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Background: There are limited data on the prognostic implications of brain natriuretic peptide (BNP) assessment in patients with mildly symptomatic heart failure (HF) who receive cardiac resynchronization therapy with a defibrillator (CRT-D)., Methods and Results: The effect of elevated baseline and 1-year BNP levels (dichotomized at the upper tertile BNP of 120 pg/mL) on the risk of HF or death was assessed among the cohort of 1197 patients with baseline BNP data enrolled in MADIT (Multicenter Automated Defibrillator Implantation Trial)-CRT. Elevated baseline BNP was associated with a significant 68% (P=0.007) and 58% (P=0.02) increase in the risk of HF or death among MADIT-CRT patients allocated to CRT-D and implantable cardioverter defibrillator-only therapy, respectively. At 1 year of follow-up, patients allocated to CRT-D displayed significantly greater reductions in BNP (26% reduction) levels compared with implantable cardioverter defibrillator-only patients (8% increase; P=0.005). Patients with CRT-D in whom 1-year BNP levels were reduced or remained low experienced a significantly lower risk of subsequent HF or death as compared with patients in whom 1-year BNP levels were high. Similarly, the echocardiographic response to CRT-D was highest among those who maintained low BNP levels or in whom BNP level at 1-year was reduced., Conclusions: Our findings suggest that assessment of baseline and follow-up BNP provides important prognostic implications in patients with mildly symptomatic HF who receive CRT.

Background: Right ventricular function (RVF) is an important determinant of outcome in patients with heart failure, and those with severe RV dysfunction have worse outcome after cardiac resynchronization therapy (CRT). We used data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) Trial to determine whether therapy with CRT is influenced by or affects RV function and to define the relationship between RV function and outcomes., Methods and Results: A total of 1820 patients were randomly assigned to CRT plus implantable cardioverter defibrillator or implantable cardioverter defibrillator-only in a 3:2 ratio. We assessed RVF as RV fractional area change by echocardiography at baseline and after 1 year of therapy (n=1511 and 1273, respectively). The median RV fractional area change was 41%, with 10.9% of patients <35% at baseline. Baseline RVF did not modify the treatment effect of CRT on the primary outcome (interaction P=0.19). Randomization to CRT-implantable cardioverter defibrillator was associated with a greater improvement in RVF (ΔRV fractional area change 8.1% versus 5.4%; P<0.001), and improvement in RVF was related to subsequent outcomes. Every 5-point increase in RV fractional area change was associated with a 22% reduction in event rates (hazard ratio, 0.78; 95% confidence interval, 0.66-0.92; P=0.003), although this was not independent of the concurrent improvement in left ventricular function. Baseline tricuspid regurgitant velocity, a measure of pulmonary systolic pressure, was predictive of events in a multivariate analysis (hazard ratio, 1.86; 95% confidence interval, 1.24-2.8; P=0.003)., Conclusions: In this population with mild heart failure symptoms, CRT was associated with improvement in RVF, which improved in parallel with improvement in left ventricular function. Patients with the best RVF at 1 year demonstrated the lowest subsequent event rates., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01294449.

Importance: Randomized clinical trials have shown that implantable cardioverter-defibrillator (ICD) therapy saves lives. Whether the survival of patients who received an ICD in primary prevention clinical trials differs from that of trial-eligible patients receiving a primary prevention ICD in clinical practice is unknown., Objective: To determine whether trial-eligible patients who received a primary prevention ICD as documented in a large national registry have a survival rate that differs from the survival rate of similar patients who received an ICD in the 2 largest primary prevention clinical trials, MADIT-II (n = 742) and SCD-HeFT (n = 829)., Design, Setting, and Patients: Retrospective analysis of data for patients enrolled in the National Cardiovascular Data Registry ICD Registry between January 1, 2006, and December 31, 2007, meeting the MADIT-II criteria (2464 propensity score-matched patients) or the SCD-HeFT criteria (3352 propensity score-matched patients). Mortality data for the registry patients were collected through December 31, 2009., Main Outcome Measures: Cox proportional hazards models were used to compare mortality from any cause., Results: The median follow-up time in MADIT-II, SCD-HeFT, and the ICD Registry was 19.5, 46.1, and 35.2 months, respectively. Compared with patients enrolled in the clinical trials, patients in the ICD Registry were significantly older and had a higher burden of comorbidities. In the matched cohorts, there was no significant difference in survival between MADIT-II-like patients in the registry and MADIT-II patients randomized to receive an ICD (2-year mortality rates: 13.9% and 15.6%, respectively; adjusted ICD Registry vs trial hazard ratio, 1.06; 95% CI, 0.85-1.31; P = .62). Likewise, the survival among SCD-HeFT-like patients in the registry was not significantly different from survival among patients randomized to receive ICD therapy in SCD-HeFT (3-year mortality rates: 17.3% and 17.4%, respectively; adjusted registry vs trial hazard ratio, 1.16; 95% CI, 0.97-1.38; P = .11)., Conclusions and Relevance: There was no significant difference in survival between clinical trial patients randomized to receive an ICD and a similar group of clinical registry patients who received a primary prevention ICD. Our findings support the continued use of primary prevention ICDs in similar patients seen in clinical practice., Trial Registration: clinicaltrials.gov Identifier: NCT00000609.

Background: The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects., Methods: We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute)., Results: During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups., Conclusions: Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310.).

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 © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The implantable cardioverter defibrillator (ICD) is highly effective in reducing mortality due to cardiac arrhythmias in high-risk cardiac patients. However, inappropriate therapies caused predominantly by supraventricular tachyarrhythmias (SVTs) remain a significant side effect of ICD therapy despite medical treatment, affecting 8-40% of patients. The MADIT-RIT is a global, prospective, randomized, nonblinded, three-arm, multicenter clinical investigation to be performed in the Unites States, Europe, Canada, Israel and Japan, and will utilize approximately 90 centers with plan to enroll 1500 patients programmed to three treatment arms. The objective of the MADIT-RIT trial is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-Arm B) and/or long delay in combination with detection enhancements (MADIT-RIT-Arm C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT-Arm A) during postimplant follow-up of patients with indication for primary prevention device therapy. This paper describes design and analytic plan for the MADIT-RIT trial., (©2012, Wiley Periodicals, Inc.)

Background: We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device., Methods and Results: The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m(2), and left atrial volume <40 mL/m(2)). Multivariate analysis showed a 13% (P<0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0-14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P=0.52); patients in the second and third quartiles derived 33% (P=0.04) and 36% (P=0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% (P<0.001) risk reduction (P for trend=0.005)., Conclusion: Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

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 © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT., Methods and Results: We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block., Conclusions: Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Aims: To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT., Methods and Results: We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001)., Conclusion: Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

Aims: Cardiac remodelling is a progressive process after myocardial infarction (MI). However, currently there are no data regarding the effect of s:elapsed time from MI on the benefit of cardiac resynchronization therapy with defibrillator (CRT-D). The present study was designed to evaluate the relationship between elapsed time from MI and the benefit of preventive CRT-D therapy in patients with ischaemic cardiomyopathy (ICM)., Methods and Results: The risk of heart failure (HF) or death as a function of elapsed time from MI to enrolment, by treatment with CRT-D vs. implantable cardioverter defibrillator (ICD)-only therapy, was assessed among 704 ICM patients with a documented MI enrolled in MADIT-CRT, and separately in a subset of ICM patients without a documented prior MI (n = 237). In ICD patients, the adjusted risk of HF or death increased by 4% (P = 0.01) for each year elapsed from MI. Multivariate analysis demonstrated that patients with remote MI [categorized at the median value (≥8 years)] derived a significantly greater benefit from CRT-D [HR = 0.42 (P < 0.001)] than those with a more recent MI [HR = 1.26 (P = 0.35); P-value for interaction <0.001]. Consistently, the benefit of CRT-D was directly related to increasing quartiles of elapsed time from MI [Q(1) (<3 years): HR = 1.67; P = 0.20, Q(2) (3-8 years): HR = 1.12; P = 0.71, Q(3) (8-15 years): HR = 0.47; P = 0.02, and Q(4) (≥15 years): HR = 0.38; P = 0.001]. The ICM subgroup with no documented MI also derived enhanced benefit from CRT-D (HR = 0.43; P = 0.003)., Conclusion: In patients with ischaemic cardiomyopathy, the risk of HF or death and the magnitude of CRT-D benefit are directly related to elapsed time from MI.

Aims: There are no data regarding the differential response to cardiac resynchronization therapy with defibrillator (CRT-D) by the aetiology of cardiomyopathy in mildly symptomatic patients. We evaluated the outcome of patients enrolled in MADIT-CRT by ischaemic and non-ischaemic aetiology of cardiomyopathy (ICM and non-ICM, respectively)., Methods and Results: The clinical response to CRT-D was assessed among ICM (n = 1046) and non-ICM (n = 774) patients enrolled in MADIT-CRT during an average follow-up of 2.4 years, and echocardiographic response was assessed at 1 year. Cardiac resynchronization therapy with defibrillator vs. ICD therapy was associated with respective 34% (P = 0.001) and 44% (P = 0.002) reductions in the risk of heart failure or death among ICM and non-ICM patients (P for interaction = 0.455). In the ICM group, CRT-D was associated with mean (±SD) 29 ± 14% and 18 ± 10% reductions in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), respectively. In the non-ICM group, CRT-D was associated with significantly greater volume reductions compared with the ICM group [37 ± 16% and 24 ± 12% reductions in LVESV and LVEDV, respectively (P < 0.001 for all)]. Risk subsets in the ICM group that showed a favourable clinical response to CRT-D included patients with QRS ≥150 ms, systolic blood pressure <115 mmHg, and left bundle branch block (LBBB), whereas in the non-ICM group females, patients with diabetes mellitus, and LBBB, displayed a favourable clinical response., Conclusion: Mildly symptomatic ICM and non-ICM patients show significant differences in the echocardiographic response to CRT-D and in the clinical benefit within risk subsets suggesting that risk assessment for CRT-D in this population should be aetiology-specific.

Background: Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population., Methods and Results: We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38; P=0.005) and the postmenopausal period (hazard ratio, 8.10; P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19; P=0.05; P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause., Conclusions: The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.

Background: This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial., Methods and Results: Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P < 0.001) lower in LBBB patients (0.47; P < 0.001) than in non-LBBB patients (1.24; P = 0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P < 0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients., Conclusions: Heart failure patients with New York Heart Association class I or II and ejection fraction ≤ 30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances)., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

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 © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) showed a significant 31 reduction in the risk of death with primary implantable cardioverter-defibrillator (ICD) therapy during a median follow-up of 1.5 years. However, currently there are no data on the long-term efficacy of primary defibrillator therapy., Methods and Results: MADIT-II enrolled 1232 patients with ischemic left ventricular dysfunction who were randomized to ICD and non-ICD medical therapy and were followed up through November 2001. For the present long-term study, we acquired posttrial mortality data through March 2009 for all study participants (median follow-up, 7.6 years). Multivariate Cox proportional hazards regression modeling was performed to calculate the hazard ratio for ICD versus non-ICD therapy during long-term follow-up. At 8 years of follow-up, the cumulative probability of all-cause mortality was 49 among patients treated with an ICD compared with 62 among non-ICD patients (P<0.001). Multivariate analysis demonstrated that ICD therapy was associated with a significant long-term survival benefit (hazard ratio for 0- through 8-year mortality=0.66 [95 confidence interval, 0.56 to 0.78]; P<0.001). Treatment with an ICD was shown to be associated with a significant reduction in the risk of death during the early phase of the extended follow-up period (0 through 4 years: hazard ratio=0.61 [95 confidence interval, 0.50 to 0.76]; P<0.001) and with continued life-saving benefit during the late phase of follow-up (5 through 8 years: hazard ratio=0.74 [95 confidence interval, 0.57 to 0.96]; P=0.02)., Conclusions: Our findings demonstrate a sustained 8-year survival benefit with primary ICD therapy in the MADIT-II population.

Background: Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function., Methods and Results: A total of 1,820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1,372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (-26.2 versus -7.4 mL/m(2)), left ventricular end-systolic volume index (-28.7 versus -9.1 mL/m(2)), left ventricular ejection fraction (11% versus 3%), left atrial volume index (-11.9 versus -4.7 mL/m(2)), and right ventricular fractional area change (8% versus 5%; P<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk (P<0.001)., Conclusions: CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Background: This trial was designed to determine whether cardiac-resynchronization therapy (CRT) with biventricular pacing would reduce the risk of death or heart-failure events in patients with mild cardiac symptoms, a reduced ejection fraction, and a wide QRS complex., Methods: During a 4.5-year period, we enrolled and followed 1820 patients with ischemic or nonischemic cardiomyopathy, an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Patients were randomly assigned in a 3:2 ratio to receive CRT plus an implantable cardioverter-defibrillator (ICD) (1089 patients) or an ICD alone (731 patients). The primary end point was death from any cause or a nonfatal heart-failure event (whichever came first). Heart-failure events were diagnosed by physicians who were aware of the treatment assignments, but they were adjudicated by a committee that was unaware of assignments., Results: During an average follow-up of 2.4 years, the primary end point occurred in 187 of 1089 patients in the CRT-ICD group (17.2%) and 185 of 731 patients in the ICD-only group (25.3%) (hazard ratio in the CRT-ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy. The superiority of CRT was driven by a 41% reduction in the risk of heart-failure events, a finding that was evident primarily in a prespecified subgroup of patients with a QRS duration of 150 msec or more. CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction. There was no significant difference between the two groups in the overall risk of death, with a 3% annual mortality rate in each treatment group. Serious adverse events were infrequent in the two groups., Conclusions: CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex. (ClinicalTrials.gov number, NCT00180271.), (2009 Massachusetts Medical Society)

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.

Background: Sudden death of a sibling is thought to be associated with greater risk of death in long QT syndrome (LQTS). However, there is no evidence of such an association., Objective: This study sought to test the hypothesis that sudden death of a sibling is a risk factor for death or aborted cardiac arrest (ACA) in patients with LQTS., Methods: We examined all probands and first-degree and second-degree relatives in the International Long QT Registry from birth to age 40 years with QTc >/= 0.45 s. Covariates included sibling death, QTc, gender by age, syncope, and implantable cardioverter-defibrillator (ICD) and beta-blocker treatment. End points were (1) severe events (ACA, LQTS-related death) and (2) any cardiac event (syncope, ACA, or LQTS-related death)., Results: Of 1915 subjects, 270 had a sibling who died. There were 213 severe events and 829 total cardiac events. More subjects with history of sibling death received beta-blocker therapy. Sibling death was not significantly associated with risk of ACA or LQTS-related death, but was associated with increased risk of syncope. QTc >/= 0.53 s (hazard ratio 2.5, P <.01), history of syncope (hazard ratio 6.1, P <.01), and gender were strongly associated with risk of ACA or LQTS-related death., Conclusion: Sudden death of a sibling prompted more aggressive treatment but did not predict risk of death or ACA, whereas QTc >/= 0.53 s, gender, and syncope predicted this risk. All subjects should receive appropriate beta-blocker therapy. The decision to implant an ICD should be based on an individual's own risk characteristics (QTc, gender, and history of syncope).

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.

Background: The availability of stored intracardiac electrograms from implantable defibrillators (ICDs) has facilitated the study of the mechanisms of ventricular tachyarrhythmia onset. This study aimed to determine the patterns of initiation of ventricular fibrillation (VF) in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients along with associated electrocardiogram (ECG) parameters and clinical characteristics., Methods: Examination of stored electrograms enabled us to evaluate the rhythm preceding each episode of VF and to calculate (intracardiac) ECG parameters including QT, QT peak (QTp), coupling interval, and prematurity index., Results: Sixty episodes of VF among 29 patients (mean age 64.4 +/- 2.5 years) were identified. A single ventricular premature complex (VPC) initiated 46 (77%) episodes whereas a short-long-short (SLS) sequence accounted for 14 (23%) episodes. Of the 29 patients studied, 23 patients had VF episodes preceded by a VPC only, two patients with SLS only, and four patients with both VPC and SLS-initiated episodes. There were no significant differences between initiation patterns in regards to the measured ECG parameters; a faster heart rate with SLS initiation (mean RR prior to VF of 655 +/- 104 ms for SLS and 744 +/- 222 ms for VPC) approached significance (P = 0.06). The two patients with SLS only were not on beta-blockers compared to 83% of the VPC patients., Conclusion: Ventricular fibrillation is more commonly initiated by a VPC than by a SLS sequence among the MADIT II population. Current pacing modes designed to prevent bradycardia and pause-dependent arrhythmias are unlikely to decrease the incidence of VPC-initiated episodes of VF.

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] >or=50 mg/dl and/or serum creatinine >or=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 >or=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 >or=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.

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.

Introduction: We aim to evaluate the mortality benefit from defibrillator therapy in eligible elderly patients. Effective primary prevention of sudden cardiac death with implantable cardioverter defibrillators is well demonstrated in patients with coronary disease and depressed ventricular function., Methods and Results: Among 1,232 patients enrolled with prior infarct and left ventricular ejection fraction < or = 0.30, 204 were > or = 75 years old. Of these 204 patients, 121 underwent defibrillator implant. Relative to the younger patients, those > or = 75 years had a higher incidence of atrial fibrillation, elevated blood urea nitrogen (BUN), widened QRS, and lower use of beta-blockers and HMG-CoA reductase inhibitors. Relevant clinical covariates were similar in elderly patients randomized to conventional and defibrillator therapy. The hazard ratio for the mortality risk in patients > or = 75 years assigned to defibrillator implant compared with those in conventional therapy was 0.56 (95 confidence interval 0.29-1.08; P = 0.08) after a mean follow-up of 17.2 months. Comparatively, the hazard ratio in patients < 75 years assigned to defibrillator implant was 0.63 (0.45-0.88; P = 0.01) after 20.8 months. Elderly patients had similar reductions in quality of life (QoL) regardless of treatment randomization. Scores through Health Utilities Index Mark III (HUI) Questionnaire changes from baseline to 1 year were -0.22 for patients with conventional therapy versus -0.20 for patients with ICD, and -0.36 versus -0.27 at 2 years, respectively (P = NS)., Conclusion: The implantable defibrillator is associated with an equivalent reduction of mortality in elderly and younger patients, with no compromise in the QoL in the older age subjects.

Background: Implantable cardioverter defibrillators (ICDs) improve survival and extend lives of patients with severe heart disease., Objective: We sought to evaluate the impact of ICDs on health-related quality of life (HRQOL) during the first 3 years after implantation., Subjects: A total of 1089 patients from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) were randomized to an ICD or medical treatment only., Measures: Health Utility Index (HUI3) at baseline, 3, 12, 24, and 36 months following randomization; survival data., Research Design: We constructed mean profiles of HRQOL for living patients, estimated overall quality-adjusted life years (QALYs), separately by treatment arm, and calculated cumulative QALY gains/losses as the difference between the areas under the treatment specific HRQOL profiles. Multivariate fixed effect regression models were developed to impute the missing HRQOL data using baseline patient characteristics (age, gender, treatment, HUI3 score, diabetes, diuretics use, and NYHA class). Bootstrapped standard errors were calculated for the estimated differences in HRQOL gains/losses between treatment arms. Similarly, we performed subgroup analyses (by gender, age, and baseline NYHA class, blood urine nitrogen, ejection fraction, and QRS)., Results: There were no differences in QALYs loss for living patients by treatment group (-0.037, P = 0.64) or in overall QALYs loss by treatment group (0.043, P = 0.37) over 3 years. In subgroup analysis, female subjects demonstrated a trend towards greater survival benefit (0.298, P = 0.07) and overall QALYs (0.261, P = 0.14)., Conclusions: Adverse effects of the ICD on HRQOL together with lower HRQOL among survivors may offset the 3-year survival benefits of ICDs.

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.

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 beta-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 (< or =30%), inferior wall MI was associated with a significantly higher risk of mortality than anterior wall MI.

Aims: The association of psychosocial and physical factors with health outcome in patients with congestive heart failure (CHF) has not been fully explored. The aim of this study was to assess the physical and mental health in relationship to health outcome in post-infarction patients with advanced left ventricular dysfunction., Methods and Results: A total of 1058 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) completed the Medical Outcome Trust Short Form (SF-12) at baseline. Physical component summary (PCS) and mental component summary (MCS) of SF-12 were analysed in relationship to survival, hospitalization due to CHF, and implantable cardioverter-defibrillator (ICD) therapy. Both baseline PCS and MCS were significantly associated with death (P < 0.001 and P < 0.016, respectively) and hospitalization due to CHF (P

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 > or =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.

Introduction: Nicotine elevates serum catecholamine concentration and is therefore potentially arrhythmogenic. However, the effect of cigarette smoking on arrhythmic risk in coronary heart disease patients is not well established., Methods and Results: The risk of appropriate and inappropriate defibrillator therapy by smoking status was analyzed in 717 patients who received an implantable cardioverter defibrillator (ICD) in the Multicenter Automatic Defibrillator Implantation Trial-II. Compared with patients who had quit smoking before study entry (past smokers) and patients who had never smoked (never smokers), patients who continued smoking (current smokers) were significantly younger and generally had more favorable baseline clinical characteristics. Despite this, the adjusted hazard ratio (HR) for appropriate ICD therapy for fast ventricular tachycardia (at heart rates >or=180 b.p.m) or ventricular fibrillation was highest among current smokers (HR = 2.11 [95% CI 1.11-3.99]) and intermediate among past smokers (HR = 1.57 [95% CI 0.95-2.58]), as compared with never smokers (P for trend = 0.02). Current smokers also exhibited a higher risk of inappropriate ICD shocks (HR = 2.93 [95% CI 1.30-6.63]) than past (HR = 1.91 [95% CI 0.97-3.77]) and never smokers (P for trend = 0.008)., Conclusions: In patients with ischemic left ventricular dysfunction, continued cigarette smoking is associated with a significant increase in the risk of life-threatening ventricular tachyarrhythmias and inappropriate ICD shocks induced by rapid supraventricular arrhythmias. Our findings stress the importance of complete smoking cessation in this high-risk population.

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 > or = 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.

Background: Implantable cardioverter-defibrillator (ICD) therapy may be associated with an increased risk for heart failure (HF). The present study evaluated the frequency, causes, and consequences of HF after ICD implantation., Methods and Results: We performed a retrospective analysis of the clinical factors and outcomes associated with postenrollment HF events in 1218 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II. The adjusted hazard ratios (HRs) of ICD:conventional therapy for first and recurrent HF events were 1.39 (P=0.02) and 1.58 (P<0.001), respectively. The risk was increased among patients who received single-chamber or dual-chamber ICDs. Development of HF was associated with an increased mortality risk (HR, 3.80; P<0.001). Among patients who received a single-chamber ICD, there was a similar survival benefit before and after the development of HF (HR, 0.59 and 0.61, respectively; P=0.92 for difference), whereas among patients with dual-chamber devices, there was a significant reduction in survival benefit after HF (HR, 0.26 and 0.83, respectively; P=0.01 for difference). Within the defibrillator arm of the trial, patients who received life-prolonging therapy from the ICD had an increased risk for first and recurrent HF events (HR, 1.90; P=0.01 and 1.74; P<0.001, respectively)., Conclusions: Patients with chronic ischemic heart disease who are treated with either single-chamber or dual-chamber ICDs have improved survival but an increased risk of HF. The present data suggest that ICD therapy transforms sudden death risk to a subsequent HF risk. These findings should direct more attention to the prevention of HF in patients who receive an ICD.

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 dollars, and the iCER was 235,000 dollars per year-of-life saved. In three alternative projections to 12 years, this ratio ranged from 78,600 dollars to 114,000 dollars., 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.

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.

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 > or =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.

Unlabelled: In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable cardioverter-defibrillator (ICD)-randomized patients underwent electrophysiologic testing. Both inducible and noninducible patients received an ICD. We correlated inducibility with the occurrence of subsequent ventricular tachycardia (VT) or ventricular fibrillation (VF). Intracardiac ICD electrograms for subsequent events were analyzed to categorize the spontaneous arrhythmia as VT or VF. The two-year Kaplan-Meier event rate for VT in inducible patients was 29.0% versus 19.3% in noninducible patients. However, ICD therapy for spontaneous VF was less common at two years in inducible patients (3.2%) than in noninducible patients (8.6%). In the MADIT II study, inducibility predicted an increased likelihood of VT but decreased VF., Objectives: We correlated electrophysiologic inducibility with spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II., Background: In the MADIT II study, 593 (82%) of 720 implantable cardioverter-defibrillator (ICD) randomized patients underwent electrophysiologic testing. Patients received an ICD whether they were inducible or not., Methods: A "standard" inducibility definition included sustained monomorphic or polymorphic VT induced with three or fewer extrastimuli or VF induced with two or fewer extrastimuli. We compared a narrow inducibility definition (only monomorphic VT) and a broad definition (standard definition plus VF with three extrastimuli). We used ICD-stored electrograms to categorize spontaneous VT or VF., Results: Inducible patients (standard definition) had a greater likelihood of experiencing ICD therapy for VT than noninducible patients (p = 0.023). Unexpectedly, ICD therapy for spontaneous VF was less common (p = 0.021) in inducible patients than in noninducible patients. The two-year Kaplan-Meier event rate for VT or VF was 29.4% for inducible patients and 25.5% for noninducible patients. Standard inducibility did not predict the combined end point of VT or VF (p = 0.280, by log-rank analysis). The narrow inducibility definition outperformed the standard definition, whereas the broad definition appeared inferior to the standard definition., Conclusions: In the MADIT II study patients, inducibility was associated with an increased likelihood of VT. Noninducible MADIT II study subjects using this electrophysiologic protocol had a considerable VT event rate and a higher VF event rate than inducible patients. Induction of polymorphic VT or VF, even with double extrastimuli, appears less relevant than induction of monomorphic VT.

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) > or =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.

Objectives: We sought to evaluate the influence of single- versus dual-chamber implantable cardioverter defibrillators (ICDs) on the occurrence of heart failure and mortality as well as appropriate and inappropriate ICD therapy in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)., Background: In MADIT-II, ICD therapy in patients with a prior myocardial infarction and ejection fraction < or =0.30 was associated with a 31% reduction in risk of mortality when compared to conventionally treated patients. An unexpected finding was an increased occurrence of hospitalization for heart failure in the ICD group., Methods: Data from 717 patients randomized to ICD therapy with single- or dual-chamber pacing devices in MADIT-II were retrospectively analyzed. Endpoints selected for analysis included death from any cause, new or worsening heart failure requiring hospitalization, death or heart failure, appropriate therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), and inappropriate ICD therapy for atrial fibrillation or supraventricular tachycardia., Results: A total of 404 single-chamber ICDs (S-ICDs) and 313 dual-chamber ICDs (D-ICDs) were implanted. Patients receiving D-ICDs were at a higher risk at baseline than those receiving S-ICDs, with older age, higher NYHA class, more frequent prior CABG, wider QRS complex, more LBBB, higher BUN level, a history of more atrial arrhythmias requiring treatment, and a longer time interval from their index myocardial infarction to enrollment. While there was a trend toward an increase in adverse outcomes in the D-ICD group, no statistically significant differences in heart failure or mortality were observed between S-ICD versus D-ICD groups., Conclusions: Patients with D-ICDs had a nonsignificant trend toward higher mortality and heart failure rates than patients with S-ICDs.

The planned MADIT-CRT trial is designed to determine if CRT-D will reduce the risk of mortality and HF events by approximately 25% in subjects with ischemic (NYHA class I-II) and non-ischemic (NYHA class II) cardiomyopathy, left ventricular dysfunction (EFor=130 ms).

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the DeltaKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the DeltaKPQ deletion., Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the DeltaKPQ deletion., Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of -27.1 ms (95% confidence interval: -36.8 ms to -17.4 ms; P<0.001) at a mean flecainide blood level of 0.11+/-0.05 microg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects., Conclusions: Chronic low-dose flecainide significantly shortens the QTc interval in LQT-3 subjects with the DeltaKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation.

This study examined the effects of beta 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 beta blockers and 433 who were receiving metoprolol (n = 192), atenolol (n = 58), or carvedilol (n = 182). Patients receiving beta blockers were divided into the upper quartile and lower 3 quartiles of the drug doses they were taking. Patients receiving the higher doses of beta 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 beta blockers (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 beta blockers (hazard ratios 0.42 to 0.44, p <0.01). In conclusion, beta blockers reduce the risk for VT or VF and improve survival in ICD-treated patients with ischemic cardiomyopathy.

In the second Multicenter Automatic Defibrillator Implantation Trial, patients with a previous myocardial infarction and left ventricular ejection fraction < or =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.

Introduction: This study was designed to assess whether right ventricular pacing in the implantable cardioverter defibrillator (ICD) arm of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II was associated with an unfavorable outcome., Methods and Results: Data on the number of ventricular paced beats were available in 567 (76%) of 742 MADIT II patients with ICDs. The number of ventricular paced beats over the total number of beats showed a bimodal distribution with patients being predominantly paced or nonpaced. Therefore, patients were dichotomized at 0-50% and 51-100% of cumulative pacing with median pacing rate 0.2% and 95.6%, respectively. Endpoints included new or worsening heart failure, appropriate ICD therapy for VT/VF, and the combined endpoint of heart failure or death. Clinical features associated with frequent ventricular pacing included age >or=65 years, advanced NYHA heart failure class, LVEF < 0.25, first degree AV and bundle branch block, and amiodarone use. During follow-up, 119 patients (21%) had new or worsened heart failure, 130 (23%) had new or worsened heart failure or death, and 142 (25%) had appropriate therapy for VT/VF. In comparison to patients with infrequent pacing, those with frequent pacing had significantly higher risk of new or worsened heart failure (hazard ratio = 1.93; P = 0.002) and VT/VF requiring ICD therapy (HR = 1.50; P = 0.02)., Conclusions: Patients in MADIT II who were predominantly paced had a higher rate of new or worsened heart failure and were more likely to receive therapy for VT/VF. These results suggest the deleterious consequences of RV pacing, particularly in the setting of severe LV dysfunction.

Background: The implanted cardioverter defibrillator (ICD) improves survival in high-risk cardiac patients. This analysis from the MADIT-II trial database examines the long-term clinical course and subsequent mortality risk of patients after termination of life-threatening ventricular tachyarrhythmias by an ICD., Methods and Results: Life-table survival analysis was performed, and proportional hazards regression analysis was used to evaluate the contribution of baseline clinical factors and time-dependent defibrillator therapy to mortality during long-term follow-up. Of 720 patients with an ICD (average follow-up 21 months), 169 patients received 701 antiarrhythmic device therapies for ventricular tachyarrhythmias. Few baseline characteristics distinguished patients who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. The probability of survival for at least 1 year after first therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) was 80%. The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who survived without receiving ICD therapy, with a high frequency of heart failure and late nonsudden cardiac death after first successful ICD therapy for VF., Conclusions: Successful appropriate therapy by an ICD for VT or VF is associated with 80% survival at 1 year after arrhythmia termination. These patients are at increased risk for heart failure and nonsudden cardiac death after device termination of VT or VF and should receive special attention for the prevention and management of progressive left ventricular dysfunction during long-term follow-up.

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).

Background: The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients., Methods and Results: We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients., Conclusions: LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.