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Title: Primary Safety Results from The LEADLESS Observational StudyAuthor block:Johannes Sperzel, MD1; Pascal Defaye, MD2; Peter-Paul Delnoy, MD3; Juan Jose Garcia Guerrero, MD4; Reinoud E. Knops, MD5; Claudio Tondo, MD6; Jean-Claude Deharo, MD7; Tom Wong, MD8; Petr Neuzil, MD, PhD9Author institutions:Kerckhoff-Klinik gGmbH, Bad Nauheim, GermanyCHU Grenoble, Grenoble, FranceIsala Klinieken, Zwolle, NetherlandsHospital Infanta Cristina, Badajoz, SpainAmsterdam Academic Medical Centre, Amsterdam, NetherlandsCentro Cardiologico Monzino, Milano, ItalyHopital La Timone, Marseille, FranceRoyal Brompton and Harefield NHS Foundation Trust, Imperial College, London, United KingdomNa Homolce Hospital, Prague 5, Czech RepublicAuthor addresses:Kerckhoff-Klinik gGmbH, Benekestra?e 2-8, Bad Nauheim, Hesse, Germany 61231CHU Grenoble – H?pital Albert Michallon, BP 217, Grenoble, France 38043Isala Klinieken, Dokter van Heesweg 2, Zwolle, Overijssel, Netherlands 8025 ABHospital Infanta Cristina, Avenida de Elvas s/n, Badajoz, Spain 6080Amsterdam Academic Medical Centre, Meibergdreef 9, Noord-Holland, Amsterdam 1105 AZCentro Cardiologico Monzino, Via C. Parea 4, Milano, Lombardy, Italy 20138H?pital La Timone, 264 rue Saint-Pierre, Provence-Alpes-Azur, Marseille, France 13005Royal Brompton Hospital, Sydney Street, London, United Kingdom SW3 6NPNa Homolce Hospital, Roentgenova 2, 15030 Prague 5, Czech RepublicCorresponding Author:Johannes Sperzel, MDaddress: Kerckhoff Heart and Thorax CenterInnere Medizin/KardiologieBenekestra?e 2-8Bad Nauheim, Germany 61231e-mail: j.sperzel@kerckhoff-klinik.deDisclosures:J. Sperzel: A - Compensation for Services; 2; St. Jude Medical. B - Speaker's Bureau; 1; St. Jude Medical. I - Research Grants; 2; St. Jude Medical. P. Defaye: A - Compensation for Services; 2; St. Jude Medical.?P. Delnoy: None. J. Garcia guerrero: A - Compensation for Services; 1; St. Jude Medical, Boston Scientific Corp., Medtronic, Inc.. B - Speaker's Bureau; 1; St. Jude Medical, Medtronic, Inc., Boston Scientific Corp.?R.E. Knops: B - Speaker's Bureau; 1; St. Jude Medical, Medtronic, Inc., Boston Scientific Corp.C. Tondo: A - Compensation for Services; 2; St. Jude Medical. J - Fellowship Support; 3; St. Jude Medical. J. Deharo: A - Compensation for Services; 1; St. Jude Medical, Boston Scientific Corp., LivaNova, Biotronik, Medtronic, Inc.. I - Research Grants; 2; St. Jude Medical, Boston Scientific Corp., LivaNova. M - Other; 1; St. Jude Medical. T. Wong: A - Compensation for Services; 2; St. Jude Medical. I - Research Grants; 3; St. Jude Medical. P. Neuzil: A - Compensation for Services; 2; St. Jude Medical.Abstract:AimsA prospective, single-arm, multi-center, post-market study was conducted to confirm short-term safety of the NanostimTM leadless pacemaker (LP). Herein, we report primary results of the LEADLESS Observational Study.MethodsSubjects meeting VVIR pacemaker indications were enrolled and followed after successful LP implant, prior to discharge and post-implant at 90 days, 180 days, and every 6 months thereafter for assessment of adverse events. The primary safety endpoint was evaluated in terms of freedom from serious adverse device effects (SADEs) at 6 months in 300 subjects. Data for all enrolled subjects are also presented. ResultsA total of 470 subjects were enrolled (75.8 ± 13.1 years, 62.8% male). The study paused in April 2014 following the occurrence of perforation events which led to changes in the protocol and investigator training. Freedom from SADEs, evaluated in subjects enrolled post-pause, was 94.6% (95% CI, 91.0 – 97.2%) and demonstrated non-inferiority to a performance goal of 86% (p<0.0001). Eighteen SADEs were observed in 16 subjects (5.3%). The most frequently occurring events were cardiac perforation (1.3%), device dislodgement (0.3%), and vascular complications (1.3%). After stratifying results in relation to the study pause, there was a statistically significant difference in final LP location (septum vs apex) (p<0.0001) and number of repositioning attempts (less than 2 vs 2 or more) (p=0.05), and decreasing trends in rates of cardiac perforation and device dislodgement.ConclusionThe primary safety endpoint at 6 months was successfully met for the Nanostim LP. Occurrence of cardiac perforation and device dislodgement declined after changes following the study pause. Keywords: Leadless pacemaker, cardiac perforation, complicationsCondensed Abstract:The primary safety endpoint – freedom from serious adverse device effects – at 6 months was successfully met for the Nanostim LP in the LEADLESS Observational Study. The occurrence of cardiac perforation and device dislodgement declined after implementation of changes following a study pause.What’s New:First report of the primary results on the 300-subject cohort used to meet the condition of Nanostim LP approval requirements in Europe, as well as additional results on the total cohort enrolled as of March 2017 in the prospective, single-arm, multi-center and post market study.First report on the study pause of April 2014 due to two separate events of cardiac perforation, presenting stratifying implant data results between pre- and post-pause, which were statistically significant.We report on the successful implantation of the Nanostim LP in 96.6% of subjects with stable device measurements at 6 months, similar to those observed in traditional pacemakers.Our report of safety data in the primary cohort confirms short-term safety of the LP, with a SADE-free rate at 6 months of 94.6%, thus meeting the primary endpoint of the study.Paper:IntroductionSince the introduction of bradycardia pacing, the design of both the pacemaker generator and leads has improved significantly such that it is now standard of care to treat bradycardia and heart block with these devices ADDIN EN.CITE <EndNote><Cite><Author>National Guideline</Author><Year>2013</Year><RecNum>38</RecNum><DisplayText>(1)</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490304453">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>National Guideline, Clearinghouse</author></authors></contributors><titles><title>2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society</title></titles><dates><year>2013</year></dates><pub-location>Rockville MD</pub-location><publisher>Agency for Healthcare Research and Quality (AHRQ)</publisher><urls><related-urls><url>;(1). Nevertheless, at least 10% of patients experience device-related complications which typically occur within 2-3 months post-implant PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5VZG88L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (2-6). The NanostimTM LP, a fully self-contained pacemaker, was shown to be safe in the pre-CE LEADLESS study conducted in 33 subjects ADDIN EN.CITE <EndNote><Cite><Author>Reddy</Author><Year>2014</Year><RecNum>53</RecNum><DisplayText>(7)</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490306373">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reddy, Vivek Y</author><author>Knops, Reinoud E</author><author>Sperzel, Johannes</author><author>Miller, Marc A</author><author>Petru, Jan</author><author>Simon, Jaroslav</author><author>Sediva, Lucie</author><author>de Groot, Joris R</author><author>Tjong, Fleur VY</author><author>Jacobson, Peter</author></authors></contributors><titles><title>Permanent leadless cardiac pacing: results of the LEADLESS trial</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>CIRCULATIONAHA. 113.006987</pages><dates><year>2014</year></dates><isbn>0009-7322</isbn><urls></urls></record></Cite></EndNote>(7). Additionally, Reddy et al., in their first report from the LEADLESS II IDE in 526 subjects, showed that primary safety and effectiveness endpoints were successfully met ADDIN EN.CITE <EndNote><Cite><Author>Reddy</Author><Year>2015</Year><RecNum>51</RecNum><DisplayText>(8)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490306312">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reddy, Vivek Y</author><author>Exner, Derek V</author><author>Cantillon, Daniel J</author><author>Doshi, Rahul</author><author>Bunch, T Jared</author><author>Tomassoni, Gery F</author><author>Friedman, Paul A</author><author>Estes III, NA Mark</author><author>Ip, John</author><author>Niazi, Imran</author></authors></contributors><titles><title>Percutaneous implantation of an entirely intracardiac leadless pacemaker</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>1125-1135</pages><volume>373</volume><number>12</number><dates><year>2015</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>(8). The LEADLESS Observational Study is a prospective, single-arm, multi-center, post-market study conducted primarily in Europe with the purpose of confirming short-term safety and evaluating the long-term safety of the Nanostim LP. We herein report primary results on the 300-subject cohort used to meet the condition of Nanostim LP approval requirements in Europe, as well as additional results on the total cohort of 470 subjects enrolled as of March 2017.MethodsStudy ParticipantsAdult patients (≥18) with clinical indications for single-chamber pacing, a life expectancy of at least one year, and deemed as suitable candidates based on overall health and well-being were eligible for study enrollment.Patients were excluded from participation if they had a mechanical tricuspid valve prosthesis, pre-existing pulmonary arterial hypertension, an implanted vena cava filter, evidence of thrombosis in one of the veins to be used for access, cardiovascular or peripheral vascular surgery/intervention within 30 days of enrollment, or the presence of leads from previous implants or system revisions.Study DesignAfter successful implant of the LP, participants were followed at pre-discharge and post-implant at 90 days, 180 days, and every 6 months thereafter for assessment of adverse events. Enrolled subjects with unsuccessful implants were followed for 30 days post-procedure and then withdrawn from the study. Additional collected data included device performance, implant success rate, procedure times (defined from sheath insertion to removal), implant procedure duration (defined from insertion of the delivery catheter to its removal) and time to discharge. The adverse events collected in the study were adjudicated by an independent Clinical Events Committee (CEC).The primary endpoint of the study was evaluation of safety via freedom from serious adverse device effects (SADEs) at 180 days in 300 subjects (primary cohort). SADEs were defined, per ISO 14155, as device- or procedure-related adverse events that resulted in death, life-threatening illness or injury, permanent impairment of a body structure or function, inpatient or prolonged hospitalization, or intervention to prevent conditions previously listed. Due to two separate events of cardiac perforation that led to patient death, all implants were paused in April 2014 in order to thoroughly investigate event circumstances. After comprehensive analyses of cine fluoroscopy videos, available source documentation, and discussions with implanting physicians, additional investigator training and updates to the protocol and Instructions For Use (IFU) were implemented across participating study sites. Consequently, the primary cohort consisted of subjects who were enrolled after the April 2014 study pause and who completed 6 months of follow-up. Patients who were implanted before the pause were enrolled under different protocol versions which did not include changes implemented post-pause. Their data was analyzed in the total cohort of 470 subjects. Statistical AnalysisAssuming a SADE-free rate at 180 days of greater than 92%, a sample size of 300 participants would have 90% power, at a two-sided 5% significance level, to demonstrate non-inferiority to a pre-determined performance goal of 86%. This performance goal was consistent with that chosen for the LEADLESS II IDE trial and was derived from the midpoint of the 95% upper confidence bounds of two previous pacemaker studies: Pakarinen et al. ADDIN EN.CITE <EndNote><Cite><Author>Pakarinen</Author><Year>2010</Year><RecNum>70</RecNum><DisplayText>(9)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1492754951">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pakarinen, Sami</author><author>Oikarinen, Lasse</author><author>Toivonen, Lauri</author></authors></contributors><titles><title>Short-term implantation-related complications of cardiac rhythm management device therapy: a retrospective single-centre 1-year survey</title><secondary-title>Europace</secondary-title></titles><periodical><full-title>Europace</full-title></periodical><pages>103-108</pages><volume>12</volume><number>1</number><dates><year>2010</year></dates><isbn>1099-5129</isbn><urls></urls></record></Cite></EndNote>(9) reported the three-month complication rate in 143 patients receiving single-chamber pacemakers to be 11.2% (95% CI, 5.9 – 16.4%) and Udo et al. ADDIN EN.CITE <EndNote><Cite><Author>Udo</Author><Year>2012</Year><RecNum>48</RecNum><DisplayText>(2)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490305907">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Udo, Erik O</author><author>Zuithoff, Nicolaas PA</author><author>van Hemel, Norbert M</author><author>de Cock, Carel C</author><author>Hendriks, Thijs</author><author>Doevendans, Pieter A</author><author>Moons, Karel GM</author></authors></contributors><titles><title>Incidence and predictors of short-and long-term complications in pacemaker therapy: the FOLLOWPACE study</title><secondary-title>Heart Rhythm</secondary-title></titles><periodical><full-title>Heart Rhythm</full-title></periodical><pages>728-735</pages><volume>9</volume><number>5</number><keywords><keyword>complication rates</keyword></keywords><dates><year>2012</year></dates><isbn>1547-5271</isbn><urls></urls></record></Cite></EndNote>(2) showed the two-month complication rate of 1517 patients in the FOLLOWPACE study was 10.5% (95% CI, 9.0 – 12.1%) after removing any reported complications related to the atrial lead. Rate of freedom from SADEs was calculated using the Kaplan-Meier method and the 95% confidence interval was estimated using the Greenwood method.Continuous variables were summarized using mean ± SD and categorical variables were presented as frequencies and percentages. Associations between implant data and pre- and post- study pause were performed using Fisher’s Exact test. To assess potential predictors of either any SADE or any cardiac perforation candidate predictors were first tested via univariate logistic regression for association with the two outcomes. These included gender, age, BMI, history of myocardial infarction, congestive heart failure, and final device location. Predictors that reached statistical significance were then applied to a model using multivariate analysis. A p-value of less than 0.05 was considered significant.ResultsFrom December 2013 to March 2017, a total cohort of 470 subjects was enrolled across 32 sites. Refer to the enrollment timeline in Figure 1. Patient characteristics of the total cohort, as well as the 300-subject primary cohort, are listed in Table 1. The total cohort was 62.8% male, had a mean age of 75.8 ± 13.1 years, and was followed for a mean of 19.5 ± 11.5 months. Indications for LP implantation included chronic and or permanent atrial fibrillation with 2/3? AV or BBB block (46.4%), sinus bradycardia with infrequent pauses or unexplained syncope with electrophysiology findings (29.1%), and normal sinus rhythm with 2/3? AV or BBB block and a low level of physical activity or short expected lifespan (24.5%). At baseline, 46 subjects (9.8%) had experienced myocardial infarction while 42 subjects (8.9%) had a medical history of congestive heart failure. Primary EndpointIn the 300-subject primary cohort, the rate of freedom from serious adverse device effects at 6 months was 94.6% (95% CI, 91.0 – 97.2%), with the majority of events (88.9%) occurring within 30 days of the LP implant (Figure 2). The lower confidence bound of the SADE-free rate exceeded the 86% performance goal, thus meeting the primary endpoint (p<0.0001). There were unsuccessful implants in eight subjects and two did not have attempted implants because one subject experienced cardiac arrest with ventricular tachycardia just before the LP implant and one subject met one exclusion criterion. Complete 6-month data was not obtained for 25 subjects due to death (9), withdrawal (5), and missed visits (11). Sixteen subjects (5.3%) experienced 18 SADEs. Of the four instances of cardiac perforation (1.3%), one pericardial perforation event did not require intervention and three cardiac tamponade events were resolved via surgical repair or pericardiocentesis. The latter three patients subsequently received conventional pacemakers. In the one subject where device dislodgement was observed (0.3%), a chest x-ray and CT scan of the thorax was performed two months post-implant which showed the device had dislodged and migrated to the right pulmonary artery. Ultimately, the device was successfully retrieved and a new LP was implanted. There were four vascular complications (1.3%), including one subject who had bleeding at the access site one day post-implant, one subject who was re-admitted six days post-implant with pain at the access site, and two subjects who developed arterioventricular fistulas during the implant procedure.Total Cohort ResultsIn the total cohort, implantation of the LP was successful in 451 out of 467 subjects with attempted implants (96.6%). Implants were not attempted in two subjects who met exclusion criteria and one subject experienced cardiac arrest with ventricular tachycardia just before the LP implant. In 8 subjects, the reasons for unsuccessful implants were due to complications: cardiac perforation (7), and inadvertent release of LP leading to device migration during implant (1). Unsuccessful implants were due to other reasons in the remaining 8 subjects: the inability to deliver the device due to heart anatomy (5), the inability to place the delivery catheter into the right ventricle (3), and stopped procedure for safety due to excessive procedural time (1). Mean procedure time of successful implants was 36.3 ± 17.2 minutes and mean implant procedure duration was 23.1 ± 14.3 minutes. Subjects spent an average of 1.2 ± 1.7 days in the hospital from implant to discharge. Final LP placement was either in the right ventricular (RV) apical septum (56.8%) or the RV apex (35.9%). Most procedures (96.5%) required either one or no repositioning of the device before successful implantation, while 16 cases (3.5%) required two or more repositioning attempts. Compared to device measurements obtained after implant, all parameters stabilized throughout subsequent follow-up visits. At 6 months, mean values for pacing capture threshold, R-wave amplitude, and lead impedance were 0.54 ± 0.47 V, 9.6 ± 2.8 mV, and 516.5 ± 148.2 respectively (Table 2). These measurements were consistent with traditional pacemaker data. When stratifying implant data results with respect to the April 2014 study pause, differences between pre- and post-pause were statistically significant (Table 3). Prior to the study pause, 77.4% of devices were implanted in the RV apex, versus 20.2% afterward (p<0.0001). Conversely, 21.8% of devices were implanted in the apical septum before April 2014, whereas the frequency increased to 70.0% in the apical septum and 8.6% in the mid-septum afterward. The frequency of implants where two or more repositions were attempted also decreased significantly from 6.5% before to 2.4% after the pause (p=0.05). The 11 occurrences of cardiac perforation (2.3%) were analyzed with respect to the study pause and showed a decreasing trend from 4.6% before to 1.5% after the study was re-started. This trend pre- and post-pause was also observed in the rate of dislodgement which declined from 0.8% to 0.3%.In October 2016, the sponsor issued an advisory and stopped all worldwide implants after reports of battery failures leading to loss of pacing output and communication with the LP. As of the cutoff date for this analysis, there were a total of 19 battery failures reported in the Leadless Observational Study. None of these resulted in patient injury. Consequently, 5 devices were retrieved and implanted with either a conventional pacemaker (1) or another leadless pacemaker (4). Fourteen (14) failed devices were abandoned and implanted with conventional pacemakers (11) or another leadless pacemaker (3). These 19 battery failures were adjudicated as SADEs and constituted a rate of 4.0% in the total cohort of 470 subjects. Overall, 53 SADEs occurred in 50 participants (10.6%) in the total cohort as shown in Table 4. Of all adjudicated SADEs, 4.0% were battery failures and 6.6% were other SADEs which were not battery failures. During follow-up, 48 deaths were reported in the total cohort (10.2%), and classified as having a cardiac cause in 14 subjects, a non-cardiac cause in 25 subjects, and an unknown cause in 9 subjects. Three of these deaths (2 with cardiac cause, 1 with unknown cause) were deemed by the CEC to potentially be related to the device and/or procedure. When assessing for potential independent predictors of experiencing any SADE via univariate regression analysis, none of the candidate covariates reached statistical significance. There was an association of BMI with experiencing any cardiac perforation (p=0.04), though the number of events was limited without power to detect a true difference. DiscussionResults from this prospective observational study demonstrated successful implantation of the Nanostim LP in 96.6% of subjects with stable device measurements at 6 months, similar to those observed in traditional pacemakers. Safety data in the primary cohort confirmed short-term safety of the LP, with a SADE-free rate at 6 months of 94.6%, thus meeting the primary endpoint of the study. The rate of cardiac perforation was 1.3%. This was similar to previously reported rates of perforation with transvenous pacemaker leads (with both active and passive fixation mechanisms), ranging from 0.5% to 2% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ISUxMPC9BdXRob3I+PFllYXI+MTk4NzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (10-13). Likewise, the dislodgement rate at 6 months of 0.3% was consistent with the 1% observed by Chauhan et al. six weeks post-implantation of a single-chamber pacemaker in 1733 patients ADDIN EN.CITE <EndNote><Cite><Author>Chauhan</Author><Year>1994</Year><RecNum>74</RecNum><DisplayText>(14)</DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1493588186">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chauhan, A</author><author>Grace, AA</author><author>Newell, SA</author><author>Stone, DL</author><author>Shapiro, LM</author><author>Schofield, PM</author><author>Petch, MC</author></authors></contributors><titles><title>Early complications after dual chamber versus single chamber pacemaker implantation</title><secondary-title>Pacing and Clinical Electrophysiology</secondary-title></titles><periodical><full-title>Pacing and clinical electrophysiology</full-title></periodical><pages>2012-2015</pages><volume>17</volume><number>11</number><dates><year>1994</year></dates><isbn>1540-8159</isbn><urls></urls></record></Cite></EndNote>(14), and the 1.2% in 431 patients within two months after pacemaker implant as reported by Aggarwal et al ADDIN EN.CITE <EndNote><Cite><Author>Aggarwal</Author><Year>1995</Year><RecNum>75</RecNum><DisplayText>(15)</DisplayText><record><rec-number>75</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1493588767">75</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aggarwal, Rajesh K</author><author>Connelly, Derek T</author><author>Ray, Simon G</author><author>Ball, Jeff</author><author>Charles, Richard G</author></authors></contributors><titles><title>Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems</title><secondary-title>British heart journal</secondary-title></titles><periodical><full-title>British heart journal</full-title></periodical><pages>571-575</pages><volume>73</volume><number>6</number><dates><year>1995</year></dates><isbn>1468-201X</isbn><urls></urls></record></Cite></EndNote>(15). The percentage of subjects who experienced SADEs at 6 months in the primary cohort (5.3%) was comparable to that observed in the LEADLESS II trial of 6.7%, and to the percentage of participants in the Micra Transcatheter Pacing Study who had major complications (4.0%) ADDIN EN.CITE <EndNote><Cite><Author>Reynolds</Author><Year>2016</Year><RecNum>59</RecNum><DisplayText>(16)</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490307168">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reynolds, Dwight</author><author>Duray, Gabor Z</author><author>Omar, Razali</author><author>Soejima, Kyoko</author><author>Neuzil, Petr</author><author>Zhang, Shu</author><author>Narasimhan, Calambur</author><author>Steinwender, Clemens</author><author>Brugada, Josep</author><author>Lloyd, Michael</author></authors></contributors><titles><title>A leadless intracardiac transcatheter pacing system</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>533-541</pages><volume>374</volume><number>6</number><dates><year>2016</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>(16). It should be noted that SADEs encompass not only major complications but other less serious complications as well. Notably, no events of infection were reported.The study pause of April 2014 reflected prompt attention to issues associated with a new therapy or new technology. Results from sponsor review led to further investigator training requirements, reinforcing various aspects of implantation technique in order to ensure patient safety. Study eligibility criteria were revised to be more consistent with that of the LEADLESS II IDE trial, such that patients with specific pre-existing pulmonary arterial hypertension or significant physiologically impairing lung disease were excluded. Patients with a pre-existing perforation or recent cardiovascular or peripheral vascular surgeries or deemed unsuitable based on overall health and well-being were also excluded. Moreover, the revised IFU incorporated additional safety information to aid investigators during LP implant, including desired implant location and methods of LP anchoring.Effects of these corrective actions were evidenced by differences observed in implant data (final device location in the RV and the number of attempted repositions) and clinical outcomes (cardiac perforation and dislodgement) when comparing pre- and post-pause results. Though changes in the latter did not reach statistical significance, the decreasing trend is a promising sign that rates of these adverse events are improving and will continue to improve as the study progresses. Outstanding QuestionsWith this new technology, longer-term follow-up is necessary to assess device safety and effectiveness. The LEADLESS nonrandomized trial, which first evaluated safety and efficacy of the LP and gained CE mark approval, recently reported follow-up data at one year in 31 of the 33 originally-implanted patients ADDIN EN.CITE <EndNote><Cite><Author>Knops</Author><Year>2015</Year><RecNum>52</RecNum><DisplayText>(17)</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="zdtzav5dcef0zledf5tvf0ams5v0sdx5srs5" timestamp="1490306340">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knops, Reinoud E</author><author>Tjong, Fleur VY</author><author>Neuzil, Petr</author><author>Sperzel, Johannes</author><author>Miller, Marc A</author><author>Petru, Jan</author><author>Simon, Jaroslav</author><author>Sediva, Lucie</author><author>de Groot, Joris R</author><author>Dukkipati, Srinivas R</author></authors></contributors><titles><title>Chronic performance of a leadless cardiac pacemaker</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title></periodical><pages>1497-1504</pages><volume>65</volume><number>15</number><dates><year>2015</year></dates><isbn>0735-1097</isbn><urls></urls></record></Cite></EndNote>(17). A retrospective review of medical records found no device-related complications and stable device measurements in all patients. Furthermore, adequate rate response was observed in all patients whose rate response sensor was activated. At the same time, longer term follow-up prompts further questions about battery longevity, and retrieval and replacement strategies. Feasibility of retrieval has been shown at up to 2.5 years in an in vivo ovine model PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3J1dGg8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (20, 21), with intact helices and minimal fibrous connective tissue attached to the distal end of the device present in all cases. Inevitably, the trajectory of leadless pacing will arc toward dual-chamber pacing and cardiac resynchronization therapy. Eventually, device design will undoubtedly overcome challenges like the unique histological terrain of the atrium and the wireless communication necessary to link multiple devices across myocardial structures. Regardless, patients now have expanded options for pacing therapy. ConclusionIn the LEADLESS Observational Study, the Nanostim LP was successfully implanted in 96.6% patients and the rate of freedom from serious adverse device effects at 6 months was 94.6% in 89% of patients in the primary cohort. Thus, the study’s primary endpoint of safety was met. Occurrence of cardiac perforation and device dislodgement declined after implementation of changes following the study pause.Figures and Tables-624840385445December 2013: Enrollment BeginsMarch 2017April 2014: Study PauseAugust 2016: Enrollment of Primary Cohort CompletedPrimary Cohort (n=300)Total Cohort (n=470)December 2013: Enrollment BeginsMarch 2017April 2014: Study PauseAugust 2016: Enrollment of Primary Cohort CompletedPrimary Cohort (n=300)Total Cohort (n=470)Figure 1: Subject Enrollment Timeline in the LEADLESS Observational StudyTable 1: Demographics and Baseline Data for Total (n = 470) and Primary (n = 300) CohortsDemographic VariableTotal Cohort (N=470)PMCF Cohort (N=300)Age?(years) Mean ± SD (n)75.8 ± 13.1 (470)75.3 ± 14.1 (300) Min, Median, Max20, 79, 10020, 78, 98Gender,?n/N?(%) Male295/470 (62.8%)183/300 (61.0%) Female175/470 (37.2%)117/300 (39.0%)BMI Mean ± SD (n)27.2 ± 6.6 (468)27.2 ± 5.4 (299) Min, Median, Max16.6, 26.2, 121.116.6, 26.3, 62.9LV?Ejection?Fraction?(%) Mean ± SD (n)57.8 ± 9.2 (276)57.9 ± 9.5 (175) Min, Median, Max30.0, 60.0, 79.030.0, 60.0, 79.0Pacemaker?Indication,?n/N?(%) Chronic and/or permanent atrial fibrillation with 2 or 3° AV or bifascicular bundle branch block (BBB block)218/470 (46.4%)136/300 (45.3%) Normal sinus rhythm with 2 or 3o AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year)115/470 (24.5%)81/300 (27.0%) Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings137/470 (29.1%)83/300 (27.7%)Medical?History,?n/N?(%) Coronary artery disease112/470 (23.8%)70/300 (23.3%) Myocardial infarction46/470 (9.8%)29/300 (9.7%) Unstable angina16/470 (3.4%)12/300 (4.0%) CABG41/470 (8.7%)23/300 (7.7%) PTCA/Stents/Atherectomy54/470 (11.5%)33/300 (11.0%) Ablation40/470 (8.5%)20/300 (6.7%) Congestive Heart Failure42/470 (8.9%)25/300 (8.3%) Tricuspid valve disease108/470 (23.0%)84/300 (28.0%) Implanted pacemaker or ICD9/470 (1.9%)5/300 (1.7%) COPD47/470 (10.0%)30/300 (10.0%) Hypertension298/470 (63.4%)182/300 (60.7%) Diabetes92/470 (19.6%)58/300 (19.3%) Renal disease54/470 (11.5%)34/300 (11.3%)Figure 2: Freedom from SADEs at 6 months in the Primary Cohort (n = 300)Time (Days)Statistics0306090120150180At risk (event*)300 (3)283 (14)277 (14)273 (16)273 (16)269 (16)267 (16)Survival Probability (95% CI)99% (96.9%, 99.7%)95.3% (92.2%, 97.2%)95.3% (92.2%, 97.2%)94.6% (91.4%, 96.7%)94.6% (91.4%, 96.7%)94.6% (91.4%, 96.7%)94.6% (91.4%, 96.7%)Table 2: Device Measurements for in Subjects with Successful Implants (n = 451)Visit TypePacing Threshold (V)at 0.4 ms pwMean ±SD R-wave amplitude (mV)Mean ±SD (n)Impedance(?)Mean ±SD (n)Implant0.80 ± 0.59 (446)7.2 ± 2.8 (400)737.9 ± 303.2 (450)Pre-discharge0.56 ± 0.50 (441)8.8 ± 2.9 (433)664.8 ± 218.6 (446)90-Day0.56 ± 0.42 (418)9.5 ± 2.8 (407)532.9 ± 158.7 (427)6-Month0.54 ± 0.47 (390)9.6 ± 2.8 (375)516.5 ± 148.2 (395)Table 3: Implant Data for Successful Implants (n = 451) Pre- and Post-PauseDemographic VariablePre-Pause(N=124)Post-Pause(N=327)Total Cohort(N=451)p-valueDevice?Location RV APEX96/124 (77.4%)66/327 (20.2%)162/451 (35.9%)<.0001 f RV MID SEPTUM1/124 (0.8%)28/327 (8.6%)29/451 (6.4%) RV SEPTUM27/124 (21.8%)229/327 (70.0%)256/451 (56.8%) OTHER0/124 (0.0%)4/327 (1.2%)4/451 (0.9%)Reposition?Attempts 0 OR 1116/124 (93.5%)319/327 (97.6%)435/451 (96.5%)0.0488 f 2 OR MORE8/124 (6.5%)8/327 (2.4%)16/451 (3.5%)f?p-value?was?computed?using?Exact?testTable 4: SADE for Total Cohort (n = 470)?Pre-Pause (n=131)Post-Pause (n=339)Total (n=470)Event Description# SADE% Subjects# SADE% Subjects# SADE% SubjectsPerforation details64.651.5112.3Cardiac Perforation10.810.320.4Cardiac Tamponade43.13?0.971.5Pericardial Effusion10.81?0.320.4Device Dislodgement10.81?0.320.4Vascular Complications0051.551.1AV Fistula003^0.930.6Access Site Bleeding001?0.310.2Pain in the Groin001?0.310.2Cardiac Arrhythmias / AV Block10.83?0.940.9Failure to / Loss of Capture002?0.620.4Battery Failures1914.500194.0Inability to Interrogate or Program due to Programmer or Device Malfunction1612.200163.4Loss of Normal Device Function due to Battery Failure or Component Malfunction32.30030.6Inadequate Device Fixation or Inadvertent Release Leading to Device Migration During Implant21.52?0.640.9Other21.530.951.1Hematoma Formation, including Retroperitoneal Hematoma/Hemorrhage10.80010.2Pacemaker Syndrome10.80010.2Progression of Congestive Heart Failure0010.310.2Syncope001?0.310.2Thrombosis001?0.310.2Death*0010.310.2Total?3130/131 = 22.92220/339 = 5.95350/470 = 10.6*Event Description "Death" was how event was reported at the time of this analysis.?Events occurred within primary cohort^2 of the 3 events occurred within the primary cohort?Patients can experience more than one SADEAcknowledgementsReferences ADDIN EN.REFLIST 1.National Guideline C. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. 2013.2.Udo EO, Zuithoff NP, van Hemel NM, de Cock CC, Hendriks T, Doevendans PA, et al. Incidence and predictors of short-and long-term complications in pacemaker therapy: the FOLLOWPACE study. Heart Rhythm. 2012;9(5):728-35.3.Kirkfeldt RE, Johansen JB, Nohr EA, J?rgensen OD, Nielsen JC. Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark. European Heart Journal. 2014;35(18):1186-94.4.Hauser RG, Hayes DL, Kallinen LM, Cannom DS, Epstein AE, Almquist AK, et al. Clinical experience with pacemaker pulse generators and transvenous leads: an 8-year prospective multicenter study. Heart Rhythm. 2007;4(2):154-60.5.Maisel WH, Hauser RG, Hammill SC, Ellenbogen KA, Epstein AE, Hayes DL, et al. Recommendations from the Heart Rhythm Society Task Force on lead performance policies and guidelines: developed in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm. 2009;6(6):869-85.6.Haghjoo M, Nikoo MH, Fazelifar AF, Alizadeh A, Emkanjoo Z, Sadr-Ameli MA. Predictors of venous obstruction following pacemaker or implantable cardioverter-defibrillator implantation: a contrast venographic study on 100 patients admitted for generator change, lead revision, or device upgrade. Europace. 2007;9(5):328-32.7.Reddy VY, Knops RE, Sperzel J, Miller MA, Petru J, Simon J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation. 2014:CIRCULATIONAHA. 113.006987.8.Reddy VY, Exner DV, Cantillon DJ, Doshi R, Bunch TJ, Tomassoni GF, et al. Percutaneous implantation of an entirely intracardiac leadless pacemaker. New England Journal of Medicine. 2015;373(12):1125-35.9.Pakarinen S, Oikarinen L, Toivonen L. Short-term implantation-related complications of cardiac rhythm management device therapy: a retrospective single-centre 1-year survey. Europace. 2010;12(1):103-8.10.HILL PE. Complications of Permanent Transvenous Cardiac Pacing: A 14‐Year Review of all Transvenous Pacemakers Inserted at One Community Hospital. Pacing and Clinical Electrophysiology. 1987;10(3):564-70.11.Sivakumaran S, Irwin ME, Gulamhusein SS, Senaratne MP. Postpacemaker Implant Pericarditis: Incidence and Outcomes with Active‐Fixation Leads. Pacing and Clinical Electrophysiology. 2002;25(5):833-7.12.Mahapatra S, Bybee KA, Bunch TJ, Espinosa RE, Sinak LJ, McGoon MD, et al. Incidence and predictors of cardiac perforation after permanent pacemaker placement. Heart Rhythm. 2005;2(9):907-11.13.Acha MR, Keaney JJ, Lubitz SA, Milan DJ, Mansour M, E HEIST K, et al. Increased Perforation Risk with an MRI‐Conditional Pacing Lead: A Single‐Center Study. Pacing and Clinical Electrophysiology. 2015;38(3):334-42.14.Chauhan A, Grace A, Newell S, Stone D, Shapiro L, Schofield P, et al. Early complications after dual chamber versus single chamber pacemaker implantation. Pacing and Clinical Electrophysiology. 1994;17(11):2012-5.15.Aggarwal RK, Connelly DT, Ray SG, Ball J, Charles RG. Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems. British heart journal. 1995;73(6):571-5.16.Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, et al. A leadless intracardiac transcatheter pacing system. New England Journal of Medicine. 2016;374(6):533-41.17.Knops RE, Tjong FV, Neuzil P, Sperzel J, Miller MA, Petru J, et al. Chronic performance of a leadless cardiac pacemaker. Journal of the American College of Cardiology. 2015;65(15):1497-504.18.Koruth JS, Rippy MK, Khairkhahan A, Ligon DA, Hubbard CA, Miller MA, et al. Percutaneous retrieval of implanted leadless pacemakers: feasibility at 2.5 years post-implantation in an in vivo ovine model. JACC: Clinical Electrophysiology. 2015;1(6):563-70.19.Koruth JS, Rippy MK, Khairkhahan A, Ligon DA, Hubbard CA, GOAR FS, et al. Feasibility and efficacy of percutaneously delivered leadless cardiac pacing in an in vivo ovine model. Journal of cardiovascular electrophysiology. 2015;26(3):322-8.20.Reddy VY, Miller MA, Knops RE, Neuzil P, Defaye P, Jung W, et al. Retrieval of the Leadless Cardiac Pacemaker. Circulation: Arrhythmia and Electrophysiology. 2016;9(12):e004626.21.Tjong FV, Stam OC, van der Wal AC, Beenen LF, Bouma BJ, de Groot JR, et al. Postmortem histopathological examination of a leadless pacemaker shows partial encapsulation after 19 months. Circulation: Arrhythmia and Electrophysiology. 2015;8(5):1293-5. ................
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