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Objectives: The 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). Background: There 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. Methods: Data 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. Results: Multivariate 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. Conclusions: In 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) [Copyright &y& Elsevier]

Background: Coronary revascularization (CR) may confer electrical stability in patients with ischemic cardiomyopathy. However, data regarding the effect of CR on the development of ventricular tachyarrhythmias in this population are limited. Objective: The purpose of this study was to evaluate the association between CR and arrhythmic risk in postmyocardial infarction (post-MI) patients with left ventricular dysfunction. Methods: The risk for life-threatening ventricular tachyarrhythmias (defined as a first appropriate defibrillator therapy for ventricular tachycardia [VT]/ventricular fibrillation [VF] or death) was compared between post-MI patients with and those without prior CR (n = 612 and 147, respectively) enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT). Results: The 3-year cumulative rate of VT/VF or death was significantly higher among patients without prior CR (42%) than in patients who underwent prior CR (32%, P = .02). Multivariate analysis demonstrated that patients without prior CR had 48% increased risk (P = .01) for VT/VF or death. Risk reduction associated with CR was related to elapsed time from CR, assessed both as a categorical variable (tertiles for time from CR: ≥7 years, hazard ratio [HR] = 1.93, P = .001; 1.5–7 years, HR = 1.70, P = .01 vs <1.5 years) and as a continuous measure (4%, P = .002, increased risk for VT/VF or death per 1-year increment of elapsed time from CR). The effect of CR on arrhythmic risk was similar in patients treated with a defibrillator alone or when combined with cardiac resynchronization therapy. Conclusion: Post-MI patients with left ventricular dysfunction who undergo CR experience a time-dependent reduction in the risk for subsequent life-threatening ventricular tachyarrhythmias. [ABSTRACT FROM AUTHOR]

Background: Data on long-term follow-up and factors influencing mortality in implantable cardioverter-defibrillator (ICD) recipients are limited. Objective: The aim of this study was to evaluate mortality during long-term follow-up and the predictive value of several risk markers in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) patients with implanted cardioverter-defibrillators (ICDs). Methods: The study involved U.S. patients from the MADIT II trial randomized to and receiving ICD treatment. Data regarding long-term mortality were retrieved from the National Death Registry. Several clinical, biochemical, and electrocardiogram variables were tested in a multivariate Cox model for predicting long-term mortality, and a score identifying high-, medium-, and lower risk patients was developed. Results: The study population consisted of 655 patients, mean age 64 ± 10 years. During a follow-up of up to 9 years, averaging 63 months, 294 deaths occurred. The 6-year cumulative probability of death was 40%, with evidence of a constant risk of about 8.5% per year among survivors. Median survival was estimated at 8 years. Multivariate analysis identified age >65 years, New York Heart Association class 3–4, diabetes, non–sinus rhythm, and increased levels of blood urea nitrogen as independent risk predictors of mortality. Patients with three or more of these risk factors were characterized by a 6-year mortality rate of 68%, compared with 43% in those with one to two risk factors and 19% in patients with no risk factors. Conclusion: A combination of a few readily available clinical variables indicating advanced disease and comorbid conditions identifies ICD patients at high risk of mortality during long-term follow-up. [Copyright &y& Elsevier]

Background: Much of prognostic implications of ventricular arrhythmia storms remain unclear.Objective: We evaluated the risk associated with electrical storm in patients with defibrillators in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) study.Methods: Electrical storm was defined as > or =3 episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) in 24 hours.Results: Of the 719 patients who received internal cardiac defibrillator (ICD) implants and had follow-up in the MADIT-II, 27 patients (4%) had electrical storm, 142 (20%) had isolated episodes of VT/VF, and the remaining 550 patients had no ICD-recorded VT events. Baseline clinical characteristics among the groups were similar. Patients who experienced electrical storm had a significantly higher risk of death. After adjustments for relevant clinical covariates, the hazard ratio (HR) for death in the first 3 months after the storm event was 17.8 (95% confidence interval [CI] 8.0 to 39.5, P <.01) in comparison with those with no VT/VF. This risk continued even after 3 months for those with electrical storm (HR of 3.5, 95% CI 1.2 to 9.8, P = .02). Study patients with isolated VT/VF episodes also were at an increased risk of dying (HR = 2.5, 95% CI 1.5 to 4.0, P <.01) when compared with patients without VT/VF episodes. Statistically significant predictors of electrical storm were interim postenrollment coronary events (myocardial infarction or angina) HR 3.1 (95% CI 1.2 to 8.1, P = .02) and isolated VT or VF HR 9.2 (95% CI 4.0 to 20.9, P <.01).Conclusion: Postinfarction patients with severe left ventricular dysfunction in whom electrical storm developed have significantly higher mortality than patients with only isolated VT/VF as well as those without any episodes of VT/VF. Patients who experienced postenrollment ventricular arrhythmias and/or interim coronary events during follow-up were at higher risk for VT/VF storms. [ABSTRACT FROM AUTHOR]

Objectives: We 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. Background: This 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. Methods: Our 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. Results: During 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. Conclusions: The 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. [Copyright &y& Elsevier]

Objectives: The 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. Background: There is limited information regarding the determinants of appropriate ICD therapy in patients with reduced ventricular function after a myocardial infarction. Methods: We used secondary analysis in one arm of a multicenter randomized clinical trial in patients with a previous myocardial infarction and reduced left ventricular function. Results: We 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). Conclusions: These 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. [Copyright &y& Elsevier]

Objectives: The study was designed to develop a simple risk stratification score for primary therapy with an implantable cardioverter-defibrillator (ICD). Background: Current guidelines recommend primary ICD therapy in patients with a low ejection fraction (EF). However, the benefit of the ICD in the low EF population may not be uniform. Methods: Best-subset proportional-hazards regression analysis was used to develop a simple clinical risk score for the end point of all-cause mortality in patients allocated to the conventional therapy arm of MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II after excluding a pre-specified subgroup of very high-risk (VHR) patients (defined by blood urea nitrogen [BUN] ≥50 mg/dl and/or serum creatinine ≥2.5 mg/dl). The benefit of the ICD was then assessed within risk score categories and separately in VHR patients. Results: The selected risk score model comprised 5 clinical factors (New York Heart Association functional class >II, age >70 years, BUN >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation). Crude mortality rates in the conventional group were 8% and 28% in patients with 0 and ≥1 risk factors, respectively, and 43% in VHR patients. Defibrillator therapy was associated with a 49% reduction in the risk of death (p < 0.001) among patients with ≥1 risk factors (n = 786), whereas no ICD benefit was identified in patients with 0 risk factors (n = 345; hazard ratio 0.96; p = 0.91) and in VHR patients (n = 60; hazard ratio 1.00; p > 0.99). Conclusions: Our data suggest a U-shaped pattern for ICD efficacy in the low-EF population, with pronounced benefit in intermediate-risk patients and attenuated efficacy in lower- and higher-risk subsets. [Copyright &y& Elsevier]

In the second Multicenter Automatic Defibrillator Implantation Trial, patients with a previous myocardial infarction and left ventricular ejection fraction ≤0.30 benefited significantly from prophylactic implantable cardioverter-defibrillator (ICD) placement. Diabetic patients who had a myocardial infarction had a worse prognosis compared with nondiabetics. The present study used data from the second Multicenter Automatic Defibrillator Implantation Trial to assess the efficacy of ICD placement on survival in diabetic patients. Of the 1,232 patients in the second Multicenter Automatic Defibrillator Implantation Trial, 489 were characterized as diabetic. They were more likely to be New York Heart Association class II to IV, be hypertensive, have renal dysfunction, have an increased body mass index, and to take diuretic drugs. Diabetic patients had a 24% greater adjusted risk of death than nondiabetic patients. The hazard ratio (HR) for the risk of death in patients treated with the ICD compared with conventional therapy was similar in diabetics (HR 0.61; 95% confidence interval [CI] 0.38 to 0.98) and nondiabetics (HR 0.71; 95% CI 0.49 to 1.05), with no evidence of interaction. Thus, diabetic patients derive a similar benefit from ICD therapy despite being sicker and having a higher mortality rate overall. [Copyright &y& Elsevier]

Objectives: This study compared the quality of life (QOL) of patients with cardiac resynchronization therapy (CRT) and an implantable cardioverter-defibrillator (ICD) to patients with an ICD only. Background: CRT with ICD is associated with a reduction in heart failure risk among minimally symptomatic patients. It is unknown whether this improves QOL. Methods: This study uses the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) data. The MADIT-CRT enrolled 1,820 patients at 110 centers across 14 countries. Patients had ischemic cardiomyopathy (New York Heart Association [NYHA] functional class I or II) or nonischemic cardiomyopathy (NYHA functional class II only), sinus rhythm, an ejection fraction of 30% or less, and prolonged intraventricular conduction with a QRS duration of 130 ms or more. QOL was evaluated on the 1,699 patients with baseline and follow-up measures using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Six dimensions (Physical Limitation, Symptom Stability, Symptom Frequency, Symptom Burden, Quality of Life, and Social Limitations) and 3 summary scores (Total Symptom, Clinical Summary, and Overall Summary) were analyzed. Results: During an average follow-up of 2.4 years, the CRT-ICD group had greater improvement than the ICD-only group on all KCCQ measures (p < 0.05 on each scale). These differences were significant among patients with left bundle branch block conduction disturbance (n = 1,204, p < 0.01 on each scale), but not among patients without left bundle branch block (n = 494). Conclusions: Compared with patients with ICD only, CRT-ICD is associated with greater improvement in QOL among relatively asymptomatic patients, specifically among those with left bundle branch conduction disturbance. [Copyright &y& Elsevier]

Objectives: This study aimed to evaluate the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the risks of first and recurrent ventricular tachyarrhythmic events (VTEs) in the MADIT-CRT. Background: Reverse remodeling associated with CRT-D therapy was suggested to reduce arrhythmic risk. However, the effect of the device on the risk of recurrent VTEs among patients who experience a first arrhythmic event has not been investigated. Methods: The CRT-D versus defibrillator-only risks for first and subsequent fast VTEs (>180 beats/min) were assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up. Results: Multivariate analysis showed that CRT-D was associated with a significant 29% (p = 0.003) reduction in the risk of a first VTE, with a pronounced effect among patients with left bundle branch block (LBBB) (hazard ratio [HR]: 0.58; p < 0.001) and no significant effect among non-LBBB patients (HR: 1.05; p = 0.82, p for the difference = 0.02). Patients with LBBB who experienced a first VTE had no change in the risk of subsequent VTEs with CRT-D (HR: 0.98; p = 0.85). In contrast, the risk of recurrent VTEs with CRT-D was significantly increased among non-LBBB patients (HR: 3.62; p = 0.002, p for the difference = 0.009). Recurrent VTEs increased the risk of subsequent heart failure or death. Conclusions: In MADIT-CRT, active treatment with CRT-D was associated with a significant reduction in the risk of life-threatening VTEs. However, our findings suggest that CRT-D does not reduce the risk of subsequent VTEs in patients who experience a first arrhythmic event and may increase subsequent arrhythmic risk in non-LBBB patients. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271) [ABSTRACT FROM AUTHOR]

Objectives: This study hypothesized that time-dependent statin therapy will reduce the risk of life-threatening ventricular tachyarrhythmias among patients with nonischemic cardiomyopathy (NICM) enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). Background: Prior studies suggested that statin therapy exerts antiarrhythmic properties among patients with coronary artery disease. However, data regarding the effect of statins on arrhythmic risk among patients with NICM are limited. Methods: Multivariate Cox proportional hazards regression modeling was used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of appropriate defibrillator therapy for fast ventricular tachycardia (VT) (defined as a rate faster than 180 beats/min)/ventricular fibrillation (VF) or death (primary endpoint) and appropriate defibrillator shocks (secondary endpoint) among 821 patients with NICM enrolled in the MADIT-CRT trial. Results: Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p < 0.001) and with a significant 46% reduction in the risk of appropriate implantable cardioverter defibrillator shocks (p = 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p = 0.006 for the overall difference during follow-up). Conclusions: Statin use was associated with a significant reduction in the risk of life-threatening ventricular tachyarrhythmias among patients with NICM. [ABSTRACT FROM AUTHOR]

Objectives: The 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. Background: In the MADIT-CRT trial, women seemed to achieve a better result from resynchronization therapy than men. Methods: All 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. Results: Female 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. Conclusions: Women 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). [Copyright &y& Elsevier]

Objectives: This study sought to identify the incidence and outcome related to inappropriate implantable cardioverter-defibrillator (ICD) shocks, that is, those for nonventricular arrhythmias. Background: The 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. Methods: Stored 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. Results: One 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). Conclusions: Inappropriate ICD shocks occurred commonly in the MADIT II study, and were associated with increased risk of all-cause mortality. [Copyright &y& Elsevier]

Objectives: This study was designed to evaluate the relationship among blood pressure (BP) levels, risk of sudden cardiac death (SCD), and benefit of the implantable cardioverter-defibrillator (ICD) in patients with ischemic left ventricular (LV) dysfunction. Background: Low BP has been shown to be associated with increased mortality in patients with LV dysfunction and heart failure. We hypothesized that increasing BP levels are associated with a reduction in the risk of SCD in this population, thereby limiting ICD efficacy in a lower-risk subset. Methods: The independent contribution of systolic blood pressure (SBP) and diastolic blood pressure (DBP) to outcome was analyzed in 1,231 patients enrolled in the prospective MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II). Results: Multivariate analysis showed that in the conventional therapy arm of the trial, 10-mm Hg increments in systolic BP were independently associated with a respective 14% (p = 0.01) and 16% (p = 0.04) reduction in the risk of cardiac mortality and SCD; similar trends were shown for DBP. Defibrillator therapy provided the least survival benefit to patients in the lower-risk, upper SBP (>130 mm Hg) and DBP (≥80 mm Hg) quartiles (hazard ratio 1.04 [p = 0.89] and 1.05 [p = 0.88], respectively), whereas a respective 39% and 38% (p = 0.002) reduction in the risk of death with ICD therapy was observed among patients with lower BP values. Conclusions: In patients with ischemic LV dysfunction, SBP and DBP levels show an inverse correlation with sudden cardiac mortality. These noninvasive hemodynamic parameters may be useful for identifying lower-risk patients, in whom the benefit of primary defibrillator implantation is more limited. [Copyright &y& Elsevier]

Location (anterior) and type (Q wave) of myocardial infarction (MI) might be considered of prognostic significance when predicting mortality. However, there are limited data regarding the prognostic significance of type and location of MI in patients with severely depressed left ventricular function. In 1,221 patients in the MADIT II, Q-wave MI was observed in 763 patients (62%), 115 (10%) had non–Q-wave MI, and 343 (28%) had conduction abnormalities. In patients with Q-wave MI, anterior MI was present in 430 (57%), inferior in 155 (20%), and combined in 178 (23%) patients. Study end points included all-cause mortality, hospitalization or death due to worsening congestive heart failure, and episodes of ventricular tachycardia or ventricular fibrillation requiring implantable cardioverter-defibrillator therapy. In a multivariate Cox proportional hazard model predicting mortality, the following clinical variables entered the predictive model at a p value <0.10: treatment (implantable cardioverter-defibrillator vs conventional therapy), age dichotomized at 65 years, angina pectoris, ejection fraction dichotomized at 25%, serum urea nitrogen dichotomized at 25 mg/dl, and β-blocker use. After adjustment for these covariates, risk of mortality was not significantly different in non–Q-wave MI versus Q-wave MI. However, when analyzing location of MI, inferior wall MI was associated with a significantly (hazard ratio 1.58, p = 0.048) higher risk of mortality than anterior wall MI. In addition, patients with conduction abnormalities had a higher risk of mortality (hazard ratio 1.36, p = 0.088) than patients with anterior wall MI. In conclusion, in the setting of severely depressed ejection fraction (≤30%), inferior wall MI was associated with a significantly higher risk of mortality than anterior wall MI. [Copyright &y& Elsevier]

Objectives: The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations. Background: The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated. Methods: The clinical characteristics of 812 mutation-confirmed LQTS patients age 18 years or older were studied with both univariate and multivariate analyses to determine the genotype-phenotype factors that influence the clinical course of adult patients with this disorder. Results: Female gender, corrected QT (QTc) interval, LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. Female gender, QTc interval ≥500 ms, and interim syncopal events during follow-up after age 18 years were associated with significantly increased risk of life-threatening cardiac events in adulthood. Beta-blockers provided a 60% reduction in risk of any cardiac event and life-threatening events, with somewhat greater effect in higher-risk subjects. Conclusions: The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, QTc duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS. [Copyright &y& Elsevier]

Implanted cardioverter defibrillator therapy has been shown to be associated with a significant reduction in the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. However, data on the relation between renal function and SCD in this population are limited, and the effect of renal dysfunction on the implanted cardioverter defibrillator benefit has not been determined. We performed a retrospective analysis of the outcome associated with renal dysfunction, as determined by the estimated glomerular filtration rate (eGFR), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II. Multivariate analysis in conventionally treated patients showed that for each 10-U reduction in eGFR, the risk of all-cause mortality and SCD increased by 16% (p = 0.005) and 17% (p = 0.03), respectively. Defibrillator therapy was associated with a survival benefit in each eGFR category of ≥35 ml/min/1.73 m2 (overall risk reduction for all-cause mortality 32%, p = 0.01 and for SCD 66%, p <0.001). However, no implanted cardioverter defibrillator benefit was shown among patients with an eGFR <35 ml/min/1.73 m2 (all-cause mortality hazard ratio 1.09, p = 0.84; SCD hazard ratio 0.95, p = 0.95). In conclusion, in patients with high-risk cardiac disease enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II, a significant increase was found in the risk of SCD with declining renal function. Defibrillator therapy was associated with a significant survival benefit among the study patients with mild to moderate or no renal disease, but no benefit was shown among patients with more advanced renal dysfunction. [Copyright &y& Elsevier]

Objectives: The study was designed to assess the effect of elapsed time from coronary revascularization (CR) on the benefit of the implantable cardioverter-defibrillator (ICD) and the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. Background: The ICD improves survival in appropriately selected high-risk cardiac patients by 30% to 54%. However, in the Coronary Artery Bypass Graft (CABG)-Patch trial no evidence of improved survival was shown among a similar population of patients in whom an ICD was implanted prophylactically at the time of elective CABG. Methods: The outcome by time from CR was analyzed in 951 patients in whom a revascularization procedure was performed before enrollment in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. Results: The adjusted hazard ratio (HR) of ICD versus conventional therapy was 0.64 (p = 0.01) among patients enrolled more than six months after CR, whereas no survival benefit with ICD therapy was shown among patients enrolled six months or earlier after CR (HR = 1.19; p = 0.76). In the conventional therapy group, the risk of cardiac death increased significantly with increasing time from CR (p for trend = 0.009), corresponding mainly to a six-fold increase in the risk of SCD among patients enrolled more than six months after CR. Conclusions: In patients with ischemic left ventricular dysfunction, the efficacy of ICD therapy after CR is time dependent, with a significant life-saving benefit in patients receiving device implantation more than six months after CR. The lack of ICD benefit when implanted early after CR may be related to a relatively low risk of SCD during this time period. [Copyright &y& Elsevier]

Objectives: We evaluated whether statins have anti-arrhythmic effects by exploring the association of statin use with appropriate implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia/ventricular fibrillation (VT/VF) in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. Background: A few studies have suggested that lipid-lowering drugs may have anti-arrhythmic effects in patients with coronary artery disease. Methods: Patients receiving an ICD (n = 654; U.S. centers only) in the MADIT-II study were categorized by the percentage of days each patient received statins during follow-up (90% to 100%, n = 386; 11% to 89%, n = 116; and 0% to 10%, n = 152). The Kaplan-Meier method with significance testing by the log-rank statistic and time-dependent proportional hazards regression analysis were used to evaluate the effect of statin use on the probability of ICD therapy for the combined end point VT/VF or cardiac death and for the end point VT/VF. Results: The cumulative rate of ICD therapy for VT/VF or cardiac death, whichever occurred first, was significantly reduced in those with ≥90% statin usage compared to those with lower statin usage (p = 0.01). The time-dependent statin:no statin therapy hazard ratio was 0.65 (p < 0.01) for the end point of VT/VF or cardiac death and 0.72 (p = 0.046) for VT/VF after adjusting for relevant covariates. Conclusions: Statin use in patients with an ICD was associated with a reduction in the risk of cardiac death or VT/VF, whichever occurred first, and was associated with a reduction in VT/VF episodes. These findings suggest that statins have anti-arrhythmic properties. [Copyright &y& Elsevier]

This study examined the effects of β blockers on (1) appropriate implantable cardioverter defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), (2) inappropriate ICD therapy for atrial fibrillation or supraventricular tachycardia, and (3) survival in 691 patients who received ICDs in the Multicenter Automatic Defibrillator Implantation Trial-II. The study population involved 258 patients who were not receiving β blockers and 433 who were receiving metoprolol (n = 192), atenolol (n = 58), or carvedilol (n = 182). Patients receiving β blockers were divided into the upper quartile and lower 3 quartiles of the drug doses they were taking. Patients receiving the higher doses of β blockers (those in the top quartile of doses) had a significant reduction in the risk for VT or VF requiring ICD therapy compared with patients not receiving β lockers (hazard ratio 0.48, p = 0.02). The frequency of inappropriate ICD therapy for supraventricular tachyarrhythmias was not significantly different among the 3 treatment groups (p = 0.32). Beta-blocker use at the 2 dosage levels was associated with significant improvement in survival compared with the nonuse of β blockers (hazard ratios 0.42 to 0.44, p &#60;0.01). In conclusion, β blockers reduce the risk for VT or VF and improve survival in ICD-treated patients with ischemic cardiomyopathy. [Copyright &y& Elsevier]

The present study retrospectively explored the reasons for delay in the onset of survival benefit from the implanted cardioverter defibrillator (ICD) in the Second Multicenter Automatic Defibrillator Implantation Trial. The cumulative probability of cause-specific death over time was estimated by the Kaplan-Meier method and by proportional hazards regression analysis. Early cardiac death survival curves were similar by treatment assignment in the 0- to 12-month period (p = 0.76). Late cardiac death survival curves by treatment assignment in the >12- to 52-month follow-up period were divergent with a lower probability of late cardiac death in the ICD arm compared with conventional therapy group (p <0.001). The time-specific hazard ratios of ICD to conventional therapy for cardiac death in the early and late periods were significantly different from each other (nominal p = 0.004). There was a significant decrease in sudden cardiac death with ICD therapy in the early (p = 0.012) and late (p <0.001) groups. In the early period, the rate of nonsudden cardiac death was significantly higher in the ICD group than in the conventional therapy group (p = 0.003). Rates of late nonsudden cardiac death were similar in the 2 treatment arms (p = 0.11). [Copyright &y& Elsevier]

: ObjectivesWe aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration.: BackgroundGenotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited.: MethodsThe LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children ≤ 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype.: ResultsDuring childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both).: ConclusionsAge and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients. [Copyright &y& Elsevier]

Although improved patient survival has been reported in several randomized trials with the implanted cardioverter-defibrillator, <15% of patients treated with defibrillators during trials receive life-saving benefit from this therapy. We evaluated the survival benefit from defibrillator therapy in relation to the severity of the mortality risk in patients with coronary heart disease. Using data from the Multicenter Automatic Defibrillator Implantation Trial, we partitioned the study population into high- and low-risk subsets for each of 3 physiologically meaningful risk factors (ejection fraction, QRS duration, and history of heart failure requiring therapy). Risk of death was evaluated by Cox proportional-hazards regression analyses in patients with single and multiple risk factors. The defibrillator was associated with a significant (p = 0.002) reduction in mortality only in high-risk subsets with ejection fraction <0.26, QRS duration > or =0.12 second, and history of heart failure requiring treatment. The Cox hazard ratio for the risk of death progressively increased >1.0 as a function of the number of risk factors present. Defibrillator therapy was associated with a progressive reduction in the hazard ratio <1.0 (improved survival) at each increased level of mortality risk. Patients at the highest mortality risk (all 3 risk factors; hazard ratio 4.33) achieved the largest mortality reduction (hazard ratio 0.20) from defibrillator therapy. In patients with chronic coronary heart disease, the magnitude of the survival benefit from the implanted defibrillator is directly related to the severity of cardiac dysfunction and its associated mortality risk. [ABSTRACT FROM AUTHOR]