Inclusion Criteria - ANZCTR
Investigator Led Study of Intravenous Milrinone in Heart Failure with Preserved Ejection Fraction (HFpEF). IV Mil for HFpEFProtocol No: MilHFpEF-IV-02Version: 1Date: 14th May 2019Investigator LedCHANGESInvestigator led not sponsorAlfred will own data, Cardiora will have access to results upon request8 patients, 6 active, 2 control. 25mcg IV Mil.INVESTIGATOR SIGNATURE PAGEBy signing this Protocol, the Investigator acknowledges and agrees:The Protocol contains all necessary details for conducting the study. The Investigator will conduct this study as detailed herein, in compliance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) ADDIN EN.CITE <EndNote><Cite><Year>July 2000</Year><RecNum>108</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>108</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1481024795">108</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) and Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) annotated with Therapeutic Goods Administration (TGA) comments 
</title><secondary-title>DSEB</secondary-title></titles><periodical><full-title>DSEB</full-title></periodical><dates><year>July 2000</year></dates><urls></urls></record></Cite></EndNote>1 and the applicable regulatory requirements, and will make every reasonable effort to complete the study within the time designated.The Protocol and all relevant information on the drug relating to pre-clinical and prior clinical experience will be made available to all physicians, nurses and other personnel who participate in the conducting of this study. The Investigator will discuss this material with them to assure that they are fully informed regarding the drug and the conduct of the study.This document contains information that is privileged or confidential. As such, it may not be disclosed unless specific prior permission is granted in writing by The Investigator or such disclosure is required by federal or other laws or regulations. Persons to whom any of this information is to be disclosed must first be informed that the information is confidential. These restrictions on disclosure will apply equally to all future information supplied, which is indicated as privileged or confidential. The conduct and results of this study will be kept confidential. The results of this study may be published. Upon completion of the Study it is the intention of the parties to prepare a joint publication regarding or describing the Study and all the results there from and both parties shall co-operate in this regard. Investigator Name:_________________________________Signature:_________________________________Date: ____________Contact DetailsPrincipal Investigator A/Prof Justin Mariani MDHeart Centre, Alfred HospitalPhone: +614 9076 3263Associate InvestigatorsProf. David Kaye Heart Centre, Alfred HospitalPhone:+61 (0)3 9076 3263Dr Shane Nanayakkara Heart Centre, Alfred HospitalPhone:+61 (0)3 9076 3263Dr Sophie Offen Heart Centre, Alfred HospitalPhone:+61 (0)3 9076 3263Abbreviations and Definitions of TermsACEAngiotensin Converting EnzymeAEAdverse EventARBAngiotensin Receptor BlockersBPBlood PressureBTTBridge to TransplantCADCoronary Artery DiseaseCPBCardio-pulmonary bypassCRFCase Report FormCVPCentral Venous PressureDTDestination TherapyECGElectrocardiogramEDVEnd Diastolic VolumeEDDEnd Diastolic DiameterEFEjection FractioneGFRestimated Glomerular Filtration RateESDEnd Systolic DiameterESVEnd Systolic VolumeGCPGood Clinical PracticeGPGeneral PractitionerICDImplantable Cardioverter DefibrillatorsIRBInstitutional Review BoardIVSIntraventricular SeptumKCCQKansas City Cardiomyopathy QuestionnaireLC/MS/MSLiquid Chromatography-Tandem Mass SpectrometryLHFLeft Heart FailureLVADLeft Ventricular Assist DeviceMAPMean Arterial PressureNT proBNPN-terminal Prohormone of Brain Natriuretic PeptideNYHANew York Heart Association classificationPAPPulmonary Artery PressurePCWPPulmonary Capillary Wedge PressurePICFPatient Informed Consent FormPVRPulmonary Vascular ResistanceRVRight Ventricle RVFRight Ventricular FailureRVSPRight ventricular Systolic PressureSAESerious Adverse EventSIRSSystemic Inflammatory Response SyndromeTAPSETricuspid Annular Plane Systolic ExcursionTEAETreatment Emergent Adverse EventTRTricuspid RegurgitationVADVentricular Assist DeviceVTVentricular TachycardiaVFVentricular FibrillationTable of Contents TOC \o "3-3" \h \z \t "1st section,1,2nd Section,2" 1.Synopsis PAGEREF _Toc8732898 \h 82.Introduction PAGEREF _Toc8732899 \h 122.1.Heart Failure with Preserved Ejection Fraction PAGEREF _Toc8732900 \h 122.2.HFpEF Management PAGEREF _Toc8732901 \h 122.3.Rationale for Performing the Study: PAGEREF _Toc8732902 \h 133.Study Objectives PAGEREF _Toc8732903 \h 133.1.Objectives PAGEREF _Toc8732904 \h 134.Study Description PAGEREF _Toc8732905 \h 145.Study Population PAGEREF _Toc8732906 \h 145.1.Selection Criteria PAGEREF _Toc8732907 \h 145.1.1.Inclusion Criteria PAGEREF _Toc8732908 \h 145.1.2.Exclusion Criteria: PAGEREF _Toc8732909 \h 145.2.Prior and Concomitant Therapies Medications PAGEREF _Toc8732910 \h 156.Investigational Product PAGEREF _Toc8732912 \h 156.1.Description PAGEREF _Toc8732913 \h 156.2.Packaging and Labeling PAGEREF _Toc8732914 \h 156.3.Storage, Dispensing and Reconciliation of Study Drug PAGEREF _Toc8732915 \h 157.Study Endpoints PAGEREF _Toc8732916 \h 157.1.Exploratory PAGEREF _Toc8732917 \h 157.2.Primary (safety) PAGEREF _Toc8732918 \h 168.Study Procedures PAGEREF _Toc8732919 \h 178.1.Exploratory Endpoints PAGEREF _Toc8732920 \h 188.2.Safety Endpoints PAGEREF _Toc8732921 \h 188.3.Study Visits PAGEREF _Toc8732922 \h 198.3.rmed Consent Process PAGEREF _Toc8732923 \h 198.3.2.Screening Visit (Day -28 to Day 1) PAGEREF _Toc8732924 \h 198.3.3.Re-Screens PAGEREF _Toc8732925 \h 208.3.4.Study Day (Day 1) PAGEREF _Toc8732926 \h 208.4.Early termination visit PAGEREF _Toc8732927 \h 209.Adverse Events PAGEREF _Toc8732928 \h 209.1.Definitions PAGEREF _Toc8732929 \h 209.2.Monitoring PAGEREF _Toc8732930 \h 219.2.1.Intensity of Adverse Events PAGEREF _Toc8732931 \h 219.2.2.Relationship to Study Medication PAGEREF _Toc8732932 \h 219.3.Serious Adverse Events PAGEREF _Toc8732933 \h 229.3.1.Reporting of Serious Adverse Events PAGEREF _Toc8732934 \h 229.4.Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs PAGEREF _Toc8732935 \h 2310.Statistical Considerations PAGEREF _Toc8732936 \h 2310.1.Sample size PAGEREF _Toc8732937 \h 2310.1.1.Safety Evaluations PAGEREF _Toc8732938 \h 2310.1.2.Exploratory Evaluations PAGEREF _Toc8732939 \h 2311.Data MANAGEMENT PAGEREF _Toc8732940 \h 2411.1.Source Data and Retention of Records PAGEREF _Toc8732941 \h 2412.Estimated Duration of the Study PAGEREF _Toc8732942 \h 2412.1.Participant Information and Informed Consent PAGEREF _Toc8732943 \h 2413.References PAGEREF _Toc8732944 \h 2414.Appendices PAGEREF _Toc8732945 \h 2814.1.Appendix 1. Patient Informed Consent Template PAGEREF _Toc8732946 \h 28SynopsisStudy Title:Investigator Led Study of Intravenous Milrinone in Heart Failure with Preserved Ejection Fraction (HFpEF). Protocol Number:MilHFpEF-IV-02Development Phase:Phase IbIndication:Efficacy study in HFpEF patientsStudy Drugs:IV milrinone No. Subjects:8 patients (6 treated and 2 placebo)Study Duration:Single day procedureEntire study estimated to be completed in 6 monthsObjectives of the Study:To investigate the effects of intravenous millrinone on rest and exercise hemodynamics in HFPEF patients.Endpoints:Exploratory endpoints:Changes compared to baseline (at rest, 20 W and peak supine exercise) in: Pulmonary capillary wedge pressurePulmonary artery pressures (mean, systolic, diastolic and pulse pressure) and derived parameters including pulmonary arterial compliance and elastanceCardiac output (thermodilution)Systemic blood pressure (measured non-invasively)Peripheral vascular resistanceHeart rateSafety Endpoint:All adverse event (AE) recording and assessments.Study Design:Randomized, double blind, placebo controlledInclusion and Exclusion CriteriaInclusion Criteria: Males and females aged 18-85. Symptoms of heart failure (NYHA class III or ambulatory class IV). Left Ventricular Ejection Fraction (LVEF) ≥50%.Heart Failure hospitalization within 12 months or NT-proBNP >125 pg/mL. Evidence of prior diagnosis of HFpEF, confirmed via: Echocardiographic parameters (one or more of the following) observed//recorded in previous 6 months:septal E/e’ ≥ 13 (a measure of LV filling pressure) orleft atrial volume index > 34ml/m2 or LV mass index ≥ 115 g/m2 (male) or ≥ 95 g/m2 (female). orHemodynamic exercise test within 12 months. Stable medical heart failure therapy including diuretics for 2 weeks.Able to give written informed consent and agree to adhere to all protocol requirements. Potassium between 4 – 5.5mmol/LExclusion Criteria:Myocardial infarction or acute coronary syndromes within 90 days. Hypotension (systolic BP <90 mmHg) at Screening or BaselineSevere Hypertension (systolic BP >180 mmHg) at Screening or BaselinePoorly controlled atrial fibrillation (ventricular rate>120bpm).History of significant ventricular arrhythmia in the past yearSignificant renal impairment (eGFR <30 ml/min/1.73 m2)Severe physical limitation defined by inability to complete a minimum exercise tolerance time of 120 seconds on two treadmill tests within 2 weeks of enrollmentRestrictive or infiltrative cardiomyopathy.PregnancyHistory of allergic reaction to milrinone or any excipients in the study drug. Participation in another clinical trialStudy Overview:This is a phase 1b, exploratory study to evaluate the effect of IV milrinone on exercise hemodynamics. This is a double blinded, placebo-controlled investigator led trial. The study cohort will comprise of 8 patients (6 active, 2 placebo). Subjects who are successfully screened will be enrolled into trial. After baseline evaluation on day 1, subjects will be randomly allocated. After the baseline rest and exercise haemodynamic evaluation, subjects will be randomised to receive either active (milrinone) or placebo (saline) infusion.At the conclusion of the infusion, rest and exercise measures will be repeated. Exercise will be conducted at individual matched workloads and durations1. The primary objective was to compare the between-group changes in exercise hemodynamics after administration of placebo versus milrinone. Parameters to be evaluated are described in the prior sections. Statistical Analyses:Changes invariables described above will be compared using a paired t-testTable SEQ Table \* ARABIC 1: Schedule of ProceduresVisitScreeningStudy day2Timing/windowDay -28 to 1Day 1Informed consentXInclusion/Exclusion criteriaXDemographicsXMedical/medication historyXXphysical examXXVital signsXXNYHA ClassXXHaematologyXBiochemistry, EUC, LFTXXBNP and NT proBNPXXTroponinXX12 Lead ECGXXRest and Exercise Hemodynamic evaluationXPlasma milrinone levels1XAdverse event monitoringX1 To be taken at the end of infusion, and at the end of exercise test. 2 plasma levels will need to be taken2 A focused cardiovascular exam will be conducted at the study visit by the PI or a designated specialist heart failure/LVAD cardiologist at day 1.IntroductionHeart Failure with Preserved Ejection FractionHeart failure (HF) is one of the most common and most disabling forms of cardiovascular disease. Moreover, HF is particularly prevalent in older individuals, affecting up to 10% of the population over 75 years ADDIN EN.CITE <EndNote><Cite><Author>Mosterd</Author><Year>2007</Year><RecNum>71</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480385786">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mosterd, A.</author><author>Hoes, A. W.</author></authors></contributors><auth-address>Department of Cardiology, Meander Medical Centre, Amersfoort, The Netherlands. a.mosterd@meandermc.nl</auth-address><titles><title>Clinical epidemiology of heart failure</title><secondary-title>Heart</secondary-title></titles><periodical><full-title>Heart</full-title></periodical><pages>1137-46</pages><volume>93</volume><number>9</number><keywords><keyword>Cause of Death</keyword><keyword>Epidemiologic Methods</keyword><keyword>Female</keyword><keyword>Heart Failure/diagnosis/*epidemiology/etiology/prevention & control</keyword><keyword>Hospitalization/statistics & numerical data</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Prognosis</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1468-201X (Electronic)
1355-6037 (Linking)</isbn><accession-num>17699180</accession-num><urls><related-urls><url>. From a clinical and epidemiologic point of view it is important to note that the diagnosis of HF is based initially upon the presence of well-recognized symptoms and signs, for example as used in the Framingham criteria ADDIN EN.CITE <EndNote><Cite><Author>McKee</Author><Year>1971</Year><RecNum>72</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>72</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480385813">72</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKee, P. A.</author><author>Castelli, W. P.</author><author>McNamara, P. M.</author><author>Kannel, W. B.</author></authors></contributors><titles><title>The natural history of congestive heart failure: the Framingham study</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1441-6</pages><volume>285</volume><number>26</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Chronic Disease</keyword><keyword>Coronary Disease/complications</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>*Health Surveys</keyword><keyword>*Heart Failure/diagnosis/epidemiology/etiology/mortality/prevention & control</keyword><keyword>Humans</keyword><keyword>Hypertension/complications</keyword><keyword>Male</keyword><keyword>Massachusetts</keyword><keyword>Middle Aged</keyword><keyword>Rheumatic Heart Disease/complications</keyword><keyword>Sex Factors</keyword></keywords><dates><year>1971</year><pub-dates><date>Dec 23</date></pub-dates></dates><isbn>0028-4793 (Print)
0028-4793 (Linking)</isbn><accession-num>5122894</accession-num><urls><related-urls><url>. Subsequent to the clinical diagnosis, the application of diagnostic investigations such as echocardiography can then be used to identify the pathophysiology of the clinical phenotype together with the provision of prognostic and therapeutic information. Amongst the echocardiographic parameters that are applied to the assessment of ventricular function, the ejection fraction remains in common use despite numerous limitations including its sensitivity to loading conditions and technical issues with endocardial border definition and geometric assumptionsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXJpZ2VtbWE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFy
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY011cnJheTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA 8. African Americans may develop HFPEF at a younger age ADDIN EN.CITE <EndNote><Cite><Author>Zile MR</Author><Year>2014</Year><RecNum>128</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>128</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1502947853">128</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Zile MR, Little W</author></authors><secondary-authors><author>Mann, D. L. Zipes D, Libby P, Bonow R</author></secondary-authors></contributors><titles><title>Heart failure with preserved ejection fraction</title><secondary-title>Braunwald's Heart Disease</secondary-title></titles><pages>557-574</pages><volume>10th Edition</volume><dates><year>2014</year></dates><publisher>Elsevier Inc</publisher><urls></urls></record></Cite></EndNote>9. Consistent with the increased age of the population, the rate of non-cardiac comorbidities is also higherPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJzaTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 10, including chronic lung disease, anaemia, chronic kidney disease, and malignancy. These co-morbidities are responsible for a significant proportion of the morbidity and mortality associated with HFPEF, although the majority of limitation to exercise intolerance is cardiac ADDIN EN.CITE <EndNote><Cite><Author>Borlaug</Author><Year>2014</Year><RecNum>127</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>127</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1502947286">127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Borlaug, B. A.</author></authors></contributors><auth-address>The Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic.</auth-address><titles><title>Mechanisms of exercise intolerance in heart failure with preserved ejection fraction</title><secondary-title>Circ J</secondary-title></titles><periodical><full-title>Circ J</full-title></periodical><pages>20-32</pages><volume>78</volume><number>1</number><keywords><keyword>Adult</keyword><keyword>*Exercise</keyword><keyword>*Heart Failure/mortality/pathology/physiopathology</keyword><keyword>Humans</keyword><keyword>*Stroke Volume</keyword></keywords><dates><year>2014</year></dates><isbn>1347-4820 (Electronic)
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ADDIN EN.CITE.DATA 14-19, relatively limited study duration in comparison to the likely duration required for the development of HFPEF and the possibility that the disease mechanisms are not yet fully understood. The main principles of the management of HFPEF are to maintain strict control of blood pressure, relieve congestion, prevent ischemia, treat co-morbid conditions, and maintain atrial function through rate or rhythm control. As in patients with HFREF, the appropriate use of diuretics in the setting of volume overload in individuals with HFPEF is an important key to symptom relief. Avoidance of over-diuresis is important given the frequent co-existence of renal impairment together with the fact that HFPEF patients typically have a reduced stroke-volume and may be particularly sensitive to excessive reductions in pre-load. Building upon the very strong evidence base for ACE inhibitors and ARBs in HFREF, several large scale trials of these agents were conducted in HFPEFPEVuZE5vdGU+PENpdGU+PFllYXI+QXByaWwgMjAwNzwvWWVhcj48UmVjTnVtPjExMDwvUmVjTnVt
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ADDIN EN.CITE.DATA 22, and trials assessing both nebivolol ADDIN EN.CITE <EndNote><Cite><Author>Jaski</Author><Year>1985</Year><RecNum>28</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480382089">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jaski, B. E.</author><author>Fifer, M. A.</author><author>Wright, R. F.</author><author>Braunwald, E.</author><author>Colucci, W. S.</author></authors></contributors><titles><title>Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>J Clin Invest</full-title></periodical><pages>643-9</pages><volume>75</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cardiotonic Agents/*administration & dosage</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Heart Failure/*drug therapy/physiopathology</keyword><keyword>Hemodynamics/drug effects</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Milrinone</keyword><keyword>Nitroprusside/administration & dosage</keyword><keyword>Pyridones/*administration & dosage</keyword><keyword>Vasodilator Agents/*administration & dosage</keyword></keywords><dates><year>1985</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0021-9738 (Print)
0021-9738 (Linking)</isbn><accession-num>3973022</accession-num><urls><related-urls><url> and carvedilol ADDIN EN.CITE <EndNote><Cite><Author>Kubo</Author><Year>1985</Year><RecNum>29</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480382156">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kubo, S. H.</author><author>Cody, R. J.</author><author>Chatterjee, K.</author><author>Simonton, C.</author><author>Rutman, H.</author><author>Leonard, D.</author></authors></contributors><titles><title>Acute dose range study of milrinone in congestive heart failure</title><secondary-title>Am J Cardiol</secondary-title></titles><periodical><full-title>Am J Cardiol</full-title></periodical><pages>726-30</pages><volume>55</volume><number>6</number><keywords><keyword>Administration, Oral</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cardiotonic Agents/*therapeutic use</keyword><keyword>Chronic Disease</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Heart Failure/*drug therapy/physiopathology</keyword><keyword>Hemodynamics/drug effects</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Milrinone</keyword><keyword>Pyridones/*administration & dosage/pharmacology</keyword><keyword>Time Factors</keyword></keywords><dates><year>1985</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>0002-9149 (Print)
0002-9149 (Linking)</isbn><accession-num>3976517</accession-num><urls><related-urls><url> in this respect have been negative. Short term use of ivabradine has been shown to improve exercise capacity ADDIN EN.CITE <EndNote><Cite><Author>Edelson</Author><Year>1986</Year><RecNum>30</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480382199">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Edelson, J.</author><author>Stroshane, R.</author><author>Benziger, D. P.</author><author>Cody, R.</author><author>Benotti, J.</author><author>Hood, W. B., Jr.</author><author>Chatterjee, K.</author><author>Luczkowec, C.</author><author>Krebs, C.</author><author>Schwartz, R.</author></authors></contributors><titles><title>Pharmacokinetics of the bipyridines amrinone and milrinone</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>III145-52</pages><volume>73</volume><number>3 Pt 2</number><keywords><keyword>Administration, Oral</keyword><keyword>Aminopyridines/administration & dosage/*metabolism/therapeutic use</keyword><keyword>Amrinone</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Half-Life</keyword><keyword>Heart Failure/*drug therapy</keyword><keyword>Humans</keyword><keyword>Infusions, Parenteral</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>Milrinone</keyword><keyword>Pyridones/administration & dosage/*metabolism/therapeutic use</keyword><keyword>Random Allocation</keyword><keyword>Time Factors</keyword></keywords><dates><year>1986</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0009-7322 (Print)
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ADDIN EN.CITE.DATA 8. Based upon the hypothesis that activation of the renin-angiotensin-aldosterone system is important in the pathogenesis of HFPEF, studies have been conducted into the utility of spironolactone. In the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) study ADDIN EN.CITE <EndNote><Cite><Author>Seino</Author><Year>1995</Year><RecNum>31</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="zxw92ws0s2tazmewpzdx5fzn5e2d9wdwvsvz" timestamp="1480382232">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Seino, Y.</author><author>Takano, T.</author><author>Hayakawa, H.</author><author>Kanmatsuse, K.</author><author>Saitoh, S.</author><author>Saitoh, T.</author><author>Kamishima, G.</author><author>Watanabe, K.</author><author>Motomiya, T.</author><author>Murata, M.</author><author>et al.,</author></authors></contributors><auth-address>Nippon Medical School Hospital, Japan.</auth-address><titles><title>Hemodynamic effects and pharmacokinetics of oral milrinone for short-term support in acute heart failure</title><secondary-title>Cardiology</secondary-title></titles><periodical><full-title>Cardiology</full-title></periodical><pages>34-40</pages><volume>86</volume><number>1</number><keywords><keyword>Acute Disease</keyword><keyword>Administration, Oral</keyword><keyword>Aged</keyword><keyword>Female</keyword><keyword>Heart Failure/*drug therapy/metabolism/physiopathology</keyword><keyword>Hemodynamics/*drug effects</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Milrinone</keyword><keyword>Prospective Studies</keyword><keyword>Pyridones/*pharmacokinetics/therapeutic use</keyword></keywords><dates><year>1995</year></dates><isbn>0008-6312 (Print)
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ADDIN EN.CITE.DATA 16. Importantly in both studies blood pressure was also lowered.Rationale for Performing the Study:Kaye previously tested the hypothesis that milrinone may be beneficial in HFpEF30 .This concept was based on the properties of milrinone, a phosphodiesterase type III inhibitor. The drug exhibits several pharmacological actions that may be favorable in HFPEF. These include beneficial effects on left ventricular diastolic function, pulmonary vasodilation and systemic vasodilation when investigated in the setting of reduced ventricular function. Milrinone exhibits positive inotropic actions which may also potentially offer some value in HFPEF, given it has been demonstrated that some aspects of LV systolic function are reduced in HFPEF. In the study performed by Kaye, the effects of a single dose of milrinone, 50ug/kg, were investigated on rest and exercise hemodynamics. The study showed the drug significantly reduced rest and exercise pulmonary capillary wedge pressures30 .Within this context, this study aims to examine the effects a lowdoseof intra-venous (iv) milrinone to determine the concentration/dose vs hemodynamic profile. Study ObjectivesObjectivesThe primary objective of the study is to:To determine the effectiveness of a low dose of iv milrinone on exercise hemodynamics in HFpEF patients. Study DescriptionThis is a phase 1b, randomized placebo controlled Investigator led study to assess the dose response of a low dose (25ug/kg) of iv milrinone or placebo in 8 subjects with HFpEF. After Screening, eligible subjects will return for the study day during which they will undergo a right heart catheterization study while receiving a specified dose of iv milrinone or placebo. Study PopulationThe study population will include patients with heart failure with preserved ejection fraction (HFpEF), recruited from stable outpatients. Selection CriteriaInclusion CriteriaPatients are enrolled only if they met the following criteria. Males and females aged 18-85. Symptoms of heart failure (NYHA class III or ambulatory class IV). Left Ventricular Ejection Fraction (LVEF) ≥50%.Heart Failure hospitalization within 12 months or NT-proBNP >125 pg/mL. Evidence of prior diagnosis of HFpEF, confirmed via: Echocardiographic parameters (one or more of the following) observed//recorded in previous 6 months:septal E/e’ ≥ 13 (a measure of LV filling pressure) orleft atrial volume index > 34ml/m2 or LV mass index ≥ 115 g/m2 (male) or ≥ 95 g/m2 (female). orHemodynamic exercise test within 6 months. Stable medical heart failure therapy including diuretics for 2 weeks.Able to give written informed consent and agree to adhere to all protocol requirements. Potassium between 4 – 5.5 mmol/LExclusion Criteria:Myocardial infarction or acute coronary syndromes within 90 days. Hypotension (systolic BP <90 mmHg) at Screening or BaselineSevere Hypertension (systolic BP >180 mmHg) at Screening or BaselinePoorly controlled atrial fibrillation (ventricular rate>120bpm).History of significant ventricular arrhythmia in the past yearSignificant renal impairment (eGFR <30 ml/min/1.73 m2)Severe physical limitation defined by inability to complete a minimum exercise tolerance time of 120 seconds on two treadmill tests within 2 weeks of enrollmentRestrictive or infiltrative cardiomyopathy.PregnancyHistory of allergic reaction to milrinone or any excipients in the study drug. Participation in another clinical trialPrior and Concomitant Therapies MedicationsAll concomitant therapies taken within 7 days of screening up until the closeout visit will be captured in the source documents and CRF. All patients are required to be on optimal medical therapy for heart failure as determined by their managing cardiologist.The following medications are prohibited from 7 days prior to screening through to the end of treatment:Intravenous inotropes (milrinone, dobutamine, epinephrine, levosimendan), cilostazolInvestigational ProductDescriptionThe product investigated is the approved product, iv milrinone (Primacor?, Appendix 1). .Packaging and LabelingThe study drug is provided in glass ampoules for dilution in 0.9% NaCl. Ampoules are labeled according to relevant guidelines and legislation.Storage, Dispensing and Reconciliation of Study DrugMilrinone will be dispensed blinded via The Alfred Clinical Trialsl Pharmacy. Randomisation log/envelope to be kept by pharmacy. Investigational product should be stored at 25oC or below. Do not freeze. Temperature excursions up to 30oC are permitted.The Principal Investigator is responsible for drug product accountability, reconciliation, and record maintenance. The Principal Investigator or designated site staff must maintain drug product accountability records throughout the course of the study including records for the amount of investigational product received, the identification of the subject for whom the drug was dispensed, the date(s) and the quantity of the drug dispensed and any amount returned.Study EndpointsExploratoryChanges compared to baseline in:Pulmonary capillary wedge pressurePulmonary artery pressures (mean, systolic, diastolic and pulse pressure) and derived parameters including pulmonary arterial compliance and elastanceTotal (thermodilution) cardiac outputSystemic blood pressure (measured non-invasively)Peripheral vascular resistanceBlood pressure and heart rateCardiac index.Blood pressure (mean and systolic, where appropriate)Plasma milrinone levelsPrimary (safety)All adverse event (AE) recording and assessments.Study ProceduresTable 2 outlines the study procedures to be completed. Table SEQ Table \* ARABIC 2: Study Procedures.VisitPre-screeningStudy day2Timing/windowDay -28 to 1Day 1Informed consentXInclusion/Exclusion criteriaDemographicsXMedical/medication historyXXphysical examXXVital signsXXNYHA ClassXXHaematologyXBiochemistry, EUC, LFTXXBNP and NT proBNPXXTroponinXX12 Lead ECGXXRest and Exercise Hemodynamic evaluationXPlasma milrinone levelsXAdverse event monitoringXConcomitant medicationsXX1 To be taken at the end of infusion, and at the end of exercise test. 2 plasma levels will need to be taken2 A focused cardiovascular exam will be conducted at the study visit by the PI or a designated specialist heart failure/LVAD cardiologist at day 1.Exploratory EndpointsHemodynamic Evaluation: Subjects will undergo right heart catheterisation via the cubital vein or internal jugular vein according to local clinical practice at baseline and follow up visits. Right atrial, right ventricular and pulmonary artery and wedge pressures will be measured at gentle held expiration. Thermodilution cardiac output measurement will be performed in triplicate. Following baseline measures, subjects will supine perform symptom-limited supine cycling at incremental levels of 20 Watts for 3 minutes (exercise will not be performed if the resting RHC unexpectedly demonstrates severe pulmonary hypertension PA systolic>60mmHg). The test will be stopped when the patient experiences limiting dyspnoea or other limiting symptoms. Measures will be obtained at rest, 20W and peak exercise.Following initial rest and exercise evaluation, patients will be randomly allocated to receive either a standard loading dose of milrinone (25 ug/kg) over 10 min or placebo. Neither the patient nor the investigator will know which group the subject has been allocated to. Rest and exercise hemodynamic (as above) will be repeated after a further 10 minutes. At the designated time point (after 20 minute infusion), blood will be drawn (2 samples) for the measurement of plasma milrinone levels. Blood samples will be collected and stored according to the Study Reference Manual. CRD-102 levels (ng/mL) will be determined using liquid chromatography- tandem mass spectrometry (LC/MS/MS) by CPR Pharma Services Pty Ltd, Adelaide, Australia.Safety EndpointsSafety will be assessed by recording of AEs, vital signs, laboratory parameters, and physical/cardiovascular examinations.Each subject will undergo a complete medical history (including weight measurement) and physical exam prior to randomization to assess their clinical status and to confirm eligibility for study participation. Physical examinations during the study will include height (at Screening only) and weight, and assessment of skin, head, neck, lymphatic, eyes, ears, nose and throat, abdomen, and respiratory, cardiovascular/peripheral vascular, endocrine, central nervous, genitourinary and musculoskeletal systems as appropriate to determine general condition. New or worsening clinically significant abnormalities will be reported as an AE. Post Screening, a symptom-directed PE will be conducted if required, based on prior findings and symptoms.A focused cardiovascular exam will be conducted at the study visit by the PI or a designated specialist heart failure cardiologist. Subjects will undergo a 12-lead ecg at the study visit. Subjects will be questioned and monitored throughout the study with regard to any AEs they may have experienced. See Section 9 for further details on recording AEs.Blood samples will be taken for safety assessments. The following specific tests will be performed at the site’s local pathology laboratory:Haematology: Haemoglobin, haematocrit, red blood cell (RBC) count, white blood cell (WBC) count with differential, and platelet count.Serum Chemistry: Sodium, potassium, urea, gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, lactate dehydrogenase (LDH), and creatinine (calculated creatinine clearance using the Cockcroft and Gault formula).Vital signs will be measured after the subject has been supine for 10 minutes and will include blood pressure (BP) on the same arm (if possible) throughout study, pulse rate, respiratory rate and temperature. Blood pressure will be measured in the semi-recumbent position, according to the preferred method by the Principal Investigator, optimized for each patient (ie Doppler, oximetry or automated oscillometry as appropriate). Blood pressure will be notated at the visit as mean or systolic according to the audible profile. Heart rate will be recorded over a 30 second period.Medical MonitoringThe Principal Investigator will designate a Medical Monitor for safety and clinical reporting. This Medical Monitor will review safety endpoints and subject data, and answer queries from both Investigators and study personnel. The Medical Monitor and the Principal Investigator will review data periodically from a 5 subject block. The Medical Monitor will provide regulatory oversight from a clinical perspective.Study VisitsThe study will be conducted over 1-day time period with 1 screening visit and 1 day-one visit. (Both screening and study visits can be performed on the same day if required). The study schedule is outlined in Table 1. Informed Consent ProcessThe Investigator must provide adequate information regarding the study conduct and obtain written informed consent from the subject before any tests or investigations outlined in the study protocol are carried out. Patients will be provided with a copy of the Participant Information and Consent Form (PICF) to read and discuss with family members, friends or family doctor. Any questions or concerns will be answered by the investigator administering the consent. Patients will be invited to participate if they demonstrate an understanding of what the study involves, the risks and the procedures involved. The PICF must be personally signed and dated by both the Investigator obtaining consent and the subject. The patient will be given a copy of the signed PICF. The original will be retained by the site.Screening Visit (Day -28 to Day 1)The purpose of the Screening visit is to confirm subject eligibility against inclusion and exclusion criteria. Screening assessments may be performed on different days within the Screening period, if required. Once written informed consent has been obtained, the following visit assessments and procedures will be performed;Review eligibility criteria.Record subject demographic data.Review and record medical and medication history, and current conditions and medications.Physical examination including height and weight (see Section 8.1).Vital signs (see Section 8.1).12 lead ECG Blood sample for BNP and NT proBNP testsSafety laboratory tests including haematology and biochemistryRe-ScreensOne repeat test of each individual screening assessment (e.g., laboratory tests, ECG) is allowed, within the screening period. Study Day (Day 1)Subjects will return to the site for hemodynamic evaluation. Review eligibility criteria.Review and record any new medical conditions since the Screening Visit as medical historyReview and record any changes to medicationsCardiovascular examination (see Section 8.1).Vital signs (see Section 8.1).12 lead ecg Record subject’s NYHA ClassSafety laboratory tests including haematology and biochemistry (see Section 8.1).Concomitant medication review.Hemodynamic exercise evaluationEarly termination visitNot applicable. Adverse EventsDefinitionsAn adverse event is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.? An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. MonitoringAdverse events will be collected and recorded in the CRF for subjects. Throughout the study, reported and observed AEs will be documented in the medical records and the CRF, along with their intensity, whether or not considered treatment-related. This will include any new signs, symptoms, injury or illness, including increased severity or frequency of previously existing signs, symptoms, injury, or illness.Conditions existing prior to screening will be recorded as part of the subject’s medical history.The investigator will be responsible for assessing the relationship of AEs to the study medication; relationship will be classified as not related, unlikely related, probably related, or definitely related. The Investigator will follow-up on all AEs until they resolve, become stable, or until they can be explained by another known cause(s) (i.e., concurrent condition or medication) and clinical judgment indicates that further evaluation is not warranted.? All findings relevant to the final outcome of an AE will be reported in the subject’s medical record. Intensity of Adverse EventsThe intensity (or severity) of AEs is characterized as mild, moderate, or severe: Mild:Causes no limitation of usual activities? Moderate:Causes some limitation of usual activities? Severe:Prevents or severely limits usual activities? Relationship to Study MedicationThe degree of “relatedness” of the AE to IV milrinone will be assigned by the PI using the following scale: Not related: AE for which there is evidence of another explanation, e.g. the adverse event is obviously explained by the subject’s disease(s), is in accordance with the known effect of a concomitant medication or has occurred prior to first administration of IV milrinone. Unlikely related: AE with a time to IV milrinone administration that makes a relationship improbable (but not impossible), and disease or other drugs provide plausible explanations Probably related: AE with reasonable time relationship to IV milrinone administration that is unlikely to be attributed to disease or other drugs. Response to IV milrinone withdrawal is clinically reasonable. Rechallenge is not required. Definitely related: AE with plausible time relationship to IV milrinone administration which cannot be explained by disease or other drugs. Response to IV Milrinone withdrawal is plausible (pharmacologically, pathologically), and event is definitive pharmacologically or phenomenologically (i.e. an objective and specific medical disorder or a recognised pharmacological phenomenon). Rechallenge, if performed/necessary, is satisfactory. Serious Adverse EventsA SAE is defined as an AE that: Results in death Is immediately life-threatening (there is an immediate risk of death from the AE as it occurred; this does not include an AE that had it occurred in a more serious form may have caused death) Results in or prolongs an in-patient hospitalization (Note: Hospitalisation is defined as in-patient admission or care regardless of duration.)Out-patient treatment in an emergency room is not in itself an SAE, although the reasons for it may be (e.g. bronchospasm, laryngeal oedema). Elective surgery, hospitalisation for social reasons (with no causal AE), or hospital admissions and/or surgical operations planned before or during this study are not considered AEs if the illness or disease existed before the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way during the study.)? Results in persistent or significant disability (permanent or substantial disruption of one’s ability to conduct normal life functions)? Is a congenital anomaly/birth defect (in offspring of a subject using the study medication regardless of time to diagnosis) Is considered an important medical event Important medical events are defined as events that, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes defining an SAE. Examples of important medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the development of drug dependency or drug abuse. Reporting of Serious Adverse EventsInvestigators and other site personnel must report SAEs to The Alfred Hospital HREC or designee within 24 hours of becoming aware of the SAE, regardless of causality.Follow-up information on SAEs must also be reported by the investigational site within the same time frame. If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided within 24 hours.Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEsAbnormal laboratory findings (e.g. clinical chemistry, hematologys) or other abnormal assessments (e.g. vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 7.2 or SAE as defined in Section 7.3. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with a disease reported in the medical history, unless judged by the investigator as more severe than expected for the subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.Statistical ConsiderationsSample size 8 patients at the dose level 25ug/kg/hr will be included in the trial. This will comprise of 6 patients receiving active (IV milrinone), and 2 patients being assigned to receiving placebo. Up to a maximum of 8 patients may be studied.Safety EvaluationsThe safety measurements evaluated will be clinical assessment of vital signs, physical examinations and cardiovascular examinations, MACCE, adverse (AE) and serious adverse event (SAE) monitoring throughout the protocol. In addition, laboratory safety assessments (haematology and biochemistry) will be conducted. All subjects who receive any amount of the drug product will be included in the Safety Population. Exploratory EvaluationsThe exploratory evaluations of the will be study will examine changes compared to baseline in: Pulmonary capillary wedge pressurePulmonary artery pressures (mean, systolic, diastolic and pulse pressure) and derived parameters including pulmonary arterial compliance and elastanceCardiac output (thermodilution)Systemic blood pressure (measured non-invasively)Peripheral vascular resistanceHeart rateBlood pressure (mean and systolic, where appropriate)Data ManagementA Case Report Form (CRF) will be completed by authorised study site personal designated by the investigator for each study subject summarising all study data. Subjects will only be referred to in the CRF by their subject number in order to retain subject confidentiality. The CRFs should always reflect the latest observations on the subjects participating in the trial; therefore, the CRFs are to be completed as soon as possible after the subject’s visit. The Investigator must verify that all data entries in the CRFs are accurate and correct. If some assessments are not done, or if certain information is not available or not applicable or unknown, this should be indicated in the CRF. The Investigator will be required to sign off on the clinical data.Source Data and Retention of RecordsSource documents are original documents, data, and records from which the subject’s CRF data are obtained. These include but are not limited to hospital records, clinical and office charts, laboratory and pharmacy records, and correspondence. In this study, CRFs may not be used as source documents.The Investigator is responsible for maintaining source documents. Data from this study may be shared with Cardiora Pty Ltd, a company that has interest in developing another form of milrinone for HFPEF subject to additional ethics review and approval at the time of sharing.Estimated Duration of the StudyIt is anticipated that this study will be conducted over a 6- month duration.Participant Information and Informed ConsentPrior to the commencement of any study specific procedure, participants are to be informed of the study, invited to participate, handed a written participant information sheet and consent form (PICF) and given the opportunity to discuss the study with family, friends, the participants General Practitioner (GP) and the study Principal Investigator (PI). The study participant will then be asked to sign the EC/IRB approved PICF, and a copy of the completed PICF given to the participant.References ADDIN EN.REFLIST 1.Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) and Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) annotated with Therapeutic Goods Administration (TGA) comments DSEB. July 2000.2.Mosterd A and Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137-46.3.McKee PA, Castelli WP, McNamara PM and Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-6.4.Aurigemma GP, Zile MR and Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006;113:296-304.5.Carabello BA. Evolution of the study of left ventricular function: everything old is new again. Circulation. 2002;105:2701-3.6.Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL and Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-9.7.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, American College of Cardiology F and American Heart Association Task Force on Practice G. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.8.McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Task Force for the D, Treatment of A, Chronic Heart Failure of the European Society of C, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P and Guidelines ESCCfP. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803-69.9.Zile MR LW. Heart failure with preserved ejection fraction. In: D. L. Z. D. Mann, Libby P, Bonow R, ed. Braunwald's Heart Disease: Elsevier Inc; 2014(10th Edition): 557-574.10.Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA and Roger VL. Systolic and diastolic heart failure in the community. JAMA. 2006;296:2209-16.11.Borlaug BA. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J. 2014;78:20-32.12.Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ and van Gilst WH. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34:1424-31.13.Lindman BR, Davila-Roman VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF and Redfield MM. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014;64:541-9.14.Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J and Investigators P-C. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338-45.15.McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-H and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.16.Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM and Investigators T. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92.17.Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ, Lewinter MM, Deswal A, Hernandez AF, Lee KL, Braunwald E and Heart Failure Clinical Research N. PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design. Circ Heart Fail. 2012;5:653-9.18.Shah RV, Desai AS and Givertz MM. The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis. J Card Fail. 2010;16:260-7.19.Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC and Deo RC. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131:269-79.20.Primacor? (milrinone lactate injection; 200 mcg/mL in 5% dextrose injection) [prescribing information]. Bridgewater, NJ: sanofi-aventis U.S. LLC. . . April 2007.21.Baim DS, McDowell AV, Cherniles J, Monrad ES, Parker JA, Edelson J, Braunwald E and Grossman W. Evaluation of a new bipyridine inotropic agent--milrinone--in patients with severe congestive heart failure. N Engl J Med. 1983;309:748-56.22.Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC and Kass DA. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114:2138-47.23.Jaski BE, Fifer MA, Wright RF, Braunwald E and Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J Clin Invest. 1985;75:643-9.24.Kubo SH, Cody RJ, Chatterjee K, Simonton C, Rutman H and Leonard D. Acute dose range study of milrinone in congestive heart failure. Am J Cardiol. 1985;55:726-30.25.Edelson J, Stroshane R, Benziger DP, Cody R, Benotti J, Hood WB, Jr., Chatterjee K, Luczkowec C, Krebs C and Schwartz R. Pharmacokinetics of the bipyridines amrinone and milrinone. Circulation. 1986;73:III145-52.26.Seino Y, Takano T, Hayakawa H, Kanmatsuse K, Saitoh S, Saitoh T, Kamishima G, Watanabe K, Motomiya T, Murata M and et al. Hemodynamic effects and pharmacokinetics of oral milrinone for short-term support in acute heart failure. Cardiology. 1995;86:34-40.27.Stroshane RM, Koss RF, Biddlecome CE, Luczkowec C and Edelson J. Oral and intravenous pharmacokinetics of milrinone in human volunteers. J Pharm Sci. 1984;73:1438-41.28.DiBianco R. Clinical results with oral milrinone in heart failure. Eur Heart J. 1989;10 Suppl C:44-52.29.Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML and et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468-75.30.Kaye DM, Nanayakkara S, Vizi D, Byrne MJ, Mariani JA.? Effects of Milrinone on Rest and Exercise Hemodynamics in Heart Failure with Preserved Ejection Fraction. Journal of the American College of Cardiology. 2016; 67(21):2553-2562.? AppendicesAppendix 1. Patient Informed Consent Template ................
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