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.

Understanding Outcomes with the EMBLEM S-ICD in Primary Prevention Patients with Low EF Study (UNTOUCHED): Clinical characteristics and perioperative results.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has shown favorable outcomes in large registries with broad inclusion criteria. The cohorts reported had less heart disease and fewer comorbidities than standard ICD populations. OBJECTIVE: The purpose of this study is to characterize acute performance for primary prevention patients with a left ventricular ejection fraction (LVEF) ≤35% (primary prevention ≤35%). METHODS: Primary prevention ≤35% patients with no prior documented sustained ventricular tachycardia (VT), pacing indication, end-stage heart failure, or advanced renal failure were prospectively enrolled. Analyses included descriptive statistics, Kaplan-Meier time to event, and multivariable linear and logistic regression. RESULTS: In 1112 of 1116 patients, an S-ICD was successfully implanted (99.6%). Predictors for longer procedure time included 3-incision technique, higher body mass index (BMI), performing defibrillation testing (DFT), imaging, younger age, black race, and European vs North American centers. Patients undergoing DFT (82%) were successfully converted (99.2%; 93.5% converting at ≤65 J). Higher BMI was predictive of failing DFT at ≤65 J. The rate of 30-day freedom from complications was 95.8%. Most complications involved postoperative healing (45%) or interventions after DFT or impedance check (19%). CONCLUSION: The procedural outcome data of UNTOUCHED reinforce that S-ICD therapy has low perioperative complication rates and high conversion efficacy of induced ventricular fibrillation, even in a higher-risk cohort with low LVEF and more comorbidities than previous S-ICD studies. Higher BMI warrants more careful attention to implant technique.

Effectiveness of single- vs dual-coil implantable defibrillator leads: An observational analysis from the SIMPLE study.

INTRODUCTION: Dual-coil leads (DC-leads) were the standard of choice since the first nonthoracotomy implantable cardioverter/defibrillator (ICD). We used contemporary data to determine if DC-leads offer any advantage over single-coil leads (SC-leads), in terms of defibrillation efficacy, safety, clinical outcome, and complication rates. METHODS AND RESULTS: In the Shockless IMPLant Evaluation study, 2500 patients received a first implanted ICD and were randomized to implantation with or without defibrillation testing. Two thousand and four hundred seventy-five patients received SC-coil or DC-coil leads (SC-leads in 1025/2475 patients; 41.4%). In patients who underwent defibrillation testing (n = 1204), patients with both lead types were equally likely to achieve an adequate defibrillation safety margin (88.8% vs 91.2%; P = 0.16). There was no overall effect of lead type on the primary study endpoint of "failed appropriate shock or arrhythmic death" (adjusted HR 1.18; 95% CI, 0.86-1.62; P = 0.300), and on all-cause mortality (SC-leads: 5.34%/year; DC-leads: 5.48%/year; adjusted HR 1.16; 95% CI, 0.94-1.43; P = 0.168). However, among patients without prior heart failure (HF), and SC-leads had a significantly higher risk of failed appropriate shock or arrhythmic death (adjusted HR 7.02; 95% CI, 2.41-20.5). There were no differences in complication rates. CONCLUSION: In this nonrandomized evaluation, there was no overall difference in defibrillation efficacy, safety, outcome, and complication rates between SC-leads and DC-leads. However, DC-leads were associated with a reduction in the composite of failed appropriate shock or arrhythmic death in the subgroup of non-HF patients. Considering riskier future lead extraction with DC-leads, SC-leads appears to be preferable in the majority of patients.

Defibrillation testing and clinical outcomes after implantable cardioverter-defibrillator implantation in patients in atrial fibrillation at the time of implant: An analysis from the SIMPLE trial.

BACKGROUND: The Shockless IMPLant Evaluation (SIMPLE) trial showed that defibrillation testing (DT) at the time of implantable cardioverter-defibrillator (ICD) implant did not improve shock efficacy or reduce mortality. There are no data regarding the risk of complications, including stroke, among patients with atrial fibrillation (AF) who undergo DT. OBJECTIVE: The purpose of this prospectively planned substudy of SIMPLE was to evaluate the effect of DT vs no DT on clinical outcomes among patients with AF. METHODS: We compared efficacy (failed appropriate shock/arrhythmic death) and safety between patients who had AF on their immediate preprocedural ECG to the rest of the study patients. Then among patients with AF we compared these outcomes between patients randomized to DT vs no DT. RESULTS: Of the 2500 patients enrolled in SIMPLE, 251 (10%) were in AF immediately before ICD implant. AF patients had an increased risk of failed appropriate shock/arrhythmic death (adjusted hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.13-2.39; P = .009) and higher all-cause mortality (adjusted HR 1.58; 95% CI 1.2-2.08; P = .001). Among AF patients, perioperative complications and stroke did not significantly differ between DT vs no-DT groups (9.2% vs 5.4%; P = .2; and 1.7% vs 1.5%; P >.999, respectively). Failed appropriate shock or arrhythmic death occurred in 35 of 251 AF patients (14%), and the no-DT group proved not inferior to the DT group (HR 0.58; 95% CI 0.30-1.15; Pnoninferiority = .006). CONCLUSION: ICD recipients with AF are at increased risk for adverse outcomes; however, DT does not improve arrhythmic survival or shock efficacy. There is no evidence that DT increased the occurrence of perioperative stroke.

Sedation strategies for defibrillation threshold testing: safety outcomes with anaesthesiologist compared to proceduralist-directed sedation: an analysis from the SIMPLE study.

Aims: No standard practice exists with respect to anaesthesiologist-directed sedation (ADS) vs. sedation by proceduralist (PDS) for defibrillation threshold (DT) testing. We aimed to evaluate adverse events and safety outcomes with ADS vs. PDS for DT testing. Methods and results: A post hoc analysis of the Shockless Implant Evaluation (SIMPLE) study was performed among the 1242 patients who had DT testing (624 ADS and 618 PDS). We evaluated both intraoperative and in-hospital adverse composite events and two safety composite outcomes at 30-days of the main trial. Propensity score adjusted models were used to compute odds ratio (OR) and 95% confidence interval (CI) to evaluate the association between adverse and safety outcomes with method of sedation and independent predictors for use of ADS. Compared to PDS, patients who received ADS were younger (62 ± 12 years vs. 64 ± 12 years, P = 0.01), had lower ejection fraction (left ventricular ejection fraction 0.31 ± 13 vs. 0.33 ± 13, P = 0.03), were more likely to receive inhalational anaesthesia, propofol, or narcotics (P < 0.001, respectively) and receive an arterial line (43% vs. 8%, P = <0.0001). Independent predictors for ADS sedation were presence of coronary artery disease (OR 1.69, 95% CI 1.0-2.72; P = 0.03) and hypertrophic cardiomyopathy (OR 2.64, 95% CI 1.19-5.85; P = 0.02). Anaesthesiologist directed sedation had higher intraoperative adverse events (2.2% vs. 0.5%; OR 4.47, 95% CI 1.25-16.0; P = 0.02) and higher primary safety outcomes at 30 days (8.2% vs. 4.9%; OR 1.72 95% CI 1.06-2.80; P = 0.03) and no difference in other outcomes compared to PDS. Conclusion: Proceduralist-directed sedation is safe, however, this could be result of selection bias. Further research is needed.

Apical versus Non-Apical Lead: Is ICD Lead Position Important for Successful Defibrillation?

INTRODUCTION: We aim to compare the acute and long-term success of defibrillation between non-apical and apical ICD lead position. METHODS AND RESULTS: The position of the ventricular lead was recorded by the implanting physician for 2,475 of 2,500 subjects in the Shockless IMPLant Evaluation (SIMPLE) trial, and subjects were grouped accordingly as non-apical or apical. The success of intra-operative defibrillation testing and of subsequent clinical shocks were compared. Propensity scoring was used to adjust for the impact of differences in baseline variables between these groups. There were 541 leads that were implanted at a non-apical position (21.9%). Patients implanted with a non-apical lead had a higher rate of secondary prevention indication. Non-apical location resulted in a lower mean R-wave amplitude (14.0 vs. 15.2, P < 0.001), lower mean pacing impedance (662 ohm vs. 728 ohm, P < 0.001), and higher mean pacing threshold (0.70 V vs. 0.66 V, P = 0.01). Single-coil leads and cardiac resynchronization devices were used more often in non-apical implants. The success of intra-operative defibrillation was similar between propensity score matched groups (89%). Over a mean follow-up of 3 years, there were no significant differences in the yearly rates of appropriate shock (5.5% vs. 5.4%, P = 0.98), failed appropriate first shock (0.9% vs. 1.0%, P = 0.66), or the composite of failed shock or arrhythmic death (2.8% vs. 2.3% P = 0.35) according to lead location. CONCLUSION: We did not detect any reduction in the ICD efficacy at the time of implant or during follow-up in patients receiving a non-apical RV lead.

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).

The rationale and design of the Shockless IMPLant Evaluation (SIMPLE) trial: a randomized, controlled trial of defibrillation testing at the time of defibrillator implantation.

Defibrillation testing (DT) has been an integral part of defibrillator (implantable cardioverter defibrillator [ICD]) implantation; however, there is little evidence that it improves outcomes. Surveys show a trend toward ICD implantation without DT, which now exceeds 30% to 60% in some regions. Because there is no evidence to support dramatic shift in practice, a randomized trial is urgently needed. The SIMPLE trial will determine if ICD implantation without any DT is noninferior to implantation with DT. Patients will be eligible if they are receiving their first ICD using a Boston Scientific device (Boston Scientific, Natick, MA). Patients will be randomized to DT or no DT at the time of ICD implantation. In the DT arm, physicians will make all reasonable efforts to ensure 1 successful intraoperative defibrillation at 17 J or 2 at 21 J. The first clinical shock in all tachycardia zones will be set to 31 J for all patients. The primary outcome of SIMPLE will be the composite of ineffective appropriate shock or arrhythmic death. The safety outcome of SIMPLE will include a composite of potentially DT-related procedural complications within 30 days of ICD implantation. Several secondary outcomes will be evaluated, including all-cause mortality and heart failure hospitalization. Enrollment of 2,500 patients with 3.5-year mean follow-up will provide sufficient statistical power to demonstrate noninferiority. The study is being performed at approximately 90 centers in Canada, Europe, Israel, and Asia Pacific with final results expected in 2013.

Frequency of atrial tachyarrhythmias in patients treated by cardiac resynchronization (from the Prospective, Multicenter Mona Lisa Study).

The continuous measurement of sustained atrial tachyarrhythmia (AT) is now possible with some permanently implanted devices. Data on this subject remain controversial. The aim of this study was to evaluate the incidence of sustained AT in patients treated with cardiac resynchronization therapy using pacemakers without backup defibrillators (CRT-P), within the first year after implantation, using strict definition criteria for sustained AT and a systematic review of all high-quality electrographically recorded episodes. The Mona Lisa study was a prospective, multicenter, cohort study carried out from February 2004 to February 2006, with a 12-month follow-up period. Sustained AT was defined as an episode lasting > or =5 minutes; episodes were confirmed by a systematic review of electrograms in the whole study population. Of the 198 patients who underwent CRT-P device implantation and were enrolled in the study, 173 were in stable sinus rhythm at baseline and were included in the analysis (mean age 70 +/- 9 years, 66% men, 91% in New York Heart Association class III, mean QRS duration 164 +/- 26 ms, mean left ventricular ejection fraction 25 +/- 7%). During a mean follow-up period of 9.9 +/- 3.6 months, 34 patients experienced > or =1 episode of sustained AT, for an incidence rate of 27.5% (95% confidence interval 18.2 to 36.7). Only a history of AT was independently associated with the occurrence of sustained AT within the 12 months after CRT-P device implantation (hazard ratio 2.3, 95% confidence interval 1.2 to 4.4, p = 0.02). In conclusion, this first prospective electrogram-based evaluation of AT incidence demonstrated that 27% of patients developed > or =1 episode of sustained AT lasting > or =5 minutes in the 12 months after CRT-P device implantation.