADDIN EN.CITE.DATA (2008)Servicio de Cirugia General, Hospital Universitario Virgen de la Arrixaca, Murcia, SpainOne arm of non-randomised controlled trialLevel: IV Quality: Q2CXP240 patientsGroup 2 standard pH monitoring: mean age 45?years (range 17–73); 9 males and 6 femalesGroup 2 Bravo monitoring: mean age 37?years (range 21–59); 8 males and 7 femalesGroup 3 (both): mean age, 36.5?years (range 18–56); 7 males and 3 femalesInclusion:General criteria: >18 years of age, informed consent of the risks, benefits and alternative tests, committed to completing follow-upControl group: less than 2 episodes of pyrosis or regurgitation per month, no dysphagia or atypical reflux symptoms, no oesophageal motility disorders, not taken medication for acid reflux, no evidence of hiatal hernia or oesophagitisPatient group: typical reflux symptoms requiring treatment, inflammatory lesions due to reflux in the oesophageal mucosa in group 2Exclusion:<18 years of age, oesophageal stenosis, oesophageal varix, lesion affecting the nostrils, severe oesophageal motor disorders, high anaesthetic risk, history of coagulopathy, haemorrhage, intake of anticoagulants or platelet antiaggregates, myocardial infarction or CVA in the past 6?months, pregnancy, history of radiotherapy in the thoracic region, digestive haemorrhage in the past 6?months, any known medical disorder that could alter the data, unable to accept study protocols Index test:System: Bravo? wireless capsule systemInsertion: transnasally (n=25) and transorally (n=10)Placement: 5 cm above the LOSDuration: 48 hoursComparator:System: Digitrapper Mark III pH monitoring (Synetics, Stockholm, Sweden)Insertion: transnasallyPlacement: 5 cm above the LOS Duration: 24 hoursTechnical efficacy:Incorrect placementEarly detachmentImmediate detachmentNusrat, Roy & Bielefeldt PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TnVzcmF0PC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2012)University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2356 patients (65% females)Mean age: 49.9 ± 0.8?yearsIndications: Evaluations of GORD, recurrent or persistent symptoms after fundoplication, chest pain, unexplained cough or other atypical symptomsInclusion:Not statedExclusion:Patients with pacemakers, implanted cardiac defibrillators, known oesophageal varices, bleeding disorders or ongoing anticoagulationIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the endoscopically localized SCJ or 5 cm above the manometrically determined upper border of the LOSDuration: 48 hoursComparator: NATechnical efficacy:Early capsule detachmentPandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2003)Northwestern University Feinberg School of Medicine, Chicago, Illinois, USACase-control studyLevel: IVQuality: Q1CX (no comparator)P344 controls (13 males, 31 females, aged 23–53?years) 41 patients (26 males, 15 females, aged 32–72?years)Inclusion:Not statedExclusion:Controls: abdominal symptoms, use of antacids or antisecretory medication, abnormal endoscopyPatients: history of surgical manipulation of the upper GI tract, history of bleeding diathesis or coagulopathy, stroke or transient ischemic attack in the past 6?months, significant medical illness, oesophageal varicesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJComparator: NATechnical efficacy:Early detachmentAttachment failureDay-to-day variability in oesophageal acid refluxPandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Department of Medicine, the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USACase-control studyLevel: IV Quality: Q2CX (no comparator)P310 normal control subjects (7 males and 3 females, aged 21–53?years) 10 patients with GORD (6 males and 4 females, aged 20–54?years)Inclusion:Controls: no history of heartburn, reflux, chest pain or atypical symptomsPatients: oesophagitis (3) or an abnormal 24-hour oesophageal pH study prior to this studyExclusion:History of surgical manipulation of the upper Gl tract, anticoagulation therapy, significant medical disease Controls: abdominal symptoms, use of antacids, abnormal upper endoscopyIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 1 cm proximal to SCJDuration: 24 hoursComparator: NATechnical efficacy:Operative successEarly detachmentConcordance capsule 1?cm vs 6?cm proximal to SCJPark et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Park</Author><Year>2013</Year><RecNum>611</RecNum><IDText>1-7</IDText><DisplayText>(2013)</DisplayText><record><rec-number>611</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">611</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Park, E. Y.</author><author>Choi, M. G.</author><author>Baeg, M.</author><author>Lim, C. H.</author><author>Kim, J.</author><author>Cho, Y.</author><author>Park, J.</author><author>Lee, I.</author><author>Kim, S.</author><author>Choi, K.</author></authors></contributors><auth-address>Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary&apos;s Hospital, The Catholic University of Korea, 505, Banpo-Dong, Seocho-Gu, Seoul, 137-040, South Korea</auth-address><titles><title>The Value of Early Wireless Esophageal pH Monitoring in Diagnosing Functional Heartburn in Refractory Gastroesophageal Reflux Disease</title><secondary-title>Digestive Diseases and Sciences</secondary-title></titles><periodical><full-title>Dig Dis Sci</full-title><abbr-1>Digestive diseases and sciences</abbr-1></periodical><pages>1-7</pages><keywords><keyword>Esophageal pH monitoring</keyword><keyword>Gastroesophageal reflux</keyword><keyword>Heartburn</keyword><keyword>Proton pump inhibitors</keyword></keywords><dates><year>2013</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(2013)Divisions of Gastroenterology, Department of internal Medicine, Seoul; St Mary’s Hospital, the Catholic University of Korea, Seoul, KoreaCase seriesLevel: IVQuality: Q1CX (no comparator)P2230 patients (101 males, 129 females)Mean age: 49.7 ± 12.4?yearsIndication: suspected GORDInclusion:≥18 years of ageExclusion: Previous oesophageal, gastric or duodenal surgery, GI organic disease, significant comorbidity or GI bleedingIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to SCJDuration: 48 hoursComparator: NATechnical efficacy:Operative successAttachment failureEarly detachmentRecording failurePrakash & Clouse PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UHJha2FzaDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2006)Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USACase seriesLevel: IVQuality: Q1CX (no comparator)P262 patients (41 females, 21 males)Mean age: 47 ± 2?yearsInclusion:Not statedExclusion:Oesophagitis, prior anti-reflux surgery, failure to maintain a complete diary of activities and symptoms, having <14?hours of good-quality tracings on each of the study daysIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJComparator: NATechnical efficacy:Day-to-day variabilityRemes-Troche et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UmVtZXMtVHJvY2hlPC9BdXRo

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran, Mexico City, MexicoProspective case seriesLevel: IVQuality: Q1CX (no comparator)P284 patients (77 patients had enough data to be included)49 females, 35 malesMean age: 44 ± 12?years (range 19–73)Indications:Persistent GORD symptoms on PPI, preoperative evaluation before surgery, previous failed transnasal pH monitoring, extraoesophageal GORDInclusion:Consecutive patients with GORD symptoms with an indication for 24-hour pH monitoringExclusion:Patients with surgical manipulation of the upper GI tract, bleeding diathesis or coagulopathy, severe GI bleeding in the past 6?months, oesophageal varices, significant comorbiditiesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Attachment failureEarly detachmentDay-to-day variability in acid exposureScarpulla et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U2NhcnB1bGxhPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2007)Gastroenterology Division, M. Raimondi Hospital, Can Cataldo, ItalyRetrospective case seriesLevel: IVQuality: Q2CX P283 patients (complete 4-day recordings were available for 34/83)44 females, 39 malesMedian age 42?years (range 18–63)Indications:Typical reflux symptoms or atypical symptoms including chest pain and extra oesophageal complaintsInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the Z lineDuration: 24, 48, 72 and/or 96?hoursComparator: NATechnical efficacy:Early detachmentTechnical failureSofi et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Sofi</Author><Year>2011</Year><RecNum>540</RecNum><IDText>243-248</IDText><DisplayText>(2011)</DisplayText><record><rec-number>540</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">540</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sofi, A.</author><author>Filipiak, C.</author><author>Sodeman, T.</author><author>Ahmad, U.</author><author>Bawany, M.</author><author>Daboul, I.</author></authors></contributors><auth-address>Department of Gastroenterology, University of Toledo Medical Center, Toledo, OH, United States</auth-address><titles><title>Comparison of esophageal placement of Bravo capsule system under direct endoscopic guidance with conventional placement method</title><secondary-title>Turkish Journal of Gastroenterology</secondary-title></titles><periodical><full-title>Turkish Journal of Gastroenterology</full-title></periodical><pages>243-248</pages><volume>22</volume><number>3</number><keywords><keyword>Bravo capsule</keyword><keyword>Direct/indirect</keyword><keyword>Technique</keyword></keywords><dates><year>2011</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(2011)Department of Gastroenterology, University of Toledo Medical Center, Toledo, Ohio, USARetrospective case series58 patientsAge range: 26–87?years17 males, 41 femalesInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the GOJComparator: NATechnical efficacy:Early detachment (none)Device malfunctionRecording failureTankurt et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VGFua3VydDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Kent Hospital, Department of Gastroenterology, Izmir, TurkeyCase seriesLevel: IVQuality: Q2CX (no comparator)P264 patients (37 males, 27 females)Mean age: 37.9 years (range 25–58)Indications: Preoperative evaluation (17), evaluation of atypical reflux symptoms (40) and ‘other’ (7)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Early detachmentTseng et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VHNlbmc8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2005)Digestive Health Center, Department of Surgery and Division of Gastroenterology, Oregon health and Science University, Portland, Oregon, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2190 procedures and 186 patients (some had the test performed twice) 72 males and 114 femalesMean age: 51?yearsIndication: Being evaluated for GORDInclusion:Patients older than 18 yearsExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5–6cm above the LOS or 5–6?m above the SCJ Duration: 48 hoursComparator:24-hour Bravo monitoringTechnical efficacy:Loss of signal/dataEarly detachmentDay-to-day variabilityTu et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Tu</Author><Year>2004</Year><RecNum>527</RecNum><IDText>1586-1589</IDText><DisplayText>(2004)</DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tu, C. H.</author><author>Lee, Y. C.</author><author>Wang, H. P.</author><author>Wu, M. S.</author><author>Chiu, H. M.</author><author>Lin, J. T.</author></authors></contributors><titles><title>Ambulatory esophageal pH monitoring by using a wireless system: A pilot study in Taiwan</title><secondary-title>Hepato-Gastroenterology</secondary-title></titles><periodical><full-title>Hepatogastroenterology</full-title><abbr-1>Hepato-gastroenterology</abbr-1></periodical><pages>1586-1589</pages><volume>51</volume><number>60</number><dates><year>2004</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><isbn>0172-6390</isbn><accession-num>CCC:000224607400004</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000224607400004</url></related-urls></urls></record></Cite></EndNote>(2004)Department of Internal Medicine and Department of Emergency Medicine, National Taiwan University Hospital, Taipei, TaiwanProspective case seriesLevel: IVQuality: Q1CX (no comparator)P230 patients20 males, 10 femalesMean age: 57.6 ± 14.3?years (range 29–83)Indications: 24 patients with GORD were evaluated for drug effectiveness before surgery, 6 patients showed typical heartburn but their endoscopic findings were normalInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the GOJDuration: 48 hoursComparator: NATechnical efficacy:Attachment failureTurner et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Turner</Author><Year>2007</Year><RecNum>536</RecNum><IDText>737-741</IDText><DisplayText>(2007)</DisplayText><record><rec-number>536</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">536</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turner, B. G.</author><author>Saltzman, J. R.</author><author>Hua, L.</author><author>Maurer, R.</author><author>Feldman, N.</author><author>Carr-Locke, D. L.</author><author>Burakoff, R.</author><author>Liu, J. J.</author></authors></contributors><titles><title>Endoscopic pH monitoring for patients with suspected or refractory gastroesophageal reflux disease</title><secondary-title>Canadian Journal of Gastroenterology</secondary-title></titles><periodical><full-title>Canadian Journal of Gastroenterology</full-title></periodical><pages>737-741</pages><volume>21</volume><number>11</number><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0835-7900</isbn><accession-num>CCC:000251481000008</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000251481000008</url><url>;(2007)Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, USACase seriesLevel: IVQuality: Q2CX (no comparator)P2198 pH studies (148 studies had enough data to be included)Off medical therapy: 115 patients, 76 females, 39 males. Mean age: 50 ± 13?yearsOn medical therapy: 33 patients, 26 females, 7 males. Mean age: 52 ± 14?yearsIndications: Typical and atypical symptoms of GORD or persistent GORD-related symptoms despite medical therapy. Patients with planned anti-reflux surgery were also evaluatedInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: (during endoscopy)Placement: 6 cm above the SCJDuration: 48 hoursComparator:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: Duration: 24 hoursTechnical efficacyEarly detachmentInsufficient data captureDay-to-day variability in oesophageal acid exposureWard et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2FyZDwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2004)Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USACase seriesLevel: IVQuality: Q2CX (no comparator)P260 patients (58 patients had enough data to be included)26 males, 34 femalesMean age: 54 years (range 27–82)Indications:Document GORD before surgery, possible GORD with negative PPI trial, evaluate response to PPI, possible supra-oesophageal GORD, non-cardiac chest pain, evaluate response to Stretta procedure, previous failed pH testInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NATechnical efficacy:Attachment failureHardware malfunctionWenner, Johnsson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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dGU+AG==

ADDIN EN.CITE.DATA (2007)Department of Surgery, Lund University Hospital, Lund, SwedenRandomised crossover trialLevel: IIQuality: 20/26CXP235 patients (31 patients had enough data to be included)15 males, 16 femalesMedian age: 52 yearsMedian BMI: 27 (range 24–28)Indications: Typical reflux symptoms (55%) and atypical reflux symptoms (45%)Inclusion:Patients referred for oesophageal pH monitoring Exclusion:Patients with coagulopathy, severe oesophagitis/stricture, portal hypertension, a pacemaker, age <20 or >70?years, previous gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline (Medtronic) Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursTechnical efficacy:Technical problemsWenner et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2008); Wenner. Johansson et al. (2007)Department of Surgery, Lund University Hospital, Lund, SwedenCase-control studyLevel: IV Quality: Q2CXP370 patients, but 64 had enough data to be included (39 males, 25 females) and 55 controls (27 males and 28 females) Not all patients are included in the distal capsule outcomesIndications: Patients with typical reflux symptomsInclusion:Patients: presence of typical reflux symptoms such as heartburn and regurgitation. Symptoms had to occur more than twice weekly. Treatment with medical acid suppression had to result in complete symptom relief or a more than 50% reduction of the symptoms Exclusion:Coagulopathy, severe oesophagitis/stricture, portal hypertension, pacemaker, <20 or >70?years of age, history of gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJTechnical efficacy:Early detachmentCapsule unable to pass through oesophagusTransmission failure / loss of signalIncorrect capsule placementStudy profiles of included studies on linked evidenceDiagnostic accuracyStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / Exclusion criteriaDiagnostic testsDiagnostic accuracy outcome assessedAyazi et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Ayazi</Author><Year>2009</Year><RecNum>497</RecNum><DisplayText>(2009)</DisplayText><record><rec-number>497</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">497</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ayazi, S.</author><author>Lipham, J. C.</author><author>Portale, G.</author><author>Peyre, C. G.</author><author>Streets, C. G.</author><author>Leers, J. M.</author><author>Demeester, S. R.</author><author>Banki, F.</author><author>Chan, L. S.</author><author>Hagen, J. A.</author><author>Demeester, T. R.</author></authors></contributors><titles><title>Bravo Catheter-Free pH Monitoring: Normal Values, Concordance, Optimal Diagnostic Thresholds, and Accuracy</title><secondary-title>Clinical Gastroenterology and Hepatology</secondary-title></titles><periodical><full-title>Clinical Gastroenterology and Hepatology</full-title></periodical><pages>60-67</pages><volume>7</volume><number>1</number><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1542-3565</isbn><accession-num>CCC:000262822000012</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000262822000012</url></related-urls></urls><electronic-resource-num>10.1016/j.cgh.2008.08.020</electronic-resource-num></record></Cite></EndNote>(2009)Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USADiagnostic case-control studyLevel: III-3Quality:Patient selection: ?Index test: ?Reference standard: Flow and timing: ?CX P325 asymptomatic subjects and 25 patientsIndications: Patients had heartburn and were responsive to PPI therapy. All had hiatal herniaInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule system, Medtronic Inc. Minneapolis MinnesotaInsertion: transnasallyPlacement: 5 cm above the LOSDuration: 48 hoursComparator: NAReference standard:Clinical diagnosis (heartburn, responsive to PPI therapy and evidence of a hiatal hernia)SensitivitySpecificityAccuracyAyazi et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Ayazi</Author><Year>2009</Year><RecNum>497</RecNum><DisplayText>(2009)</DisplayText><record><rec-number>497</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">497</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ayazi, S.</author><author>Lipham, J. C.</author><author>Portale, G.</author><author>Peyre, C. G.</author><author>Streets, C. G.</author><author>Leers, J. M.</author><author>Demeester, S. R.</author><author>Banki, F.</author><author>Chan, L. S.</author><author>Hagen, J. A.</author><author>Demeester, T. R.</author></authors></contributors><titles><title>Bravo Catheter-Free pH Monitoring: Normal Values, Concordance, Optimal Diagnostic Thresholds, and Accuracy</title><secondary-title>Clinical Gastroenterology and Hepatology</secondary-title></titles><periodical><full-title>Clinical Gastroenterology and Hepatology</full-title></periodical><pages>60-67</pages><volume>7</volume><number>1</number><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1542-3565</isbn><accession-num>CCC:000262822000012</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000262822000012</url></related-urls></urls><electronic-resource-num>10.1016/j.cgh.2008.08.020</electronic-resource-num></record></Cite></EndNote>(2009)11Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USADiagnostic case-control studyLevel: III-3Quality:Patient selection: Index test: ?Reference standard: Flow and timing: CXP3115 symptomatic patients who were tested for GORD (28 patients with strong clinical evidence, 77 with intermediate evidence, and 10 with minimal evidence, of GORDInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule system, Medtronic Inc. Minneapolis MinnesotaInsertion: transnasallyPlacement: 5 cm above the LOSDuration: 48 hoursComparator:NAReference standard:Clinical diagnosis (primary symptoms of heartburn and/or regurgitation, response to PPI therapy >50%, hiatal hernia >2?cm, oesophageal mucosal injury)SensitivitySpecificityPPV NPVAccuracyBansal et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmFuc2FsPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology and Hepatology, Hopital Hotel Dieu, Nantes, FranceIn-subject simultaneous recording studyLevel: II Quality: Patient selection: ?Index test: Reference standard: ?Flow and timing: C1 P240 patients(probe successfully attached in 36 patients)21 males, 19 femalesMean age: 50 yearsIndications:Heartburn (n=7), regurgitation (n=6) or both symptoms (n=26)Inclusion:Patients suggestive of GORD and referred to the functional laboratory of four French academic centres for pH monitoringExclusion:Severe oesophageal motility disorders, severe oesophagitis (Los Angeles grade C or above), pregnancy, women who were not using reliable contraceptionIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the Z lineDuration: 48 hoursComparator:System: Mark III or Digitrapper pH, Medtronic, Stockholm, SwedenInsertion: transnasallyPlacement: adjusted to the same level as the index testDuration: 24 hoursSensitivitySpecificityPPV NPVLR+LR–Hakanson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+SGFrYW5zb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2009)Department of Surgery, Center of Gastrointestinal Disease, Ersta Hospital, Stockholm, SwedenCase-control study with in-subject simultaneous recordingLevel: III-3 Quality: Patient selection: ?Index test: Reference standard: ?Flow and timing: C1 P253 volunteers and 55 patients (45 volunteers and 47 patients had enough data to be included)30 females and 15 males in volunteer group27 females and 20 males in patient groupMean age: Volunteers: 47?years (range 21–68)Patients: 50?years (range 23–69)Indication: Patients had symptoms including mainly heartburn, acid regurgitation, and chest or epigastric painInclusion:Patients: referred to the clinic for investigation of GORDExclusion:Volunteers: history of GORD or any other pathology of the upper GI tract, taking acid-suppressing agents or medication known to affect GI motilityIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJ Duration: 48 hoursComparator:System: Slimline, Medtronic, Skovlunde, DenmarkInsertion: transnasallyPlacement: 5 cm proximal to the upper border of the LOSDuration: 24 hoursSensitivitySpecificityPPV NPVLR+LR–Pandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2003)Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADiagnostic case-control studyLevel: III-3Quality: Patient selection: Index test: ?Reference standard: ?Flow and timing: Q1CX (clinical diagnosis)P344 controls (13 males, 31 females, aged 23–53?years) 41 patients (26 males, 15 females, aged 32–72?years)Inclusion:Not statedExclusion:Controls: abdominal symptoms, use of antacids or antisecretory medication, abnormal endoscopyPatients: history of surgical manipulation of the upper GI tract, history of bleeding diathesis or coagulopathy, stroke or transient ischemic attack in the past 6?months, significant medical illness, oesophageal varicesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJComparator: NAReference standard (diagnosis of patients in study population):25 patients had erosive oesophagitis, 6 had an abnormal 24-hour pH study, 10 were diagnosed clinically with typical GORD symptoms that resolved with PPI therapySensitivitySpecificityPPVNPVLR+LR–Wenner, Johnsson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2007)Department of Surgery, Lund University Hospital, Lund, SwedenRandomised crossover trialLevel: IIQuality: Patient selection: Index test: Reference standard: ?Flow and timing: C1 P235 patients (31 patients had enough data to be included)15 males, 16 femalesMedian age: 52 yearsMedian BMI: 27 (range 24–28)Indications: Typical reflux symptoms (55%) and atypical reflux symptoms (45%)Inclusion:Patients referred for oesophageal pH monitoring Exclusion:Patients with coagulopathy, severe oesophagitis/stricture, portal hypertension, a pacemaker, age <20 or >70?years, previous gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline (Medtronic) Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursSensitivitySpecificityPPVNPVLR+LR–Wenner et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2008); Wenner, Johansson et al. (2007)Department of Surgery, Lund University Hospital, Lund, SwedenDiagnostic case-control studyLevel: III-3 Quality: Patient selection: Index test: ?Reference standard: Flow and timing: ?CXP370 patients, but 64 had enough data to be included (39 males, 25 females) 55 controls (27 males and 28 females) Not all patients are included in the distal capsule outcomesIndications: Patients with typical reflux symptomsInclusion:Patients: presence of typical reflux symptoms such as heartburn and regurgitation. Symptoms had to occur more than twice weekly. Treatment with medical acid suppression had to result in complete symptom relief or a more than 50% reduction of the symptoms Exclusion:Coagulopathy, severe oesophagitis/stricture, portal hypertension, pacemaker, <20 or >70 years of age, history of gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJReference standard (for sensitivity and specificity):Clinical diagnosis: symptoms suggestive of GORD and responding to acid suppressionSensitivitySpecificityLR+LR–Other accuracy—(incremental) diagnostic yield and concordance outcomesStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / Exclusion criteriaDiagnostic testsDiagnostic accuracy outcome assessedAng et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QW5nPC9BdXRob3I+PFllYXI+

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ADDIN EN.CITE.DATA (2010)Division of Gastroenterology, Department of Medicine, Changi General Hospital, SingaporeComparative diagnostic yield studyLevel: III-2 Quality: 14/26C1P2125 patients(only 66 with catheter-free monitoring and 51 with catheter-based monitoring were analysed, 4 were unable to complete the catheter study due to intolerance)51 males and 70 femalesMean age: 45.14?years (range 22–82)Race:76.9% Chinese5.8% Malay10.7% Indian7.4% OtherIndication:Typical or atypical reflux symptoms in the absence of endoscopic features of reflux oesophagitisInclusion:Patients who were referred for investigation of persistent reflux-like symptoms suspected to be related to NERD despite the presence of a normal gastroscopy over a 50-month period from January 2004 to February 2009Exclusion:A history of bleeding tendency, coagulopathy, peptic ulcer disease, previous oesophageal or gastric surgery, known oesophageal or fundic varices, active GI bleeding, endoscopic features of oesophagitis based on Los Angeles classification, Barrett’s oesophagus, peptic strictures, herpetic or Candida oesophagitis, Zollinger-Ellison syndrome, progressive systemic sclerosis, oesophageal or upper small intestinal Chrohn’s disease, active solid tumor neoplastic tissue, pregnancy, presence of a pacemaker or implantable cardiac defibrillator, a history of severe cardiopulmonary disease or symptoms suggestive of oesophageal motor disorders Index test:System: Bravo? wireless capsule system, Medtronic Inc. Minneapolis, MinnesotaInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:Catheter: calibrated antimony pH electrode (Slimline, Medtronic, Shoreview, Minnesota, USA)Insertion: transnasallyPlacement: 5 cm above the proximal border of the LOSDuration: 24 hoursAccuracy:Comparative diagnostic yield Concordance (acid exposure time and reflux events)Ayazi et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXlhemk8L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2011)Division of Thoracic Foregut Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, California, USADiagnostic yield studyLevel: IV310 patients (158 males and 152 females)Median age: 52 years (IQR=42–63)Inclusion:Patients with no history of foregut surgery who had the Bravo capsule placed transnasally without sedation and who were monitored while off acid suppression therapyExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transnasallyPlacement: 5 cm above the manometrically determined border of the LOSDuration: 48 hoursAccuracy:Diagnostic yieldAzzam et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXp6YW08L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2012)Sao Paulo University Medical School, Sao Paulo, BrazilIn-subject simultaneous recording studyLevel: II Quality: 17/26C1 P225 patients21 females, 4 malesMean age: 52.4 years (range 34–73)Indications:All patients had as predominant symptom the typical GORD complaints, 64% had atypical complaints and 76% had associated extraoesophageal complaintsInclusion:Heartburn and/or regurgitation as the main clinical complaint; at least 18?years of age, recent upper GI endoscopy (within the past 2?months), interruption in the administration of PPIs for 7?days and signature on the free and informed consent formExclusion:Oesophageal diverticula; strictures and varices; hiatal hernia greater than or equal to 3?cm; erosive oesophagitis Los Angeles grades C or D; Barrett’s oesophagus; neoplasms; obstructive diseases; previous surgery of the GI tractIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 3 cm above the superior border of the LOSDuration: 48 hoursComparator:System: Alacer (Brazil) pH-monitor catheter with Medtronic/Synetics (USA) recording deviceInsertion: transnasallyPlacement: Distal sensor was placed 3?cm above the superior border of the LOS, proximal sensor was positioned 5?cm above the superior border of the LOSDuration: 24 hoursAccuracy:Concordance (acid exposure time) Comparative diagnostic yieldBansal et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmFuc2FsPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2009)Divisions of Gastroenterology and Hepatology, University of Kansas, School of Medicine and Veterans affairs Medical Center, Kansas City, Missouri, USADiagnostic yield study Level: IV48 patients (43 males, 5 females) 22 controls (22 males)Mean age:Patients: 57 ± 13?yearsControls: 59 ± 9?yearsIndication: Patients: reflux symptomsInclusion:Patients: answering ‘yes’ to either heartburn or regurgitation, having a score of >2 on the RDQControls: answering ‘no’ to heartburn and regurgitation, having a score of 0 on the RDQExclusion:Patients: cancer or mass lesion in the oesophagus, advanced chronic liver disease, severe uncontrolled coagulopathy, history of oesophageal or gastric surgeryControls: use of acid suppression, evidence of erosive oesophagitisIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 1 cm above the GOJDuration: 24 hoursAccuracy:Diagnostic yieldBhat, McGrath & Bielefeldt PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmhhdDwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2006)Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADiagnostic yield studyLevel: IV217 patients (203 patients had enough data to be included)140 females, 77 malesMean age: 51 years (range 42–58)Indications:Preoperative workup for fundoplication, possible extra oesophageal manifestations of reflux disease, symptoms after fundoplication, refractory symptoms on medication, atypical symptomsInclusion:Adult patients undergoing endoscopy with wireless pH studies at the University of Pittsburgh Medical Center between 9 April 2004 and 31 March 2005Exclusion:Individuals unable to give informed consent, pregnant women, prisoners, patients with oesophageal varices, patients requiring continuing anticoagulation, patients with cardiac defibrillatorsIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursAccuracy:Diagnostic yield Croffie et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q3JvZmZpZTwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2007)Section of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana, USARandomised controlled trialLevel: IIQuality:14.5/26C1P266 patients (but 5 patients were excluded due to operative failure, failed recording etc.)32 males, 34 femalesMean age: 9.4 years (range 4–16.5)Indications:Persistent epigastric or substernal pain, persistent vomiting, heartburn, chronic nocturnal cough or wheezing, persistent throat clearance, dental abnormalities suspected to be caused by refluxInclusion:Children between the ages of 4 and 18?years and weighing at least 30?lb who were undergoing oesophagogastroduodenoscopy and oesophageal pH monitoring for symptoms suggestive of gastro-oesophageal refluxExclusion:Children younger than 4?years of age or weighing <30?lb, having anatomic abnormalities of the oesophagus, a history of a surgical procedure of the oesophagus, stomach or duodenum, a history of coagulopathy or bleeding diathesis, presence of oesophageal varices, significant medical illnessIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: at 87% of the distance from the incisors to the Z lineDuration: 48 hoursComparator:System: not stated (catheter-based)Insertion: transnasallyPlacement: tip at 87% of the distance from the nostril to the GOJDuration: 24 hoursAccuracy:Concordance (acid exposure time)des Varannes et al.PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+ZGVzIFZhcmFubmVzPC9BdXRo

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ADDIN EN.CITE.DATA (2005)Department of Gastroenterology and Hepatology, Hopital Hotel Dieu, Nantes, FranceIn-subject simultaneous recording studyLevel: II Quality: 20/26C1P240 patients(probe successfully attached in 36 patients)21 males, 19 femalesMean age: 50 yearsIndications:Heartburn (n=7), regurgitation (n=6) or both symptoms (n=26)Inclusion:Patients suggestive of GORD and referred to the functional laboratory of four French academic centres for pH monitoringExclusion:Severe oesophageal motility disorders, severe oesophagitis (Los Angeles grade C or above), pregnancy, women who were not using reliable contraceptionIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the Z lineDuration: 48 hoursComparator:System: Mark III or Digitrapper pH, Medtronic, Stockholm, SwedenInsertion: transnasallyPlacement: adjusted to the same level as the index testDuration: 24 hoursAccuracy:Concordance (acid exposure time and reflux events)Domingues, Moraes-Filho & Domingues PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RG9taW5ndWVzPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2011)Motility laboratory (Gastro Resolucao Diagnostico, Laboratorio de Motilidade Digestive), Rio de Janeiro, BrazilDiagnostic yield studyLevel: IV100 patients(probe successfully attached in 95 patients)39 female, 61 maleMean age: 53 years (range 18 –81)Indications:82% of patients referred to diagnose GORD, 18% referred due to persistent symptoms despite PPI useInclusion:Patients referred to a GI motility laboratory to investigate GORD with typical or atypical symptoms, persistent GORD symptoms on medical therapy or recurrent GORD symptoms after surgical fundoplication, between 2004 and 2009Exclusion:<18?years of age, history of bleeding tendency or coagulopathy, significant concomitant medical co-morbidities, severe GI bleeding in the past 6?months, a history of upper GI surgery, medication with PPIs, presence of oesophageal varices, Barrett’s oesophagus, oesophageal stenosis, erosive oesophagitis, pacemaker or implantable cardiac defibrillator in situIndex test:System: Bravo? wireless capsule systemInsertion: 5 cm above the upper border of the LOS (manometry) or 6?cm above the LOS (endoscopy)Placement: transorallyDuration: 48 hoursAccuracy:Diagnostic yieldGarrean et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FycmVhbjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2008)Division of Gastroenterology, Northwestern University Freiberg School of Medicine, Chicago, Illinois, USADiagnostic yield studyLevel: IV60 patients (22 males and 38 females) Age: 19–80?years40 patients had complete 4-day data acquisitionIndications: Acid reflux symptoms, chest pain, laryngeal symptoms that were poorly responsive to twice-daily PPI therapy for a minimum of 6?weeksInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: 6 cm above the SCJComparator: NAAccuracy:Diagnostic yieldIncremental diagnostic yieldGillies et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2lsbGllczwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2007)Departments of Upper Gastrointestinal Surgery and Gastrointestinal Physiology, Royal Berkshire Hospital, Reading, UKDiagnostic yield studyLevel: IV95 patientsIndication: Symptoms suggestive of GORD or documenting the outcome of laparoscopic anti-reflux surgeryInclusion:See indicationExclusion:No specific exclusion criteria existIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursAccuracy:Diagnostic yieldGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2011)Department of Gastroenterology, Universita Degli Studi and Fondazione IRCCS Ca Granada, Ospedale Maggiore Policlinico, Milan, ItalyMatched-pairs retrospective cohort studyLevel: III-2 Quality: 16.5/26C1 P2102 patientsCatheter group: 51 patients, 20 males, mean age 48?years (range 22–78) Bravo group: 51 patients, 22 males, mean age 48?years (range 23–82)Inclusion:All consecutive patients who underwent wireless 96-hour pH monitoring between January and December 2007 off PPI therapy, and patients undergoing traditional 24-hour pH monitoring in the same period, after matching for the most troublesome symptom potentially related to GORD, sex and ageExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJDuration: 48–96 hoursComparator for concordance:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach, or 5?cm above the upper margin of the LOS Duration: 24 hoursAccuracy:Diagnostic yieldConcordance (acid exposure time)Incremental diagnostic yield (of prolonged monitoring) Gunnarsdottir, Stenstrom & Arnbjornsson PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3VubmFyc2RvdHRpcjwvQXV0

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ADDIN EN.CITE.DATA (2009)Department of Surgery, Center of Gastrointestinal Disease, Ersta Hospital, Stockholm, SwedenCase-control study with in-subject simultaneous recordingLevel: II Quality: 14/26C1P253 volunteers and 55 patients (45 volunteers and 47 patients had enough data to be included)30 females and 15 males in volunteer group27 females and 20 males in patient groupMean age: Volunteers: 47?years (range 21–68)Patients: 50?years (range 23–69)Indication: Patients had symptoms including mainly heartburn, acid regurgitation, and chest or epigastric painInclusion:Patients: referred to the clinic for investigation of GORDExclusion:Volunteers: history of GORD or any other pathology of the upper Gl tract, taking acid-suppressing agents or medication known to affect GI motilityIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJ Duration: 48 hoursComparator:System: Slimline, Medtronic, Skovlunde, DenmarkInsertion: transnasallyPlacement: 5 cm proximal to the upper border of the LOSDuration: 24 hoursAccuracy:Concordance (acid exposure time)Comparative diagnostic yieldKaramanolis et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Karamanolis</Author><Year>2012</Year><RecNum>268</RecNum><IDText>169-73</IDText><DisplayText>(2012)</DisplayText><record><rec-number>268</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karamanolis, G.</author><author>Triantafyllou, K.</author><author>Psatha, P.</author><author>Vlachogiannakos, I.</author><author>Gaglia, A.</author><author>Polymeros, D.</author><author>Fessatou, S.</author><author>Triantafyllou, M.</author><author>Papanikolaou, I. S.</author><author>Ladas, S. D.</author></authors></contributors><auth-address>Hepatogastroenterology Unit, 2nd Department of Internal Medicine - Propaedeutic, Attikon University General Hospital, Athens Medical School, Athens, Greece.</auth-address><titles><title>Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors</title><secondary-title>J Neurogastroenterol Motil</secondary-title><alt-title>Journal of neurogastroenterology and motility</alt-title></titles><periodical><full-title>J Neurogastroenterol Motil</full-title><abbr-1>Journal of neurogastroenterology and motility</abbr-1></periodical><alt-periodical><full-title>Journal of Neurogastroenterology and Motility</full-title></alt-periodical><pages>169-73</pages><volume>18</volume><number>2</number><edition>2012/04/24</edition><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2093-0887 (Electronic)&#xD;2093-0879 (Linking)</isbn><accession-num>22523725</accession-num><urls><related-urls><url>;(2012)2nd Department of Internal Medicine, Propaedeutic Attikon University General Hospital, Athens, GreeceDiagnostic yield studyLevel: IV32 patients18 males, 14 femalesMean age: 45.3 ± 12.5?yearsIndications:3 episodes of non-cardiac chest pain per weekInclusion:Patients with at least 3 episodes of chest pain per week and normal oesophageal manometry (in order to exclude the presence of any oesophageal motility disorder)Exclusion:Patients that were using aspirin or NSAIDs, a history of upper GI surgery, gastric or duodenal ulcer, connective tissue disease and severe liver, lung, renal or haematological diseaseIndex test:System: Bravo? wireless capsule systemInsertion: transorally Placement: 6 cm proximal to the SCJDuration: 48 hoursComparator:(24-hour Bravo pH monitoring)Accuracy:Incremental diagnostic yield (of prolonged monitoring)Kushnir, Sayuk & Gyawali PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+S3VzaG5pcjwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2011)Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USAComparative study of diagnostic yieldLevel: IVQuality: 13.5/26C1P2462 patients (286 females and 176 males) in the wireless group 1,605 patients (1,092 females and 513 males) in the catheter groupInclusion:Adult patients referred for ambulatory pH monitoring for all indications at the medical centre over a 7-year periodExclusion:Subjects who had undergone prior anti-reflux procedures or oesophageal surgery, incomplete studies with <14?hours of interpretable data, studies contaminated by artefactIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: NSDuration: 28 hoursComparator:System: NS (catheter-based)Insertion: NSPlacement: NSDuration: 24 hoursAccuracy:Comparative diagnostic yieldLacy, Chehade & Crowell PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2011)Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USADiagnostic yield studyLevel: IVQuality: Q1CX (no comparator)P2358 patients (257 females, 101 males)Mean age: 51 ± 14?yearsPredominantly (97%) Caucasian Indications: Symptoms thought secondary to GORDInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the GOJ or 5?cm above the upper border of the LOSDuration: 48 hoursComparator: NAAccuracy:Diagnostic yieldMartinez de Haro et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TWFydGluZXogZGUgSGFybzwv

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ADDIN EN.CITE.DATA (2008)Servicio de Cirugia General, Hospital Universitario Virgen de la Arrixaca, Murcia, SpainNon-randomised controlled trial Level: III-2 Quality: 11/26C1P240 patientsGroup 2 standard pH monitoring: mean age 45?years (range 17–73) 9 males and 6 femalesGroup 2 Bravo monitoring: mean age 37?years (range 21–59), 8 males and 7 femalesGroup 3 (both): mean age 36.5?years (range 18–56), 7 males and 3 femalesInclusion:General criteria: >18?years of age, informed consent of the risks, benefits and alternative tests, committed to completing follow-upControl group: less than 2 episodes of pyrosis or regurgitation per month, no dysphagia or atypical reflux symptoms, no oesophageal motility disorders, not taken medication for acid reflux, no evidence of hiatal hernia or oesophagitisPatient group: typical reflux symptoms requiring treatment, inflammatory lesions due to reflux in the oesophageal mucosa in group 2.Exclusion:<18 years of age, oesophageal stenosis, oesophageal varix, lesion affecting the nostrils, severe oesophageal motor disorders, high anaesthetic risk, history of coagulopathy, haemorrhage, intake of anticoagulants or platelet antiaggregates, myocardial infarction or CVA in the past 6?months, pregnancy, history of radiotherapy in the thoracic region, digestive haemorrhage in the past 6?months, any known medical disorder that could alter the data, unable to accept study protocols Index test:System: Bravo? wireless capsule systemInsertion: transnasally (n=25) and transorally (n=10)Placement: 5 cm above the LOSDuration: 48 hoursComparator:System: Digitrapper Mark III pH monitoring (Synetics, Stockholm, Sweden)Insertion: transnasallyPlacement: 5 cm above the LOS Duration: 24 hoursAccuracy:Concordance (acid exposure time) Martinez de Haro et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TWFydGluZXogZGUgSGFybzwv

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ADDIN EN.CITE.DATA (2008)Servicio de Cirugia General, Hospital Universitario Virgen de la Arrixaca, Murcia, SpainDiagnostic yield studyLevel: IVCX (no comparison)P240 patientsGroup 2 standard pH monitoring: mean age 45?years (range 17–73) 9 males and 6 femalesGroup 2 Bravo monitoring: mean age 37?years (range 21–59), 8 males and 7 femalesGroup 3 (both): mean age 36.5?years (range 18–56), 7 males and 3 femalesInclusion:General criteria: >18?years of age, informed consent of the risks, benefits and alternative tests, committed to completing follow-upControl group: less than 2 episodes of pyrosis or regurgitation per month, no dysphagia or atypical reflux symptoms, no oesophageal motility disorders, not taken medication for acid reflux, no evidence of hiatal hernia or oesophagitisPatient group: typical reflux symptoms requiring treatment, inflammatory lesions due to reflux in the oesophageal mucosa in group 2.Exclusion:<18?years of age, oesophageal stenosis, oesophageal varix, lesion affecting the nostrils, severe oesophageal motor disorders, high anaesthetic risk, history of coagulopathy, haemorrhage, intake of anticoagulants or platelet antiaggregates, myocardial infarction or CVA in the past 6?months, pregnancy, history of radiotherapy in the thoracic region, digestive haemorrhage in the past 6?months, any known medical disorder that could alter the data, unable to accept study protocols Index test:System: Bravo? wireless capsule systemInsertion: transnasally (n=25) and transorally (n=10)Placement: 5 cm above the LOSDuration: 48 hoursAccuracy:Concordance (acid exposure time) Pandolfino et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGFuZG9sZmlubzwvQXV0aG9y

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ADDIN EN.CITE.DATA (2003)Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADiagnostic yield studyLevel: IV44 controls (13 males, 31 females, age range 23–53?years) 41 patients (26 males, 15 females, age range 32–72?years)Inclusion:Not statedExclusion:Controls: abdominal symptoms, use of antacids or antisecretory medication, abnormal endoscopyPatients: history of surgical manipulation of the upper GI tract, history of bleeding diathesis or coagulopathy, stroke or transient ischemic attack in the past 6?months, significant medical illness, oesophageal varicesIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJAccuracy:Incremental diagnostic yield (of prolonged monitoring)Diagnostic yieldPark et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Park</Author><Year>2013</Year><RecNum>611</RecNum><IDText>1-7</IDText><DisplayText>(2013)</DisplayText><record><rec-number>611</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">611</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Park, E. Y.</author><author>Choi, M. G.</author><author>Baeg, M.</author><author>Lim, C. H.</author><author>Kim, J.</author><author>Cho, Y.</author><author>Park, J.</author><author>Lee, I.</author><author>Kim, S.</author><author>Choi, K.</author></authors></contributors><auth-address>Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary&apos;s Hospital, The Catholic University of Korea, 505, Banpo-Dong, Seocho-Gu, Seoul, 137-040, South Korea</auth-address><titles><title>The Value of Early Wireless Esophageal pH Monitoring in Diagnosing Functional Heartburn in Refractory Gastroesophageal Reflux Disease</title><secondary-title>Digestive Diseases and Sciences</secondary-title></titles><periodical><full-title>Dig Dis Sci</full-title><abbr-1>Digestive diseases and sciences</abbr-1></periodical><pages>1-7</pages><keywords><keyword>Esophageal pH monitoring</keyword><keyword>Gastroesophageal reflux</keyword><keyword>Heartburn</keyword><keyword>Proton pump inhibitors</keyword></keywords><dates><year>2013</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(2013)Divisions of Gastroenterology, Department of Internal Medicine, Seoul; St Mary’s Hospital, the Catholic University of Korea, Seoul, KoreaDiagnostic yield studyLevel: IV230 patients (101 males, 129 females)Mean age: 49.7 ± 12.4?yearsIndication: Suspected GORDInclusion:≥18?years of ageExclusion: Previous oesophageal, gastric or duodenal surgery, GI organic disease, significant comorbidity, or GI bleedingIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to SCJDuration: 48 hoursAccuracy:Diagnostic yieldPrakash & Clouse ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Prakash</Author><Year>2005</Year><RecNum>522</RecNum><DisplayText>(2005)</DisplayText><record><rec-number>522</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">522</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Prakash, C.</author><author>Clouse, R. E.</author></authors></contributors><titles><title>Value of extended recording time with wireless pH monitoring in evaluating gastroesophageal reflux disease</title><secondary-title>Clinical Gastroenterology and Hepatology</secondary-title></titles><periodical><full-title>Clinical Gastroenterology and Hepatology</full-title></periodical><pages>329-334</pages><volume>3</volume><number>4</number><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1542-3565</isbn><accession-num>CCC:000234105200006</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://CCC:000234105200006</url></related-urls></urls><electronic-resource-num>10.1016/s1542-3565(05)00021-2</electronic-resource-num></record></Cite></EndNote>(2005)Division of Gastroenterology, Washington University, School of Medicine, St Louis, Missouri, USADiagnostic yield studyLevel: IV157 patients (100 females, 57 males)Mean age: 47 ± 1?years121 subjects were off therapy, 36 subjects were on therapyIndications: Typical reflux symptoms (55.4%) or atypical symptoms potentially attributable to GORD (44.6%)Inclusion:Patients who had been referred for pH monitoring to evaluate a predefined, suspected reflux symptom and who recorded this symptom at least once during the 2-day monitoring period were identifiedExclusion:OesophagitisIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJAccuracy:Incremental diagnostic yield (of prolonged monitoring)Scarpulla et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U2NhcnB1bGxhPC9BdXRob3I+

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ADDIN EN.CITE.DATA (2007)Department of General, Visceral, and Transplant Surgery, University Hospital of Tubingen, Tubingen, GermanyNon-randomised controlled trialLevel: III-2Quality: 9/26CXP3123 patientsBravo group: 36 males and 32 females, mean age 51?years (range 34–67)Catheter group: 29 males and 26 females, mean age 43?years (range 32–59)Inclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 5 cm above the upper border of the LESDuration: 48 hoursComparator:System: not statedInsertion: transnasallyPlacement: not statedDuration: 24 hoursAccuracy:Concordance (acid exposure, number of reflux episodes)Sweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA (2009)Functional GI Disease Unit, Clinic for Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland Diagnostic yield studyLevel: IV134 patients Mean age: 60?years (range 18–76) 58 males, 76 females Compared with 110 consecutive catheter pH controlsMean age: 57?years (range 16–85) 44 males, 66 femalesIndications Patients:Intolerance of catheter insertion, intolerance of catheter after intubation, or vomiting of catheter within 24?hours of the monitoring periodInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 48 hoursAccuracy:Diagnostic yieldSweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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Tm90ZT4A

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Tm90ZT4A

ADDIN EN.CITE.DATA (2011)Guy’s and St Thomas Hospitals, London, UKDiagnostic yield studyLevel: IV38 patients13 males, 25 femalesMedian age: 41.6?years (range 17–75)Indication: Reflux symptoms and no diagnosis of GORD on catheter-based pH monitoringInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 96 hoursComparator:24-, 48-, 72-hour Bravo pH monitoringAccuracy:Incremental diagnostic yield (of prolonged monitoring)Ward et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2FyZDwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2004)Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USADiagnostic yield studyLevel: IVQuality: Q2CX (no comparator)P260 patients (58 patients had enough data to be included)26 males, 34 femalesMean age 54?years (range 27–82)Indications:Document GORD before surgery, possible GORD with negative PPI trial, evaluate response to PPI, possible supra-oesophageal GORD, non-cardiac chest pain, evaluate response to Stretta procedure, previous failed pH testInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursAccuracyDiagnostic yieldWenner, Johnsson et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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dGU+AG==

ADDIN EN.CITE.DATA (2007)Department of Surgery, Lund University Hospital, Lund, SwedenRandomised crossover trialLevel: IIQuality: 20/2635 patients (31 patients had enough data to be included)15 males, 16 femalesMedian age: 52 yearsMedian BMI: 27 (range 24–28)Indications: Typical reflux symptoms (55%) and atypical reflux symptoms (45%)Inclusion:Patients referred for oesophageal pH monitoring Exclusion:Patients with coagulopathy, severe oesophagitis/stricture, portal hypertension, a pacemaker, age <20 or >70?years of age, previous gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJDuration: 48 hoursComparator:System: Slimline (Medtronic) Insertion: transnasallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursAccuracy:Concordance in acid exposure timeComparative diagnostic yieldWenner et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V2VubmVyPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2008); Wenner & Johansson et al. (2007)Department of Surgery, Lund University Hospital, Lund, SwedenComparative diagnostic yield studyLevel: III-2 Quality: 11.5/26CXP370 patients, but 64 had enough data to be included (39 males, 25 females) 55 controls (27 males and 28 females).Not all patients are included in the distal capsule outcomesIndications: Patients with typical reflux symptomsInclusion:Patients: presence of typical reflux symptoms such as heartburn and regurgitation. Symptoms had to occur more than twice weekly. Treatment with medical acid suppression had to result in complete symptom relief or a more than 50% reduction of the symptoms Exclusion:Coagulopathy, severe oesophagitis/stricture, portal hypertension, pacemaker, <20 or >70?years of age, history of gastro-oesophageal surgery, severe cardiopulmonary disease, symptoms suggestive of oesophageal motor disordersIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm above the SCJReference standard (for sensitivity and specificity):Clinical diagnosis: symptoms suggestive of GORD and responding to acid suppressionAccuracy:Comparative diagnostic yieldWong et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+V29uZzwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2005)The Neuro-Enteric Clinical Research Group, Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System and University of Arizona Health Sciences Center, Tucson, Arizona, USARandomised controlled trialLevel: IIQuality: 16.5/2650 patients Mean age: 50.2?years (range 21–79)26 males and 24 femalesIndication: Failure in controlling symptoms while on PPI therapy or for evaluation before anti-reflux surgeryInclusion:Not statedExclusion:Patients with a history of bleeding tendency or coagulopathy, significant concomitant medical co-morbidity, severe GI bleeding within the past 6?months, a history of upper GI surgery, oesophageal varices, pacemaker, implantable cardiac defibrillator, being unable to complete the 24-hour pH monitoring, unable to report daily activityIndex test:System: Bravo? wireless capsule systemInsertion: transnasally or transorallyPlacement: 5 cm above the upper border of the LOSDuration: 24 hoursComparator:System: Digitrapper Mark III (Medtronic)Insertion: transnasallyPlacement: 5 cm above the proximal margin of the LOS Duration: 24 hoursAccuracyConcordance (acid exposure time)Change in managementStudy settingStudy design / Quality appraisalStudy populationInclusion criteria / exclusion criteriaDiagnostic testsChange in management outcome assessedGawron et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2F3cm9uPC9BdXRob3I+PFll

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ADDIN EN.CITE.DATA (2012)Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USARetrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2The final sample consisted of 90 patients with a negative test, 66 Bravo monitoring and 24 impedance (75.6% female)Mean age: 48.4?yearsInclusion:Patients who had undergone Bravo monitoring from January 2006 to January 2010 while withholding PPI therapy, had total acid exposure <5% and a negative symptom index on both days Exclusion:Being on PPI therapy at the time of the test, prior surgery, Barrett’s oesophagus, oesinophilic oesophagitisIndex test:System: Bravo? wireless capsule systemInsertion: NSPlacement: NSDuration: 48 hoursComparator: NAManagement: % of patients who use PPIsGrigolon et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R3JpZ29sb248L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2011)Department of Gastroenterology, Universita Degli Studi and Fondazione IRCCS Ca Granada, Ospedale Maggiore Policlinico, Milan, ItalyMatched-pairs retrospective cohort studyLevel: III-2 Quality: 16.5/26CXP2102 patientsCatheter group: 51 patients, 20 males, mean age 48?years (range 22–78) Bravo group: 51 patients, 22 males, mean age 48?years (range 23–82)Inclusion:All consecutive patients who underwent wireless 96-hour pH monitoring between January and December 2007 off PPI therapy, and patients undergoing traditional 24-hour pH monitoring in the same period, after matching for the most troublesome symptom potentially related to GORD, sex and ageExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: NAPlacement: 6 cm above the SCJDuration: 48–96 hoursComparator:System: Slimline mod 901P3001, Medtronic, DenmarkInsertion: transnasallyPlacement: 6 cm above the point of sudden change in pH from acid to neutral as detected by means of continuous rapid withdrawal from the stomach, or 5 cm above the upper margin of the LOS Duration: 24 hoursManagement:Concordance between results of the test and treatmentLacy et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2009)Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USAProspective case seriesLevel: IVQuality: Q1CX (no comparator)P251 patients (50 patients had enough data to be included)24 males, 26 femalesMean age: 13?years (range 5–17)Indications: Heartburn, regurgitation, abdominal pain, nausea and/or vomiting, chest painInclusion:Not statedExclusion:Prior surgery to the oesophagus or stomach, known intestinal obstruction or oesophageal varices, achalasia, inability to understand the procedure, inability to undergo oesophageal manometry or sedationIndex test:System: Bravo? wireless capsule systemInsertion: not statedPlacement: 6 cm above the SCJDuration: 48 hoursComparator: NAManagement:Change in management (%)Lacy, Chehade & Crowell PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TGFjeTwvQXV0aG9yPjxZZWFy

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ADDIN EN.CITE.DATA (2011)Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USAProspective case seriesLevel: IVQuality: Q2CX (no comparator)P2309 patientsMean age: 48 ± 15?years107 males, 202 femalesIndications:Symptoms of acid reflux, evaluation of chest pain, preoperative testing, chronic cough, ENT symptomsInclusion:Adult patients (>18?years of age) referred for wireless pH-monitoring from October 2005 to December 2006Exclusion:Women who were pregnant, history of major facial or nasal trauma, presence of any serious medical condition that would prevent safe deployment of the wireless capsuleIndex test:System: Bravo? wireless capsule systemInsertion: transorally or transnasallyPlacement: 6 cm above the SCJ (orally) or 5 cm above the upper border of the LOS (nasally)Duration: 48 hoursComparator: NAManagement:Change in diagnosis (%)Change in management (%)Sweis et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3dlaXM8L0F1dGhvcj48WWVh

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Tm90ZT4A

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Tm90ZT4A

ADDIN EN.CITE.DATA (2011)Guy’s and St Thomas Hospitals, London, UKCase series Level: IVQuality: Q2CX (no comparator)P238 patients13 males, 25 femalesMedian age: 41.6?years (range 17–75)Indication: Reflux symptoms and no diagnosis of GORD on catheter-based pH monitoringInclusion:Not statedExclusion:Not statedIndex test:System: Bravo? wireless capsule systemInsertion: transorallyPlacement: 6 cm proximal to the SCJDuration: 96 hoursComparator: NAManagement Change in treatment Does management change health outcomes?True positivesStudy settingStudy design / Quality appraisalStudy population / Included studiesInclusion criteria / exclusion criteriaIntervention and comparatorHealth outcomes assessedAllgood & Bachmann PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QWxsZ29vZDwvQXV0aG9yPjxZ

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ADDIN EN.CITE.DATA (2000)Department of Social Medicine, MRC Health Services Research Collaboration, University of Bristol, Bristol, UKSystematic reviewLevel: III-2Quality: 14/27Six randomised controlled trials and three cohort studies that compared medical and surgical management of GORD were included, study population ranged from 15 to 155 patients per arm, 7/9 studies had fewer than 100 patients per arm Inclusion:All controlled trials of medical and surgical management of objectively diagnosed chronic GORD. Randomised trials were regarded as being most relevant, but non-randomised trials were also included, with an emphasis on assessing potential bias. There were no age or sex restrictionsExclusion:Not statedIntervention:Surgical treatment for GORDComparator: Medical treatment for GORDTime to treatment failureMean lower oesophageal pressureMean DeMeester acid reflux scoreReduction in grade of endoscopic oesophagitisMean % time pH <4 / absence of refluxDecrease in pulmonary medicationDevelopment of atrophic gastritisGalmiche et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FsbWljaGU8L0F1dGhvcj48

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ADDIN EN.CITE.DATA (2013)Health Services Research Unit, University of Aberdeen, Aberdeen, UKRandomised controlled trialLevel: IIQuality: 17/26810 original participants, 357 were randomised178 patients allocated to surgery, 111 received surgery, 127 had 5-year follow-up179 patients allocated to medication, 10 received surgery, 119 had 5-year follow-up Inclusion:Patients had had >12?months of maintenance treatment with PPIs (or alternative), reasonable control of GORD symptoms, evidence of GORD (endoscopy or pH monitoring), were suitable for both treatments and the recruiting doctor was uncertain which management policy to followExclusion:Not statedIntervention:Anti-reflux fundoplication (type of surgery was chosen by the surgeon)Comparator:Optimised continued medical management (reviewed and adjusted as judged best by local gastroenterologist)Health-related quality of life (REFLUX)Health status (SF-36, EuroQol)Use of anti-reflux drugsSurgical complicationsIndividual symptomsWileman et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Wileman Samantha</Author><Year>2010</Year><RecNum>613</RecNum><DisplayText>(2010)</DisplayText><record><rec-number>613</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">613</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>Wileman Samantha, M.</author><author>McCann, Sharon</author><author>Grant Adrian, M.</author><author>Krukowski Zygmunt, H.</author><author>Bruce, Julie</author></authors></contributors><titles><title>Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title></periodical><number>3</number><keywords><keyword>Fundoplication [methods]</keyword><keyword>Gastroesophageal Reflux [surgery] [therapy]</keyword><keyword>Health Status</keyword><keyword>Quality of Life</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Adult[checkword]</keyword><keyword>Humans[checkword]</keyword><keyword>Hm-uppergi</keyword></keywords><dates><year>2010</year></dates><publisher>John Wiley &amp; Sons, Ltd</publisher><accession-num>CD003243</accession-num><urls><related-urls><url>;(2010)Cochrane Collaboration, the Cochrane LibrarySystematic reviewLevel: IQuality: 23/27Four randomised controlled trials were included. Two studies were performed in multiple studies in the UK, one study was conducted in 11 European countries, and one study was conducted in a centre in Canada. Sample sizes ranged from 104 to 554 participants, with a total of 1,232 randomised patients Inclusion:All randomised controlled trials and quasi-randomised controlled trials comparing medical management with laparoscopic fundoplication surgeryExclusion:Non-randomised studiesIntervention:Surgery: laparoscopic fundoplication surgery (all types)Comparator:Medical management: either PPIs or histamine receptor antagonists (H2RAs)Health-related quality of lifeGORD-specific quality of lifeHeartburnRegurgitation (acid reflux)DysphagiaOther GORD-related symptomsConversion to open surgeryIntraoperative complicationsPostoperative complicationsAdmission to intensive treatment unit / high-dependency unitReoperationMortality during index admissionMedication use Length of operationLength of hospital stayTime off workVisits to GP due to GORDVisits to hospital due to GORDpH monitoring (% time pH <4 / DeMeester score)Manometry (LOS pressure)EndoscopyOther complications or adverse eventsFalse positivesStudy settingStudy design Study population / Included studiesInclusion criteria / exclusion criteria‘True diagnosis’ and misdiagnosisHealth outcomes assessedAuvin et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QXV2aW48L0F1dGhvcj48WWVh

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ADDIN EN.CITE.DATA (2012)Insitut National de la Santé et de la Recherche Medicale, Paris, FranceRetrospective case series83 infants diagnosed with infantile spasms were included (19 in Paris, 20 in Naples, 44 in Baltimore)Median age of onset symptoms: 6 months 28 patients (34%) were diagnosed more than 30?days after initial presentationInclusion:Not statedExclusion: Patients for whom data on diagnostic delay were unavailableTrue diagnosis: West syndrome or infantile spasmsMisdiagnosis:No diagnosis (behavioural symptoms, not organic): 301/362 physicians, 83.3%GORD: 7%Constipation: 7%Colitis: 3%Seizures at age 2?yearsPsychomotor development at age 2?yearsNapuri et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Napuri</Author><Year>2010</Year><RecNum>618</RecNum><IDText>1164-1166</IDText><DisplayText>(2010)</DisplayText><record><rec-number>618</rec-number><foreign-keys><key app="EN" db-id="xzw5efdflddz5ae2x035rp2fz22sewrvr0wr">618</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Napuri, S.</author><author>Le Gall, E.</author><author>Dulac, O.</author><author>Chaperon, J.</author><author>Riou, F.</author></authors></contributors><auth-address>Department of Child and Adolescent Medicine, CHU de Rennes, Rennes, France&#xD;Paediatric Neurology Department, H?pital Necker-Enfants Malades, AP-HP, Inserm U663, Paris, France&#xD;Faculty of Medicine, University Paris Descartes, Paris, France&#xD;Public Health Department, CHU de Rennes, Rennes, France</auth-address><titles><title>Factors associated with treatment lag in infantile spasms</title><secondary-title>Developmental Medicine and Child Neurology</secondary-title></titles><periodical><full-title>Developmental Medicine and Child Neurology</full-title></periodical><pages>1164-1166</pages><volume>52</volume><number>12</number><dates><year>2010</year><pub-dates><date>//</date></pub-dates></dates><urls><related-urls><url>;(2010)Department of Child and Adolescent Medicine, Rennes, FranceRetrospective case series156 infants diagnosed with infantile spasms were included87 male (55%), 69 female (45%)45 (29%) symptomatic spasmsMedian age onset: 20?weeks, mean age onset: 22.4?weeks (SD 13.3?weeks)Time lag from first symptom to diagnosis ranged from a few days to 44?weeks with a peak at 4?weeksInclusion:A combination of clusters of spasms, altered psychomotor development and paroxysmal EEG activity, as defined by the International League Against EpilepsyExclusion: Not statedTrue diagnosis:Infantile spasmsMisdiagnosis:Epilepsy: 96 (62%)GORD: 26 (17%)Healthy: 29 (18%)Miscellaneous: 5 (3%)Response to treatmentNA = not available; SCJ = squamo-columnar junction; LOS = lower oesophageal sphincter; GORD = gastro-oesophageal reflux disease; GI = gastrointestinal; PPIs = proton pump inhibitors; GOJ = gastro-oesophageal junction; RDQ = Reflux Disease Questionnaire; NS = not significantAppendix DExcluded studiesConference abstractsAng, D, Ang, TL, Lim, KB, Kiong, TE & Fock, KM 2009, 'To Bravo or not? wireless pH monitoring versus conventional nasopharyngeal pH catheter monitoring in the evaluation of gastroesophageal reflux disease in a multiracial Asian cohort', Gastroenterology, vol. 136, no. 5, pp. A295–A296.Ang, D, Ang, TL, Lim, KB, Teo, EK & Fock, KM 2010, 'Efficacy and safety of the wireless capsule pH monitoring system in the evaluation of gastroesophageal reflux disease (GERD): results from a multiracial Asian cohort', Gastroenterology, vol. 138, no. 5, p. S494.Ang, D, Ang, TL, Xu, Y, Poh, CH, Law, NM, Tan, M & Fock, KM 2012, 'Wireless oesophageal pH monitoring: feasibility, safety and establishing values in a multiracial cohort of asymptomatic Asian subjects', Journal of Gastroenterology and Hepatology, vol. 27, pp. 286–287.Bradley, AG, Crowell, MD, DiBaise, JK, Kim, HJ, Sharma, VK & Fleischer, DE 2009, 'Patient characteristics predict variation in tolerance of wireless pH-metry', Gastroenterology, vol. 136, no. 5, pp. A525–A526.Chander, B, Hanley-Williams, N, Deng, Y & Sheth, AA 2011, '48-hour BRAVO (wireless) esophageal pH monitoring improves symptom correlation as compared to 24-hour studies alone', Gastroenterology, vol. 140, no. 5, p. S251.Chehade, RJ, Lacy, BE & Crowell, MD 2010, 'Gastroesophageal reflux disease: a prospective study comparing a symptom-based reflux disease questionnaire to BRAVO pH capsule monitoring', Gastroenterology, vol. 138, no. 5, p. 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S390.Gillies, RS, Stratford, JM, Jones, L, Sohanpal, J, Booth, MI & Dehn, TCB 2004, 'Does a 48-hour Bravo pH study facilitate the diagnosis of gastro-oesophageal reflux disease', Gut, vol. 53, pp. A30.Gomez, J, Bohm, M & Richter, J 2009, 'Refractory gastroesophageal reflux disease (RGERD) patients with normal upper endoscopy (EGD) should have pH testing off proton pump inhibitors (PPIs)', Gastroenterology, vol. 136, no. 5, p. 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A291.Kushnir, V, Sayuk, GS & Gyawali, CP 2009, 'Improving diagnostic utility of ambulatory pH testing', Gastroenterology, vol. 136, no. 5, p. A84.Lee, SY, Park, YD, Yoon, SJ, Chung, YJ, Jeon, SW, Cho, CM, Tak, WY, Kweon, YO, Kim, SR, Choi, YH & Kim, JY 2007, 'Wireless esophageal pH monitoring: is it really tolerable?', Neurogastroenterology and Motility, vol. 19, pp. 65–66.Lin, E, Waring, JP, Ramaswamy, A, Swafford, V, Tucker, A, Khaitan, L, Ramshaw, BJ & Smith, CD 2003, 'Analysis of 245 consecutive studies using 48-hour wireless pH (BRAVO) probes for GERD evaluation', Gastrointestinal Endoscopy, vol. 57, no. 5, pp. AB100.Macdonald, J, Porter-Ritchie, V, Mackie, B & McNamara, D 2011, 'Assessment of tolerance, safety and efficacy of ambulatory oesophageal ph monitoring using the catheter-free Bravo system in a scottish population', Gut, vol. 60, pp. A182-A183.McCann, V & Nompleggi, D 2012, 'Chest discomfort with catheter-free ambulatory ph monitoring can be predicted by response to ppis', American Journal of Gastroenterology, vol. 107, p. S27.Morley-Fletcher, A, Souza, ALL, Nurko, S & Rodriguez, L 2009, 'Experience with BRAVO wireless pH study in children', Gastroenterology, vol. 1, p. A513.Rao, N, Campbell, DI, Narula, P, Taylor, C, Thomson, M & Rao, P 2012, 'Two year experience of a catheter-free, radio telemetric, oesophageal pH-monitoring (Bravo (TM)) system in children at a single UK tertiary centre', Archives of Disease in Childhood, vol. 97, p. A56.Rodriguez, L, Rosengaus, L, Morley-Fletcher, A & Nurko, S 2011, 'Does general anesthesia change the amount of gastroesophageal reflux in children? A study using BRAVO wireless ph capsule', Gastroenterology, vol. 140, no. 5, p. S748.Seren, S, Bayraktar, UD & Ehrinpreis, MN 2007, 'Esophageal pH monitoring with Bravo (TM) capsule in patients with suspected gastroesophageal reflux disease', American Journal of Gastroenterology, vol. 102, pp. S130.Seza, A, Odaka, T, Kobayashi, M, Yamaguchi, T, Genn, S, Suzuki, T & Saisho, H 2006, 'Esophageal and intragastric pH monitoring using a wireless system (BRAVO) to evaluate esophageal acid exposure and gastric acid secretion', Gastroenterology, vol. 130, no. 4, pp. A166.Sifrim, D 2012, '24-h esophageal pH-monitoring: why do we need more?', Diseases of the Esophagus, vol. 25, p. 7A.Souza, ALL, Morley-Fletcher, A, Nurko, S & Rodriguez, L 2009, 'BRAVO wireless pH in children: is there an effect of anesthesia?', Gastroenterology, vol. 136, no. 5, p. A510.Strohl, A, Khatri, N, Palese, C, Evans, S & Benjamin, S 2010, 'Is 48-hr Bravo pH monitoring more efficacious than 24-hr ph monitoring for patients with refractory gerd undergoing evaluation for Nissen fundoplication?', American Journal of Gastroenterology, vol. 105, p. S16.Sweis, R, Anggiansah, A, Anggiansah, R, Fox, MR & Wong, T 2009, '96 hour BRAVO increases yield in patients with negative 24-hour esophageal catheter pH test results', Gastroenterology, vol. 1, p. A286.Sweis, RR, Anggiansah, A, Anggiansah, R, Fox, M & Wong, T 2009, '96 hour Bravo increases yield in patients with negative 24-hour oesophageal catheter ph tests results', Gut, vol. 58, p. A33.Xu, B, Yuan, Y & Zhu, Q 2009, '48-hour wireless esophageal pH monitoring increases sensitivity in detecting abnormal esophageal acid exposure', Digestion, vol. 1, p. 71.Incorrect/irrelevant interventionCaparello, C, Bravi, I, Cantu, P, Grigolon, A, Tenca, A, Mauro, A & Penagini, R 2012, 'Traditional vs wireless intragastric pH monitoring: are the two techniques comparable?', Neurogastroenterology and Motility, vol. 24, no. 10, pp. 44– 49.Li, JN, Liu, CL & Tao, XH 2013, 'Clinical utility and tolerability of JSPH-1 wireless esophageal pH-monitoring system', BMC Gastroenterology, vol. 13, p. 10.Yamaguchi, T, Seza, A, Odaka, T, Shishido, T, Ai, M, Gen, S, Kouzu, T & Saisho, H 2006, 'Placement of the Bravo wireless pH-monitoring capsule onto the gastric wall under endoscopic guidance', Gastrointestinal Endoscopy, vol. 63, no. 7, pp. 1046–1050.Irrelevant outcomesGonzalez, JO & Barkin, JS 2005, 'Endoscopic visualization of deployment of the Bravo pH System to prevent malplacement', Gastrointestinal Endoscopy, vol. 62, no. 1, pp. 178–180.Unable to retrieve full textArmas, H & Cabrera, R 2005, 'Esophageal pH monitoring: indications and techniques', PHmetría esofágica: indicaciones y técnica, An Pediatr Contin, vol. 3, no. 4, pp. 253–256.Becmeur, F, Rebeuh, J & Molinaro, F 2009, 'Gastroesophageal reflux in children', [Le reflux gastro-?sophagien chez l'enfant], Médecine et Thérapeutique Pédiatrie, vol. 12, no. 1, pp. 45–51.Hagemann, D & Schmitz, F 2006, 'Esophageal pH monitoring with the BRAVO capsule: safety, tolerability and variability of the reflux pattern', [?sophagus-pH-metrie mit der BRAVO-Kapsel: Sicherheit, vertr?glichkeit und variabilit?t der refluxmuster], Der Gastroenterologe, vol. 1, no. 1, pp. 56–59.Hellmig, S & F?lsch, UR 2007, 'Gastroesophageal reflux disease: diagnosis and treatment of an endemic disease', [Gastro?sophageale refluxerkrankung: diagnostik und therapie einer volkskrankheit], Medizinische Klinik, vol. 102, no. 5, pp. 373–380.Labenz, J & Borkenstein, DP 2003, 'Pathophysiology and diagnosis of gastroesophageal reflux disease', [Pathophysiologie und diagnostik der refluxkrankheit], Internist, vol. 44, no. 1, pp. 11–19.Magistà, AM, Lionetti, E, Boscarelli, G, Chiarelli, T, Latela, S, Rigillo, N, Miniello, VL & Francavilla, R 2003, 'Instrumental diagnosis of gastroesophageal reflux', [Diagnostica strumentale del reflusso gastro-esofageo], Otorinolaringologia Pediatrica, vol. 13-14, pp. 26–33.Moreno, JP, Martínez, C, Del Mar Tolín Hernani, M & Calatayud, G? 2013, 'Diagnosis and treatment of gastroesophageal reflux', [Diagnóstico y tratamiento del reflujo gastroesofágico], Publicado en An Pediatr Contin, vol. 11, no. 1, pp. 1–10.Not in English, and not of a higher level of evidence than the English language literature des Varannes, BS, Roman, S, Mion, F, Letard, JC & Zerbib, F 2012, 'Wireless pH-monitoring: technical aspects and clinical contribution', Hepato-Gastro, vol. 19, no. 1, pp. 21–27.Carmona-Sánchez, R & Solana-Sentíes, S 2004, '[Efficacy, diagnostic utility and tolerance of intraesophageal pH ambulatory determination with wireless pH-testing monitoring system]', Revista de Gastroenterología de México, vol. 69, no. 2, pp. 69–75, <;.[No authors listed] 2007, '[Clinical guidelines of diagnosis and treatment of gastroesophageal reflux disease]', Revista de Gastroenterología de México, vol. 72, no. 2, pp. 163–176.Dantas, RO 2008, '[Electrode placement for esophageal pH recording]', Arquivos de Gastroenterologia, vol. 45, no. 4, pp. 259–260.Gonzalez Martinez, MA 2004, '[Ambulatory esophageal pH-monitoring with wireless system]', Revista de Gastroenterología de México, vol. 69, no. 2, pp. 111–113.Marchese, M, Spera, G, Spada, C & Costamagna, G 2004, 'Wireless pH-monitoring. [Italian] Capsula per studio pH-metrico', Giornale Italiano di Endoscopia Digestiva, vol. 27, no. 2, pp. 129–132.M?nkemüller, K, Neumann, H, Fry, LC, Kolfenbach, S & Malfertheiner, P 2009, '[Catheter-free pH-metry using the Bravo capsule versus standard pH-metry in patients with non-erosive reflux disease (NERD)]' Zeitschrift für Gastroenterologie, vol. 47, no. 4, pp. 351–356, DOI 10.1055/s-2008-1027945, < Diaz, MA, Remes Troche, JM, Ruiz Aguilar, JC, Schmulson, MJ & Valdovinos-Andraca, F 2004, 'Successful esophageal pH monitoring with Bravo capsule in patients with gastroesophageal reflux disease. [Spanish] [‘Medicion exitosa del pH esofagico con la capsula Bravo en pacientes con enfermedad por reflujo gastroesofagico'], Revista de Gastroenterología de México, vol. 69, no. 2, pp. 62–68.Irrelevant or incorrect study designBittinger, M & Messmann, H 2007, 'Gastroesophageal reflux disease and Barrett's esophagus', Endoscopy, vol. 39, no. 2, pp. 118–123.Chotiprashidi, P, Liu, J, Carpenter, S, Chuttani, R, DiSario, J, Hussain, N, Somogyi, L & Petersen, BT 2005, 'ASGE Technology Status Evaluation Report: wireless esophageal pH-monitoring system', Gastrointestinal Endoscopy, vol. 62, no. 4, pp. 485–487.Dranove, JE 2008, 'Focus on diagnosis: new technologies for the diagnosis of gastroesophageal reflux disease', Pediatrics in Review, vol. 29, no. 9, pp. 317–320.Fox, M 2006, 'Bravo wireless versus catheter pH-monitoring systems', Gut, vol. 55, no. 3, pp. 434–435.Federa??o Brasileira de Gastroenterologia, Sociedade Brasileira de Endoscopia Digestiva, Colégio Brasileiro de Cirurgia Digestiva & Sociedade Brasileira de Pneumologia e Tisiologia. 'Gastroesophageal reflux disease: diagnosis', 2011, Revista da Associacao Medica Brasileira, vol. 57, no. 5, pp. 489–497.Grigolon, A, Bravi, I, Duca, P, Pugliese, D & Penagini, R 2010, 'Prolonged wireless pH monitoring: importance of how to analyse oesophageal acid exposure', Scandinavian Journal of Gastroenterology, vol. 45, no. 9, pp. 1133–1134.Herbella, FA, Nipominick, I & Patti, MG 2009, 'From sponges to capsules: the history of esophageal pH monitoring', Diseases of the Esophagus, vol. 22, no. 2, pp. 99–103.Hess, T, Hahn, EG & Konturek, PC 2009, 'BRAVO wireless 48-hour pH-metric system', Medical Science Monitor, vol. 15, no. 1, pp. RA17–RA21.Holloway, RH 2005, 'Capsule pH monitoring: is wireless more?', Gut, vol. 54, no. 12, pp. 1672–1673.Horton, BE, Schweitzer, S, DeRouin, AJ & Ong, KG 2011, 'A varactor-based, inductively coupled wireless pH sensor', Ieee Sensors Journal, vol. 11, no. 4, pp. 1061–1066.Javors, BR & Bukman, R 2011, 'Radiographic demonstration of a wireless capsule pH monitor in the esophagus', Dysphagia, vol. 26, no. 2, pp. 193–195.Kahrilas, PJ & Pandolfino, JE 2005, 'Review article: oesophageal pH monitoring--technologies, interpretation and correlation with clinical outcomes', Alimentary Pharmacology & Therapeutics, vol. 22, Suppl 3, pp. 2–9.Lee, JS 2012, 'Is wireless capsule pH monitoring better than catheter systems?', Journal of Neurogastroenterology and Motility, vol. 18, no. 2, pp. 117–119.Malfertheiner, P, Asaka, M, Freston, JW 2006, 'Looking to the future: unmet needs in understanding and managing upper GI diseases', Drugs, vol. 66, pp. 1–33.Mainie, I, Tutuian, R & Castell, DO 2006, 'The limitations of pH monitoring for detecting gastroesophageal reflux', Clinical Gastroenterology and Hepatology, vol. 4, no. 9, p. 1184.Perez-de-la-Serna, J, Ruiz-de-Leon-San-Juan, A & Sevilla-Mantilla, C 2010, 'Proximal esophageal pH-monitoring', Revista Espa?ola de Enfermedades Digestivas, vol. 102, no. 7, pp. 403–405.Richter, JE 2009, 'Optimal utilization of esophageal pH monitoring in GERD patients', Gastroenterology and Hepatology, vol. 5, no. 4, pp. 249–251.Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) 2006, 'Special report: wireless esophageal pH monitoring', Executive summary, TEC Assessments, vol. 21, no. 2, pp. 1–2.Vaezi, MF 2006, 'Should we Bravo?', Gastroenterology, vol. 130, no. 7, pp. 2238–2239.Williams, C, Neshev, E, Heitman, S, Storr, M, Cole, M & Andrews, C 2009, 'A prospective, randomized trial comparing non-endoscopic, unsedated Bravo (TM) wireless pH capsule insertion versus conventional catheter-based pH monitoring', Canadian Journal of Gastroenterology, vol. 23, Supplement SA, Poster 137.Did not meet inclusion criteria regarding populationAng, D, Xu, Y, Ang, TL, Law, NM, Poh, CH, Teo, EK & Fock, KM 2013, 'Wireless oesophageal pH monitoring: Establishing values in a multiracial cohort of asymptomatic Asian subjects', Digestive and Liver Disease, vol. 45, no. 5, pp. 371–376.Friedman, M & Schalch, P 2007, 'Upper esophageal pH monitoring: transnasal placement of the Bravo wireless capsule system', Operative Techniques in Otolaryngology–Head & Neck Surgery, vol. 18, no. 4, pp. 324–328.Pandolfino, JE, Schreiner, MA, Lee, TJ, Zhang, Q, Boniquit, C & Kahrilas, PJ 2005, 'Comparison of the Bravo (TM) wireless and Digitrapper (TM) catheter-based pH-monitoring systems for measuring esophageal acid exposure', American Journal of Gastroenterology, vol. 100, no. 7, pp. 1466–1476.Pandolfino, JE, Zhang, Q, Ghosh, SK, Roth, MP, Boniquit, C & Kahrilas, PJ 2007, 'Does the Bravo (TM) pH capsule affect esophageal motor function?', Diseases of the Esophagus, vol. 20, no. 5, pp. 406–410.Pandolfino, JE, Zhang, Q, Schreiner, MA, Ghosh, S, Roth, MP & Kahrilas, PJ 2005, 'Acid reflux event detection using the Bravo wireless versus the Slimline catheter pH systems: why are the numbers so different?', Gut, vol. 54, no. 12, pp. 1687–1692.Appendix E Safety data Table 70Complications and adverse events of catheter-free monitoring compared with catheter-based monitoring in adultsStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringp-valueAdditional notesWenner, Johnsson et al. (2007) Level IIQuality: 20/26CXP2Randomised crossover trial31 participants catheter group31 participants wireless groupPatients’ experience, median cm VAS (IQR) Nose/throat symptoms: 0.2 (0.0–1.9)Swallow-induced symptoms: 2.1 (0.5–5.0)Chest symptoms: 2.4 (0.3–5.9)All adverse symptoms: 2.1 (0.5–4.6)Interference work activities: 0.3 (0.0–1.4)Interference physical activities: 0.6 (0.2–2.7)Interference food intake: 1.4 (0.2–4.9)Interference normal daily life: 0.7 (0.2–3.4)Patients’ experience, median cm VAS (IQR) Nose/throat symptoms: 6.5 (1.5–8.0)Swallow-induced symptoms: 5.2 (2.1–6.7)Chest symptoms: 1.1 (0.3–2.9)All adverse symptoms: 5.1 (2.0–6.6)Interference work activities: 6.8 (1.7–9.0)Interference physical activities: 5.0 (2.6–8.5)Interference food intake: 4.0 (1.8–7.0)Interference normal daily life: 5.7 (2.3–8.0)-<0.00010.0330.084<0.0010.005<0.00010.056<0.0001-Andrews et al. (2012)Level IIQuality: 19/26CXP2Dual centre, randomised, non-blinded trial43 participants catheter group43 participants wireless grouppH placement discomfort (mm VAS ± SE)Nasal: 6 ± 2Throat: 32 ± 4Chest: 14 ± 3Overall: 29 ± 4-pH-test discomfort (mm VAS ± SE)Nasal: 10 ± 3Throat: 19 ± 4Chest: 29 ± 4Overall: 26 ± 4Eating/drinking: 75 ± 5 Ability usual activities: 92 ± 2pH placement discomfort (mm VAS ± SE)Nasal: 36 ± 4Throat: 37 ± 3Chest: 13 ± 3Overall: 33 ± 4-pH-test discomfort (mm VAS ± SE)Nasal: 39 ± 3Throat: 43 ± 4Chest: 14 ± 3Overall: 39 ± 4Eating/drinking: 51 ± 4Ability usual activities: 75 ± 5-<0.0010.3170.9680.406--<0.001<0.0010.0010.012<0.001<0.0012 patients were unable to tolerate the nasal (standard) pH catheter and 1 patient did not tolerate peroral insertion of the capsule due to excessive gagging and anxietyWong et al. (2005)Level IIQuality: 16.5/26CXP2Randomised controlled trial25 participants catheter group25 participants wireless groupNose pain: 8 (32%)Runny nose: 13 (52%)Throat pain: 4 (16%)Throat discomfort: 12 (48%)Cough: 5 (20%)Chest discomfort: 9 (36%)Headache: 5 (20%)Nose bleeding: 1 (4%)Nose pain: 15 (60%)Runny nose: 24 (96%)Throat pain: 12 (48%)Throat discomfort: 23 (92%)Cough: 7 (28%)Chest discomfort: 2 (8%)Headache: 14 (56%)Nose bleeding: 00.0470.0010.0320.0010.5080.0370.0091.0-Grigolon et al. (2007)Level III-1Quality: 13.5/26CXP2Pseudo-randomised controlled trial78 participants catheter group55 participants wireless groupPlacement discomfort (mm VAS ± SE) 29 ± 4Discomfort during whole test (mm VAS ± SE)22 ± 3Limitation of food intake (score 0–3)0.4 ± 0.1Limitation of daily activities (score 0–3)0.2 ± 0.1None to mild discomfort: 41/55 (74.5%)Chest discomfort: 17/55 (30.9%)Placement discomfort (mm VAS ± SE) 32 ± 3Discomfort during whole test (mm VAS ± SE)37 ± 3Limitation of food intake (score 0–3)0.9 ± 0.1Limitation of daily activities (score 0–3)1.2 ± 0.1None to mild discomfort: 40/78 (51.3%)NS<0.001<0.05<0.001<0.0517/55 catheter-free monitoring: chest discomfort Sweis et al. (2009)Level III-2Quality: 15/26CXP1Cohort study110 participants catheter group134 participantswireless groupOverall satisfaction: 4.4/5Overall satisfaction: 3.5/5<0.001Bradley et al. (2011)Level III-2Quality: 15/26CXP2Cohort study106 participants catheter group234 participants wireless groupForeign body chest: 62%Foreign body throat: 21%Chest discomfort: 51%Chest pain: 33%Difficulty swallowing: 42%Painful swallowing: 44%Early fullness: 29%Diminished appetite: 24%Abdominal pain: 19%Nausea: 18%Vomiting: 6%Foreign body chest: 34% Foreign body throat: 22%Chest discomfort: 26%Chest pain: 19%Difficulty swallowing: 91%Painful swallowing: 62%Early fullness: 22%Diminished appetite: 32%Abdominal pain: 14%Nausea: 20%Vomiting: 6%0.0000.8870.0000.0090.0000.0020.1880.1440.3540.7661.000Ang et al. (2010)Level III-2Quality: 14/26CXP2Cohort study59 participants catheter group66 participants wireless group0 intolerance for device (0%)4 intolerance for device (6.8%)?Hakanson et al. (2009)Level III-2Quality: 14/26CXP2Case-control study45 volunteers and 47 patients (simultaneous recording) 0 complications0 complicationsNSGillies et al. (2007)Level III-2Quality: 13.5/26CXP2Non-randomised controlled trial 100 participants catheter group 85 participants wireless group (but 100 studies)27% no overall discomfort23% discomfort score >586% no impact on work attendance3% no overall discomfort45% discomfort score >518% no impact on work attendance<0.0001NS<0.0001Pandolfino et al. (2003)Level III-2Quality: 11.5/26CXP3Case-control study30 participants catheter group29 participants wireless groupSatisfaction (the lower the better): 0.8 ± 0.1Throat discomfort: 4/29Oesophageal discomfort: 10/29Change daily routine: 0/29Affected diet: 3%Affected activity: 0%Disrupted sleep: 2/22Satisfaction (the lower the better): 1.9 ± 0.2Throat discomfort: 22/30Oesophageal discomfort: 5/30Change daily routine: 11/30Affected diet: 47%Affected activity: 60%Disrupted sleep: 9/30<0.001<0.001<0.05<0.001<0.001NSWireless group: 2 subjects had discomfort to the extent that the capsule had to be removed; 1 non-detachment; 4 had moderate chest painSchneider et al. (2007)Level III-2Quality: 9/26CXP3 Non-randomised controlled trial55 participants catheter group78 participants wireless groupThroat discomfort: 3 (3.8%)Oesophagus discomfort: 14 (17.9%)Reduced activities: 5 (6.4%)Reliability: 75 (96.1%)Throat discomfort: 52 (94.5%)Oesophagus discomfort: 18 (32.7%)Reduced activities: 55 (100%)Reliability: 54 (98.1%)0.001NS0.0001NSTable 71Complications and adverse events of catheter-free monitoring compared with catheter-based monitoring in childrenStudyLevel and qualityNWireless pH monitoringCatheter-based pH monitoringp-valueCroffie et al. (2007)Level IIQuality: 14.5/25CXP2Randomised controlled trial16 participants catheter group18 participants wireless group Vomiting more than usual 6/18 (33%)Chest pain 7/18 (39%)Throat pain 8/18 (44%)Oesophageal discomfort 7/18 (39%)Appetite on scale from 1–5: 3.54Activity on scale from 1–5: 3.66 Overall satisfaction on scale from 1–5: 4.31Vomiting more than usual 3/16 (19%)Chest pain 1/16 (6%)Throat pain 15/16 (94%) Oesophageal discomfort 11/16 (69%)Appetite on scale from 1–5: 2.72Activity on scale from 1–5: 2.33Overall satisfaction on scale from 1–5: 3.110.250.020.0010.060.0290.0010.003Table 72Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in adultsStudyLevel and qualityPopulation Complications per procedureLacy et al. (2011)Level IVQ1Post-test case series375 patients1/375 procedures1 transient chest discomfortNusrat, Roy & Bielefeldt (2012)Level IVQ1Retrospective case series356 patients0/356 proceduresAll patients tolerated the study without significant side effectsCrowell et al. (2008)Level IVQ1Case series294 patients?/294 procedures147 foreign-body sensation121 chest discomfort82 chest pain82 diminished appetiteTseng et al. (2005)Level IVQ1Retrospective case series190 procedures, 186 patients?/190 procedures1 extreme gagging2 sufficient chest painMost patients noted a foreign-body sensationAhlawat et al. (2006)Level IVQ1Retrospective case series82 patients4/82 procedures4 severe chest pain53 patients were physically aware of the presence of the pH-monitoring capsule in the oesophagus, symptoms ranging from a foreign-body sensation to a mild discomfort, to chest painTharavej et al. (2006)Level IVQ1Case series80 patients10/80 procedures10 new onset chest painIn 6 of these patients the chest pain was associated with hypertensive oesophageal contractionsRemes-Troche et al. (2005)Level IVQ1Prospective case series77 patients51/77 procedures26 chest pain11 foreign-body sensation5 nausea9 patients had more than one symptomdes Varannes et al. (2005)1Level IVQ1In-subject simultaneous recording study40 patients4/40 procedures2 placement failures due to poor tolerance with vomiting1 dizzy spell during insertion1 epistaxisMarchese et al. (2006)Level IVQ1Prospective case series39 patients7/39 procedures2 severe retrosternal chest pain2 mild epistaxis3 pharyngeal irritationKaramanolis et al. (2012)Level IVQ1Post-test case series32 patients4/32 procedures3 throat pain2 back pain1 globus sensation1 patient with 2 symptomsTu et al. (2004)Level IVQ1Prospective case series30 patients1/30 procedures1 mucosal abrasion and minor haemorrhageAzzam et al. (2012)aLevel IVQ1In-subject simultaneous recording study25 patients0/25 proceduresNo patient experienced severe chest pain or any other symptom requiring endoscopic removal of the capsulePrakash et al. (2006)Level IVQ2Retrospective case series452 patients8/452 procedures (but this only gives the major side effects of the patients who requested removal of the capsule)7 severe chest pain and/or odynophagia1 severe foreign-body sensationBhat, McGrath & Bielefeldt (2006)Level IV Q2Prospective case series203 patients19/203 procedures18 significant chest discomfort1 rashTurner et al. (2007)Level IVQ2Case series191 patients1/191 procedures1 intolerable chest pain requiring capsule removalDomingues, Moraes-Filho & Domingues (2011)Level IVQ2Retrospective case series74 patients19/74 procedures17 mild foreign-body sensation2 chest pain during meal periodsScarpulla et al. (2007)Level IVQ2Retrospective case series83 patients21/83 procedures21 occasional retrosternal discomfort on swallowingFrancis (2008)Level IVQ2Retrospective case series76 patients 4/76 procedures1 severe chest pain1 capsule dislodgement in the mouth1 capsule dislodgement in the pyriform sinus1 capsule dislodgement in the stomachde Hoyos & Esparza (2010); de Hoyos, Esparza & Loredo (2010)Level IVQ2Prospective case series66 patients2/66 procedures1 intolerable chest pain1 detachment failureTankurt et al. (2011)Level IVQ2Case series64 patients11/64 procedures11 mild to moderate retrosternal pain or discomfortGarrean et al. (2008)Level IVQ2Post-test case series60 patients8/60 procedures3 back pain3 throat pain1 globus sensation1 chest painBelafsky et al. (2004)Level IVQ2Prospective case series46 patients9/46 procedures2 laryngospasm 2 epistaxis1 vasovagal reaction4 foreign-body sensationSweis et al. (2011)Level IVQ2Case series38 patients0/38 proceduresNo patient complained of severe symptoms during the study and no capsule needed to be removedCalabrese et al. (2008)Level IVQ2Post-test case series24 patients5/24 procedures5 occasional retrosternal discomfort on swallowingHirano et al. (2005)Level IVQ2Post-test case series18 patients0/18 proceduresNo patient reported any adverse events of the Bravo procedure such as chest pain, dysphagia or bleedingPandolfino et al. (2006)aLevel IVQ2Case-control study10 control subjects and 10 patients with GORD7/20 procedures7 mild chest discomfort or foreign-body sensationSofi et al. (2011)Level IVQ3Retrospective case series58 patients?/58 procedures19 sore throat17 dysphagia13 chest pain (2 with severe chest pain)6 cough12 patients had day(s) off workLee et al. (2005)Level IVQ3Post-test case series40 patients18/40 procedures1 retrosternal discomfort with protuberant mucosal lesion17 retrosternal foreign-body discomfortaThese studies are not case series but are still included as level IV safety evidence because they do not report a(n) (appropriate) comparison regarding complications or adverse events.Table 73Complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoring in childrenStudyLevel and qualityPopulation Complications per procedureCabrera et al. (2011)Level IVQ1Prospective case series289 children1/289 procedures1 failure to release capsule with tear of oesophageal mucosaGunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008)Level IVQ1Case series58 children 5/58 procedures1 mild chest discomfort1 period of coughing3 dysphagiaHochman & Favaloro-Sabatier (2005)Level IVQ2Retrospective case series38 children26/38 procedures26 discomfort7 significant discomfortBothwell, Phillips & Bauer (2004)Level IVQ2Retrospective case series25 children1/25 procedures1 superficial mucosal tearTable 74Case reports reporting complications and adverse events resulting from catheter-free (wireless) oesophageal pH monitoringStudyStudy designPopulationComplications per procedureAgrawal, Kerman & Rich (2009)Case report1 patient1/1 procedure:1 severe retrosternal chest discomfortFajardo et al. (2006)Case report1 patient1/1 procedure:1 oesophageal perforationHogan et al. (2009)Case report1 patient1/1 procedure:1 retention (>2?years) of the capsule in a colonic diverticulum Kramer & Chokhavatia (2012)Case report1 patient1/1 procedure:1 capsule dislodgement in the left pyriform sinusShahid & Fisher (2011)Case report1 patient1/1 procedure:1 capsule dislodgement in the left mainstem bronchusTriester et al. (2005)Case report1 patient1/1 procedure:1 sharp substernal chest pain and dyspnoeaRenteln et al. (2008)Case report1 patient1/1 procedure:1 capsule aspiration and decreased oxygen saturationTable 75Chest discomfort / complications resulting from catheter-free (wireless) oesophageal pH monitoring in adultsStudyLevel and qualityPopulation Chest discomfort / complications per procedureLacy et al. (2011)Level IVQ1Post-test case series375 patients1/375 procedures1 transient chest discomfortCrowell et al. (2008)Level IVQ1Case series294 patients203/294 procedures121 chest discomfort82 chest painTseng et al. (2005)Level IVQ1Retrospective case series190 procedures, 186 patients2/190 procedures2 sufficient chest painAhlawat et al. (2006)Level IVQ1Retrospective case series82 patients4/82 procedures4 severe chest pain53 patients were physically aware of the presence of the pH-monitoring capsule in the oesophagus, with symptoms ranging from a foreign-body sensation to a mild discomfort, to chest painTharavej et al. (2006)Level IVQ1Case series80 patients10/80 procedures10 new onset chest painIn 6 of these patients the chest pain was associated with hypertensive oesophageal contractionsRemes-Troche et al. (2005)Level IVQ1Prospective case series77 patients26/77 procedures26 chest painMarchese et al. (2006)Level IVQ1Prospective case series39 patients2/39 procedures2 severe retrosternal chest painAzzam et al. (2012)aLevel IVQ1In-subject simultaneous recording study25 patients0/25 proceduresNo patient experienced severe chest pain or any other symptom requiring endoscopic removal of the capsulePrakash et al. (2006)Level IVQ2Retrospective case series452 patients7/452 procedures (but this only gives the major side effects of the patients who requested removal of the capsule)7 severe chest pain and/or odynophagiaBhat, McGrath & Bielefeldt (2006)Level IV Q2Prospective case series203 patients18/203 procedures18 significant chest discomfortTurner et al. (2007)Level IVQ2Case series191 patients1/191 procedures1 intolerable chest pain requiring capsule removalDomingues, Moraes-Filho & Domingues (2011)Level IVQ2Retrospective case series74 patients2/74 procedures2 chest pain during meal periodsScarpulla et al. (2007)Level IVQ2Retrospective case series83 patients21/83 procedures21 occasional retrosternal discomfort on swallowingFrancis (2008)Level IVQ2Retrospective case series76 patients1/76 procedures1 severe chest painde Hoyos & Esparza (2010); de Hoyos, Esparza & Loredo (2009)Level IVQ2Prospective case series66 patients1/66 procedures1 intolerable chest painTankurt et al. (2011)Level IVQ2Case series64 patients11/64 procedures11 mild to moderate retrosternal pain or discomfortGarrean et al. (2008)Level IVQ2Post-test case series60 patients1/60 procedures1 chest painCalabrese et al. (2008)Level IVQ2Post-test case series24 patients5/24 procedures5 occasional retrosternal discomfort on swallowingHirano et al. (2005)Level IVQ2Post-test case series18 patients0/18 proceduresNo patient reported any adverse events of the Bravo procedure such as chest pain, dysphagia or bleedingPandolfino et al. (2006)aLevel IVQ2Case-control study10 control subjects and 10 patients with GORD7/20 7 mild chest discomfort or foreign-body sensationSofi et al. (2011)Level IVQ3Retrospective case series58 patients13/5811 chest pain2 severe chest painLee et al. (2005)Level IVQ3Post-test case series40 patients18/40 procedures1 retrosternal discomfort with protuberant mucosal lesion17 retrosternal foreign-body discomfortaThese studies are not case series but are still included as level IV safety evidence because they do not report a(n) (appropriate) comparison regarding complications or adverse events.Appendix F Non-comparative technical efficacy dataTable 76Technical efficacy of catheter-free (wireless) oesophageal pH monitoring in adultsStudyStudy designN Technical/operative/equipment/recording failureLacy et al. (2011)Case seriesLevel: IVQuality: Q1CX P2358 patients6/358 procedures: (1.7%)6 early detachments or loss of signalNusrat, Roy & Bielefeldt (2012)Retrospective case seriesLevel: IVQuality: Q1CX P2356 patients6/356 procedures: (1.7%)6 early detachmentsPark et al. 2013(2013)Case seriesLevel: IVQuality: Q1CXP2230 patients32/230 procedures: (13.9%)17 early detachments10 attachment failures or misplacements5 recording failuresTseng et al. (2005)Retrospective case seriesLevel: IVQuality: Q1CX P2209 patients (and 213 procedures)23/213 procedures (10.8%):18 incomplete data captures (<18?hours on at least 1?day)5 early detachmentCrowell et al. (2009)Case seriesLevel: IVQuality: Q1CXP2180 patients15/180 procedures (8.3%)15 early detachmentsDoma et al. (2010)Post-test case seriesLevel: IVQuality: Q1CX P2161 patients56/161 procedures: (38.0%)56 errors in placement (inaccurate placement of the capsule)Iqbal et al. (2007)Retrospective case seriesLevel: IVQuality: Q1CX P2100 patients11/100 procedures (11.0%)11 early detachmentsAhlawat et al. (2006)Retrospective case seriesLevel: IVQuality: Q1CX P290 patients9/90 procedures: (10.0%)3 failure to transmit data to receiver1 capsule failed to deploy from catheter4 incomplete data captures1 failure of attachment to the oesophageal mucosaPandolfino et al. (2003)aCase-control studyLevel: IVQuality: Q1CX (clinical diagnosis)P341 patients and 44 volunteers3/85 procedures (3.5%):2 capsules failed to deploy from catheter1 detachment failureRemes-Troche et al. (2005)Prospective case seriesLevel: IVQuality: Q1CX P284 patients7/84 procedures (8.3%):4 attachment failures3 early detachmentsBansal et al. (2009)Case seriesLevel: IVQuality: Q1CXP248 patients8/48 procedures: (16.7%)4 premature detachments2 cardia placements2 incomplete data capturesMarchese et al. (2006)Prospective case seriesLevel: IVQuality: Q1CX P238 patients2/38 procedures (5.3%):1 capsule displacement (in the stomach)1 failure because of previous nasal surgery (tight nasal vault?)Tu et al. (2004)Prospective case seriesLevel: IVQuality: Q1CXP230 patients1/30 procedures (3.3%)1 attachment failureBhat, McGrath & Bielefeldt (2006)Prospective case seriesLevel: IVQuality: Q2CX P2217 patients10/217 procedures (4.6%):1 capsule failed to deploy from catheter2 receiver malfunction7 early detachmentsTurner et al. (2007)Case seriesLevel: IVQuality: Q2CX P2191 patients42/191 procedures (22.0%):27 incomplete data captures15 early detachmentGillies et al. (2007)aNon-randomised controlled trialLevel IVQuality: Q2CXP2100 procedures (85 patients) in catheter-free group 17/100 procedures (17%)7 early detachments4 incomplete or no data capture6 failures of attachment to the oesophageal mucosaDomingues, Moraes-Filho & Domingues (2011)Retrospective case seriesLevel: IVQuality: Q2CX P2100 patients7/100 procedures (7.0%):1 failure of attachment to the oesophageal mucosa2 early detachments2 recording failure2 downloaded data lostScarpulla et al. (2007)Retrospective case seriesLevel: IVQuality: Q2CX P283 patients9/83 procedures (10.8%):4 failures to deploy or transmission failures5 early detachmentsFrancis (2008)Retrospective case seriesLevel: IVQuality: Q2CX P276 patients9/76 procedures (11.8%):5 technical failures2 early detachments4 failures of attachment to the oesophageal mucosaWenner et al. (2007 & 2008)aDiagnostic case-control studyLevel: IVQuality: Q2CXP370 patients4/70 procedures (5.7%):1 failure to pass through the upper oesophagus1 early detachment1 technical failure1 placement failurede Hoyos & Esparza (2010); de Hoyos, Esparza & Loredo (2009)Prospective case seriesLevel: IVQuality: Q2CX P266 patients9/66 procedures (13.6%):3 capsules had poor data reception3 early detachments1 transmission failure1 detachment failure1 error in placementTankurt et al. (2011)Case seriesLevel: IVQuality: Q2CXP264 patients2/64 procedures (3.1%):2 early detachmentsWard et al. (2004)Case seriesLevel: IVQuality: Q2CX P260 patients9/60 procedures (15%):7 failures of attachment to the oesophageal mucosa2 failures to retrieve data from recorderGarrean et al. (2008)Post-test case series Level: IVQuality: Q2CX P260 patients1/60 procedures (1.7%):1 capsule malfunctionGrigolon et al. (2011)aOne arm of matched pairs retrospective cohort studyLevel: IVQuality: Q2CXP257 patients in the catheter-free group 6/57 procedures (10.5%):3 incomplete data capture3 early detachmentBelafsky et al. (2004)Prospective case seriesLevel: IVQuality: Q2CXP246 patients6/46 procedures (13.0%):2 failures because of tight nasal vault 2 early detachments1 lost data recorder1 capsule failed to deploy from catheterSweis et al. (2011)Case seriesLevel: IVQuality: Q2CX P238 patients0/38 procedures (0%):0 early detachments (detachment occurred between 48 and 72?hours in 5 patients and between 72 and 96?hours in 12 patients)Martinez de Haro et al. (2008)aOne arm of non-randomised controlled trialLevel: IVQuality: Q2CXP225 patients and 10 volunteers6/35 procedures (17.1%)3 incorrect placements2 early detachments1 immediate detachment with aspirationBechtold et al. (2007)Retrospective case seriesLevel: IVQuality: Q2CXP227 patients1/27 procedures (3.7%): 1 early detachmentFrancis et al. (2012)aRandomised blinded controlled trialLevel: IV Quality: Q2C1P222 patients0/22 procedures (0%):All capsules were placed successfully on the first attemptPandolfino et al. (2006)aCase-control studyLevel: IV Quality: Q2CX (clinical diagnosis)P310 patients and 10 volunteers2/20 procedures (10%):2 early detachmentsSofi et al. (2011)Retrospective case seriesLevel: IVQuality: Q3CXP258 patients5/58 procedures (8.6%):2 malfunctions of the device during insertion3 transmission failuresLee et al. (2005)Prospective case seriesLevel: IVQuality: Q3CX P240 patients4/40 procedures (10%):3 attachment failures1 early detachmentaThese studies are not case series but are still included as level IV safety evidence because they do not report a(n) (appropriate) comparison regarding technical efficacy.Table 77Technical efficacy of catheter-free (wireless) oesophageal pH monitoring in childrenStudyStudy designNTechnical/operative/equipment/recording failureCabrera et al. (2011)Prospective case seriesLevel: IVQuality: Q1CXP2289 children41/289 procedures (14.2%)3 capsules failed to calibrate8 failures of attachment to the oesophageal mucosa4 capsules failed to deploy from catheter1 recording failure4 early detachments21 incomplete data capturesGunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008)Case seriesLevel: IVQuality: Q1CX P258 children3/58 procedures (5.2%):1 transmission failure2 attachment failuresHochman & Favaloro-Sabatier (2005)Retrospective case seriesLevel: IVQuality: Q2CX P250 children5/50 procedures (10%):1 failure of attachment to the oesophageal mucosa4 shorter monitoring periods Appendix G Day-to-day variability in oesophageal acid exposureTable 78Day-to-day variability in oesophageal acid exposure with catheter-free monitoring in adultsStudyLevel and qualityNOutcomesDay 1Day 2p-value Correlation co-efficientdes Varannes et al. (2005)In-subject simultaneous recording studyLevel: II Quality: 20/26CXP230 patientsMedian % total time pH <4 (25%–75%)Number of reflux episodes >5 minutesNumber of reflux episodes24-hour acid exposure values2.4 (0.7–3.9)2 (1–5)23 (10–32)3.3 (1.4–7.5)4 (2–8)23 (13–36)<0.040.07NS0.79Grigolon et al. (2007)Pseudo-randomised controlled trialLevel: III-1Quality: 13.5/26CXP255 patients% total time pH <4 3.4 (0.6–9.8)4.9 (1.7–8.3)NSGillies et al. (2007)Non-randomised Controlled trialLevel: III-2Quality: 13.5/26CXP289 patientsMedian % total time pH <4 (IQR)Median % upright time pH <4 (IQR)Median % supine time pH <4 (IQR)DeMeester score4.0 (1.2–10.3)5.0 (1.4–12.0)0.5 (0–5.0)15.9 (5.1–34.6)4.3 (1.0–10.0)5.0 (1.5–11.3)0.5 (0–3.9)16.2 (4.5–34.8)0.640.560.230.90Hakanson et al. (2009)Case-control study with in-subject simultaneous recordingLevel: III-2Quality: 14/26C1 (for accuracy)P255 patientsMedian % total time pH <4 in 1st series of patients (5th–95th percentile)Median % total time pH <4 in 2nd series of patients (5th–95th percentile)3.2(0.1–7.9)2.4(0–9.6)6.9 (0.7–16.3)5.2 (0.2–14.8)Pandolfino et al. (2003)Case seriesLevel: Q2Quality: 11.5/26CX (clinical diagnosis)P337 patientsMean % total time pH <4 (SEM)Mean % upright time pH <4 (SEM)Mean % supine time pH <4 (SEM)6.6 (0.8–27.6)7.9 (1.40–29.1)1.2 (0.0–23.9)7.7 (0.9–28.6)7.2 (1.1–31.1)1.5 (0.0–45.5)NSNSNSAyazi et al. (2011)Case seriesLevel: IVQuality: Q1CX (no comparator)P2310 patients% total time pH <4% upright time pH <4% supine time pH <4Number of reflux episodesNumber of episodes >5 minutesLongest reflux episode (minutes)Composite pH scoreAbnormal composite pH score on 1 of the 2 daysOnly abnormal pH score on day 1Only abnormal pH score on day 2% total time pH <4 (day 1 vs day 2)Composite pH score (day 1 vs day 2)3.7 (1.0–9.9)4.5 (1.2–12.1)0.3 (0.0–11.5)39 (13–74)2 (0–7)10 (3–25)13.1 (4.7–32.0) 19% (60/310)45% (27/60)55% (33/60)4.5 (0.9–9.7)4.8 (1.0–11.5)0.3 (0.0–6.3)36 (14.5–76)2 (0–7)9 (3.0–21.5)14.4 (3.9–30.5)0.16790.52380.49630.57460.38690.30060.65520.94 (0.93-0.95)0.83 (0.79-0.86)Tseng et al. (2005)Retrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2190 patients% total time pH <4 more than 5.3% (N)DeMeester score >14.7 (N)961068778Crowell et al. (2009)Case seriesLevel: IVQuality: Q1CX (no comparator)P2165 patients% total time pH <46.97.60.20Chander et al. (2012)Retrospective case seriesLevel: IVQuality: Q1CX (no comparator)P2124 patientsMedian % total time pH <4 (range)Median % upright time pH <4 (range)Median % supine time pH <4 (range)Median number of reflux episodes (range)DeMeester scores3.55 (0.00–29.90)4.50 (0.00–35.30)0.80 (0.00–46.40)35.50 (0.00-253.00)13.25 (0.30-104.00)3.75 (0.00–29.10)5.50 (0.00–32.10)0.20 (0.00–28.80)38.5 (0.00–299.00)15.15 (0.00–96.20)0.80920.54640.1778<0.0001NAAhlawat et al. (2006)Retrospective case seriesLevel: IVQuality: Q1CX (no comparator)P282 patientsSignificant correlation in reflux patterns in patients from day 1 to day 2No predictable pattern of reflux seen 74.4%28% (23/82)Remes-Troche et al. (2005)Prospective case seriesLevel: IVQuality: Q1CX (no comparator)P277 patientsMedian % total time pH <4 (range)Median % upright time pH <4 (range)Median % supine time pH <4 (range)Mean number of reflux episodes ± SEMean number of long reflux episodes ± SE5.5 (0–35)5.9 (0–22)1.4 (0–31.3)45.3 ± 34.2 ± 0.55.7 (0–22)6.0 (0–20)0.66 (0–24)65 ± 53.05 ± 0.9NSNSNS0.004NSPrakash & Clouse (2006)Case seriesLevel: IVQuality: Q1CX (no comparator)P262 patients% total time pH <4 off therapy% total time pH <4 on therapy5.2 ± 0.81.6 ± 0.45.6 ± 0.90.8 ± 0.4Lacy et al. (2009)Prospective case seriesLevel: IVQuality: Q1CX (no comparator)P250 patientsMean % total time pH <4 (SD)Mean total time pH <4 (SD)Mean total number of reflux episodes (SD)Mean total number of long reflux episodes (SD)Mean DeMeester score (SD)Abnormal study (% time pH <4 is more than 6%)6.6 ± 5.990.2 ± 82.780 ± 523 ± 424.7 ± 21.628 (56%)5.4 ± 4.674.6 ± 64.267 ± 443 ± 319.4 ± 15.921 (42%)Bhat, McGrath & Bielefeldt (2006)Prospective case seriesLevel: IVQuality: Q2CX (no comparator)P2203 patients% time abnormal pH5.5 (CI = 2.1–10.4)4.2 (CI = 1.2–9.2)<0.001Turner et al. (2007)Case seriesLevel: IVQuality: Q2CX (no comparator148 patients% total time pH <4 is more than 4% (N)% upright time pH <4 is more than 6.3% (N)% supine time pH <4 is more than 1.2% (N)7667546551530.03Korrapati et al. (2011)Retrospective case seriesLevel: IVQuality: Q2CX (no comparator)P2108 patients% total time pH <4: mean, median, SD (range)% upright time pH <4: mean, median, SD (range)% supine time pH <4: mean, median, SD (range)DeMeester score: mean, median, SD (range)6.36, 4.85, 7.60 (0.0–48.1)7.31, 5.70, 7.55 (0.0–41.4)4.01, 0.25, 8.94 (0.0–60.2)22.0, 16.3, 25.7 (0.0–163.7)6.02, 4.25, 8.02 (0.0–67.1)6.52, 4.85, 7.89 (0.0–59.6)4.66, 0.00, 12.20 (0.0–87.4)21.1, 15.2, 25.6 (0.0–213.0)0.730.05760.560.90Domingues, Moraes-Filho & Domingues (2011)Retrospective case seriesDiagnostic yield studyLevel: IVQuality: Q2CX (no comparator)P274 patientsAbnormal pH data (total time pH <4 is >4.4%)Positive SAP51 (68.9%)19 (44.1%)49 (70.2%)17 (40.4%)Belafsky et al. (2005)Retrospective case seriesLevel: IVQuality: Q2CX (no comparator)P278 sedated placements and 128 unsedated placementsMean reflux episodes (sedated group)Mean reflux episodes (unsedated group)% total time pH <4 (sedated group)% total time pH <4 (unsedated group) Mean composite score (sedated group)Mean composite score (unsedated group)Number of reflux episodes day 1 : day 2% total time pH <3 day 1 : day 2 Composite score day 1 : day 2Number of long reflux episodes day 1 : day 246565.56.718.323.346525.16.818.222.20.7150.6500.6940.773Garrean et al. (2008)Post-test case seriesLevel: IVQuality: Q2CX (no comparator)P260 patientsNumber of reflux episodes (median)2420NSBechtold et al. (2007)Retrospective case seriesLevel: IVQuality: Q2CX (no comparator)P226 patients% total time pH <4% total upright time pH <4% total supine time pH <4Number of reflux episodes (mean)Number of long reflux episodes (mean)Mean duration of long refluxes (minutes)Total heartburn episodesHeartburn episodes with pH <4Symptom score10.411.79.465.36.826.56.22.50.3237.16.310.055.63.819.78.02.90.2540.00490.00510.85960.02570.00770.06170.27520.6860.1353NS = not significantTable 79Day-to-day variability in oesophageal acid exposure with catheter-free monitoring in childrenStudyLevel and qualityNOutcomesDay 1Day 2p-value Croffie et al. (2007)Level: IIQuality:14.5/26Randomised controlled trial27 childrenMedian reflux index (range)2.3 (0.4–16.6)2.8 (0.2–15.6)0.345Gunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008)Case seriesLevel: IVQuality: Q1CX (no comparator)P258 childrenMedian % total time pH <4, SD (range)Median number of reflux episodes, SD (range)Median number of long reflux episodes, SD (range)Median longest reflux episode, SD (range)DeMeester score, SD (range)5.4 ± 6.8 (0–32.2)60 ± 47 (0–203)3 ± 5 (0–70)13 ± 15 (0–70)20.5 ± 23.7 (0.3–112.4)6.2 ± 8.4 (0–41.2)59 ± 51 (0–258)3 ± 5 (0–26)17 ± 20 (0–83)22.9 ± 28.7 (0.3–140.8)NSNSNSNSNSHochman & Favaloro-Sabatier (2005)Retrospective case seriesLevel: IVQuality: Q2CX (no comparator)P244 childrenMedian number of reflux episodes (range)Median number of long reflux episodes (range)Median % total time pH <4 (range)Median reflux time (minutes) (range)Longest reflux time (minutes) (range)28 (0, 83)2 (0, 13)4.2 (0, 23.6)54.5 (0, 309)10.5 (0, 53)22 (2, 96)1 (0, 14)2.6 (0.1–18.6)31 (1, 257)5 (1, 46)0.990.110.010.010.0007No correlation co-efficients calculated.NS = not significantAppendix H Non-comparative diagnostic yieldTable 80Non-comparative diagnostic yield with catheter-free monitoring in adultsStudyNDiagnostic yield (%) wireless pH monitoring Ayazi et al. (2011)310 patients suspected of GORDBased on composite pH scoreBoth days: 123 (39.7) On 1 day only: 60 (19.4) Ayazi et al. (2009)28 patients with strong clinical GORD evidence (1) and 77 patients with indeterminate clinical evidence of GORD (2)Based on composite pH score1: Both days: 19 (67.9)1: Overall: 26 (92.9)2: Day 1: 40 (52)2: Day 2: 42 (55)2: Both days: 31 (40)Bansal et al. (2009)20 patients with erosive oesophagitis (EO) and 20 patients with non-erosive reflux disease (NERD)EO proximal: 15 (75)EO distal: 17 (85)NERD proximal: 11 (51)NERD distal: 6 (30)Bhat, McGrath & Bielefeldt (2006)209 patients suspected of GORD95 (45.5)Domingues, Moraes-Filho & Domingues (2011)74 patients suspected of GORDOverall: 58 (78.3)Day 1: 51 (68.9)Day 2: 49 (70.2)Gillies et al. (2007)95 patients suspected of GORD, or following anti-reflux surgeryOverall: 66 (69)Only on day 1 (normal day 2): 7 (7)Only on day 2 (normal day 1): 10 (10)Grigolon et al. (2011)51 patients suspected of GORDDay 1: 24 (47.1)Overall (48h): 25 (49.0)Overall (96h): 29 (56.9)Karamanolis et al. (2012)32 patients with non-cardiac chest pain17 (53.1)Lacy et al. (2011)175 patients on PPI therapy and 177 patients off PPI therapyOn PPI therapy: 45 (25.7)Off PPI therapy: 108 (61.0)Pandolfino et al. (2003)37 GORD patientsBoth days: 24 (64.9)Day 1: 25 (67.6)Worst day: 31 (83.8)Scarpulla et al. (2007)34 patients suspected of GORDDay 1: 12 (35.3)48h: 14 (41.2)72h: 16 (47.1)96h: 19 (55.9)Worst day: 21 (61.8)Turner et al. (2007)115 patients suspected of GORDBoth days: 58 (50.4)Only on day 1 (normal day 2): 18 (15.7)Only on day 2 (normal day 1): 7 (6.1)On 1 day only: 25 (21.7)Day 1: 76 (66.1)Day 2: 65 (56.5)Ward et al. (2004)58 patients suspected of GORD30 (52)Table 81Non-comparative diagnostic yield with catheter-free monitoring in childrenStudyNDiagnostic yield (%) wireless pH monitoring Gunnarsdottir, Stenstrom & Arnbjornsson (2007, 2008)49 children suspected of GORDBased on DeMeester scores:33 (67.3)Appendix I MBS items for anti-reflux surgeryTable 82Anti-reflux surgery MBS item descriptors and claims from July 2012 to June 2013MBS item numberDescriptionNumber of claims 2012–1343951GASTRO-OESOPHAGEAL REFLUX with or without hiatus hernia, laparotomy and fundoplication for, without gastrostomy, Fee: $871.308643954GASTRO-OESOPHAGEAL REFLUX with or without hiatus hernia, laparotomy and fundoplication for, with gastrostomy, Fee: $1,065.75531464ANTIREFLUX OPERATION BY FUNDOPLASTY, via abdominal or thoracic approach, with or without closure of the diaphragmatic hiatus, by laparoscopic technique - not being a service to which item 30601 applies, Fee: $871.301,12930527ANTIREFLUX OPERATION by fundoplasty, via abdominal or thoracic approach, with or without closure of the diaphragmatic hiatus not being a service to which item 30601 applies, Fee: $871.3030930530ANTIREFLUX operation by cardiopexy, with or without fundoplasty, Fee: $784.20305Figure 10Claims for anti-reflux procedures for GORD, July 2012 – June 2013, per age groupAppendix JEconomic literature searchTable 83Literature search in PubMed 21 November 2013Add to builderQueryItems found#13AddSearch (#9 and #12)6#12AddSearch pH monitoring194301#9AddSearch (#4) AND model62#4AddSearch (#2) AND #3758#3AddSearch ((economic) OR cost-effective) OR cost-utility693357#2AddSearch ((gastroesophageal reflux) OR GORD) OR GERD26220#1AddSearch ((gastroesophageal reflux) OR GORD) OR GORD25124Table 84Literature containing economic models relating to pH monitoring and management of GORD symptoms Author, JournalTitleDescription, CommentKleiman DA, Beninato T, Bosworth BP, Brunaud L, Ciecierega T, Crawford CV Jr, Turner BG, Fahey TJ 3rd and Zarnegar R 2014Journal of Gastrointestinal Surgery, vol. 18, no. 1, pp. 2–33; discussion pp. 33–34. Early referral for esophageal pH monitoring is more cost-effective than prolonged empiric trials of proton-pump inhibitors for suspected gastroesophageal reflux diseaseCost analysis of routine pH monitoring (after 8-week trial of PPI) vs ongoing treatment and delayed pH monitoring. Modelled cohort-based analysis with up to 10?years of costing data (retrospective). No outcome analysis. US setting. Some clinical inputs/assumptions are applicable.Lee WC, Yeh YC, Lacy BE, Pandolfino JE, Brill JV, Weinstein ML, Carlson AM, Williams MJ, Wittek MR and Pashos CL 2008Current Medical Research and Opinion, vol. 24, no. 5, pp. 1317–1327.Timely confirmation of gastro-esophageal reflux disease via pH monitoring: estimating budget impact on managed care organizationsModelled cost analysis of wireless pH monitoring vs empiric treatment in patients with normal endoscopy. One-year time horizon. No outcome analysis. US setting. Some clinical inputs/assumptions are applicable.Ofman JJ, Dorn GH, Fennerty MB and Fass R 2002Alimentary Pharmacology & Therapeutics, vol. 16, no. 2, pp. 261–273. The clinical and economic impact of competing management strategies for GORDCost-effectiveness analysis of diagnostic management of GORD; ‘step-up management [H2RAs reg then high-dose, PPIs reg then high-dose, endoscopy, pH monitoring] vs high-dose PPI trial. Results presented as costs/symptom-free patient and cost/QALY. One-year time horizon. US setting. Structure/inputs not directly applicable. Botoman VA 2002Journal of Clinical Gastroenterology, vol. 34, no. 1, pp. 6–14.Non-cardiac chest painOpinion piece – no economic modelling.Borzecki AM, Pedrosa MC, Prashker MJ 2000Archives of Internal Medicine, vol. 160, no. 6, pp. 844–452.Should non-cardiac chest pain be treated empirically? A cost-effectiveness analysisCost-minimisation analysis of empirical medication vs series of investigations. US setting. Not directly applicable.Ancona E, Zaninotto G, Costantini M, Polo R and Origbe E 1991Minerva Chirurgica vol. 46, 7 Suppl, pp. 263–271. [Esophageal manometry and pH-monitoring: cost–benefit analysis]Article in Italian and inadequate detail in abstract to be useful. Not reviewed further.H2RA = histamine-2 receptor antagonist, PPI = proton pump inhibitorAppendix KAdditional information relating to the economic evaluationTable 85A summary of variables used in the modelParameterValueAlternatives testedSource and DiscussionPrevalence40%20% to 80%Broeders et al 2010, for the base case. Range approximates Lacy et al 2011 to Domingues et al 2011).Sensitivity of wireless testing100%86%, 90%, 95%,Assumption, informed by the clinical report and with sensitivity analysis based on clinical report findings.Specificity of wireless testing100%77%, 90%, 95%Assumption, informed by the clinical report and with sensitivity analysis based on clinical report findings.Sensitivity of catheter-based testing100%80.5%Specified as the reference standard in the DAP specification. Sensitivity analysis informed by diagnostic yield in the report findings and expert opinion.Specificity of catheter-based testing100%No testedSpecified as the reference standard in the DAP specification.Technical failure rate of wireless testing7.50%22.5% (i.e. trebled)Main body of Report. Although this technically refers to the failure rate during insertion, reports vary considerably and a learning curve may exist. Technical failure rate of catheter-based testing0.89%-Main body of Report. A conservative estimate given that it its less than one third the rate attributed to wireless monitoring, yet the best comparative evidence suggested a RR of failure of 3.0.Technical failure re-attempt rate50%90%Arbitrary estimates.Standard GORD treatment effectiveness 89%Effectiveness of high dose GORD medication or routine fundoplication surgery (in patients with acid-related conditions) assumed equivalent, based on Beck et al 2009, Broeders et al 2010, Grant, Boachie, 2013).Surgery uptake in +ve patients25%75%Calibration of Medicare data on catheter-based testing and surgery rates.Surgery revision rate10%*Medicare revision surgery rate. Note: Sensitivity analysis were surgery costs are increased by $10,000pp is equivalent to base case surgery cost and revision rate >100%.Surgery Mortality rate0.05%nil - 0.5%Base case from Grant et al 2008. Alternative; Epstein et al 2009.Medication compliance100%-Applies to both PPIs and alternative medications – assumption.Investigation for alternative diagnosis90%50%-100%Arbitrary estimate, consistent with expert opinion and conservative approach.Treatment success for alternative conditions (non-acid related)100%-Specified assumption in DAPTable 86Scenario/sensitivity tests around other inputs into the economic model (Model 1 vs empirical treatment)Cost (wireless pH monitoring)Outcomes (wireless pH monitoring)Costs (no test)Outcomes (no test)ICERBase-case$8,7057.874$6,927 7.751$14,457No discounting vs 5% per year discounting costs and outcomes$8,9248.137$7,1588.01$13,907Surgical mortality rate 0.1% vs base-case rate of 0.05%$8,7057.874$6,9277.751$14,457Surgical mortality rate 0.5%vs base-case rate of 0.05%$8,7017.871$6,9277.751$14,785Technical failure rate tripled to 22.5%vs base-case rate of 7.5%$8,8287.864$6,9277.751$16,827Re-test after failure uptake: 90%vs base-case rate of 50%$8,7567.878$6,9277.751$14,403Surgery costs (incl. revisions) with additional cost of $10,000 per patient($17,294 vs base-case of $7,294)$9,6677.874$6,9277.751$22,278Costs of alternative treatment investigation/treatment increased by $1000/month in the initial 12 months. (i.e. up to ($1050/month vs $50/month)$14,6077.874$12,7237.751$16,050Prevalence of acid-related condition in refractory population; 20% (vs base case rate of 40%)$8,3087.917$6,6617.750$9,863Prevalence of acid-related condition in refractory population; 80% (vs base case rate of 40%)$9,4997.787$7,4607.755$63,723Appendix LAdditional information for the financial and costing analysisTable 87Copy of “Table 1. Bravo pH Monitoring System components and costs” as published in the ‘ASGE Technology Status Evaluation Report: wireless esophageal pH monitoring system’ (Chotiprashidi et al, 2005).DescriptionPrice (US$)Bravo pH capsule with delivery system, box of 5$1,125AA lithium batteries (pack of 4)$15Bravo pH receiver$6,900Calibtration buffer pH 1.07 (500mL bottle)$22Calibtration buffer pH 7.01 (500mL bottle)$22Bravo Kit (includes 2 Bravo receivers, Datalink, calibration stand, vacuum pump, calibration buffers pH 7.01 and 1.07, 4 pack AA lithium batteries)$16,649Bravo Kit with software (includes 2 Bravo receivers, POLYGRAM NET pH Testing Application software, Datalink, calibration stand, vacuum pump, calibration buffers pH 7.01 and 1.07, 4 pack AA lithium batteries)$22,149Bravo Kit with softare and Workstation (includes 2 Bravo receivers, POLYGRAM NET pH Testing Application software, Datalink, calibration stand, vacuum pump, calibration buffers pH 7.01 and 1.07, 4 pack AA lithium batteries, Gastro Workstation - Standing)$28,139Bravo-in-a-box (includes 2 Bravo receivers, POLYGRAM NET pH Testing Application software, Datalink, calibration stand, vacuum pump, calibration buffers pH 7.01 and 1.07, 4 pack AA lithium batteries, dedicated notebook computer, HP Desk Jet color printer)$25,704Filter$4.50System tubing (canister-to-filter)$6Patient tubing (Bravo delivery system-to-filter)$4.50References ADDIN EN.REFLIST Agrawal, D, Akerman, PA & Rich, H 2009, 'Removal of a Bravo 24-hour pH capsule with endoscopic scissors', Gastrointestinal Endoscopy, vol. 70, no. 2, pp. 385–386.Ahlawat, SK, Novak, DJ, Williams, DC, Maher, KA, Barton, F & Benjamin, SB 2006, 'Day-to-day variability in acid reflux patterns using the BRAVO pH-monitoring system', Journal of Clinical Gastroenterology, vol. 40, no. 1, pp. 20–24.Al Talalwah, N & Woodward, S 2013, 'Gastro-oesophageal reflux. 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