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ObjectivesThe purpose of this study was to prospectively examine the role of clinical, laboratory, echocardiographic, and electrophysiological variables as predictors of appropriate initial implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) or death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) population.BackgroundThere is limited information regarding the determinants of appropriate ICD therapy in patients with reduced ventricular function after a myocardial infarction.MethodsWe used secondary analysis in one arm of a multicenter randomized clinical trial in patients with a previous myocardial infarction and reduced left ventricular function.ResultsWe analyzed baseline and follow-up data on 719 patients enrolled in the ICD arm of the MADIT-II study. Appropriate ICD therapy was observed in 169 subjects. Clinical, laboratory, echocardiographic, and electrophysiological variables, along with measures of clinical instability such as interim hospitalization for congestive heart failure (IH-CHF) and interim hospitalization for coronary events (IH-CE), were examined with proportional hazards models and Kaplan-Meier time-to-event curves before and after first interim hospitalization. Interim hospitalization-CHF, IH-CE, no beta-blockers, digitalis use, blood urea nitrogen (BUN) >25, body mass index (BMI) ≥30 kg/m2, and New York Heart Association functional class >II were associated with increased risk for appropriate ICD therapy for VT, VF, or death. In a multivariate (stepwise selection) analysis, IH-CHF was associated with an increased risk for the end point of either VT or VF (hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.69 to 3.74, p < 0.001) and for the combined end point of VT, VF, or death (HR 2.97, 95% CI 2.15 to 4.09, p < 0.001). Interim hospitalization-CE was associated with an increased risk for VT, VF, or death (HR 1.66, 95% CI 1.09 to 2.52, p = 0.02).ConclusionsThese results provide important mechanistic information, suggesting that worsening clinical condition and cardiac instability, as reflected by an IH-CHF or IH-CE, are subsequently associated with a significant increase in the risk for appropriate ICD therapy (for VT/VF) and death.

ObjectivesThe evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy).BackgroundThere are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE.MethodsData with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up.ResultsMultivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality.ConclusionsIn the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271)

ObjectivesThe purpose of this study was to investigate the factors related to sex-specific outcomes for death and heart failure events in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) trial.BackgroundIn the MADIT-CRT trial, women seemed to achieve a better result from resynchronization therapy than men.MethodsAll 1,820 patients (453 female and 1,367 male) enrolled in the MADIT-CRT trial were included in this sex-specific outcome analysis that compared the effect of cardiac resynchronization therapy with defibrillator (CRT-D) relative to implanted cardioverter-defibrillator (ICD) on death or heart failure (whichever came first), heart failure only, and death at any time.ResultsFemale patients were more likely to have nonischemic cardiomyopathy and left bundle branch block and less likely to have renal dysfunction than male patients. Overall, female patients had a better result from CRT-D therapy than male patients, with a significant 69% reduction in death or heart failure (hazard ratio: 0.31, p < 0.001) and 70% reduction in heart failure alone (hazard ratio: 0.30, p < 0.001). Women had a significant 72% reduction in all-cause mortality in the total population (hazard ratio: 0.28, p = 0.02) and significant 82% and 78% reductions in mortality in those with QRS ≥150 ms and with left bundle branch block conduction disturbance, respectively, with sex-by-treatment interactions for mortality reduction significant at p < 0.05 in each of these 3 patient groups. These beneficial CRT-D effects among women were associated with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men.ConclusionsWomen in the MADIT-CRT trial obtained significantly greater reductions in death or heart failure (whichever came first), heart failure alone, and all-cause mortality with CRT-D therapy than men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

ObjectivesWe sought to evaluate the cost implications of the implantable cardioverter-defibrillator (ICD), using utilization, cost, and survival data from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.BackgroundThis trial showed that prophylactic implantation of a defibrillator reduces the rate of mortality in patients who experienced a previous myocardial infarction and low left ventricular ejection fraction. Given the size of the eligible population, the cost effectiveness of the ICD has substantial implications.MethodsOur research comprises the cost-effectiveness component of the randomized controlled trial, MADIT-II, based on utilization, cost, and survival information from 1,095 U.S. patients who were assigned randomly to receive an ICD or conventional medical care. Utilization data were converted to costs using a variety of national and hospital-specific data. The incremental cost-effectiveness ratio (iCER) was calculated as the difference in discounted costs divided by the difference in discounted life expectancy within 3.5 years. Secondary analyses included projections of survival (using three alternative assumptions), corresponding cost assumptions, and the resulting cost-effectiveness ratios until 12 years after randomization.ResultsDuring the 3.5-year period of the study, the average survival gain for the defibrillator arm was 0.167 years (2 months), the additional costs were $39,200, and the iCER was $235,000 per year-of-life saved. In three alternative projections to 12 years, this ratio ranged from $78,600 to $114,000.ConclusionsThe estimated cost per life-year saved by the ICD in the MADIT-II study is relatively high at 3.5 years but is projected to be substantially lower over the course of longer time horizons.

ObjectivesThis study sought to identify the incidence and outcome related to inappropriate implantable cardioverter-defibrillator (ICD) shocks, that is, those for nonventricular arrhythmias.BackgroundThe MADIT (Multicenter Automatic Defibrillator Implantation Trial) II showed that prophylactic ICD implantation improves survival in post-myocardial infarction patients with reduced ejection fraction. Inappropriate ICD shocks are common adverse consequences that may impair quality of life.MethodsStored ICD electrograms from all shock episodes were adjudicated centrally. An inappropriate shock episode was defined as an episode during which 1 or more inappropriate shocks occurred; another inappropriate ICD episode occurring within 5 min was not counted. Programmed parameters for patients with and without inappropriate shocks were compared.ResultsOne or more inappropriate shocks occurred in 83 (11.5%) of the 719 MADIT II ICD patients. Inappropriate shock episodes constituted 184 of the 590 total shock episodes (31.2%). Smoking, prior atrial fibrillation, diastolic hypertension, and antecedent appropriate shock predicted inappropriate shock occurrence. Atrial fibrillation was the most common trigger for inappropriate shock (44%), followed by supraventricular tachycardia (36%), and then abnormal sensing (20%). The stability detection algorithm was programmed less frequently in patients receiving inappropriate shocks (17% vs. 36%, p = 0.030), whereas other programming parameters did not differ significantly from those without inappropriate shocks. Importantly, patients with inappropriate shocks had a greater likelihood of all-cause mortality in follow-up (hazard ratio 2.29, p = 0.025).ConclusionsInappropriate ICD shocks occurred commonly in the MADIT II study, and were associated with increased risk of all-cause mortality.