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Data are limited regarding the characteristics and outcomes of patients with cancer who are found eligible for primary defibrillator therapy. We performed a single-center retrospective analysis of patients with preexisting cancer diagnoses who become eligible for a primary prevention implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) defibrillator. Multicenter Automatic Defibrillator Implantation Trial-ICD (MADIT-ICD) benefit scores were calculated. The study included 75 cancer patients at a median age of 73 (interquartile range 64, 81) years at heart failure diagnosis. Active cancer was present in 51%. Overall, 55% of the cohort had coronary artery disease and 37% were CRT eligible. We found that 48%, 49%, and 3% of cohorts had low, intermediate, and high MADIT-ICD Benefit scores, respectively. Only 27% of patients underwent primary defibrillator implantation. Using multivariate analysis, indication for CRT and intermediate/high MADIT-ICD Benefit categories were found as independent predictors for implantation (odds ratio 8.42 p <0.001 and odds ratio 3.74 p = 0.040, respectively). During a median follow-up of 5.3 (interquartile range 4.5, 7.2) years, one patient (5%) with a defibrillator had appropriate shock therapy and 2 patients (10%) had bacteremia. Of 13 patients with CRT defibrillator-implants, one patient was admitted for heart failure exacerbation (8%). Using a time-varying covariate model, we did not observe statistically significant differences in the survival of patients with cancer implanted versus those not implanted with primary defibrillators (hazard ratio 0.521, p = 0.127). In conclusion, although primary defibrillator therapy is underutilized in patients with cancer, its relative benefit is limited because of competing risk of nonarrhythmic mortality. These findings highlight the need for personalized cardiologic and oncologic coevaluation., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization with defibrillators (CRT-D) reduces heart failure and mortality compared with defibrillators alone. Whether this applies to all ages is unclear., Methods and Results: We assessed the association of age on heart failure and death as a post hoc analysis of the MADIT-CRT follow-up study, in which 1,281 patients with class I/II heart failure (HF) were randomized to CRT-D or implantable cardioverter-defibrillators alone. Different age groups (<60, 60-74, and ≥75 years) were evaluated over 7 years for mortality and HF events. Among the 3 age groups, there were 399, 651, and 231 patients, respectively. We compared events with the use of a multivariate regression model. CRT-D compared with defibrillators alone significantly reduced the composite of HF or death across all age groups: <60 years: relative risk reduction (RRR) = 36%; 60-74 years: RRR = 61%; ≥75 years: RRR = 56%. CRT-D significantly reduced HF in all age groups: <60 years: RRR = 49%; 60-74 years: RRR = 62%; ≥75 years: RRR = 74%. CRT-D was associated with significant mortality reduction only in the 60-74 year age group: RRR = 59%., Conclusions: CRT-D reduced HF events and the composite of mortality or HF events during long-term follow-up in all age groups. CRT-D reduced mortality only in the 60-74 year age group., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Relative wall thickness (RWT), defined as 2 times posterior wall thickness divided by the left ventricular (LV) diastolic diameter, is a measure of LV geometry and may be a marker for adverse events in patients with LV dysfunction., Objectives: The aim of this study was to investigate the relationship between RWT and the risk for ventricular tachyarrhythmia (VA) in patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study., Methods: The study population comprised 1,260 patients with mild heart failure and left bundle branch block., Results: In a multivariable model, RWT was the most powerful echocardiographic measure for estimating the risk of VAs compared with commonly used echocardiographic variables. Patients with low RWT (<0.24) had 83% (p < 0.001) increased risk for VA and 68% (p < 0.001) increase in VA risk or death (VA/death) compared with patients with higher RWT values. Each 0.01-unit decrease in RWT was associated with 12% (p < 0.001) and 10% (p < 0.001) increases in the risk of VA and VA/death, respectively. Treatment with cardiac resynchronization therapy with defibrillator (CRT-D; CRT with implantable cardioverter-defibrillator) was associated with a greater increase in RWT compared with implantable cardioverter-defibrillator at 12 months (4.6 ± 6.8% vs. 1.5 ± 2.7%; p < 0.001), and every 10% increase in RWT in CRT-D patients was associated with 34% (p = 0.027) and 36% (p = 0.009) reductions in the risk of subsequent VA and VA/death, respectively., Conclusions: In patients with mild heart failure and left bundle branch block, decreased RWT was associated with an increase in the risk of VA and VA/death. CRT-D therapy was associated with a favorable increase in RWT and reduction in risk of VA and VA/death. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: It is not known whether the number of revascularizations modifies clinical outcomes in patients with ischemic cardiomyopathy (ICM) implanted with cardiac resynchronization therapy defibrillator (CRT-D) vs. an implantable cardioverter-defibrillator (ICD)-only., Methods: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), we evaluated the effect of CRT-D vs. ICD-only on heart failure (HF) or death, on ventricular tachycardia (VT), ventricular fibrillation (VF) or death, and on reverse remodeling in 592 ICM patients with left bundle branch block, by the number of pre-enrollment revascularizations (0, 1 or ≥ 2 revascularizations)., Results: There was a risk reduction of HF/death with CRT-D vs. ICD-only in all three sub-groups: ICM with no need for revascularization (HR 0.51 [0.26-1.02]; p = 0.055), ICM with 1 revascularization (HR 0.45 [0.30-0.70]; p < 0.001), and ICM with 2 or more revas-cularizations (HR 0.37 [0.20-0.66]; p < 0.001). Similarly, there was a risk reduction of VT/ /VF/death with CRT-D vs. ICD-only in patients with no need for revascularization (HR 0.55 [0.31-0.99]; p = 0.044); with 1 revascularization (HR 0.77 [0.51-1.18]; p = 0.23); or with ≥ 2 revascularizations (HR 0.63 [0.34-1.17]; p = 0.14). There was a similar degree of left ventricular reverse remodeling in all three subgroups (p > 0.05 for LVESV, LVEDV, and LAV percent change at 1-year follow-up)., Conclusions: In ICM patients, CRT-D is associated with a reduction in HF or death and VT/VF or death - irrespective of the frequency of pre-enrollment revascularization procedures - and is accompanied by a similar degree of beneficial left ventricular reverse remodeling.

Previous studies suggested that statin therapy reduces the risk of occurrence and recurrence of atrial fibrillation mainly in patients with coronary artery disease. Data regarding the effect of statins on the risk for the entire range of supraventricular arrhythmias (SVA) in mild heart failure (HF) with different disease causes are lacking. Multivariate Cox proportional hazards regression models were used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of SVA and recurrent SVA (defined as atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachycardia) that were inappropriately treated with implantable cardioverter-defibrillator device in 1,790 patients enrolled in the Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy trial. Statin users constituted 68% of the study patients (n = 1209). They were older and more frequently men; they were more likely to have ischemic cardiomyopathy, diabetes, hypertension, and previous atrial arrhythmias. During the 3.7-year median follow-up time, 160 patients had an SVA event, and the total number of recurrent events was 335. Time-dependent statin therapy was independently associated with a significant 29% reduction of the first SVA event (p = 0.046) and 33% reduction of recurrent SVA events (p = 0.003), consistent across all prespecified subgroups. In conclusion, in mild HF with either cardiac resynchronization therapy with a defibrillator or an implantable cardioverter-defibrillator device, statin therapy was associated with significant reduction of occurrence and recurrence of inappropriately treated SVA., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: We hypothesized that the relationship between LVEF and the risk of life-threatening ventricular tachyarrhythmias (VTAs) may modify the effect of a CRT device with a defibrillator (CRT-D) on VTA risk., Methods and Results: The risk of fast (≥200 b.p.m.) ventricular tachycardia/ventricular fibrillation (VT/VF) and the benefit of CRT-D in reducing VT/VF were assessed by baseline LVEF (categorized as ≤30% or 30% and assessed as a continuous measurement) in 1783 patients with mild heart failure (HF) implanted with an implantable cardioverter defibrillator (ICD) or CRT-D, enrolled in MADIT-CRT. Higher LVEF (>30%) at baseline was associated with a significantly lower risk of fast VT/VF [hazard ratio (HR) 0.54, P = 0.006], VT/VF (HR 0.62, P = 0.005), and VT/VF/death (HR 0.64, P = 0.003). Treatment with CRT-D was shown to reduce the risk of fast VT/VF in patients with LVEF ≤ 30% (n = 1100) [HR 0.64, 95% confidence interval (CI) 0.48-0.85, P = 0.002], but not among those with LVEF > 30% (n = 683) (HR 1.19, 95% CI 0.73-1.91, P = 0.502, interaction P-value = 0.03). When LVEF was assessed as a continuous measure, each 5% increment was shown to be associated with a significant 30% (P < 0.001) reduction in the risk for fast VT/VF, and with a corresponding linear reduction in the benefit of CRT-D in reducing fast VTA risk (P -value for treatment by LVEF interaction = 0.003)., Conclusions: Our data suggest that in mild HF patients with cardiomyopathy there is an inverse correlation between LVEF and the risk of life-threatening VTAs, possibly contributing to the attenuation in the antiarrhythmic properties of CRT with increasing left ventricular function., Trial Registration: NCT00180271., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Previous studies have shown that low blood pressure is associated with increased mortality and heart failure (HF) in patients with left ventricular dysfunction. Cardiac resynchronization therapy (CRT) was shown to increase systolic blood pressure (SBP). Therefore, we hypothesized that treatment with CRT would provide incremental benefit in patients with lower SBP values., Methods and Results: The independent contribution of SBP to outcome was analyzed in 1267 patients with left bundle brunch block enrolled in Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). SBP was assessed as continuous measures and further categorized into approximate quintiles. The risk of long-term HF or death and CRT with defibrillator versus implantable cardioverter defibrillator benefit was assessed in multivariate Cox proportional hazards regression models. Multivariate analysis showed that in the implantable cardioverter defibrillator arm, each 10-mm Hg decrement of SBP was independently associated with a significant 21% (P<0.001) increased risk for HF or death, and patients with lower quintile SBP (<110 mm Hg) experienced a corresponding >2-fold risk-increase. CRT with defibrillator provided the greatest HF or mortality risk reduction in patients with SBP<110 mm Hg hazard ratio of 0.34, P<0.001, when compared with hazard ratio of 0.52, P<0.001, in those with 110>SBP≥136 mm Hg and hazard ratio of 0.94, P=0.808, with SBP>136 mm Hg (P for trend=0.001)., Conclusions: In patients with mild HF, prolonged QRS, and left bundle brunch block, low SBP is related to higher risk of mortality or HF with implantable cardioverter defibrillator therapy alone. Treatment with CRT is associated with incremental clinical benefits in patients with lower baseline SBP values., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271., (© 2015 American Heart Association, Inc.)

There are limited data regarding the effect of age on the risk of ventricular tachyarrhythmias (VTAs). The present study was designed to compare the risk for VTAs in young and older patients with left bundle branch block (LBBB) and mildly symptomatic heart failure who receive device therapy. The risk of the first ventricular tachycardia (VT) or ventricular fibrillation (VF) event and the risk of first appropriate implantable cardioverter defibrillator (ICD) shock was compared between young (<75 years, n = 1,037) and older (≥75 years, n = 227) patients with LBBB enrolled in Multicenter Automatic Implantation Trial with Cardiac Resynchronization Therapy. The cumulative incidence of a first VTA through 2 years of follow-up was significantly lower in older patients than in younger patients. Multivariate analysis showed that older patients experienced a significantly lower risk of VT/VF (hazard ratio 0.38, 95% confidence interval 0.22 to 0.64, p <0.001) and a significantly lower risk of appropriate ICD shocks (hazard ratio 0.37, 95% confidence interval 0.17 to 0.82, p = 0.014) compared with younger patients. Each increasing decade of life was associated with a 19% (p = 0.002) and 22% (p = 0.018) reduction in the risk of VT/VF and appropriate ICD shocks, respectively. The lower risk of VT/VF and appropriate ICD shocks in older patients was evident in patients implanted with an ICD only and in those implanted with a cardiac resynchronization therapy with defibrillator. In conclusion, in patients with LBBB and mild symptoms of heart failure, aging is associated with a significant decrease in the incidence of VT/VF and ICD shocks., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Low pulse pressure (PP) is associated with poor outcome in hospitalized patients with systolic heart failure (HF). However, the relation between PP and response to cardiac resynchronization therapy with defibrillator (CRT-D) is unknown. We aimed to evaluate the relation between preimplantation PP and echocardiographic response to CRT-D and subsequent clinical outcome after 1 year. The relation between preimplantation PP and echocardiographic response to CRT-D (defined as >15% reduction in left ventricular (LV) end-systolic volume at 1 year) was evaluated in 754 patients with CRT-D with left bundle branch block enrolled in Multicenter Automatic Defibrillator Cardioverter Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. The association between PP at 1 year and the risk for subsequent HF or death was evaluated using multivariate Cox model. Patients with high versus low PP (>40 vs ≤40 mm Hg [lower quartile]) had a significantly greater reduction in LV end-systolic volume, LV end-diastolic volume, and LV dyssynchrony (p<0.01 for all comparisons). In multivariate analysis, the presence of high PP was associated with a 3.5-fold (p<0.001) increase in the likelihood of a positive echocardiographic response to CRT-D. Patients with high PP (>40 mm Hg, >lower quartile) 1 year after CRT-D implantation experienced a 50% reduction in the risk of subsequent HF or death (p=0.001) and 63% reduction in death only (p=0.001), compared with patients with low PP. In conclusion, high baseline PP is an independent predictor of echocardiographic response to CRT-D, and high PP after device implantation is associated with improved subsequent clinical outcome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

There are limited data regarding risk factors for the development of ischemic events (IEs) among patients with ischemic cardiomyopathy (IC) who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and their effect on the efficacy of the device. The present study population comprised 1,045 patients with IC enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. We used multivariate Cox proportional hazards regression modeling to identify risk factors for the development of IE (comprising hospitalization for acute coronary syndromes and/or coronary interventions during the trial) among study patients. Time-dependent analysis was performed to identify the effect of IE on the risk for subsequent heart failure (HF) or death in CRT-D recipients. Independent predictors for the development of IE among study patients included previous revascularization (coronary artery bypass surgery: hazard ratio [HR] 1.88, p = 0.003; percutaneous coronary intervention: HR 3.21, p <0.001) and increased systolic blood pressure (HR 1.67, p = 0.02), whereas a left bundle branch block pattern on the baseline electrocardiogram was associated with reduced risk for IE (HR 0.62, p = 0.02). Treatment with CRT-D did not have a significant effect on IE risk compared with defibrillator-only therapy (HR 0.87, p = 0.51). Time-dependent analysis showed that the development of IEs among CRT-D recipients was associated with more than twofold (p = 0.01) increased risk for subsequent heart failure or death. In conclusion, our data suggest that treatment with CRT-D does not reduce the risk of IE in patients with IC and that the benefit of CRT-D is attenuated after the development of IEs in this population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is increasingly recognized for its ability to reduce ventricular tachyarrhythmias, possibly associated with left ventricular reverse remodeling, but the role of the right ventricle (RV) in this process has not been examined., Objective: The purpose of this study was to investigate the relationship between ventricular tachyarrhythmias and change in RV dimensions in patients receiving CRT with a defibrillator (CRT-D)., Methods: Multivariate Cox proportional hazards regression modeling was used to assess the risk for fast (≥180 bpm) ventricular tachycardia/ventricular fibrillation (VT/VF) or death by baseline and follow-up RV size (defined as right ventricular end-diastolic area [RVEDA]) among 1495 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT)., Results: Multivariate analysis showed that treatment with CRT-D was independently associated with a 27% (P = .003) reduction in the risk of VT/VF or death among patients with larger RVs (>first quartile RVEDA ≥13 mm(2)/m(2)) compared with implantable cardioverter-defibrillator (ICD)-only therapy, whereas in patients with smaller RVs there was no significant difference in the risk of VT/VF between the 2 treatment arms (hazard ratio = 1.00, P = .99). At 1-year follow-up, CRT-D patients displayed significantly greater reductions in RVEDA compared to ICD-only patients (P <.001), associated with a corresponding reduction in the risk of subsequent VT/VF or death (>first quartile reduction in RVEDA with CRT-D vs ICD-only: hazard ratio = 0.55, P <.001) independent of changes in left ventricular dimensions., Conclusion: Our findings suggest that the RV may have an important role in determining the antiarrhythmic effect of CRT independent of the effect of the device on the left ventricle., (© 2013 Heart Rhythm Society. All rights reserved.)

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: The optimal atrioventricular pacing delay (AVD) in cardiac resynchronization therapy (CRT) remains to be determined., Objective: To determine whether programming CRT devices to short AVD (S-AVD) will improve clinical response secondary to greater reductions in dyssynchrony., Methods: The study population comprised 1235 patients with left bundle branch block enrolled in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy (MADIT-CRT). We assessed the relationship between AVD and outcomes. Patients programmed to S-AVD (median value of <120 ms; n = 337) vs long AVD (L-AVD; ≥120 ms; n = 390) were assessed for the end points of heart failure (HF) or death, death alone, and echocardiographic response to the CRT at 1-year follow-up. Outcomes were also compared to the left bundle branch block implantable cardioverter-defibrillator-only group (n = 508)., Results: Multivariate analysis showed that patients programmed to S-AVD experienced a significant 33% (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.44-0.85; P = .037) reduction in the risk of HF or death and a 47% (HR 0.53; 95% CI 0.29-0.94; P = .031) reduction in death alone as compared with those programmed to L-AVD. Patients with CRT-programmed S-AVD and L-AVD experienced 63% (HR 0.37; 95% CI 0.26-0.53; P < .001) and 46% (HR 0.54; 95% CI 0.31-0.96; P < .001) reduction, respectively, in the risk of HF or death compared to patients with implantable cardioverter-defibrillator alone. At 1 year of follow-up, S-AVD vs L-AVD was associated with a greater reduction in left ventricular end-systolic volume (34.2% vs 30.8%; P = .002) along with a significantly greater improvement in dyssynchrony (22.3% vs 9.4%; P = .036)., Conclusions: Our findings indicate that in MADIT-CRT programming, the CRT AVD <120 ms was associated with a greater clinical and echocardiographic response to CRT., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Mildly symptomatic heart failure (HF) patients derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D) as shown in MADIT-CRT. The presence of QRS axis deviation may influence response to CRT-D. The objective of this study was to determine whether QRS axis deviation will be associated with differential benefit from CRT-D., Methods: Baseline electrocardiograms of 1,820 patients from MADIT-CRT were evaluated for left axis deviation (LAD: quantitative QRS axis -30 to -90) or right axis deviation (RAD: QRS axis 90-180) in left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific interventricular conduction delay QRS morphologies. The primary endpoints were the first occurrence of a HF event or death and the separate occurrence of all-cause mortality as in MADIT-CRT., Results: Among LBBB patients, those with LAD had a higher risk of primary events at 2 years than non-LAD patients (20% vs 16%; P = 0.024). The same was observed among RBBB patients (20% vs 10%; P = 0.05) but not in IVCD patients (22% vs 23%; P = NS). RAD did not convey any increased risk of the primary combined endpoint in any QRS morphology subgroup. When analyzing the benefit of CRT-D in the non-LBBB subgroups, there was no significant difference in hazard ratios for CRT-D versus ICD for either LAD or RAD. However, LBBB patients without LAD showed a trend toward greater benefit from CRT therapy than LBBB patients with LAD (HR for no LAD: 0.37, 95% CI: 0.26-0.53 and with LAD: 0.54, 95% CI: 0.36-0.79; P value for interaction = 0.18)., Conclusions: LAD in non-LBBB patients (RBBB or IVCD) is not associated with an increased benefit from CRT. In LBBB patients, those without LAD seem to benefit more from CRT-D than those with LAD., (© 2012 Wiley Periodicals, Inc.)

Objectives: The aim of this study was to evaluate the relationship between left ventricular (LV) ejection fraction and clinical outcome to cardiac resynchronization therapy (CRT) in mild heart failure patients enrolled in MADIT-CRT [corrected]., Background: Left ventricular ejection fraction (LVEF) is a surrogate marker of heart failure (HF) status and associated risk. Data on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF and better LVEF are limited., Methods: In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, the echocardiography core laboratory assessed baseline LVEF independent of the enrolling centers and identified a range of LVEFs, including those >30% (i.e., beyond the eligibility criteria). Echocardiographic response with CRT, defined as percent change in left ventricular end-diastolic volume (LVEDV), was analyzed in 3 prespecified LVEF groups: >30%, 26% to 30%, and ≤25%. The primary endpoint was HF or death. Secondary endpoint included all-cause mortality., Results: LVEF was evaluated in 1,809 study patients. There were 696 (38%) patients with LVEF >30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF ≤25% (11%). The mean reduction in LVEDV with CRT-D therapy at the 1-year follow-up was directly related to increasing LVEF (LVEF >30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF ≤25%: 18.7% reduction, respectively [p = 0.001]). CRT-D treatment similarly reduced the risk of HF/death in patients with LVEF >30% (hazard ratio [HR]: = 0.56 [95% confidence interval (CI): 0.39 to 0.82], p = 0.003), LVEF 26% to 30% (HR: 0.67: [95% CI: 0.50 to 0.90], p = 0.007), and LVEF ≤25% (HR: 0.57 [95% CI: 0.35 to 0.95], p = 0.03; all p values for LVEF-by-treatment interactions >0.1)., Conclusions: In MADIT-CRT, the clinical benefit of CRT was evident regardless of baseline LVEF, including those with LVEF >30%, whereas the echocardiographic response was increased with increasing LVEF, indicating that CRT might benefit patients with better LVEF. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)., (Copyright © 2013 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.)

Heart failure (HF) due to left ventricular (LV) systolic dysfunction contributes significantly to cardiovascular morbidity and is a major cause of mortality throughout the world. Its prevalence is increasing as the population ages. Age-related structural and functional changes of the heart in combination with multiple coexisting comorbid conditions significantly reduce cardiovascular reserve capacity and increase the risks of developing symptomatic HF in the elderly. Cardiac resynchronization therapy (CRT) has been demonstrated to reduce HF-related hospitalization as well as mortality and has become an important part of treatment for qualified patients with advanced HF. More recent studies showed a significant reduction in the risk of HF and mortality among CRT recipients with asymptomatic and mildly symptomatic HF (New York Heart Association functional class I–II), LV systolic dysfunction and widened QRS complex, supporting the notion that CRT may prevent or delay disease progression. Although data on the benefit of preventive CRT in the elderly are limited to retrospective subgroup analyses with relatively small numbers of elderly patients, accumulating data suggest that CRT confers similar or greater clinical benefit among elderly patients compared with their younger counterparts. As the proportion of elderly patient with LV systolic dysfunction is increasing dramatically, further research is warranted to confirm these possible clinically beneficial effects of CRT in this population.

Background: Mildly symptomatic heart failure (HF) patients were shown to derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D) in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. However, the relationship between functional capacity (FC) and CRT-D benefit in the trial was not assessed., Objective: To evaluate the association between FC and response to CRT-D in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy., Methods: We evaluated the association between preimplantation FC and the benefit of CRT-D in reducing the risk of HF or death in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. Functional status was assessed by a 6-minute walk test (6MWT), dichotomized at the median value as poor (<350 m) or good (≥350 m)., Results: Implantable cardioverter-defibrillator-only patients with a poor FC had an adjusted 73% increased risk for HF or death (P <.001) and a 2.4-fold (P = .001) increased risk for all-cause mortality. CRT-D therapy was associated with 63% (P <.001) and 44% (P <.001) reductions in the risk of HF or death among left bundle branch block patients with a poor FC and a good FC, respectively (P for interaction = .10). Among left bundle branch block patients with a poor FC, CRT-D was also associated with a significant reduction in the risk of all-cause mortality (hazard ratio 0.52; P = .015) whereas the survival benefit of CRT-D was not observed among those who had a higher FC at enrollment (hazard ratio 1.01; P = .98; P for interaction = .10)., Conclusions: Poor FC is a strong independent predictor for mortality and HF events in patients with mildly symptomatic HF. Left bundle branch block patients with poor baseline FC derive a pronounced benefit from CRT-D, manifest by a significant reduction in mortality., (Copyright © 2012 Heart Rhythm Society. 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.)

Men and women with heart failure display important differences in clinical characteristics that might affect their responses to pharmacological and nonpharmacological therapies. In women, heart failure is associated with a higher frequency of hypertension, nonischemic cardiomyopathy and left bundle branch block than in men. Subgroup analyses of data from randomized clinical trials suggest that these differences result in a differential response to heart failure therapies, including a somewhat better response to β-blockers, a worse prognosis with digoxin therapy, and a lower survival benefit with implantable cardioverter-defibrillators in women. Importantly, female patients with heart failure also derive significantly greater improvements in cardiac volumes from cardiac resynchronization therapy than do male patients, and this treatment is associated with reduced risks of all-cause mortality and heart failure events among women with mild symptoms. These data suggest that sex-related differences might exist in response to both medical and device therapies for patients with heart failure.

Background: Diabetes mellitus (DM) increases the risk for the development of both ischemic and nonischemic cardiomyopathy. We aimed to identify differences in response to cardiac resynchronization therapy with a defibrillator (CRT-D) among DM patients with ischemic or nonischemic cardiomyopathy., Methods: Cox proportional hazards regression modeling was used to assess clinical response to CRT-D (defined as CRT-D vs. defibrillator-only reduction in the risk of heart failure [HF] or death) and echocardiographic response (defined as percent reduction in left ventricular end diastolic and systolic volume [LVEDV and LVESV, respectively] at 12 month of follow-up compared with baseline values) among 552 diabetic patients with ischemic (n = 367) or nonischemic (n = 185) cardiomyopathy enrolled in MADIT-CRT., Results: The clinical benefit of CRT-D was more pronounced among nonischemic patients (HR = 0.30 [P < 0.001] than among ischemic patients (HR = 0.59 [P = 0.004]; P for interaction = 0.10). Nonischemic patients also experienced significantly greater reductions in LVESV and LVEDV at 12 months with CRT-D compared with ischemic patients (P < 0.001 for both). Subgroup analysis showed that the most pronounced reduction in HF or death with CRT-D therapy occurred in nonischemic patients who were women (83% risk-reduction [P < 0.001]), had a lower BMI (<30/kg/m(2) : 79% risk-reduction [P < 0.001]), or had left bundle branch block at enrollment (82% risk-reduction [P < 0.001])., Conclusions: The present study shows that treatment with CRT-D in at-risk cardiac patients with DM is associated with substantial reductions in the risk of HF or death and improvement in cardiac remodeling in those with ischemic and nonischemic cardiomyopathy, with a more pronounced benefit in patients with nonischemic disease., (© 2012, Wiley Periodicals, Inc.)

Aims: We aimed to evaluate within the MADIT-CRT database whether different enrollment characteristics between US and non-US centres affected the clinical course of study patients., Methods and Results: We evaluated differences in baseline characteristics, procedure-associated complications, clinical as well as echocardiographic response to cardiac resynchronization therapy with a defibrillator (CRT-D), between patients enrolled in 87 US centres (n = 1271) and 23 non-US centres (n = 549) in MADIT-CRT. Non-US patients displayed significant differences in baseline characteristics from US patients, including a higher frequency of left bundle branch block, a more advanced heart failure (HF) functional class >3 months prior to enrollment, and larger baseline cardiac volumes. Procedure-related complications occurred at a significantly higher frequency among patients enrolled in non-US centres (17%) than among those enrolled in US centres (10%; P < 0.001). During follow-up, CRT-D was associated with 42% (P = 0.003) and 38% (P < 0.001) reductions in the risk of HF or death in the two respective groups (P for the difference = 0.80), and with similar reductions in cardiac volumes (all P > 0.10). Subgroup analysis showed a more pronounced effect of CRT-D among women in the US group, including a significant 71% (P = 0.02) reduction in the risk of death, whereas CRT-D therapy was associated with a significant clinical benefit in men only in the non-US group., Conclusion: Patients enrolled in US and non-US centres in MADIT-CRT displayed significant differences in baseline clinical and echocardiographic characteristics and in the frequency of procedure-related complications, but experienced an overall similar clinical and echocardiographic response to CRT-D.

Objectives: We hypothesized that reductions in left atrial volume (LAV) with a cardiac resynchronization therapy-defibrillator (CRT-D) would translate into a subsequent reduction in the risk of atrial tachyarrhythmias (AT)., Background: There is limited information regarding the effect of CRT-D on the risk of AT., Methods: Percent reduction in LAV at 1 year following CRT-D implantation (pre-specified as low [lowest quartile: <20% reduction in LAV] and high [≥20% reduction in LAV] response to CRT-D) were related to the risk of subsequent AT (comprising atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachyarrhythmias) among patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)., Results: The cumulative probability of AT 2.5 years after assessment of echocardiographic response was lowest among high LAV responders to CRT-D (3%) and significantly higher among both low LAV responders to CRT-D (9%) and implantable cardioverter-defibrillator-only patients (7%; p = 0.03 for the difference among the 3 groups). Consistently, multivariate analysis showed that high LAV responders to CRT-D experienced a significant 53% (p = 0.01) reduction in the risk of subsequent AT as compared with implantable cardioverter-defibrillator-only patients, whereas low LAV responders did not derive a significant risk reduction with CRT-D therapy (hazard ratio [HR]: 1.05 [95% confidence interval (CI): 0.54 to 2.00]; p = 0.89). Patients who developed in-trial AT experienced significant increases in the risk for both the combined endpoint of heart failure or death (HR: 2.28 [95% CI: 1.45 to 3.59]; p < 0.001) and the separate occurrence of all-cause mortality (HR: 1.89 [95% CI: 1.08 to 3.62]; p = 0.01)., Conclusions: In the MADIT-CRT study, favorable reverse remodeling of the left atrium with CRT-D therapy was associated with a significant reduction in risk of subsequent AT. (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: 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: Elderly patients comprise a large portion of patients with heart failure (HF). Limited data exist on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF symptoms in this population., Methods and Results: The benefit of CRT-D compared with ICD-only therapy in reducing HF or death was assessed by age categories (prespecified as <60 [n = 548], 60-74 [n = 941], and ≥75 [n = 331] years) among 1,820 patients in MADIT-CRT. In patients with ICD-only, there was a graded age-related increase in the Kaplan-Meier cumulative probability of HF or death at 3-year follow-up (19%, 33%, and 36%, in patients aged <60, 60-74, and ≥75 years, respectively, P = 0.003). Multivariate analysis demonstrated that CRT-D therapy was associated with a significant reduction in the risks of HF or death in patients aged 60-74, and ≥75 years (HR = 0.57, P = <0.001 and HR = 0.59, P = 0.017, respectively), and no significant benefit in patients aged <60 years (HR = 0.81, P = 0.3; P-value for all treatment-by-age interactions >0.10). There was no significant difference in the rate of device-related adverse events within 90 days following CRT-D implantation among age-subgroups (16.7%, 15.7%, and 11.7%, in patients <60, 60-74, and ≥75 years, respectively, P = 0.42)., Conclusion: CRT-D was associated with a significant clinical benefit in older patients (≥60 years) during an average 2.4-year follow-up. These effects were preserved for the elderly patients ≥75 years of age but attenuated in patients <60 years. Elderly patients had no increase in device-related adverse events compared with younger patients., (© 2011 Wiley Periodicals, Inc.)

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.

Objectives: We aimed to evaluate the relationship between echocardiographic response to cardiac resynchronization therapy (CRT) and the risk of subsequent ventricular tachyarrhythmias (VTAs)., Background: Current data regarding the effect of CRT on the risk of VTA are limited and conflicting., Methods: The risk of a first appropriate implantable cardioverter-defibrillator (ICD) therapy for VTA (including ventricular tachycardia, ventricular fibrillation, and ventricular flutter) was compared between high- and low-echocardiographic responders to CRT defibrillator (CRT-D) therapy (defined as ≥ 25% and <25% reductions, respectively, in left ventricular end-systolic volume [LVESV] at 1 year compared with baseline) and ICD-only patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy)., Results: The cumulative probability of a first VTA at 2 years after assessment of echocardiographic response was highest among low responders to CRT-D (28%), intermediate among ICD-only patients (21%), and lowest among high responders to CRT-D (12%), with p < 0.001 for the overall difference during follow-up. Multivariate analysis showed that high responders to CRT-D experienced a significant 55% reduction in the risk of VTA compared with ICD-only patients (p < 0.001), whereas the risk of VTA was not significantly different between low responders and ICD-only patients (hazard ratio [HR]: 1.26; p = 0.21). Consistently, assessment of response to CRT-D as a continuous measure showed that incremental 10% reductions in left ventricular end-systolic volume were associated with corresponding reductions in the risk of subsequent VTA (HR: 0.80; p < 0.001), VTA/death (HR: 0.79; p < 0.001), ventricular tachycardia (HR: 0.80; p < 0.001), and ventricular fibrillation/ventricular flutter (HR: 0.75; p = 0.044)., Conclusions: In patients with left ventricular dysfunction enrolled in the MADIT-CRT trial, reverse remodeling was associated with a significant reduction in the risk of subsequent life-threatening VTAs. (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: An important determinant of successful cardiac resynchronization therapy for heart failure is the position of the left ventricular (LV) pacing lead. The aim of this study was to analyze the impact of the LV lead position on outcome in patients randomized to cardiac resynchronization-defibrillation in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) study., Methods and Results: The location of the LV lead was assessed by means of coronary venograms and chest x-rays recorded at the time of device implantation. The LV lead location was classified along the short axis into an anterior, lateral, or posterior position and along the long axis into a basal, midventricular, or apical region. The primary end point of MADIT-CRT was heart failure (HF) hospitalization or death, whichever came first. The LV lead position was assessed in 799 patients, (55% patients ≥65 years of age, 26% female, 10% LV ejection fraction ≤25%, 55% ischemic cardiomyopathy, and 71% left bundle-branch block) with a follow-up of 29±11 months. The extent of cardiac resynchronization therapy benefit was similar for leads in the anterior, lateral, or posterior position (P=0.652). The apical lead location compared with leads located in the nonapical position (basal or midventricular region) was associated with a significantly increased risk for heart failure/death (hazard ratio=1.72; 95% confidence interval, 1.09 to 2.71; P=0.019) after adjustment for the clinical covariates. The apical lead position was also associated with an increased risk for death (hazard ratio=2.91; 95% confidence interval, 1.42 to 5.97; P=0.004)., Conclusion: LV leads positioned in the apical region were associated with an unfavorable outcome, suggesting that this lead location should be avoided in cardiac resynchronization therapy. Clinical Trial Registration- URL: http://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: Cardiorenal interactions have been shown to affect outcome in heart failure patients but were not related to response to cardiac resynchronization therapy (CRT)., Objective: The purpose of this study was to test our hypothesis that assessment of markers of prerenal failure may help identify mildly symptomatic HF patients with diminished effective circulating blood volume who will benefit from CRT., Methods: The benefit of CRT with a defibrillator (CRT-D) as compared with defibrillator-only therapy in reducing the risk of HF or death was assessed by renal function parameters (including serum creatinine [SCr], blood urea nitrogen [BUN], and the ratio of BUN to SCr [BUN:SCr], dichotomized at median values and into approximate quartiles) among 1,803 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy., Results: Multivariate analysis showed that the benefit of CRT-D was inversely related to SCr levels and directly related to BUN levels. Combined assessment of the two renal function parameters showed a significant difference in the benefit of CRT-D between patients with low (≤ 18 mg/dL, HR = 0.85, P = .28) and elevated (> 18 mg/dL, HR = 0.46, P < .001) BUN:SCr (P-value for interaction = .005). Consistently, the benefit of CRT-D was significantly increased with increasing quartiles of BUN:SCr (Q(1): HR = 1.06 [P = .79], Q(2): HR = 0.64 [P = .04], Q(3): HR = 0.47 [P < .001], Q(4): HR = 0.44 [P < .001]; P-value for trend = .005)., Conclusions: In MADIT-CRT, patients with an elevated ratio of BUN to SCr experienced a significantly greater reduction in the risk of HF or death with CRT-D therapy as compared with patients with a low ratio. These findings suggest an association between prerenal function and response to CRT., (Copyright © 2010 Heart Rhythm Society. 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.)

Aims: MADIT-CRT showed that cardiac resynchronization therapy with a defibrillator (CRT-D) improves long-term outcomes in currently mildly symptomatic heart failure (HF) patients with LBBB regardless of the presence of prior advanced HF symptoms. We aimed to evaluate the long-term benefit of CRT-D in patients who never experienced advanced HF symptoms prior to device implantation.Methods and Results: Interaction term analysis was used to compare the clinical and echocardiographic benefit of CRT-D vs. implantable cardioverter defibrillator (ICD)-only therapy during long-term follow-up (median 5.6 years) between LBBB patients with or without a history of advanced HF [defined as NYHA class ≥ III or past hospitalization for worsening HF >3 months prior to enrolment in MADIT-CRT (n = 529 and 752, respectively)]. Multivariable analysis showed that treatment with CRT-D was associated with a significant reduction in the risk of HF or death during long-term follow-up regardless of the presence of prior advanced HF symptoms [hazard ratio 0.53 (P < 0.001) and 0.47 (P < 0.001) in the respective groups of patients with and without prior advanced HF; interaction P for the difference = 0.58]. Echocardiographic response to CRT at 1 year was also similar between the two groups (P > 0.10 for all comparisons).Conclusion: Our findings suggest that treatment with CRT-D is associated with pronounced echocardiographic and long-term clinical benefit in patients with LV dysfunction and LBBB who never experienced advanced HF symptoms. These data further emphasize the benefit of early intervention with CRT in this population. [ABSTRACT FROM AUTHOR]

There are limited data regarding factors associated with spontaneous left ventricular reverse remodeling (S-LVRR) among mildly symptomatic heart failure (HF) patients and its prognostic implications on clinical outcomes.Best subsets logistic regression analysis was used to identify factors associated with S-LVRR (defined as ≥15% reduction in left ventricular end-systolic volume at 1-year of follow-up) among 612 patients treated with internal cardioverter defibrillator-only therapy in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) and to create a score for the prediction of S-LVRR. Cox proportional hazards regression modeling was used to assess the clinical outcome of all internal cardioverter defibrillator-only patients (n=714) with a high S-LVRR score. S-LVRR occurred in 25% of internal cardioverter defibrillator-only patients. Predictors of S-LVRR included systolic blood pressure≥140 mm Hg, serum creatinine<1.0 mg/dL, QRS 130 to 160 ms, and nonischemic cardiomyopathy. Multivariate analysis showed that each 1-point increment in S-LVRR score (range, 0-7) was associated with an 11% (P=0.019) reduction in the risk of HF or death. Treatment with cardiac resynchronization therapy was associated with a significant reduction in the risk of HF or death only among internal cardioverter defibrillator-treated patients with a low (Q1-3) S-LVRR score (hazard ratio=0.55; P<0.001), but not among those with a higher (Q4) score (hazard ratio=1.06; P=0.72).Our data suggest that approximately one quarter of mild HF patients eligible for biventricular pacing experience S-LVRR. Combined assessment of clinical factors associated with S-LVRR can be used to identify mild HF patients with a low risk for clinical events without cardiac resynchronization therapy intervention.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. [ABSTRACT FROM AUTHOR]

Aims Anodal stimulation (ANS) is a recognized phenomenon among patients with cardiac resynchronization therapy (CRT); this is noted during left ventricular (LV) pacing by the LV tip to right ventricular (RV) ring configuration. Its incidence varies according to the implanted hardware. We aim at evaluating the incidence of ANS and its acute haemodynamic effects among CRT patients. Methods and results We screened all our patients who previously had an implanted CRT-P/D devices for ANS. After excluding all non-eligible devices, the initial screening was done by evaluating the programmer electrocardiogram (ECG) during device interrogation while pacing LV only from LV tip to RV ring. Those with ANS underwent screening by 12-lead ECG during biventricular pacing with VV interval programmed to 0. Patients with electrocardiographic evidence of ANS underwent detailed echocardiography. We screened 224 patients, 187 patients were excluded due to various causes. Thirty-seven subjects were analysed for this study. Anodal stimulation was found in 29 patients (78.4%) by primary screening. Twelve patients (41.4%) showed electrocardiographic evidence of ANS by 12-lead ECG. The ANS threshold was significantly higher than true bipolar LV threshold (4.5 ± 1.7 vs. 1.1 ± 0.3 V, respectively, P = < 0.0001). Ten patients, with ECG evidence of ANS, underwent detailed echocardiography during biventricular pacing with and without ANS. Overall, there were no significant differences in the haemodynamic, echocardiographic, or resynchronization effects with and without ANS, two patients showed significant reduction in LV function with ANS. Conclusion Anodal stimulation is a common phenomenon among CRT patients. In many cases ANS is seen with LV pacing only, while these changes may not be seen by ECG during biventricular pacing. Echocardiography did not show any significant acute haemodynamic benefit during ANS, and some patients may even deteriorate. [ABSTRACT FROM PUBLISHER]