Performance of Leadless Pacemaker in Japanese Patients vs. Rest of the World. Results From a Global Clinical Trial

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1 Circ J 2017; 81: doi: /circj.CJ ORIGINAL ARTICLE Arrhythmia/Electrophysiology Performance of Leadless Pacemaker in ese Patients vs. Rest of the World Results From a Global Clinical Trial Kyoko Soejima, MD; Taku Asano, MD; Toshiyuki Ishikawa, MD; Kengo Kusano, MD; Toshiaki Sato, MD; Hideo Okamura, MD; Katsumi Matsumoto, MD; Wataru Taguchi, PhD; Kurt Stromberg; Jeff Lande, PhD; Youichi Kobayashi, MD; Micra Transcatheter Pacing Study Group Background: A global study designed to demonstrate the safety and efficacy of a transcatheter pacing system included 38 ese patients enrolled at 4 sites. Subgroup analysis to evaluate the performance of the leadless intracardiac transcatheter pacing system in ese patients was performed. Methods and Results: Safety and efficacy outcomes, patient and implant procedure characteristics, and patient and physician acceptability from the ese population were compared with those from outside. Differences in patient characteristics, implant procedure characteristics and patient acceptability were observed. There were no major complications in ese patients and pacing thresholds remained low and stable throughout follow-up. There were no observable differences between ese patients and patients from outside in the freedom from major complication rate at 12-months post-implant (100.0% vs. 95.7%, P=0.211) or physician acceptability. Conclusions: Although some differences in specific baseline characteristics, such as body size and pacing indication, and in implant procedure characteristics, including anticoagulation strategy and hospitalization period, were observed in the ese patients, transcatheter pacemaker performance was similar to that in the global trial. (Clinical Trial Registration: ClinicalTrials.gov ID NCT ) Key Words: ese patients; Leadless pacemaker; Transcatheter pacing system Permanent cardiac pacing is the only effective treatment for symptomatic bradycardia, and over 50,000 patients receive pacemakers in annually. 1 Traditional pacemakers consist of an electrical generator and one or more transvenous leads and have a history of over half a century; however, 1 in 8 patients experiences a complication. 2,3 Complications include lead-related complications ( %), pocket-related complications ( %), pneumothorax ( %), or device infection ( %). 2,3 Recently, the Transcatheter Pacing System (TPS, Medtronic plc, MN, USA) was introduced to overcome these lead- and pocket-associated problems. In a prospective global clinical study, including ese centers, the TPS was successfully implanted in 99.2% of 725 patients, and met prespecified safety and efficacy criteria. 4 Editorial p 1576 The freedom from major complications at 6-month postimplant among the 725 patients with a TPS implant attempt was 96.0%. The percentage of patients with a low and stable pacing capture threshold measured at 6 months post-implant was 98.3%. Similarly, through the 12 months post-implant, the freedom from major complications rate was 96.0% and pacing thresholds remained low and stable throughout the follow-up period. 5 No significant interregional differences have been reported in traditional leaded pacing therapy, but the TPS is a novel device and requires a new implant procedure. The purpose of this study was to compare outcomes in the global study results Received March 15, 2017; revised manuscript received April 22, 2017; accepted April 25, 2017; released online May 30, 2017 Time for primary review: 19 days Department of Cardiology, Kyorin University Hospital, Tokyo (K. Soejima, T.S.); Department of Cardiology, Showa University Hospital, Tokyo (T.A., Y.K.); Department of Cardiology, Yokohama City University Hospital, Yokohama (T.I., K.M.); Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita (K.K., H.O.); Medtronic Co., Ltd., Tokyo (W.T.); Institute for Medical Regulatory Science, Waseda University, Tokyo (W.T.), ; and Medtronic plc, Mounds View, MN (K. Stromberg, J.L.), USA Mailing address: Kyoko Soejima, MD, Department of Cardiology, Kyorin University Hospital, Shinkawa, Mitaka, Tokyo ,. skyoko@ks.kyorin-u.ac.jp ISSN All rights are reserved to the ese Circulation Society. For permissions, please cj@j-circ.or.jp

2 1590 SOEJIMA K et al. Figure 1. Transcatheter Pacing System (TPS) in the right ventricle. The TPS is an investigational product and not approved for use in as of <manuscript submission date>. between and outside. Methods Study Design The TPS global study was a prospective, non-randomized, single-arm, multi-site, international clinical study to evaluate the safety and efficacy of the TPS. The study design and primary results have been published previously. 4 6 Patients Enrolled patients met a class I or II guideline-based indication 7 9 for de novo ventricular pacing with no restriction by comorbidity. All patients provided written informed consent. The protocol was approved by the institutional review board at each participating site and was also approved by associated national and local regulatory agencies. Study Device The TPS consists of single-use delivery catheter and pacemaker. The pacemaker is a miniaturized single-chamber ventricular pacemaker with a volume of 0.8 ml, a length of 25.9 mm, an outer diameter of 6.7 mm, and a weight of 2.0 g. It sits in a steerable delivery catheter and is inserted through a femoral vein using a 23-Fr introducer (Figure 1). Follow-up and Endpoints Successfully implanted patients had scheduled study visits at hospital discharge, 1, 3, and 6 months post-implant, and every 6 months thereafter. Adverse events and device function were evaluated at each follow-up visit. The primary safety endpoint was freedom from system-related or procedure-related major complications at 6 months, though for this report we also provide the safety data through 12 months as all the 12-month study visits were completed at the time of this analysis. Major complications were defined as events resulting in death, permanent loss of device function as a result of mechanical or electrical dysfunction, hospitalization, prolongation of hospitalization by at least 48 h, or system revision. The primary efficacy endpoint was the combination of a low ( 2 V at a pulse width of 0.24 ms) and stable (increase 1.5 V from the implant) pacing capture threshold at the 6-month visit; however, for this analysis, we focused on electrical performance through 12 months. Secondary and ancillary endpoints included accuracy of ventricular capture management feature, implant procedure characteristics, estimation of battery longevity and electrical performance. Additional endpoints included reporting on device-handling questionnaire responses by implanting physicians and satisfaction questionnaire responses by patients. For the device-handling questionnaire, the implanting physician selected one of the response choices (extremely difficult, difficult, neutral, easy, and extremely easy) for each question: (1) navigation of the delivery system to the right ventricle, (2) device deployment, (3) pull and hold test (used to verify device fixation, as previously described 10 and (4) overall impression, following each implant procedure. For the satisfaction questionnaire, evaluated at the 3-month visit, the patient selected one of the response choices (very satisfied, satisfied, neutral, dissatisfied, and very dissatisfied) for each question: (1) recovery, (2) cosmetic appearance and (3) level of activity. Statistical Analysis The study protocol and sample size allowed for up to 3 planned interim analyses of the 2 primary endpoints when 300, 450, and 600 patients completed the 6-month visit. The study also had a prespecified long-term safety objective that occurred when all patients had the opportunity to complete the 12-month visit. Because the long-term safety assessment has been completed, 5 the 12-month major complication free rates are reported. Baseline demographics, medical history, implant procedure characteristics, devicehandling questionnaire, and the patient satisfaction questionnaire were compared between patients at the ese centers ( patients) and those outside ( Outside of patients) using t-tests or the Wilcoxon rank-sum test (continuous variables) or Fisher s exact test (discrete variables). The major complication rates through 12 months were compared between the and Outside of patients using a log-rank test. The accuracy of Micra s ventricular capture management feature was compared between the and patients using Fisher s exact test. The analysis cohort for the longterm safety endpoint included all patients with a Micra implant attempt. The analysis cohort for the secondary

3 Leadless Pacemaker in ese Patients 1591 endpoint of ventricular capture management feature accuracy included all patients with pacing thresholds measured both manually and using Micra s ventricular capture management feature at the 6-month visit. Electrical parameters were summarized at each study visit using means and standard deviations. Battery longevity was projected using Monte Carlo methods by combining bench-measured static current drain distributions combined with actual-use conditions obtained via 12-month device interrogation files, plus 6 half-hour telemetry sessions per year. Results Patients A total of 745 patients were enrolled at 56 centers in 19 countries worldwide, and 726 patients underwent an implantation attempt. In, 38 patients were enrolled at 4 centers and 36 patients underwent an implant attempt by 6 operators. The 2 patients left the study before pacemaker implantation was attempted because they did not meet eligibility criteria; 1 was likely to relocate during the follow-up and the other had a narrow femoral vein. The analysis included 726 patients (including 36 ese patients) who underwent pacemaker implantation, 695 patients (including 35 ese patients) who completed the 3-month visit, 684 patients (including 36 ese patients) who completed the 6-month visit, and 656 (including 36 ese patients) who completed the 12-month visit (Figure 2). Baseline characteristics of the and patients are shown in Table 1 and Table 2. patients were significantly shorter and smaller than the Outside of patients (P<0.001). Pacing indication associated with atrial fibrillation (AF) was lower in patients compared with patients (42% vs. 65%, P=0.007). Of the patients, 21 (58.3%) had indications unrelated to AF and included: sinus node dysfunction (n=15, 41.7%), atrioventricular (AV) block (n=5, 13.9%), and trifascicular block with presyncope (n=1, 2.8%). The rationales for single-chamber pacemaker selection in the patients, which were not mutually exclusive, were: Figure 2. Patient flow diagram. Geo, geographic regions. infrequent pacing (66.7%), old age (61.1%), persistent AF (41.7%), low activity (16.7%), post- or planned AV node ablation (5.6%), anatomical difficulty with atrial lead insertion (2.8%), serious comorbidity that affected prognosis (2.8%), and possible high risk of complications with a dualchamber system (2.8%). None of the patients had a history of cardiomyopathy and more patients presented with congestive heart failure caused by bradycardia (39% vs. 17%, P=0.003). Fewer patients had coronary artery disease compared with the patients (11% vs. 29%, P=0.021). Implant Procedure Characteristics Procedural characteristics of the and Outside of patients are shown in Table 3. All attempts at Micra implant were successful in the 36 (100%) patients. Procedure time from introducer placement to introducer removal was longer in the patients compared with the patients (39.3±16.9 vs. 34.5±24.4 min, Table 1. Characteristics of the Patients at Baseline (n=690*) P value Age (years) Mean ± SD 78.2± ± Min. max Sex Male, n (%) 24 (66.7) 403 (58.4) 0.39 Height (cm) Mean ± SD 159.1± ±10.4 <0.001 Min. max Weight (kg) Mean ± SD 58.8± ±18.1 <0.001 Min. max BMI Mean ± SD 23.1± ±5.3 <0.001 Min. max *Height and weight for 2 patients not available. Calculated using Fisher s exact test for discrete variables and t-test for continuous variables. BMI, body mass index; max., maximum; min., minimum; SD, standard deviation.

4 1592 SOEJIMA K et al. Table 2. Characteristics of the Patients Medical Histories (n=690) Pacing indication associated with AF 41.7% 65.1% Cardiomyopathy 0.0% 11.7% Congestive heart failure 38.9% 17.0% Coronary artery disease 11.1% 29.1% Hypertension 69.4% 79.1% 0.21 Myocardial infarction 8.3% 10.7% 1.00 Pulmonary hypertension 2.8% 11.7% 0.11 Valve dysfunction, tricuspid 19.4% 26.5% 0.44 COPD 8.3% 12.9% 0.61 Diabetes 25.0% 28.7% 0.71 Renal dysfunction 30.6% 20.0% 0.14 Chronic lung disease 33.3% 29.4% 0.58 *Calculated using Fisher s exact test for discrete variables and t-tests for continuous variables. AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease. Table 3. Characteristics of the Implant Procedure (n=684) Implant success rate, % Procedure time, min Mean ± SD 39.3± ± ** Median Device location, n (%) Apex 23 (63.9%) 452 (66.1%) 0.68 Septum/mid-septum 13 (36.1%) 214 (31.3%) Other 0 (0.0%) 18 (2.6%) No. of deployments 5, n (%) 32 (88.9%) 655 (95.8%) 0.08 Preprocedure OAC/antiplatelet use, n (%) 28 (77.8%) 446 (65.2%) 0.15 Intraprocedure anticoagulation, n (%) 36 (100.0%) 341 (49.9%) <0.001 Anticoagulation antagonist, n (%) 23 (63.9%) 46 (6.7%) <0.001 Closure method: manual pressure+suture, n (%) 36 (100.0%) 354 (51.8%) <0.001 Time to ambulation (h), mean ± SD 18.6± ±6.9 <0.001 Days of hospitalization for implant, mean ± SD 5.1± ±2.7 <0.001 *Calculated using Fisher s exact test for discrete variables and t-test for continuous variables; **calculated using Wilcoxon rank-sum test. Denominator: 690 patients outside of with implant attempt. Procedure time: from the beginning of introducer placement to the end of introducer removal. OAC, oral anticoagulant. P=0.007). The location of the device was similar, and was positioned with 5 deployments in the majority of patients (88.9% vs. 95.8%; P=0.08) in both groups. Most patients were anticoagulated prior to the implant, and all patients received intraprocedural anticoagulation, whereas only 49.9% of the patients received anticoagulation during the procedure (P<0.001). Prior to sheath removal and hemostasis, an anticoagulation antagonist was used more frequently in the patients (63.9% vs. 6.7%; P<0.001). Hemostasis with suture and manual pressure was the only closure method used in patients, but was used less frequently in the Outside of patients (100.0% vs. 51.8%; P<0.001). Time to ambulation and days of hospitalization for the implant were longer in patients (18.6± 6.2 vs. 10.1±6.9 h; P<0.001 and 5.1±1.8 vs. 2.0±2.7 days; P<0.001, respectively). Long-Term Safety Outcome: System- or Procedure-Related Major Complications There were 5 complications related to the system or procedure experienced by 5 of the patients (presyncope, incision site hematoma, incision site hemorrhage, pericardial effusion, and hypotension). None of these complications met the criteria for a major complication which was defined as an event resulting in death, permanent loss of device function, hospitalization, prolongation of hospitalization, or system revision. Presyncope occurred during the implant procedure, possibly caused by vagal reflex. Incision site hematoma and hemorrhage were related to the implant procedure and introducer. Pericardial effusion was classified as a complication because it required an invasive intervention (pericardiocentesis) for resolution. Hypotension was observed during the implant procedure and was an adverse effect of the sedative agent. The freedom from

5 Leadless Pacemaker in ese Patients 1593 Figure 3. (A C) Electrical performance characteristics by study visit. Data in the graphs are mean values, and I bars represent mean ± standard deviations. N values are the numbers of patients for whom data were available at each time point. PHD, pre-hospital discharge. system- or procedure-related major complications through 12 months was 100.0% (95% confidence interval (CI) %) in the patients and was not significantly different from (95.7%, 95% CI %, P=0.211). Electrical Performance The average pacing capture threshold among patients at both implant and the 12-month visit was 0.54 V compared with 0.63 V and 0.61 V for patients outside (Figure 3A). The average R-wave amplitude among patients at implant was 11.3 mv and 14.2 mv at 12-month visit compared with 11.2 mv and 15.1 mv, respectively, in patients outside (Figure 3B). The average pacing impedance among patients was 753 ohms at implant and 566 ohms at the 12-month visit compared with 722 ohms and 597 ohms, respectively, among patients outside of (Figure 3C). Based on the use conditions of the 36 patients through 12 months, mean estimated battery longevity was 12.5 years with a range of years. Responses to Device-Handling Questionnaire by Implant Physicians Physicians responses to the questionnaire were similar in both groups (Table 4). The majority of physicians felt the navigation delivery was extremely easy/easy (91.6% vs. 89.0% for patients vs. patients, P=0.173), device deployment was extremely easy/easy (94.4% vs. 94.6% for patients vs. patients, P=0.557), pull and hold test was extremely easy/ easy (91.7% vs. 77.8% for patients vs. Outside of patients, P=0.153), and overall impression was extremely easy/easy (91.7% vs. 88.4% for vs. Outside of patients, P=0.638).

6 1594 SOEJIMA K et al. Table 4. Physicians Responses to Device-Handling Questionnaire Device-handling questions (n=683) Navigation of delivery system to RV Extremely difficult/difficult 3 (8.3%) 32 (4.7%) Neutral 0 (0.0%) 43 (6.3%) Extremely easy/easy 33 (91.6%) 608 (89.0%) Device deployment Extremely difficult/difficult 0 (0.0%) 13 (1.9%) Neutral 2 (5.6%) 24 (3.5%) Extremely easy/easy 34 (94.4%) 646 (94.6%) Tug test Extremely difficult/difficult 0 (0.0%) 36 (5.3%) Neutral 3 (8.3%) 116 (17.0%) Extremely easy/easy 33 (91.7%) 531 (77.8%) Overall impression Extremely difficult/difficult 2 (5.5%) 30 (4.4%) Neutral 1 (2.8%) 49 (7.2%) Extremely easy/easy 33 (91.7%) 604 (88.4%) *Calculated using Fisher s exact test for discrete variables and t-tests for continuous variables. RV, right ventricle. Table 5. Patient Satisfaction at 3 Months Satisfaction questions (n=35) (n=658) Recovery Very dissatisfied/dissatisfied 2 (5.7%) 20 (3.0%) Neutral 7 (20.0%) 34 (5.2%) Very satisfied/satisfied 26 (74.3%) 604 (91.8%) Cosmetic appearance Very dissatisfied/dissatisfied 0 (0.0%) 3 (0.5%) Neutral 3 (8.6%) 22 (3.3%) Very satisfied/satisfied 32 (91.4%) 633 (96.2%) Level of Activity Very dissatisfied/dissatisfied 2 (5.7%) 35 (5.3%) Neutral 12 (34.3%) 131 (19.9%) Very satisfied/satisfied 21 (60.0%) 492 (74.9%) *Calculated using Fisher s exact test for discrete variables and t-tests for continuous variables. Responses to Satisfaction Questionnaire by Patients All 35 patients and 658 of 660 patients with a 3-month visit at the time of the primary analysis completed satisfaction questionnaires (Table 5). Patients responses were similar for cosmetic appearance and level of activity. However, more patients outside of were very satisfied or satisfied with their recovery than patients (74.3% vs. 91.8%, P=0.002). Discussion In this study, there were no significant differences in longterm safety, electrical performance, or patient and physician acceptability observed between patients inside and outside, except in patient satisfaction with recovery. This is despite there being differences in specific baseline characteristics and implant procedure characteristics between the 2 groups. These findings suggested that the favorable safety and efficacy results from the global study may be extended to ese patients, despite -specific medical practices and environments. Implantation There were 5 events in 5 patients (13.9%) that were considered complications requiring invasive intervention such as intravenous medications to resolve the event. None were considered major complications, and no dislodgements or systemic infections were observed. There was 1 case of pericardial effusion that occurred in a ese patient during an implant procedure. The patient was an 81-yearold male with a history of chronic obstructive pulmonary disease, emphysema, and pleural effusion. The pericardial effusion was classified as a minor complication because it required pericardiocentesis, but it did not meet the definition of a major complication because the event did not result in death, hospitalization, prolongation of hospitalization, loss of device functionality, or system revision. Because the TPS only has one size and shape and the

7 Leadless Pacemaker in ese Patients 1595 catheter requires a large-bore introducer, the adaptability of the system to small or short patients was a major concern prior to starting the study. Although the ese patients enrolled in the study were considerably smaller than patients from the rest of the world, TPS implantation was successful in all of them and there were no procedurerelated major complications, including groin puncture site major complications. In addition, all ese patients had low and stable pacing threshold, sensitivity, and impedance. The most common device location was the apex, and the distribution of placement location was similar in patients inside and outside of. One ese patient left the study prior to implant attempt because a narrow femoral vein confirmed by preoperative CT scan. Preoperative imaging, such as MRI, CT scan or venogram, is thought to be useful to confirm if the femoral vein s size and anatomy can accommodate a 23-Fr introducer, especially in patients with small stature. The TPS is ideal for elderly and thin patients, as it does not require a subcutaneous pocket. It is expected that ese patients, who tend to be thin, will receive more benefit from the TPS. For ese patients, implant procedure time was longer, most likely because of anticoagulation, monitoring of the activated clotting time during the procedure, and reversing anticoagulation prior to sheath removal. Also, hemostasis with figure-of-eight suture and manual pressure was used for all ese patients. These findings suggested that there was more concern surrounding potential bleeding complications in the ese patients. Time before ambulation and length of hospital stay were longer for ese patients, which might be explained by the use of the same clinical pathway that is used for conventional pacemaker implantation. However, given the physician satisfaction survey results and patient condition following the implant, hospital stays could be shortened, which will have additional benefit, especially for elderly and frail patients. Satisfaction Survey A total of 9 of 35 ese patients were not satisfied with their recovery and there was a significant difference in patient response regarding recovery between and outside. It is plausible that the medical history of the patients and adverse events associated with the implant procedure had a negative effect on their satisfaction with recovery. In fact, 6 of the 9 ese patients, including 2 patients who were very dissatisfied or dissatisfied with recovery, had congestive heart failure. The remaining 3 patients were experiencing an adverse event: worsening of AF or epilepsy at their 3-month visit. One ese patient who was very dissatisfied with recovery had congestive heart failure and reported cardiac failure deterioration at the 3-month visit. None of the ese patients developed pacemaker syndrome. Study Limitations The TPS global study was not designed to evaluate interregional differences between and outside. The number of ese patients who underwent an implant attempt with the TPS was only 36, accounting for approximately 5% of the entire study cohort. However, the study was conducted simultaneously around the globe following a single protocol. This makes it easier to generalize the study results to individual geographic regions. Conclusions TPS was successfully implanted in 100% of ese patients. Despite some differences in baseline characteristics and implant procedure characteristics in ese patients, safety and efficacy performance were favorable and similar to the global trial performance. Further, the TPS was favorably accepted by implanting physicians and patients. None. Name of Grants Disclosures K. Stromberg and J.L. work for Medtronic. W.T. was an employee of Medtronic. References 1. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: Calendar year 2009: A World Society of Arrhythmia s project. Pacing Clin Electrophysiol 2011; 34: Udo EO, Zuithoff NPA, 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: Kirkfeldt RE, Johansen JB, Nohr EA, Jorgensen OD, Nielsen JC. Complications after cardiac implantable electronic device implantations: An analysis of a complete, nationwide cohort in Denmark. Eur Heart J 2014; 35: Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, et al. A leadless intracardiac transcatheter pacing system. N Engl J Med 2016; 374: Duray GZ, Ritter P, El-Chami M, Narasimhan C, Omar R, Tolosana JM, et al. Long-term performance of a transcatheter pacing system: 12-month results from the Micra Transcatheter Pacing Study. Heart Rhythm 2017; 14: Ritter P, Duray GZ, Zhang S, Narasimhan C, Soejima K, Omar R, et al. The rationale and design of the Micra Transcatheter Pacing Study: Safety and efficacy of a novel miniaturized pacemaker. Europace 2015; 17: Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol 2008; 51: e1 e Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006; 8: JCS Joint Working Group. Guidelines for non-pharmacotherapy of cardiac arrhythmias (JCS 2011): Digest version. Circ J 2013; 77: El-Chami MF, Roberts PR, Kypta A, Omdahl P, Bonner MD, Kowal RC, et al. How to implant a leadless pacemaker with a tine-based fixation. J Cardiovasc Electrophysiol 2016; 27: