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Background: Many patients in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a significant improvement (> 10%) in the left ventricular ejection fraction (LVEF) during the course of the study, but the factors and outcomes associated with such improvement are uncertain. Methods: We examined factors and rates of mortality, cause-specific mortality, and implantable cardioverter defibrillator (ICD) shocks associated with improvement in LVEF by analyzing patients in the SCD-HeFT who were randomized to placebo or an ICD and who had an LVEF checked during follow-up. Results: During a median follow-up of 3.99 years, of 837 patients who had at least two follow-up LVEF measurements, 276 (33%) patients had > 10% improvement in LVEF and 561 (67%) patients had no significant change in LVEF. Factors significantly associated with LVEF improvement included female sex, white race, history of hypertension, a QRS duration < 120 ms, and beta-blocker use. Improvement in LVEF was associated with a significant improvement in survival. There was no significant association between improvement in LVEF and cause-specific death, but there was a significant association between improvement in LVEF and reduced risk of receiving appropriate ICD shocks. Conclusions: About a third of patients in this analysis, who were randomized to placebo or an ICD in SCD-HeFT, had a significant improvement in LVEF during follow-up; improvement in LVEF was associated with improved survival but not with cause-specific death, and with decreased likelihood of receiving appropriate ICD shocks.

Background Patients with sudden cardiac arrest occurring in the acute phase of myocardial infarction (MI-SCA) are believed to be at similar risk of death after revascularization compared with MI patients without SCA (MI-no SCA). Among patients with anterior MI, we examined whether those with MI-SCA were at greater risk of all-cause mortality or sudden cardiac death (SCD) than MI-no SCA patients. Methods The Home Automated External Defibrillator Trial enrolled patients with anterior MI who had not received or were candidates for an implantable cardioverter defibrillator (ICD). Our cohort included patients with a reported SCA event, in the acute phase of an MI, prior to HAT trial enrollment. Cox proportional hazards models examined the adjusted association between MI-SCA versus MI-no SCA patients and all-cause mortality and sudden cardiac death (SCD). We also determined whether the relationship between prior SCA and outcomes changed with subsequent events (syncope, revascularization, and recurrent MI) during follow-up. Results Of 6849 patients, 650 (9.5%) had MI-SCA before trial enrollment. Approximately 48% of patients had the MI-SCA event ≤ 1 year prior to enrollment; 71% of SCA events were in-hospital. MI-SCA patients were younger, more frequently white, and had higher rates of prior PCI versus MI-no SCA patients. There were no differences in adjusted all-cause mortality (hazard ratio [HR 0.95; 95% CI 0.65-1.38]) or SCD (HR 1.12; 95% CI 0.68-1.83) for MI-SCA vs. MI-no SCA. After ICD implantation, MI-SCA patients experienced higher all-cause mortality risk (HR 5.01, 95% CI 1.05-23.79) versus MI-no SCA patients; there was no mortality difference between MI-SCA and MI-no SCA patients without ICD implantation (HR 0.89, 95% CI 0.60- 1.31), [interaction p=0.035]. Conclusions Patients with MI-SCA had similar adjusted risk of all-cause mortality and SCD compared with MI-no SCA. After ICD implantation, MI-SCA patients had higher mortality compared with MI-no SCA patients.

BACKGROUND: Rhythm control strategies for atrial fibrillation (AF), including catheter ablation, are substantially underused in racial/ethnic minorities in North America. OBJECTIVE: To describe outcomes in the CABANA trial as a function of race/ethnicity. METHODS: CABANA randomized 2204 symptomatic participants with AF to ablation or drug therapy including rate and/or rhythm control drugs. Only participants in North America were included in this analysis, and participants were subgrouped as racial/ethnic minority or non-minority using National Institutes of Health definitions. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. RESULTS: Of 1280 participants enrolled in CABANA in North America, 127 (9.9%) were racial and ethnic minorities. Compared with non-minorities, racial and ethnic minorities were younger with median age 65.6 versus 68.5 years, had more symptomatic heart failure (37.0% versus 22.0%, respectively), hypertension (92.1% versus 76.8%, respectively), and an ejection fraction

Background: In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). Methods: The CABANA trial randomized 2204 patients with AF who were ≥65 years old or II at baseline and form the subject of this article. The CABANA trial’s primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Results: Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction Conclusions: In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508 ; Unique identifier: NCT0091150.

Background The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) randomized 2,521 patients with moderate heart failure (HF) to amiodarone, placebo drug, or implantable cardioverter-defibrillator (ICD) therapy. Original trial follow-up ended October 31, 2003. Over a median 45.5-month follow-up, amiodarone, compared with placebo, did not affect survival, whereas randomization to an ICD significantly decreased all-cause mortality by 23%. Objectives This study sought to describe the extended treatment group survival of the SCD-HeFT cohort. Methods Mortality outcomes for the 1,855 patients alive at the end of the SCD-HeFT trial were collected between 2010 and 2011. These data were combined with the 666 deaths from the original study to compare long-term outcomes overall and for key pre-specified subgroups. Results Median (25th to 75th percentiles) follow-up was 11.0 (10.0 to 12.2) years. On the basis of intention-to-treat analysis, the ICD group had overall survival benefit versus placebo drug (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.028). When treatment benefit was examined as a function of time from randomization, attenuation of the ICD benefit was observed after 6 years (p value for the interaction = 0.0015). Subgroup analysis revealed long-term ICD benefit varied according to HF etiology and New York Heart Association (NYHA) functional class: ischemic HF HR: 0.81; 95% CI: 0.69 to 0.95; p = 0.009; nonischemic HF HR: 0.97; 95% CI: 0.79 to 1.20; p = 0.802; NYHA functional class II HR: 0.76; 95% CI: 0.65 to 0.90; p = 0.001; NYHA functional class III HR: 1.06; 95% CI: 0.86 to 1.31; p = 0.575. Conclusions Follow-up of SCD-HeFT patients to 11 years demonstrated heterogenous treatment-related patterns of long-term survival with ICD benefit most evident at 11 years for ischemic HF patients and for those with NYHA functional class II symptoms at trial enrollment. (SCD-HeFT 10 Year Follow-up [SCD-HeFT10 Yr]; NCT01058837 )

The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial randomized 2,204 patients with atrial fibrillation (AF) to catheter ablation or drug therapy. Analysis by intention-to-treat showed a nonsignificant 14% relative reduction in the primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.The purpose of this study was to assess recurrence of AF in the CABANA trial.The authors prospectively studied CABANA patients using a proprietary electrocardiogram recording monitor for symptom-activated and 24-h AF auto detection. The AF recurrence endpoint was any post-90-day blanking atrial tachyarrhythmias lasting 30 s or longer. Biannual 96-h Holter monitoring was used to assess AF burden. Patients who used the CABANA monitors and provided 90-day post-blanking recordings qualified for this analysis (n = 1,240; 56% of CABANA population). Treatment comparisons were performed using a modified intention-to-treat approach.Median age of the 1,240 patients was 68 years, 34.4% were women, and AF was paroxysmal in 43.0%. Over 60 months of follow-up, first recurrence of any symptomatic or asymptomatic AF (hazard ratio: 0.52; 95% confidence interval: 0.45 to 0.60; p 0.001) or first symptomatic-only AF (hazard ratio: 0.49; 95% confidence interval: 0.39 to 0.61; p 0.001) were both significantly reduced in the catheter ablation group. Baseline Holter AF burden in both treatment groups was 48%. At 12 months, AF burden in ablation patients averaged 6.3%, and in drug-therapy patients, 14.4%. AF burden was significantly less in catheter ablation compared with drug-therapy patients across the 5-year follow-up (p 0.001). These findings were not sensitive to the baseline pattern of AF.Catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared with drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type. (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial [CABANA]; NCT00911508).

Background Outcomes of patients with nonischemic cardiomyopathy and low ejection fraction implanted with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with a defibrillator (CRT-D), especially in contemporary, real-life cohorts, are not fully understood. Objective We aimed to better characterize outcomes of death and ventricular tachyarrhythmias in patients with nonischemic cardiomyopathy, implanted with an ICD or CRT-D, and specifically assess differences by sex. Methods The AnaLysIs of Both Sex and Device Specific FactoRs on Outcomes in PAtients with Non-Ischemic Cardiomyopathy (BIO-LIBRA) study was designed to prospectively assess outcomes of device-treated ventricular tachyarrhythmias and all-cause mortality events in nonischemic cardiomyopathy patients, indicated for an ICD or CRT-D implantation for the primary prevention of sudden cardiac death (SCD), with a specific focus on sex differences. We will enroll a total of 1000 subjects across 50 U.S. sites and follow patients for up to 3 years. Results The primary objective of BIO-LIBRA is to evaluate the combined risk of all-cause mortality and treated ventricular tachycardia (VT) or ventricular fibrillation (VF) events by subject sex and by implanted device type. We will also assess all-cause mortality, VT or VF alone, cardiac death, and SCD in the total cohort, as well as by subject sex and by the implanted device type. In addition, the previously validated Seattle Proportional Risk Model (SPRM) will be used to compare the SPRM predicted incidence of SCD to the observed incidence. Conclusions The BIO-LIBRA study will provide novel and contemporary information regarding outcomes in patients with a NICM who receive a defibrillator.

Background: The CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) was a randomized, prospective trial of left atrial catheter ablation versus drug therapy for treatment of atrial fibrillation (AF). As part of CABANA, a prospective imaging substudy was conducted. The main objectives were to describe the patterns of changes in the dimensions of the left atrium and pulmonary veins (PVs), and the relationship between these changes with treatment assignment and clinical outcomes. Methods: Computed tomography or magnetic resonance imaging was acquired at baseline and follow-up in 121 ablation (median follow-up 101 days) and 85 drug patients (median follow-up 97 days). Left atrial volume index, mean PV ostial diameter, and ostial diameters of each PV separately were computed. We examined the relationship between the change from baseline to follow-up with subsequent clinical outcomes (composite of death, disabling stroke, serious bleeding, or cardiac arrest [CABANA primary end point], total mortality or cardiovascular hospitalization, first AF recurrence after the 90-day blanking period, first AF/atrial flutter/atrial tachycardia after the 90-day blanking period) using Cox proportional-hazards models. Results: The median (25th to 75th) change from baseline for left atrial volume index was −7.8 mL/m 2 (−16.4 to 0.2), ablation arm and −3.5 mL/m 2 (−11.4 to 2.6), drug therapy arm. The left atrial volume index decreased in 52.9% of ablation patients versus 40.0% of drug therapy patients. Change for mean PV was −2.7 mm (−4.2 to −1.3) in the ablation arm versus −0.1 mm (−1.5 to 0.8) in the drug therapy arm. Changes in left atrium and PV dimensions had no consistent relationship with the risk of developing the study primary end point. Reductions in left atrial volume index, and in mean PV diameter were associated with decreased risk of AF recurrence. Conclusions: Ablation patients demonstrated more frequent and larger atrial structural changes compared with drug patients. These changes suggest a critical relationship between structural features and AF generation.

Orthotropic heart transplantation remains the most effective therapy for patients with end-stage heart failure, with a median survival of ≈13 years. Yet, a number of complications are observed after orthotropic heart transplantation, including atrial and ventricular arrhythmias. Several factors contribute to arrhythmias, such as autonomic denervation, effect of the surgical technique, acute and chronic rejection, and transplant vasculopathy among others. To minimize risk of future arrhythmias, the bicaval technique and minimizing ischemic time are current surgical standards. Sinus node dysfunction is the most common indication for early (within 30 days) pacemaker implantation, whereas atrioventricular block incidence increases as time from transplant increases. Atrial fibrillation can occur in the first few weeks following transplantation but is uncommon in the long term unless secondary to a precipitant such as acute rejection. The most common atrial arrhythmias are atrial flutters, which are mainly typical, but atypical circuits can be observed such as those that involve the remnant donor atrium in regions immediately adjacent to the atrioatrial anastomosis suture line. Choosing the appropriate pharmacological therapy requires careful consideration due to the potential interaction with immunosuppressive agents. Despite historical concerns, adenosine is effective and safe at reduced doses if administered under cardiac monitoring. Catheter ablation has emerged as an effective treatment strategy for symptomatic supraventricular tachycardias, including ablation of atypical flutter circuits. Cardiac allograft vasculopathy is an important risk factor for sudden cardiac death, yet the role of prophylactic implantable cardioverter-defibrillator implant for sudden death prevention is unclear. Current indications for implantable cardioverter-defibrillator implantation are as in the nontransplant population. A number of questions for future research are posed.

Background: Among patients with atrial fibrillation (AF), women are less likely to receive catheter ablation and may have more complications and less durable results. Most information about sex-specific differences after ablation comes from observational data. We prespecified an examination of outcomes by sex in the 2204-patient CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). Methods: CABANA randomized patients with AF age ≥65 years or Results: CABANA randomized 819 (37%) women (ablation 413, drug 406) and 1385 men (ablation 695, drug 690). Compared with men, women were older (median age, 69 years versus 67 years for men), were more symptomatic (48% Canadian Cardiovascular Society AF Severity Class 3 or 4 versus 39% for men), had more symptomatic heart failure (42% with New York Heart Association Class ≥II versus 32% for men), and more often had a paroxysmal AF pattern at enrollment (50% versus 39% for men) ( P P =0.043), and complications from treatment were infrequent in both sexes. For the primary outcome, the hazard ratio for those who underwent ablation versus drug therapy was 1.01 (95% CI, 0.62–1.65) in women and 0.73 (95% CI, 0.51–1.05) in men (interaction P value=0.299). The risk of recurrent AF was significantly reduced in patients undergoing ablation compared with those receiving drug therapy regardless of sex, but the effect was greater in men (hazard ratio, 0.64 [95% CI, 0.51–0.82] for women versus hazard ratio, 0.48 [95% CI, 0.40–0.58] for men; interaction P value=0.060). Conclusions: Clinically relevant treatment-related strategy differences in the primary and secondary clinical outcomes of CABANA were not seen between men and women, and there were no sex differences in adverse events. The CABANA trial results support catheter ablation as an effective treatment strategy for both women and men. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00911508.

Background The CABANA trial compared drug vs ablation therapy yet did not identify a difference in the primary endpoint of death, stroke, severe bleeding, or cardiac arrest or the secondary endpoint of all-cause mortality by intention to treat (ITT) analysis. Nevertheless, there was evidence of improved outcomes and survival in the as-treated and per-protocol analyses. Objectives To determine how the treatment strategies of drug therapy vs ablation impact the atrial fibrillation progression and regression. Methods CABANA randomized 2204 pts with AF ≥65 yrs old or Results Following treatment with ablation, 64% maintained sinus rhythm with elimination of AF, 11% experienced AF regression, and only 7% had progression of AF. In contrast, in those randomized to drug therapy, only 48% experienced maintenance of sinus rhythm, 10% experienced AF regression, and 13% had progression of AF. Moreover, in the drug arm there was a 32% increase in long-standing persistent compared with a 49% reduction in the ablation arm. Conclusion Catheter ablation significantly alters the natural history of atrial fibrillation. Intention to treat analysis reveals that catheter ablation provides superior elimination of AF, protection against AF progression, and dramatically lower risks of long-standing persistent AF. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health

Background Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19). Objective The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this. Methods In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9, 2020, and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation. Results A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62 ± 16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant corrected QT (QTc) prolongation was observed in a minority (n = 5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in prespecified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors. Conclusions In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy.

Background: Dilated cardiomyopathy is associated with increased risk of major cardiovascular events. Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging is a unique tissue-based marker that, in single-center studies, suggests strong prognostic value. We retrospectively studied associations between LGE presence and adverse cardiovascular events in patients with dilated cardiomyopathy in a multicenter setting as part of an emerging global consortium (MINICOR [Multi-Modal International Cardiovascular Outcomes Registry]). Methods: Consecutive patients with dilated cardiomyopathy referred for cardiac magnetic resonance (2000–2017) at 12 institutions in 4 countries were studied. Using multivariable Cox proportional hazard and semiparametric Fine and Gray models, we evaluated the association between LGE and the composite primary end point of all-cause mortality, heart transplantation, or left ventricular assist device implant and a secondary arrhythmic end point of sudden cardiac death or appropriate implantable cardioverter-defibrillator shock. Results: We studied 1672 patients, mean age 56±14 years (29% female), left ventricular ejection fraction 33±11%, and 25% having New York Heart Association class III to IV; 650 patients (39%) had LGE. During 2.3 years (interquartile range, 1.0–4.3) follow-up, 160 patients experienced the primary end point, and 88 experienced the arrhythmic end point. In multivariable analyses, LGE was associated with 1.5-fold (hazard ratio, 1.45 [95% CI, 1.03–2.04]) risk of the primary end point and 1.8-fold (hazard ratio, 1.82 [95% CI, 1.20–3.06]) risk of the arrhythmic end point. Primary end point risk was increased in patients with multiple LGE patterns, although arrhythmic risk was higher among patients receiving primary prevention implantable cardioverter-defibrillator and widening QRS. Conclusions: In this large multinational study of patients with dilated cardiomyopathy, the presence of LGE showed strong prognostic value for identification of high-risk patients. Randomized controlled trials evaluating LGE-based care management strategies are warranted.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent control trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive HCQ (400mg BID x1day, followed by 200mg BID x9days) or placebo-equivalent (ascorbic acid) and AZ (500mg, then 250mg daily x4days) or placebo-equivalent (folic acid), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected mid-turbinate nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Incident LRTI occurred in six participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in nine (four control, two HCQ, three HCQ/AZ). There were no deaths. Median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. HCQ but not HCQ/AZ had faster time to viral clearance (HR=1.62, 95% CI=1.01-2.60, p=0.047 & HR=1.25, 95% CI=0.75-2.07, p=0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group. Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Trial Registration Number: ClinicalTrials.gov: NCT04354428 Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Conflict of Interest: Declaration of interests: CJ reports grants from BMGF for conduct of the study, and grants from CDC and NIH outside of the submitted work. HSK reports funding from NIH. PAN and MJA have a potential financial relationship with AliveCor related to QT assessment using the device, however the investigators would receive no financial benefit for use of the technology for patients at Mayo Clinic or for its use in the current study. AB reports consulting for Gates Ventures and grants from BMGF and NIH outside of the submitted work. HYC reports consulting for BMGF, Pfizer, Ellume, and Merck, and grants from Gates Ventures, NIH, CDC, BMGF, DARPA, Apple Inc., Sanofi-Pasteur, and Roche-Genentech, outside of the submitted work. Ethical Approval: Study visits were conducted via Health Insurance Portability and Accountability Act (HIPAA)-compliant telemedicine. The Western Institutional Review Board (WIRB) approved this study with reliance agreements with collaborating institutions.

The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA,NCT00911508)(1) trial is testing the hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art pharmacologic therapy. This international 140-center clinical trial was designed to randomize 2200 patients to a strategy of catheter ablation versus state-of-the-art rate or rhythm control drug therapy. Inclusion criteria include: 1) age> 65, or ≤65 with≥ 1 risk factor for stroke, 2) documented AF warranting treatment, and 3) eligibility for both catheter ablation and≥ 2 anti-arrhythmic or≥ 2 rate control drugs. Patients were followed every 3 to 6 months (median 4 years) and underwent repeat trans-telephonic monitoring, Holter monitoring, and CT/MR in a subgroup of patient studies to assess the impact of treatment on AF recurrence and atrial structure. With 1100 patients in each treatment arm, CABANA is projected to have 90% power for detecting a 30% relative reduction in the primary composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest. Secondary endpoints include total mortality; mortality or cardiovascular hospitalization; a combination of mortality, stroke, hospitalization for heart failure or acute coronary artery events; cardiovascular death alone; and heart failure death, as well as AF recurrence, quality of life, and cost effectiveness. At a time when AF incidence is rising rapidly, CABANA will provide critical evidence with which to guide therapy and shape health care policy related to AF for years to come.

Patients with childhood heart disease are living longer and entering adulthood, and may undergo implantable cardioverter-defibrillator (ICD) implantation to reduce the risk of sudden death. We evaluated the characteristics of adult patients with congenital heart disease or left ventricular noncompaction cardiomyopathy (LVNC) in the National Cardiovascular Disease Registry ICD Registry and determined ICD-related in-hospital complications. Patients with LVNC or transposition of the great arteries, tetralogy of Fallot, Ebstein's anomaly, atrial septal defect, ventricular septal defect, or common ventricle were identified in the registry. In-hospital complications were compared among different diagnoses using the chi-square test for categorical variables and the F-test in analyses of variance for continuous variables. A total of 3,077 patients were identified. The mean age was 48.0 ± 16.0 years, and 39.9% were female. Single-chamber ICDs were implanted in 25.2%, dual chamber in 41.9%, and cardiac resynchronization in 30.8%. Intraprocedural or postprocedural complications occurred in 70 patients (2.3%); there were 6 in-hospital deaths (0.2%). The most frequent complications were acute lead dislodgments, pneumothorax, and hematomas. Patients with Ebstein's anomaly had the greatest complication rate (8.3%, p = 0.03). The complication rate was 1.55% in single-chamber devices, 1.86% in dual chamber, and 3.5% in cardiac resynchronization (p < 0.001). For initial implants, the complication rate was 2.55%, 1.62% in generator replacements, and 8.77% in lead revisions (p = 0.001). In conclusion, in this large contemporary adult cohort of congenital heart disease and LVNC patients who underwent ICD implant procedures, periprocedural complication rates were low. Lead-related risks predominated.

Cardiac arrest is defined as the termination of cardiac activity associated with loss of consciousness, of spontaneous breathing, and of circulation. Sudden cardiac arrest and sudden cardiac death (SCD) are terms often used interchangeably. Most patients with out-of-hospital cardiac arrest have shown coronary artery disease or symptoms during the hour before the event. Cardiac arrest is potentially reversible by cardiopulmonary resuscitation, defibrillation, cardioversion, cardiac pacing, or treatments targeted at the underlying disease (e.g., acute coronary occlusion). We restrict SCD hereafter to cardiac arrest due to ventricular fibrillation, including rhythms shockable by an automatic external defibrillator (AED), implantable cardioverter-defibrillator (ICD), or wearable cardioverter-defibrillator (WCD). We summarize the state of the art related to defibrillation in treating SCD, including a brief history of the evolution of defibrillation, technical characteristics of modern AEDs, strategies to improve AED access and increase survival, ancillary treatments, and use of ICDs or WCDs.

[Figure][1] It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so. —Mark Twain [(1)][2] Previous studies have shown us that cardiomyopathy patients of a nonischemic etiology (NICM) have a lower absolute risk for cardiac

Background Prior studies suggest that catheter ablation (ABL) for atrial fibrillation (AF) is a treatment option for patients (pts) with paroxysmal AF (PAF). Pts with persistent (Per) or long-standing persistent (LSP) were routinely excluded from most ABL based clinical trials. The effectiveness of ABL compared to drug therapy (MED) in relation to underlying AF type has not been evaluated in a large randomized clinical trial. Objective To assess the impact of AF type on clinical outcomes of ABL vs. MED in pts with AF. Methods The CABANA trial randomized 2204 pts with AF at 126 sites worldwide to ABL vs. MED with rate or rhythm control drugs. The primary endpoint was a composite of death, disabling stroke, severe bleeding, or cardiac arrest. Key secondary endpoints included mortality and recurrence of AF. Outcomes of ABL vs. MED were compared within subgroups defined by AF type using Intention-to-Treat (ITT) analyses. Results Of the 2204 pts, 946 had PAF, 1042 had Per and 215 presented with LSP. There were baseline differences among AF types in age, gender, HTN, LVH, CHF and NYHA Class. For the primary endpoint, there were no significant differences between ABL and MED in pts with PAF (hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.51, 1.31), Per (HR 0.87; 95% CI 0.59, 1.28), or LSP (HR 1.01, 95% CI 0.39, 2.61). Likewise, there were no significant treatment differences in mortality; PAF (HR 0.84; 95% CI 0.46, 1.52), Per (HR 0.90; 95% CI 0.56, 1.46) and LSP (HR 0.67, 95% CI 0.23, 1.94). Post-blanking AF (time to first recurrence) was significantly reduced by ABL compared to MED across all AF types (PAF by 51%), (Per by 47%) and (LSP by 36%). Clinical Characteristics and Outcomes Clinical Outcomes Comparing ABL vs. MED (HR and 95% CI) Interaction p-value Primary Endpoint 0.82 (0.51, 1.31) 0.87 (0.59, 1.28) 1.01 (0.39, 2.61) 0.925 Mortality 0.84 (0.46, 1.52) 0.90 (0.56, 1.46) 0.67 (0.23, 1.94) 0.881 Recurrent AF 0.49 (0.38, 0.62) 0.53 (0.43, 0.65) 0.64 (0.41, 1.01) 0.564 Conclusion Pts with LSP have a lower proportion of women, and a higher proportion with manifestations of heart failure despite lower CHA2DS2VASc scores. By ITT analysis, there is no significant effect of ABL compared to MED in the primary endpoint or mortality in any AF group. However, ABL is more effective than MED for reducing recurrences of AF regardless of AF type, but with a greater effect in PAF vs Per vs LSP. Acknowledgement/Funding NIH, St Jude Medical Foundation and Corporation, Biosense Webster Inc., Medtronic Corporation, and Boston Scientific Corporation

Background Sex-specific outcomes may differ amongst patients receiving catheter ablation for atrial fibrillation (AF). Purpose Assess sex-specific outcomes in the patients randomized to catheter ablation or drug therapy in CABANA. Methods CABANA randomized 2204 pts with AF to catheter ablation or drug therapy (rate/rhythm-control). The outcomes of combined death, disabling stroke, severe bleeding, or cardiac arrest (intention to treat-ITT) or all-cause death were not different. But, ablation significantly improved combined death or CV hospitalization. This analysis compares clinical characteristics by sex and determines sex-specific hazard ratios based on a comparison of ablation vs drug therapy. Results Females were 37.3% of ablation and 37.0% of drug therapy patients. Females were older, more often white race, had less CAD, or sleep apnea, but had higher NYHA Class, higher CHA2DS2VASc, and more often had paroxysmal (v. persistent) AF, and prior AF hospitalization. (Table) HTN, CVA and diabetes were the same (Table). For the CABANA primary endpoint, an ITT comparison of ablation vs. drug therapy, showed a female hazard ratio (HR) of 1.14 (95% confidence interval (CI) 0.70–1.86), and a male HR of 0.74, (95% CI 0.52–1.06). For all-cause mortality, the female HR was 0.75 (95% CI 0.41–1.40) and male HR was 0.91 (95% CI 0.59–1.40) and for all-cause mortality or CV hospitalization, the female HR was 0.90 (95% CI 0.75–1.09) and male HR was 0.79 (95% CI 0.69–0.92). All interaction p values were non-significant. Recurrent AF (post 90-day blanking) was significantly reduced for both females and males: female HR 0.64 (95% CI 0.51–0.82), male HR 0.46 95% CI 0.39–0.56), p=0.035 Clinical Characteristics and Outcomes Baseline Characteristics Female (N=818) Male (N=1385) p-value Age: Median (Q1, Q3) 69 (65, 74) 66 (60, 71) Conclusion Significant sex-specific outcomes differences were not observed. Sex should not be used as a determining factor in selecting patients for AF therapy. Acknowledgement/Funding NIH, St Jude Medical Foundation and Corporation, Biosense Webster Inc., Medtronic Corporation, and Boston Scientific Corporation

Background Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is recommended before primary prevention implantable cardioverter-defibrillator (ICD) placement. Adherence to this recommendation and associated outcomes are unknown. Objectives This study examined the use of GDMT (≥1 prescription filled for both a renin-angiotensin inhibitor [RAI] and a heart failure–approved beta-blocker [HFBB]) within 90 days before primary prevention ICD placement in patients with HFrEF. Methods Data from the National Cardiovascular Data Registry ICD Registry were merged with a 40% random sample of Medicare administrative data. Prescription fills for recipients of primary prevention ICD between 2007 and 2011 were examined, analyzing GDMT overall and for each U.S. hospital referral region. We identified characteristics associated with GDMT and the association with 1-year mortality. Results Among 19,733 patients with HFrEF and primary prevention ICD, 61.1% filled any GDMT before implantation. Across hospital referral regions, GDMT was applied in 51% to 71%. The strongest predictors of any GDMT included absence of chronic renal disease or nonsustained ventricular tachycardia, low-income prescription benefits subsidy, and less recent left ventricular ejection fraction evaluation. Patients receiving GDMT versus those without had a lower 1-year mortality rate after ICD implantation (11.1% vs. 16.2%), even after adjustment for comorbidities, left ventricular ejection fraction, and functional heart failure class. Conclusions Rates of GDMT for HFrEF before primary prevention ICD implantation were low, and failure to achieve GDMT was associated with significantly decreased 1-year survival.

The beneficial effects of cardiac resynchronization therapy (CRT) have been well established in large, randomized trials. Despite the documented success of this treatment strategy, a significant proportion of patients with heart failure do not achieve the desired response. The aim of this review was to delineate factors contributing to a successful CRT response, emphasizing the interrelated roles of QRS morphology and QRS interval duration. More data are available on QRS duration, as this factor has been used as an enrollment criterion in clinical trials. Response to CRT seems to increase as the QRS duration becomes longer, with greatest benefit in QRS duration ≥150 ms. Recent data have placed more emphasis on QRS morphology, demonstrating variability in clinical response between patients with left bundle branch block, non-left bundle branch block, and right bundle branch block morphology. Notably, myocardial scarring and cardiac dimensions, among other variables, may alter heterogeneity in ventricular activation. Understanding the electrophysiological underpinnings of the QRS complex has become important not only to predict response but also to facilitate the patient-specific delivery of resynchronization therapy.

Background No precise tools exist to predict appropriate shocks in patients with a primary prevention ICD. We sought to identify characteristics predictive of appropriate shocks in patients with a primary prevention implantable cardioverter defibrillator (ICD). Methods Using patient-level data from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), we identified patients with any appropriate shock. Clinical and demographic variables were included in a logistic regression model to predict appropriate shocks. Results There were 1,463 patients randomized to an ICD, and 285 (19%) had ≥1 appropriate shock over a median follow-up of 2.59 years. Compared with patients without appropriate ICD shocks, patients who received any appropriate shock tended to have more severe heart failure. In a multiple logistic regression model, predictors of appropriate shocks included NYHA class (NYHA II vs I: OR 1.65, 95% CI 1.07-2.55; NYHA III vs I: OR 1.74, 95% CI 1.10-2.76), lower LVEF (per 1% change) (OR 1.04, 95% CI 1.02-1.06), absence of beta blocker therapy (OR 1.61, 95% CI 1.23-2.12), and single chamber ICD (OR 1.67, 95% CI 1.13-2.45). Conclusion In this meta-analysis of patient level data from MADIT-II and SCD-HeFT, higher NYHA class, lower LVEF, no beta blocker therapy, and single chamber ICD (versus dual chamber) were significant predictors of appropriate shocks. This article is protected by copyright. All rights reserved

Aim There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes. Methods and results A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015). Conclusion Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

Background Primary prevention implantable cardioverter defibrillator (ICD) reduce all-cause mortality by reducing sudden cardiac death. There are conflicting data regarding whether patients with more advanced heart failure derive ICD benefit owing to the competing risk of nonsudden death. Methods We performed a patient-level meta-analysis of New York Heart Association (NYHA) class II/III heart failure patients (left ventricular ejection fraction ≤35%) from 4 primary prevention ICD trials (MADIT-I, MADIT-II, DEFINITE, SCD-HeFT). Bayesian-Weibull survival regression models were used to assess the impact of NYHA class on the relationship between ICD use and mortality. Results Of the 2,763 patients who met study criteria, 68% (n = 1,867) were NYHA II and 52% (n = 1,435) were randomized to an ICD. In a multivariable model including all study patients, the ICD reduced mortality (hazard ratio [HR] 0.65, 95% posterior credibility interval [PCI]) 0.40-0.99). The interaction between NYHA class and the ICD on mortality was significant (posterior probability of no interaction = .036). In models including an interaction term for the NYHA class and ICD, the ICD reduced mortality among NYHA class II patients (HR 0.55, PCI 0.35-0.85), and the point estimate suggested reduced mortality in NYHA class III patients (HR 0.76, PCI 0.48-1.24), although this was not statistically significant. Conclusions Primary prevention ICDs reduce mortality in NYHA class II patients and trend toward reducing mortality in the heterogeneous group of NYHA class III patients. Improved risk stratification tools are required to guide patient selection and shared decision making among NYHA class III primary prevention ICD candidates.

Patients with diabetes mellitus, prior myocardial infarction, older age, and a relatively preserved left ventricular ejection fraction remain at risk for sudden cardiac death that is potentially amenable by the subcutaneous implantable cardioverter defibrillator with a good risk-benefit profile. The launched MADIT S-ICD study is designed to test the hypothesis that post–myocardial infarction diabetes patients with relatively preserved ejection fraction of 36%-50% will have a survival benefit from a subcutaneous implantable cardioverter defibrillator.

Objectives The purpose of this study was to determine if 6-min walk test data assists in treatment decisions for patients with heart failure. Background In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), a pre-specified subgroup analysis showed that patients with New York Heart Association functional class III symptoms did not benefit from implantable cardioverter-defibrillator (ICD) therapy and appeared to be harmed by amiodarone, whereas New York Heart Association functional class II patients obtained significant survival benefit from ICD. We postulated that a more objective measure of functional capacity, such as 6-min walk (6MW) distance, might provide a better tool for selecting these preventive therapies. Methods A 6MW test was performed before randomization in 2,397 patients. Median follow-up was 45.5 months. All-cause mortality was the primary endpoint, with cause-specific mortality (heart failure, arrhythmic) examined in secondary analyses. Results The hazard ratios (HRs) for ICD therapy compared to placebo were estimated within tertiles of baseline 6MW distance: HR: 0.42 (95% confidence interval [CI]: 0.26 to 0.66) for 6MW distance >386 m (top tertile); HR: 0.57 (95% CI: 0.39 to 0.83) for 6MW distance 288 to 386 m (middle tertile); and HR: 1.02 (95% CI: 0.75 to 1.39) for 6MW distance Conclusions A baseline 6MW distance NCT00000609 )

Objectives: This study sought to determine whether circadian patterns in ventricular arrhythmias (VAs) occur in a current primary prevention defibrillator (implantable cardioverter-defibrillator [I...

Catheter ablation is more effective than drug therapy in restoring sinus rhythm in patients with atrial fibrillation (AF), but its incremental effect on long-term quality of life (QOL) is uncertain.To determine whether catheter ablation is more beneficial than conventional drug therapy for improving QOL in patients with AF.An open-label randomized clinical trial of catheter ablation vs drug therapy in 2204 symptomatic patients with AF older than 65 years or 65 years or younger with at least 1 risk factor for stroke. Patients were enrolled from November 2009 to April 2016 from 126 centers in 10 countries. Follow-up ended in December 2017.Pulmonary vein isolation, with additional ablation procedures at the discretion of the investigators, for the catheter ablation group (n = 1108) and standard rhythm and/or rate-control drugs selected and managed by investigators for the drug therapy group (n = 1096).Prespecified co-primary QOL end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (range, 0-100; 0 indicates complete disability and 100 indicates no disability; patient-level clinically important difference, ≥5 points) and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (range, 0-40; 0 indicates no symptoms and 40 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.6 points) and severity score (range, 0-30; 0 indicates no symptoms and 30 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.3 points).Among 2204 randomized patients (median age, 68 years; 1385 patients [63%] were men, 946 [43%] had paroxysmal AF, and 1256 [57%] had persistent AF), the median follow-up was 48.5 months, and 1968 (89%) completed the trial. The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7-6.9]; P .001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, -1.7 points [95% CI, -2.3 to -1.2]; P .001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, -1.5 points [95% CI, -2.0 to -1.1]; P .001).Among patients with symptomatic atrial fibrillation, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months. These findings can help guide decisions regarding management of atrial fibrillation.ClinicalTrials.gov Identifier: NCT00911508.

Background Dual coil implantable cardioverter-defibrillator (ICD) leads with a superior vena cava (SVC) electrode have been considered standard of care despite sparse data suggesting improved ICD defibrillation efficacy. SVC coils increase lead complexity, cost, risk of lead failure, and lead removal. Objective To compare all-cause mortality, sudden cardiac death, implant defibrillation threshold (DFT) test energies, appropriate shock rates, and first shock efficacy for ventricular tachyarrhythmias for dual coil vs single coil leads in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Methods In SCD-HeFT, 811 patients with heart failure received a single lead transvenous ICD (Medtronic model 7223) and underwent protocol-driven DFT testing. The selection of a dual vs single coil right ventricular (RV) lead was at the physician's discretion. DFT data were available in 717 patients. Results Dual coil leads were used in 563 and single coil in 246 patients. After 45.5-month follow-up, overall mortality was similar (19.4% for dual coil vs 21.5% for single coil; adjusted hazard ratio 0.95; 95% confidence interval 0.68–1.34; P = .78). Sudden cardiac death was also similar (3.6% for dual coil vs 3.7% for single coil; P = .96). First shock efficacy was 82.2% vs 91.9% (dual coil vs single coil; unadjusted odds ratio 0.41; 95% confidence interval 0.15–1.13; P = .085). Mean DFT was 12.1 ± 4.7 J vs 12.8 ± 4.8 J (dual coil vs single coil; P = .087). Conclusions In the SCD-HeFT, the addition of an SVC coil for left-sided implants was not associated with improved outcome measures. We advocate returning to single coil RV ICD leads as the standard of care to decrease chronic lead complications.

The benefit of cardiac resynchronization therapy (CRT) for most heart failure (HF) patients with low ejection fraction (EF) and widened QRS is undisputed. Mortality and HF hospitalization are reduced, and multiple measures of cardiac function are improved. It remains of clinical importance that

Background— Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction ≤35%, many such patients do not require ICD shocks over long-term follow-up. Methods and Results— Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), whereas the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest-risk group versus 24% in the highest-risk group ( P =0.009 for interaction) and decreased relative risk of total mortality by 54% in the lowest-risk group versus no benefit (2%) in the highest-risk group ( P =0.014 for interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0%, and −4.9% across risk quintiles. In highest-risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patient’s predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. Conclusions— A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

Ejection fraction (EF) is an important method of mortality prediction among cardiac patients, and has been used to identify the highest risk patients for enrollment in the defibrillator primary prevention trials. Evidence suggests that measures of EF by different imaging modalities may not be equivalent. In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), the type of imaging modality for EF assessment was not mandated.Baseline assessment of EF was performed using either echocardiography, radionuclide angiography (RNA), or contrast angiography. Multivariable analysis using a Cox proportional hazards model was used to examine whether the modality of assessing EF affected the likelihood of survival.Among the 2,521 patients enrolled in SCD-HeFT, EF was measured by RNA in 616 (24%), echocardiography in 1,469 (58%), and contrast angiography in 436 (17%). Mean EF as measured by RNA was 25.1% +/- 6.9%; by echocardiography, 23.8 +/- 6.9%; and by angiography, 21.9 +/- 6.9%. These measures were significantly different (P.001), and each pairwise comparison differed significantly (P.001 for each). Multivariable analysis showed no significant difference in survival between patients enrolled based on RNA versus echocardiography (HR 1.06, 95% CI 0.88-1.28), RNA versus angiography (HR 1.25, 95% CI 0.97-1.62), or echocardiography versus angiography (HR 1.18, 95% CI 0.94-1.48).Among patients enrolled in SCD-HeFT, the distribution of ejection fractions measured by radionuclide angiography differed from those measured by echocardiography or contrast angiograms. Survival did not differ according to modality of EF assessment.

Introduction: The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter defibrillator (ICD) therapy reduced overall mortality in patients with class II or III heart failure and left ventricular ejection fraction (LVEF) ≤ 35%, while amiodarone had no effect on survival. There are limited data regarding the influence of gender on outcome of patients receiving ICDs for primary prevention. Methods: We examined gender differences in response to treatment and outcome in this cohort. Results: Women comprised 23% of the SCD-HeFT cohort, with similar percentages in the amiodarone, ICD, and placebo groups. Compared with men, women were more likely to be non-Caucasian, to have class III heart failure, and nonischemic heart disease. After adjustment for baseline differences, overall mortality risk was lower in women than in men. The gender difference in overall mortality was seen in the placebo group, while no gender difference in overall mortality was seen in the ICD group. There was a significantly lower absolute risk of death in the placebo arm women, compared with the placebo arm men (annual mortality rate approximately 4% vs. 6%). Conclusions: The impact of ICD therapy appears to differ between men and women in this trial, with a smaller ICD benefit among women. However, the test for an interaction between gender and therapy was not significant. The lower overall mortality risk in women in the placebo group and the smaller number of women enrolled may help to explain why treatment differences in women were much smaller and difficult to detect.

The most common location of out-of-hospital sudden cardiac arrest is the home, a situation in which emergency medical services are challenged to provide timely care. Consequently, home use of an automated external defibrillator (AED) might offer an opportunity to improve survival for patients at risk.We randomly assigned 7001 patients with previous anterior-wall myocardial infarction who were not candidates for an implantable cardioverter-defibrillator to receive one of two responses to sudden cardiac arrest occurring at home: either the control response (calling emergency medical services and performing cardiopulmonary resuscitation [CPR]) or the use of an AED, followed by calling emergency medical services and performing CPR. The primary outcome was death from any cause.The median age of the patients was 62 years; 17% were women. The median follow-up was 37.3 months. Overall, 450 patients died: 228 of 3506 patients (6.5%) in the control group and 222 of 3495 patients (6.4%) in the AED group (hazard ratio, 0.97; 95% confidence interval, 0.81 to 1.17; P=0.77). Mortality did not differ significantly in major prespecified subgroups. Only 160 deaths (35.6%) were considered to be from sudden cardiac arrest from tachyarrhythmia. Of these deaths, 117 occurred at home; 58 at-home events were witnessed. AEDs were used in 32 patients. Of these patients, 14 received an appropriate shock, and 4 survived to hospital discharge. There were no documented inappropriate shocks.For survivors of anterior-wall myocardial infarction who were not candidates for implantation of a cardioverter-defibrillator, access to a home AED did not significantly improve overall survival, as compared with reliance on conventional resuscitation methods. (ClinicalTrials.gov number, NCT00047411 [ClinicalTrials.gov].).

Objectives The outcome of congestive heart failure (CHF) patients with syncope is understood incompletely. Background We analyzed data from patients enrolled in the SCD-HeFT (Sudden Cardiac Death Heart Failure Trial) to determine whether syncope predicted outcomes in patients with CHF. Methods We compared outcomes (and associated clinical characteristics) in patients with and without syncope enrolled in SCD-HeFT. Results In SCD-HeFT, 162 (6%) patients had syncope before randomization, 356 (14%) had syncope after randomization (similar incidence in each randomized arm), and 46 (2%) had syncope before and after randomization. A QRS duration ≥120 ms and absence of beta-blocker use predicted syncope during follow-up (hazard ratio [HR] 1.30 and 95% confidence interval [CI] 1.06 to 1.61, p = 0.014 and HR 1.25, 95% CI 1.01 to 1.56, p = 0.048, respectively). Syncope recurrence did not differ by randomization arm. However, in the implantable cardioverter-defibrillator (ICD) arm, syncope, before and after randomization, was associated with appropriate ICD discharges (HR 1.75, 95% CI 1.10 to 2.80, p = 0.019 and HR 2.91, 95% CI 1.89 to 4.47, p = 0.001, respectively). Post-randomization syncope predicted total and cardiovascular death (HR 1.41, 95% CI 1.13 to 1.76, p = 0.002 and HR 1.55, 95% CI 1.19 to 2.02, p = 0.001, respectively). The elevated relative risk of mortality for syncope versus nonsyncope patients did not vary significantly across treatment arms (ICD, HR 1.54, 95% CI 1.04 to 2.27; amiodarone, HR 1.33, 95% CI 0.91 to 1.93; and placebo, HR 1.39, 95% CI 0.96 to 2.02, test for difference p = 0.86). Conclusions For CHF patients with ICDs, syncope was associated with appropriate ICD activations. Syncope was associated with increased mortality risk in SCD-HeFT regardless of treatment arm (placebo, amiodarone, or ICD). (SCD-HeFT Trial; NCT00000609)

Background The SCD-HeFT demonstrated that implantable cardioverter/defibrillator (ICD) therapy significantly improved survival compared to medical therapy alone in stable moderately symptomatic heart failure patients with an ejection fraction ≤35%. The purpose of this report is to describe the outcomes in African Americans (AAs) and other minorities. Methods Of 2521 patients enrolled, 23% were minorities and 17% were AAs. Baseline demographic, clinical variables, socioeconomic status, and long-term outcomes were compared according to race. Two major prespecified subgroups were examined: heart failure cause (ischemic vs nonischemic) and New York Heart Association class (II vs III). Results At baseline, compared to whites, AAs were younger and had more nonischemic heart failure, lower ejection fractions, worse New York Heart Association functional class, and higher prevalence of a history of nonsustained ventricular tachycardia. Comparable percentages of whites and AAs held paid jobs, but whites had a significantly higher educational level and household income ( P = .001). Compliance with ICD implantation and medical therapy was comparable in both subgroups. No significant difference was observed in the rate of ICD discharge among whites and AAs. Adjusted mortality risk was significantly higher in AAs compared to whites (hazard ratio 1.27, P = .038). Mortality was equally reduced in both race groups receiving ICD therapy compared to placebo (hazard ratio 0.65 in AAs and 0.73 in whites). Conclusions Survival benefits from ICD therapy in SCD-HeFT were not dependent on race. In addition, in this clinical trial setting, there was no evidence that AAs were less willing to accept ICD therapy than whites.

Background Recent observations suggest statin treatment may be associated with lower mortality in heart failure (HF). The SCD-HeFT was a study of 2521 functional class II and III HF patients with left ventricular ejection fractions ≤35% and ischemic and nonischemic cardiomyopathy followed up for a median of 45.5 months. The study length, size, and degree of background HF, including the use of implantable defibrillator therapy, provide a unique opportunity to evaluate the impact of statin use in HF with mechanistic insights from subgroup analyses. Methods and Results Statin use was reported in 965 (38%) of 2521 patients at baseline and 1187 (47%) at last follow-up. The relationships between statin use, randomization arm, disease category, and functional class and all cause mortality were assessed. Statin use was studied as a time-dependent covariate in a multivariable Cox proportional hazards model, adjusted for imbalances between statin and no-statin groups. Mortality risk was significantly lower in those taking a statin (HR [95% CI], 0.70 [0.58-0.83]). Mortality risk was lower with statin use in all prespecified subgroups: ischemic cardiomyopathy (0.69 [0.56-0.86]), nonischemic cardiomyopathy (0.67 [0.47-0.96]), implantable cardioverter defibrillator (ICD) (0.66 [0.46-0.95], non-ICD (0.71 [0.57-0.87]), New York Heart Association II (0.62 [0.48-0.79]), and New York Heart Association III (0.79 [0.61-1.03]). Conclusions Statin use is associated with reduced all-cause mortality in HF patients. Statins appear to benefit patients with nonischemic and ischemic cardiomyopathy similarly. Statin benefits are similar in ICD and non-ICD patients.

In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), a significant fraction of the patients with congestive heart failure ultimately did not die suddenly of arrhythmic causes. Patients with CHF will benefit from better tools to identify if implantable cardioverter-defibrillator (ICD) therapy is needed.We aimed to identify predictor variables from baseline SCD-HeFT patients' R-R intervals that correlate to arrhythmic sudden cardiac death (SCD) and mortality and to design an ICD therapy screening test.Ten predictor variables were extracted from prerandomization Holter data from 475 patients enrolled in the ICD arm of the SCD-HeFT by using novel and traditional heart rate variability methods. All variables were correlated to SCD using the Mann-Whitney-Wilcoxon test and receiver operating characteristic analysis. ICD therapy screening tests were designed by minimizing the cost of false classifications. Survival analysis, including log-rank test and Cox models, was also performed.A short-term fractal exponent, α1, and a long-term fractal exponent, α2, from detrended fluctuation analysis, the ratio of low- to high-frequency power, the number of premature ventricular contractions per hour, and the heart rate turbulence slope are all statistically significant for predicting the occurrences of SCD (P.001) and survival (log-rank, P.01). The most powerful multivariate predictor tool using the Cox proportional hazards regression model was α2 with a hazard ratio of 0.0465 (95% confidence interval 0.00528-0.409; P.01).Predictor variables extracted from R-R intervals correlate to the occurrences of SCD and distinguish survival functions among patients with ICDs in SCD-HeFT. We believe that SCD prediction models should incorporate Holter-based R-R interval analysis to refine ICD patient selection, especially to exclude patients who are unlikely to benefit from ICD therapy.

Background Patients with heart failure are at increased risk of both sudden death and pump failure death. Strategies to better identify those who have greatest net benefit from implantable cardioverter-defibrillator (ICD) implantation could reduce morbidity and maximize cost-effectiveness of ICDs. Objective We aimed to identify baseline variables in patients with cardiomyopathy that are independently associated with a disproportionate fraction of mortality risk attributable to sudden death vs nonsudden death. Methods We used data from 9885 patients with heart failure without ICDs, of whom 2552 died during an average follow-up of 2.3 years. Using commonly available baseline clinical and demographic variables, we developed a multivariate regression model to identify variables associated with a disproportionate risk of sudden death. Results We confirmed that lower ejection fraction and better functional class were associated with a greater proportion of mortality due to sudden death. Younger age, male sex, and higher body mass index were independently associated with a greater proportional risk of sudden death, while diabetes mellitus, hyper/hypotension, higher creatinine level, and hyponatremia were associated with a disproportionately lower risk of sudden death. The use of several heart failure medications, left ventricular end-diastolic dimension, or NT-pro brain natriuretic peptide concentrations were not associated with a disproportionate risk of sudden death. Conclusion Several easily obtained baseline demographic and clinical variables, beyond ejection fraction and New York Heart Association functional class, are independently associated with a disproportionately increased risk of sudden death. Further investigation is needed to assess whether this novel predictive method can be used to target the use of lifesaving therapies to populations who will derive greatest mortality benefit .

Implantable cardioverter defibrillator (ICD) therapy has been extensively evaluated in patients at high risk of sudden cardiac death. Most recently, the Sudden Cardiac Death in Heart Failure Trial found that patients with moderate symptoms of congestive heart failure, whether due to an ischemic or a nonischemic cause, have reduced mortality compared with patients treated only with conventional medical therapy for heart failure. The results of this trial confirm those of earlier trials finding a benefit of ICD therapy in patients with coronary artery disease and reduced left ventricular systolic function, and extend the indications for ICD therapy to those without coronary artery disease.

Background— In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), implantable cardioverter-defibrillator (ICD) therapy significantly reduced all-cause mortality rates compared with medical therapy alone in patients with stable, moderately symptomatic heart failure, whereas amiodarone had no benefit on mortality rates. We examined long-term economic implications of these results. Methods and Results— Medical costs were estimated by using hospital billing data and the Medicare Fee Schedule. Our base case cost-effectiveness analysis used empirical clinical and cost data to estimate the lifetime incremental cost of saving an extra life-year with ICD therapy relative to medical therapy alone. At 5 years, the amiodarone arm had a survival rate equivalent to that of the placebo arm and higher costs than the placebo arm. For ICD relative to medical therapy alone, the base case lifetime cost-effectiveness and cost-utility ratios (discounted at 3%) were $38 389 per life-year saved (LYS) and $41 530 per quality-adjusted LYS, respectively. A cost-effectiveness ratio Conclusions— Prophylactic use of single-lead, shock-only ICD therapy is economically attractive in patients with stable, moderately symptomatic heart failure with an ejection fraction ≤35%, particularly those in NYHA class II, as long as the benefits of ICD therapy observed in the SCD-HeFT persist for at least 8 years.

background Sudden death from cardiac causes remains a leading cause of death among patients with congestive heart failure (CHF). Treatment with amiodarone or an implantable cardioverter–defibrillator (ICD) has been proposed to improve the prognosis in such patients. methods We randomly assigned 2521 patients with New York Heart Association (NYHA) class II or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conventional therapy for CHF plus placebo (847 patients), conventional therapy plus amiodarone (845 patients), or conventional therapy plus a conservatively programmed, shockonly, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary end point was death from any cause. results The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P=0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class. conclusions In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent.