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.
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.
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.
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.
While LAA closure has recently been incorporated into both European and US guidelines for stroke prevention, uncertainties regarding post-procedural drug therapy so far limit its adoption. The aim of ...this analysis is to compare real-world outcome data stratified for the post-procedural drug regimen employed.
One thousand and five patients were implanted with a WATCHMAN device in the prospective EWOLUTION study at 47 centres; 73.5% of the patients were deemed contraindicated for long-term OAC therapy. Here we report on three-month data including the first follow-up TOE exam for 94% of the study population. Following LAA closure, patients received DAPT, VKA, NOAC, single antiplatelet or no therapy (60.3%, 15.4%, 10.9%, 7% and 6.5%, respectively). Device thrombus (2.6%), stroke (0.4%) and major bleeding SAE (2.6%) rates were low overall and did not vary by post-implantation medication strategy. Patients on NOAC had the lowest bleeding rate, without an increase in device thrombus or stroke rates.
LAA closure with the WATCHMAN device is feasible in patients with a relative or absolute contraindication to oral anticoagulation. Neither DAPT nor NOAC therapy leads to a significant increase in device thrombus, stroke or bleeding compared to the standard VKA regimen. Numerically, NOAC therapy had the lowest event rate.
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.
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.
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).
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.).
Summary 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).
Abstract
Aims
The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular ...fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks.
Methods and results
The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability.
Conclusions
We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.
Graphical Abstract
Aims
We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and ...identify patients with beneficial response to cardiac resynchronization therapy (CRT).
Methods and results
We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT‐CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT‐D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K‐means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT‐D on the primary outcome (all‐cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT‐D on the primary outcome hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19–0.64; P = 0.0005 and HR 0.36; 95% CI 0.19–0.68; P = 0.001 than observed in the other groups (interaction P = 0.02).
Conclusions
Our results serve as a proof‐of‐concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies.
Abstract Background The NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the ...study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS. Methods Ninety-six patients were randomized 2:1 to active or inactive VNS for 6 months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality. Results Ninety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18 months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion). Left ventricular systolic volume decreased in the crossover group (VNS OFF → ON; 144 ± 37 to 139 ± 40, p < 0.05) after VNS activation; LVESD (5.02 ± 0.77 to 4.96 ± 0.82, p > 0.05) and LVEF (33.2 ± 4.9 to 33.3 ± 6.5, p > 0.05) did not change. A new technique to detect subtle heart rate changes during Holter recordings, i.e. “heat maps”, revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12 months with active VNS. Conclusions Although a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models.
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.
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.
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.
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.
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.
NCT00677014 and NCT03089281
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The entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies ...(IDE S-ICD System IDE Clinical Investigation and EFFORTLESS Boston Scientific Post Market S-ICD Registry) have reported 6-month to 1-year data on the S-ICD.
The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population.
Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time.
Eight hundred eighty-two patients who underwent implantation were followed for 651±345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n=111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device-related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD-related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%).
The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry EFFORTLESS; NCT01085435; S-ICD® System IDE Clinical Study; NCT01064076).
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