A Modular Communicative Leadless Pacing-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown. METHODS: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%). RESULTS: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure. CONCLUSIONS: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.).

Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.

BACKGROUND: Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed field ablation as compared with conventional thermal ablation are not known. METHODS: In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy end point was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety end point included acute and chronic device- and procedure-related serious adverse events. RESULTS: A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At 1 year, the primary efficacy end point was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, -5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in 6 patients (estimated incidence, 2.1%) who underwent pulsed field ablation and 4 patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, -1.5 to 2.8; posterior probability of noninferiority, >0.999). CONCLUSIONS: Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed field ablation was noninferior to conventional thermal ablation with respect to freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. (Funded by Farapulse-Boston Scientific; ADVENT ClinicalTrials.gov number, NCT04612244.).

Pulmonary vein narrowing after pulsed field versus thermal ablation.

AIMS: When it occurs, pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is associated with significant morbidity. Even mild-to-moderate PV narrowing may have long-term implications. Unlike thermal ablation energies, such as radiofrequency (RF) or cryothermy, pulsed field ablation (PFA) is a non-thermal modality associated with less fibrotic proliferation. Herein, we compared the effects of PFA vs. thermal ablation on PV narrowing after AF ablation. METHODS AND RESULTS: ADVENT was a multi-centre, randomized, single-blind study comparing PFA (pentaspline catheter) with thermal ablation-force-sensing RF or cryoballoon (CB)-to treat drug-refractory paroxysmal AF. Pulmonary vein diameter and aggregate cross-sectional area were obtained by baseline and 3-month imaging. The pre-specified, formally tested, secondary safety endpoint compared a measure of PV narrowing between PFA vs. thermal groups, with superiority defined by posterior probability > 0.975. Among subjects randomized to PFA (n = 305) or thermal ablation (n = 302), 259 PFA and 255 thermal ablation (137 RF and 118 CB) subjects had complete baseline and 3-month PV imaging. No subject had significant (≥70%) PV stenosis. Change in aggregate PV cross-sectional area was less with PFA (-0.9%) than thermal ablation (-12%, posterior probability > 0.999)-primarily driven by the RF sub-cohort (-19.5%) vs. CB sub-cohort (-3.3%). Almost half of all PFA PV diameters did not decrease, but the majority (80%) of RF PVs decreased, regardless of PV anatomic location. CONCLUSION: In this first randomized comparison of PFA vs. thermal ablation, PFA resulted in less PV narrowing-thereby underscoring the qualitatively differential and favourable impact of PFA on PV tissue.

Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction (UNTOUCHED) Trial.

BACKGROUND: The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms. METHODS: Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points. RESULTS: S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%. CONCLUSIONS: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379.

Combining left atrial appendage closure and catheter ablation for atrial fibrillation: 2-year outcomes from a multinational registry.

AIMS: Clinical practice guidelines do not recommend discontinuation of long-term oral anticoagulation in patients with a high stroke risk after catheter ablation for atrial fibrillation (AF). Left atrial appendage closure (LAAC) with Watchman has emerged as an alternative to long-term anticoagulation for patients accepting of the procedural risks. We report on the long-term outcomes of combining catheter ablation procedures for AF and LAAC from multicentre registries. METHODS AND RESULTS: Data were pooled from two prospective, real-world Watchman LAAC registries running in parallel in Europe/Middle-East/Russia (EWOLUTION) and Asia/Australia (WASP) between 2013 and 2015. Of the 1140 patients, 142 subjects at 11 centres underwent a concomitant AF ablation and LAAC procedure. The mean CHA2DS2-VASc score was 3.4 ± 1.4 and HAS-BLED score 1.5 ± 0.9. Successful LAAC was achieved in 99.3% of patients. The 30-day device and/or procedure-related serious adverse event rate was 2.1%. After a mean follow-up time of 726 ± 91 days, 92% of patients remained off oral anticoagulation. The rates of the composite endpoint of ischaemic stroke/transient ischaemic attack/systemic thromboembolism were 1.09 per 100 patient-years (100-PY); and for non-procedural major bleeding were 1.09 per 100-PY. These represent relative reductions of 84% and 70% vs. expected rates per risk scores. CONCLUSION: The long-term outcomes from these international, multicentre registries show efficacy for all-cause stroke prevention and a significant reduction in late bleeding events in a population of high stroke risk post-ablation patients who have been withdrawn from oral anticoagulation.

Incidence of pericardial effusion after left atrial appendage closure: The impact of underlying heart rhythm-Data from the EWOLUTION study.

INTRODUCTION: Pericardial effusion/tamponade (PE/PT) is a rare but serious complication following left atrial appendage closure (LAAC). It may be speculated that LAA contraction during sinus rhythm (SR) exerts mechanical force on the device that eventually leads to PE. We sought to determine the incidence and predictors of PE following LAAC using Watchman with special emphasis on the underlying heart rhythm during implant. METHODS AND RESULTS: From 47 centers in 13 European countries 1,020 patients underwent LAAC and data on baseline rhythm were available from 1,010 patients (mean age 73 ± 9 years, 60% male, median CHA2DS2-VASc = 4). Data were collected via electronic case report forms. A Cox proportional hazard model was calculated adjusting for multiple variables: age, gender, number of recaptures, and device oversizing. During implant, 41% and 59% of patients were in SR and atrial fibrillation (AF), respectively. PE/PT rate was significantly lower in patients implanted during AF at day 30 postimplant (n = 1; 0.2% vs. n = 6; 1.5%; P = 0.02). No PE requiring intervention occurred in the AF group compared to 5 events (1.2%) in the SR group (P = 0.01). While univariate analysis identified SR and gender as predictors for PE/tamponade, multivariate analysis only showed a statistical trend for both variables. CONCLUSION: The overall incidence of PE/PT was very low after LAAC using Watchman. Although SR was not identified as an independent predictor of PE/PT, all events requiring intervention occurred in patients with SR. It may be advisable to perform an extended echocardiographic follow-up in that patient population.

Combining Watchman left atrial appendage closure and catheter ablation for atrial fibrillation: multicentre registry results of feasibility and safety during implant and 30 days follow-up.

Aims: Long-term results from catheter ablation therapy for atrial fibrillation (AF) remain uncertain and clinical practice guidelines recommend continuation of long-term oral anticoagulation in patients with a high stroke risk. Left atrial appendage closure (LAAC) with Watchman has emerged as an alternative to long-term anticoagulation for patients accepting of the procedural risks. We report on the initial results of combining catheter ablation procedures for AF and LAAC in a multicentre registry. Methods and results: Data were pooled from two prospective, real-world Watchman LAAC registries running in parallel in Europe/Middle-East/Russia (EWOLUTION) and Asia/Australia (WASP) between 2013 and 2015. Of the 1140 patients, 139 subjects at 10 centres underwent a concomitant AF ablation and LAAC procedure. The mean CHA2DS2-VASc score was 3.4 ± 1.4 and HAS-BLED score 1.5 ± 0.9. Successful Watchman implantation was achieved in 100% of patients. The overall 30-day serious adverse event (SAE) rate was 8.7%, with the device and/or procedure-related SAE rate of 1.4%. One pericardial effusion required percutaneous drainage, but there were no strokes, device embolization, or deaths at 30 days. The 30-day bleeding SAE rate was 2.9% with 55% of patients prescribed NOAC and 38% taking warfarin post-procedure. Conclusion: The outcomes from these international, multicentre registries support the feasibility and safety of performing combined procedures of ablation and Watchman LAAC for patients with non-valvular AF and high stroke risk. Further data are needed on long-term outcomes for the hybrid technique on all-cause stroke and mortality.

Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry.

AIMS: Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk patients with non-valvular atrial fibrillation. The objective of the multicentre EWOLUTION registry was to obtain clinical data on procedural success and complications, and long-term patient outcomes, including bleeding and incidence of stroke/transient ischaemic attack (TIA). Here, we report on the peri-procedural outcomes of up to 30 days. METHODS AND RESULTS: Baseline/implant data are available for 1021 subjects. Subjects in the study were at high risk of stroke (average CHADS2 score: 2.8 ± 1.3, CHA2DS2-VASc: 4.5 ± 1.6) and moderate-to-high risk of bleeding (average HAS-BLED score: 2.3 ± 1.2). Almost half of the subjects (45.4%) had a history of TIA, ischaemic stroke, or haemorrhagic stroke; 62% of patients were deemed unsuitable for novel oral anticoagulant by their physician. The device was successfully deployed in 98.5% of patients with no flow or minimal residual flow achieved in 99.3% of implanted patients. Twenty-eight subjects experienced 31 serious adverse events (SAEs) within 1 day of the procedure. The overall 30-day mortality rate was 0.7%. The most common SAE occurring within 30 days of the procedure was major bleeding requiring transfusion. Incidence of SAEs within 30 days was significantly lower for subjects deemed to be ineligible for oral anticoagulation therapy (OAT) compared with those eligible for OAT (6.5 vs. 10.2%, P = 0.042). CONCLUSION: Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure.

Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE).

BACKGROUND: Defibrillation testing by induction and termination of ventricular fibrillation is widely done at the time of implantation of implantable cardioverter defibrillators (ICDs). We aimed to compare the efficacy and safety of ICD implantation without defibrillation testing versus the standard of ICD implantation with defibrillation testing. METHODS: In this single-blind, randomised, multicentre, non-inferiority trial (Shockless IMPLant Evaluation [SIMPLE]), we recruited patients aged older than 18 years receiving their first ICD for standard indications at 85 hospitals in 18 countries worldwide. Exclusion criteria included pregnancy, awaiting transplantation, particpation in another randomised trial, unavailability for follow-up, or if it was expected that the ICD would have to be implanted on the right-hand side of the chest. Patients undergoing initial implantation of a Boston Scientific ICD were randomly assigned (1:1) using a computer-generated sequence to have either defibrillation testing (testing group) or not (no-testing group). We used random block sizes to conceal treatment allocation from the patients, and randomisation was stratified by clinical centre. Our primary efficacy analysis tested the intention-to-treat population for non-inferiority of no-testing versus testing by use of a composite outcome of arrhythmic death or failed appropriate shock (ie, a shock that did not terminate a spontaneous episode of ventricular tachycardia or fibrillation). The non-inferiority margin was a hazard ratio (HR) of 1·5 calculated from a proportional hazards model with no-testing versus testing as the only covariate; if the upper bound of the 95% CI was less than 1·5, we concluded that ICD insertion without testing was non-inferior to ICD with testing. We examined safety with two, 30 day, adverse event outcome clusters. The trial is registered with ClinicalTrials.gov, number NCT00800384. FINDINGS: Between Jan 13, 2009, and April 4, 2011, of 2500 eligible patients, 1253 were randomly assigned to defibrillation testing and 1247 to no-testing, and followed up for a mean of 3·1 years (SD 1·0). The primary outcome of arrhythmic death or failed appropriate shock occurred in fewer patients (90 [7% per year]) in the no-testing group than patients who did receive it (104 [8% per year]; HR 0·86, 95% CI 0·65-1·14; pnon-inferiority <0·0001). The first safety composite outcome occurred in 69 (5·6%) of 1236 patients with no-testing and in 81 (6·5%) of 1242 patients with defibrillation testing, p=0·33. The second, pre-specified safety composite outcome, which included only events most likely to be directly caused by testing, occurred in 3·2% of patients with no-testing and in 4·5% with defibrillation testing, p=0·08. Heart failure needing intravenous treatment with inotropes or diuretics was the most common adverse event (in 20 [2%] of 1236 patients in the no-testing group vs 28 [2%] of 1242 patients in the testing group, p=0·25). INTERPRETATION: Routine defibrillation testing at the time of ICD implantation is generally well tolerated, but does not improve shock efficacy or reduce arrhythmic death. FUNDING: Boston Scientific and the Heart and Stroke Foundation (Ontario Provincial office).

Predictable and SuStainable Implementation of National Cardiovascular Registries (PASSION) infrastructure: A think tank report from Medical Device Epidemiological Network Initiative (MDEpiNet).

The MDEpiNet is a public-private partnership between the US Food and Drug Administration's Center for Devices and Radiological Health and participating partners. The PASSION program is an MDEpiNet-sponsored program that aims to demonstrate the goals of MDEpiNet by using cardiovascular medical device registries to bridge evidence gaps across the medical device total product life cycle. To this end, a PASSION Think Tank meeting took place in October 2014 in Silver Spring, MD, to facilitate discussion between stakeholders about the successes, challenges, and future novel applications of medical device registries, with particular emphasis on identifying pilot projects. Participants spanned a broad range of groups including patients, device manufacturers, regulators, physicians/academicians, professional societies, providers, and payers. The meeting focus included 4 areas of cardiovascular medicine intended to cultivate interest in 4 MDEpiNet disease-specific/device-specific working groups: coronary intervention, electrophysiology, valvular disease, and peripheral vascular disease. In addition, more general issues applying to registry-based infrastructure and analytical methodologies for assessing device benefit/risk were considered to provide context for the working groups as PASSION programs going forward. This article summarizes the discussions at the meeting and the future directions of the PASSION program.

EWOLUTION: Design of a registry to evaluate real-world clinical outcomes in patients with AF and high stroke risk-treated with the WATCHMAN left atrial appendage closure technology.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and the rate of ischemic stroke attributed to non-valvular AF is estimated at 5% per year. Several multi-center studies established left atrial appendage closure as a safe and effective alternative to oral anticoagulation, but there is a need for additional real world data. METHODS: The purpose of this observational, prospective, single-arm, multicenter clinical study is to compile real-world clinical outcome data for WATCHMAN™ LAA (left atrial appendage) Closure Technology. One thousand subjects at up to 70 institutions in Europe, the Middle East, and Russia will be enrolled. Patients will be followed for 2 years after WATCHMAN implantation, according to standard medical practice. Primary endpoints include procedural and long-term data including stroke/embolism, bleeding, and death. This article presents the background of the LAAC device and describes the design of the study. RESULTS: Results for peri-procedural analyses are expected toward the end of 2015; long-term follow-up data are expected in the latter half of 2017. CONCLUSION: The EWOLUTION study will formally expand knowledge of LAA closure into a broader real world setting. © 2015 Wiley Periodicals, Inc.

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial.

AIM: The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. METHODS: Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. RESULTS: Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. CONCLUSION: Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

Plasma galectin-3 and heart failure outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy).

BACKGROUND: Elevated circulating levels of the protein galectin-3, a mediator of fibrogenesis, have previously been associated with adverse outcomes in heart failure (HF) patients and appear to modify response to certain pharmacologic therapies. This study investigated the relationship between galectin-3 level and clinical outcomes in HF patients randomized to implantable cardioverter defibrillator (ICD-only) or cardiac resynchronization therapy (CRT-D). METHODS AND RESULTS: Plasma galectin-3 concentrations were measured in 654 New York Heart Association functional class I/II patients participating in the MADIT-CRT trial. A heterogeneity of response was detected between pre-implantation galectin-3 and randomization group (CRT-D or ICD-only) on the primary MADIT-CRT trial end point of nonfatal HF event or death (P = .045). Among patients with baseline galectin-3 levels in the top quartile of the distribution, CRT-D was associated with a 65% reduction in risk of the primary end point (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.19-0.67), whereas among patients with lower baseline galectin-3 values CRT-D was associated with a 25% decrease in risk (HR 0.75, 95% CI. 0.51-1.11). Baseline galectin-3 level also was observed to be an independent predictor of the primary end point (multivariable adjusted HR per log unit increase: 1.55; 95% CI 1.01-2.38; P = .043). CONCLUSIONS: Elevated galectin-3 was found to be an independent predictor of adverse HF outcome in patients with mildly symptomatic HF. A significant interaction of device randomization group with pre-implantation galectin-3 level was detected, with HF patients with the highest baseline galectin-3 levels deriving a disproportionately larger benefit from CRT-D.

Atrioventricular optimization improves cardiac resynchronization response in patients with long interventricular electrical delays: A pooled analysis of the SMART-AV and SMART-CRT trials.

BACKGROUND: The utility of atrioventricular (AV) optimization (AVO) algorithms remains in question. A substudy of the SMART-AV trial found that patients with prolonged interventricular delays ≥70 ms were more likely to benefit from cardiac resynchronization therapy (CRT) with AVO. The SMART-CRT trial evaluated AVO on the basis of these results, but the study was underpowered. OBJECTIVE: To increase statistical power, data from SMART-AV patients meeting the inclusion criterion of interventricular delay ≥70 ms were pooled with data from SMART-CRT to reassess AVO. METHODS: SMART-CRT and SMART-AV were prospective, randomized, multicenter clinical trials. Patients in both studies were randomized to be programmed with an AVO algorithm (SmartDelay) or fixed AV delay (120 ms). Paired echocardiograms obtained at baseline and 6 months were compared, with CRT response defined as ≥15% reduction in left ventricular end-systolic volume. RESULTS: A total of 451 complete patient data sets were pooled and analyzed. The baseline demographics between studies did not differ statistically in terms of age, sex, left ventricular ejection fraction, or left ventricular end-systolic volume. The AVO group had a greater proportion of CRT responders (SmartDelay, 73.9%; fixed, 63.1%; P = .014) and greater changes in measures of reverse remodeling. SmartDelay patients with a recommended sensed AV delay outside the nominal range (100-120 ms) had 2.3 greater odds of CRT response than fixed AV delay patients. CONCLUSION: Greater CRT response and measures of reverse remodeling were observed in patients with SmartDelay enabled vs a fixed AV delay. This study supports the use of SmartDelay in patients with a CRT indication and interventricular delay ≥70 ms. GOV REGISTRATION: NCT00677014 and NCT03089281.

Effects of Atrioventricular Optimization on Left Ventricular Reverse Remodeling With Cardiac Resynchronization Therapy: Results of the SMART-CRT Trial.

BACKGROUND: The role of atrioventricular optimization (AVO) to improve cardiac resynchronization therapy outcomes remains controversial. Previous post hoc analyses of a multicenter trial showed that measures of electrical dyssynchrony (right ventricular-left ventricular [LV] or LV electrical delay durations) are associated with patients who benefit from AVO. METHODS: This was a global, multicenter, prospective, randomized trial of de novo cardiac resynchronization therapy implant patients with an right ventricular-LV duration ≥70 ms to determine whether AVO results in greater reverse remodeling. Patients were randomized 1:1 for either an AVO algorithm (SmartDelay) that determines atrioventricular delay and pacing chamber, biventricular or LV only, or a fixed atrioventricular delay of 120 ms with biventricular pacing. Paired echocardiograms performed at baseline and 6 months were evaluated. The primary end point was echocardiographic cardiac resynchronization therapy response, defined dichotomously as a >15% reduction in LV end-systolic volume. RESULTS: A total of 310 patients (n=120 women) were randomized and had completed 6 months of follow-up. The echocardiographic cardiac resynchronization therapy response rate did not statistically differ between the groups (SmartDelay, 74.8%; fixed, 67.7%; P=0.17). Analyses of prespecified secondary end points demonstrated significant improvements in the absolute (median: SmartDelay, -41.0 mL; fixed, -33.0 mL; P=0.01) and relative change in LV end-systolic volume (SmartDelay, -38.3%; fixed, -27.8%; P=0.03) for patients with SmartDelay optimization. Similar results were observed for the relative improvement in LV ejection fraction (SmartDelay, 46.7%; fixed, 32.1%; P=0.050); absolute improvement in LV ejection fraction trended to be higher with SmartDelay (P=0.06). CONCLUSIONS: Analysis of reverse remodeling parameters demonstrated that AVO via SmartDelay, relative to the nonoptimized fixed atrioventricular delay comparator group, improved absolute and relative changes in LV function in patients with longer right ventricular-LV duration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03089281.

Design and rationale of the MODULAR ATP global clinical trial: A novel intercommunicative leadless pacing system and the subcutaneous implantable cardioverter-defibrillator.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has demonstrated safety and efficacy for the treatment of malignant ventricular arrhythmias. However, a limitation of the S-ICD lies in the inability to either pace-terminate ventricular tachycardia or provide prolonged bradycardia pacing support. Objective: The rationale and design of a prospective, single-arm, multinational trial of an intercommunicative leadless pacing system integrated with the S-ICD will be presented. Methods: A technical description of the modular cardiac rhythm management (mCRM) system (EMPOWER leadless pacemaker and EMBLEM S-ICD) and the implantation procedure is provided. MODULAR ATP (Effectiveness of the EMPOWER™ Modular Pacing System and EMBLEM™ Subcutaneous ICD to Communicate Antitachycardia Pacing) is a multicenter, international trial enrolling up to 300 patients at risk of sudden cardiac death at up to 60 centers trial design. The safety endpoint of freedom from major complications related to the mCRM system or implantation procedure at 6 months and 2 years are significantly higher than 86% and 81%, respectively, and all-cause survival is significantly >85% at 2 years. Results: Efficacy endpoints are that at 6 months mCRM communication success is significantly higher than 88% and the percentage of subjects with low and stable thresholds is significantly higher than 80%. Substudies to evaluate rate-responsive features and performance of the pacing module are also described. Conclusion: The MODULAR ATP global clinical trial will prospectively test the safety and efficacy of the first intercommunicating leadless pacing system with the S-ICD. This trial will allow for robust validation of device-device communication, pacing performance, rate responsiveness, and system safety.

Quantifying Benefit-Risk Preferences for Heart Failure Devices: A Stated-Preference Study.

BACKGROUND: Regulatory and clinical decisions involving health technologies require judgements about relative importance of their expected benefits and risks. We sought to quantify heart-failure patients' acceptance of therapeutic risks in exchange for improved effectiveness with implantable devices. METHODS: Individuals with heart failure recruited from a national web panel or academic medical center completed a web-based discrete-choice experiment survey in which they were randomized to one of 40 blocks of 8 experimentally controlled choice questions comprised of 2 device scenarios and a no-device scenario. Device scenarios offered an additional year of physical functioning equivalent to New York Heart Association class III or a year with improved (ie, class II) symptoms, or both, with 30-day mortality risks ranging from 0% to 15%, in-hospital complication risks ranging from 0% to 40%, and a remote adjustment device feature. Logit-based regression models fit participants' choices as a function of health outcomes, risks and remote adjustment. RESULTS: Latent-class analysis of 613 participants (mean age, 65; 49% female) revealed that two-thirds were best represented by a pro-device, more risk-tolerant class, accepting up to 9% (95% CI, 7%-11%) absolute risk of device-associated mortality for a one-year gain in improved functioning (New York Heart Association class II). Approximately 20% were best represented by a less risk-tolerant class, accepting a maximum device-associated mortality risk of 3% (95% CI, 1%-4%) for the same benefit. The remaining class had strong antidevice preferences, thus maximum-acceptable risk was not calculated. CONCLUSIONS: Quantitative evidence on benefit-risk tradeoffs for implantable heart-failure device profiles may facilitate incorporating patients' views during product development, regulatory decision-making, and clinical practice.