Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Research Articles

Abstract 13917: Predictors of Ventricular Arrhythmias in Patients With Left Ventricular Ejection Fraction Improvement to >35% Following Cardiac Resynchronization Therapy

Introduction: Patients undergoing cardiac resynchronization therapy with a defibrillator (CRT-D) show significant improvement in LVEF. We designed this study to identify predictors of ventricular arrhythmic (VA) events among patient with LVEF improvement > 35% after one year of treatment with CRT-D. Hypothesis: We hypothesized that LVEF improvement > 35% is associated with a decreased risk of VA events. Methods: Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial with LVEF > 35% at 12 months were included in this analysis (N=651). Predictors of an appropriate ICD therapy for VA subsequent to one year were evaluated by cox regression model. Cumulative probability of first event was analyzed by Kaplan Meier Method with time for follow-up beginning at 1 year after device implantation. Results: The average follow-up was 2.04 ± 0.83 years. We identified 3 independent predictors of VA among patients treated with CRT-D subsequent to LVEF improvement to > 35%: (1) baseline non-LBBB morphology (HR=1.93; 95% CI,1.23-3.04; p= 0.004); (2) the occurrence of VA during first year post CRT-D implant (HR=4.91 [95% CI, 2.99-8.07]; p<0.001); and (3) lower range improvement in LVEF (36-40% vs. >40%; HR =1.97 [95% CI 1.21-3.20]; p= 0.006). When compared with patients with 0 risk factors, having one and 2 or more risk factors had significantly higher risk of VTA (2-year rate of VT/VF = 4%, 11% and 32% respectively; HRs = 2.9 [p=0.002]and 7.9 [p=<0.001], respectively [Figure]). Conclusions: We identify a sub-group of patients who remain at high risk of VTA despite improvement in LVEF > 35% with CRT-D. Having a baseline non-LBBB morphology, experiencing VA during the first year post CRT-D, and lower-range LVEF improvement are associated with high risk of future arrhythmias, with a cumulative effect.

CHA2DS2-VASc Score and the Risk of Ventricular Tachyarrhythmic Events and Mortality in MADIT-CRT.

BackgroundWe hypothesized that multiple cardiovascular comorbidities, incorporated in the CHA 2 DS 2‐VASc score, may be useful in the assessment of ventricular tachyarrhythmias (VTAs) and mortality risk in heart failure (HF) patients.Methods and ResultsWe evaluated the association between the CHA 2 DS 2‐VASc score (dichotomized as high at the upper quartile [≥5] and further assessed as a continuous measure) and the risk of VTA and death among 1804 patients enrolled in MADIT‐CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). A high CHA 2 DS 2‐VASc score (n=464; 26%) was inversely associated with the risk of any VTA (hazard ratio [HR]: 0.64; P=0.001), fast VTA >200 beats/min (HR; 0.51; P<0.001), and appropriate implantable cardioverter‐defibrillator shocks (HR: 0.60; P<0.001). In contrast, a high score was directly correlated with mortality risk (HR: 1.92; P<0.001) and the risk of HF or death (HR: 1.60; P<0.001). Consistently, each 1‐U increment in CHA 2 DS 2‐VASc was associated with a significant 13% (P=0.003) reduction in VTA risk but a corresponding 33% (P<0.001) increase in mortality risk. Patients with a high CHA 2 DS 2‐VASc score and left bundle‐branch block derived a pronounced 53% (P<0.001) reduction in the risk of HF or death with cardiac resynchronization therapy with defibrillator versus implantable cardioverter‐defibrillator–only therapy.ConclusionsOur findings suggest that a high CHA 2 DS 2‐VASc score can be used to identify patients with mild HF who have low VTA risk and high morbidity or mortality risk and may derive a pronounced clinical benefit from cardiac resynchronization therapy without a defibrillator. These data suggest a possible role for the CHA 2 DS 2‐VASc score in device selection among candidates for biventricular pacing.

4301Diastolic dysfunction is an independent predictor of adverse events in patients with systolic dysfunction. Insights from the MADIT-CRT trial

Abstract Background Diastolic dysfunction (DD) is common in patients with heart failure with reduced ejection fraction (HFrEF). However, its prognostic relevance in HFrEF, on top of conventional risk factors including natriuretic peptides, is unknown Purpose To show the prognostic contribution of DD in HFrEF Methods We analyzed 1155 baseline echocardiograms (63% of all available exams) in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, comprising HFrEF patients with LVEF≤30%, QRS duration ≥130 ms, and NYHA class I/II. We classified DD according to ASE 2016 classification, based on transmitral Doppler velocities, mitral annular Tissue Doppler velocities, pulmonary venous flow velocities, and left atrial volumes. Using Cox regression and C-statistics we assessed the independent prognostic value of DD for nonfatal HF or death. We also evaluated CART (Classification And Regression Tree) analysis Results Patients were 64±11 years-old, 24% females, and mean LVEF was 24±5%. While 45% had impaired relaxation, 33% had pseudo-normal filling, 12% restrictive patter, 6% had indeterminate diastolic function, and 4% were not classifiable due to missing data. During a mean follow-up of 2.1±1.0 years, there were 233 adverse events. After multiple adjustment, compared to patients with impaired relaxation, those with pseudo-normal and restrictive filling had greater risk of HF/death (respectively HR 1.76, 95% CI 1.16–2.66, p=0.007; HR 2.70, 95% CI 1.58–4.60, p&lt;0.001), independently of assigned treatment (p-interaction 0.34). Adding DD to conventional markers of risk improved prediction (C-statistic 0.733, 95% CI 0.689–0.776 versus 0.708, 95% CI 0.663–0.753, p=0.024). Finally, at CART analysis DD was the first parameter to be considered to risk stratify patients (Figure) Risk stratification tree Conclusions DD is a strong independent predictor of death or heart failure in HFrEF patients with mild symptoms and should be considered in assessment of risk in this population

Risk of Ventricular Tachyarrhythmic Events in Patients Who Improved BeyondGuidelines for a Defibrillator inMADIT-CRT.

This study assessed the arrhythmic risk of cardiac resynchronization therapy (CRT) patients who improved beyond Heart Rhythm Society/European Society of Cardiology guidelines for an implantable cardioverter-defibrillator (ICD) (ischemic cardiomyopathy: left ventricular ejection fraction [LVEF] >35% or New York Heart Association [NYHA] functional class I and if LVEF was 31% to 35%; nonischemic cardiomyopathy: LVEF >35% or NYHA functional class I and if LVEF was≤35%). It is currently unknown whether protection with a defibrillator is still warranted in patients who respond to CRT. This study compared the risk of ICD therapy for any ventricular tachyarrhythmia (VTA) and for fast VTA (≥200 beats/min) among patients implanted with a CRT with a defibrillator (CRT-D) in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) (N=734) who improved at 1year beyond guideline recommendations for primary ICD therapy (group A) with those who remained within guideline recommendations for an ICD at 1 year (group B). Most patients implanted with a CRT-D device improved at 1 year beyond guideline indications for an ICD(90%). Multivariate analysis showed lower risks for any VTA and fast VTA among group A patients versus group Bpatients(57% risk reduction; p=0.0006 and 46% risk reduction; p=0.068, respectively). However, the 2-year rates of any VTA and fast VTA among CRT patients who improved beyond guidelines indications for an ICD was still substantial (VTA: 13% and 29%, and fast VTA: 7% and 16%, respectively). Most patients with mild heart failure implanted with a CRT device experience an improvement in left ventricular function and/or NYHA functional class beyond guideline recommendations for primary ICD therapy. However,despite this pronounced CRT response, there remains a substantial VTA risk, and protection with a defibrillator may stillbe warranted in this population.

Left Ventricular Reverse Remodeling in Cardiac Resynchronization Therapy and Long-TermOutcomes.

The aim of this study was to evaluate the association between improvement in left ventricular end-systolic volume (LVESV) with cardiac resynchronization therapy (CRT) and mortality and whether this relationship was modified by the presence of a left bundle branch block (LBBB) electrocardiographic pattern. Left ventricular reverse remodeling in patients receiving CRT has been shown to predict outcomes. However, the extent to which reverse remodeling contributes to long-term survival is not well understood. Changes in LVESV were assessed in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) patients receiving CRT with a defibrillator (CRT-D) and echocardiograms available at 1 year (n=752), stratified by LBBB, relative to long-term all-cause mortality, compared with those with implantable cardioverter-defibrillators (ICDs) only (n=684). In patients with LBBB, a reduction in LVESV of >35% (median) translated into significantly lower risk for long-term mortality (hazard ratio [HR]: 0.34; p<0.001), heart failure (HF) events (HR: 0.21; p<0.001), and HF or death (HR: 0.27; p<0.001) compared with patients with ICDs only. Patients with reductions in LVESV≤35% had a significantly lower risk for HF, and HF or death, and a nonsignificantly lower rate of death compared with those with ICDs only (HR:0.74; p=0.13). Risk reduction in HF events was uniform across all LVESV quartiles. In patients without LBBB, there was no survival benefit (HR: 0.68; p=0.271) despite an LVESV reduction greater than the median (>27.6%). CRT-D patients without LBBB with the least reverse remodeling (quartile 1) had a more than 3-fold increased risk for death compared with those with ICDs only (HR: 3.11; p<0.001). In patients with LBBB, CRT-D-induced reduction in LVESV at 1 year is associated with long-term survival benefit. Despite left ventricular reverse remodeling with CRT-D, there is no survival benefit and potential harm in patients without LBBB.

Prognostic Importance of Defibrillator-Appropriate Shocks and Antitachycardia Pacing in Patients With Mild Heart Failure.

BackgroundPatients with heart failure and an implantable cardioverter‐defibrillator (ICD) for primary prevention are at increased mortality risk after receiving shock therapy. We sought to determine the prognostic significance of ICD therapies, both shock and antitachycardia pacing, delivered for different ventricular arrhythmia (VA) rates.Methods and ResultsWe evaluated mortality risk among 1790 ICD‐implanted patients from MADIT‐CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). For the first analysis, patients were divided into mutually exclusive groups by the rate of treated VA only: slow VA (<200 beats per minute) and fast VA (≥200 beats per minute or ventricular fibrillation). In a secondary analysis, both the type of ICD therapy and VA rate were used. The reference group was always patients who had no ICD therapy. ICD therapy for fast VA was associated with increased mortality risk (hazard ratio [HR], 2.27; 95% CI, 1.48–3.48; P<0.001). However, mortality risk after ICD therapy for slow VA was similar to the risk related to no ICD therapy (HR, 1.45; 95% CI, 0.86–2.44; P=0.162). Consistently, shocks (HR, 2.96; 95% CI, 1.91–4.60; P<0.001) and antitachycardia pacing (HR, 2.22; 95% CI, 0.96–5.14; P=0.063) for fast VA were both associated with increased mortality risk. Shocks and antitachycardia pacing for slow VA were not significantly associated with increased mortality risk (HR, 1.43 [95% CI, 0.52–3.92; P=0.489]; and HR, 1.43 [95% CI, 0.80–2.56; P=0.232], respectively).ConclusionsIn patients with mild heart failure receiving ICD for primary prevention, mortality is associated with the rate of underlying VA rather than the type of therapy. These findings suggest that fast VA is a marker for increased mortality rather than shock therapy directly contributing to increased risk.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Quality of life predicting long-term outcomes in cardiac resynchronization therapy patients.

While improvement in quality of life (QoL) has been widely reported in cardiac resynchronization therapy (CRT) patients, its predictive value is not well-understood. We aimed to assess the predictive role of baseline QoL on long-term heart failure (HF) or death events in mild HF patients enrolled in Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). A total of 1791 of 1820 patients had their QoL evaluated at baseline, using the EuroQol-5 dimensions (EQ-5D) and the Kansas City Cardiomyopathy Questionnaires (KCCQ). Kaplan-Meier survival analyses and multivariate Cox models were utilized. Issues within any of the domains of the baseline EQ-5D questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were associated with long-term mortality (median follow-up 5.6 years) (all P < 0.05). Heart failure or death events were predicted by issues in baseline mobility [hazard ratio (HR) = 1.41, P < 0.001], usual activities (HR = 1.41, P < 0.001), and anxiety/depression (HR = 1.21, P = 0.035). The risk of HF events alone was significantly higher in patients with baseline mobility issues (HR = 1.42, P < 0.001) or usual activity (HR = 1.35, P = 0.003). Every 10% increase in the visual analogue scale (0-100) was associated with an 8% lower risk of all-cause mortality (P = 0.006), and a 6% lower risk of HF/death (P = 0.002). Mobility issues also predicted echocardiographic reverse remodelling (-33.08 mL vs. -31.17 mL, P = 0.043). Using the KCCQ, patients in the lower tertile of the clinical summary or physical limitations score had a significantly higher risk of long-term HF or death (P < 0.05). In mild HF patients enrolled in MADIT-CRT, multiple baseline QoL questionnaire domains were predictors of echocardiographic remodelling, long-term all-cause mortality, and HF events.

Machine learning‐based phenogrouping in heart failure to identify responders to cardiac resynchronization therapy

We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and identify patients with beneficial response to cardiac resynchronization therapy (CRT). We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT-D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K-means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT-D on the primary outcome (all-cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT-D on the primary outcome [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19-0.64; P = 0.0005 and HR 0.36; 95% CI 0.19-0.68; P = 0.001] than observed in the other groups (interaction P = 0.02). Our results serve as a proof-of-concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies.

Comparison of Long-Term Survival Benefits With Cardiac Resynchronization Therapy in Patients With Mild Heart Failure With Versus Without Diabetes Mellitus (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT

We have previously shown a reduction in HF events with cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild heart failure (HF) and diabetes mellitus (DM). It remains unknown whether HF remission in DM patients with CRT-D translates into reduced mortality. The effects of CRT-D versus an implantable cardioverter-defibrillator (ICD) alone to reduce long-term mortality were assessed in patients with left bundle branch block with DM (n = 386) and without DM (n = 982), enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). We further subdivided DM patients by insulin and noninsulin therapy. Kaplan-Meier survival analyses and multivariate cox proportional hazards regression models were utilized. At the 7-year follow-up, CRT-D was associated with a lower mortality in DM patients compared with ICD alone (21% vs 42%, p = 0.02), similar to non-DM patients (16 vs 24%, p = 0.014). CRT-D was associated with a 41% reduction in the risk of long-term all-cause mortality in DM patients (hazard ratio [HR] 0.59, 95% confidence interval 0.36 to 0.96, p = 0.033) and a similar reduction in non-DM patients (HR 0.69, 95% confidence interval 0.48 to 0.99, p = 0.045, treatment-diabetes interaction p = 0.611). Among DM patients, mortality benefit was evident in insulin-treated patients only (HR 0.40, p = 0.030). Reductions in HF events were present in all groups. In the MADIT-CRT, patients with mild HF with DM derive significant long-term survival benefit from CRT-D, similar to those without DM. The mortality benefit from CRT-D within the DM subgroup seems to be confined to patients with insulin treated diabetes.

Multiple Comorbidities and Response to Cardiac Resynchronization Therapy: MADIT-CRT Long-Term Follow-Up

BackgroundData regarding cardiac resynchronization therapy (CRT) in patients with multiple comorbidities are limited. ObjectivesThis study evaluated the association of multiple comorbidities with the benefits of CRT over implantable cardioverter-defibrillator (ICD) alone. MethodsWe examined 1,214 MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study patients with left bundle branch block (LBBB) and 0, 1, 2, or ≥3 comorbidities, including renal dysfunction, hypertension (HTN), diabetes, coronary artery disease, history of atrial arrhythmias, history of ventricular arrhythmias, current smoking, and cerebrovascular accident. In an adjusted analysis, we analyzed risk of heart failure (HF) events or death by comorbidity group in all patients and in patients with CRT with defibrillator (CRT-D) versus ICD. Then we examined percent change in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, left atrial volume, and LV dyssynchrony at 1-year in CRT-D patients by comorbidity group. ResultsThere was an inverse relationship between comorbidity burden and improvements in LV end-systolic volume, LV end-diastolic volume, left ventricular ejection fraction, left atrial volume, and LV dyssynchrony. In an adjusted model, there was an increasing risk of death or nonfatal HF events with increasing comorbidity burden regardless of treatment group (p < 0.001). During a mean follow-up of 4.65 years, there was no interaction with respect to comorbidity burden and the benefit of CRT-D versus ICD only for death or nonfatal HF events (interaction p = 0.943). In the groups with greatest comorbidity burden (2 and ≥3), the absolute risk reduction associated with CRT-D over ICD alone appeared greater than that seen for groups with less comorbidity burden (0 and 1). ConclusionsDuring long-term follow-up of MADIT-CRT study patients with LBBB randomized to CRT-D, there were differences in HF or death risk and in the degree of reverse remodeling among comorbidity groups. However, the burden of comorbidity does not appear to compromise the clinical benefits of CRT-D compared with ICD alone.

Predictive value of device-derived activity level for short-term outcomes in MADIT-CRT

There are limited data on the prognostic importance of declining activity level in patients with heart failure. We aimed to assess the association of reduced activity level with adverse cardiovascular outcomes in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Final device interrogations from patients enrolled in the MADIT-CRT with cardiac resynchronization devices capable of recording percent daily activity level were assessed. To determine temporal change, standardized activity levels (SALs) comparing each week to the monthly activity 3 months prior were obtained. Death, heart failure events (HFEs)/death, and ventricular tachyarrhythmias (VTAs)/death were the primary end points of this study. The average absolute activity level and SAL of the final week prior to death or end of study were significantly lower in patients who died compared with those in patients who did not. The total cohort (N = 1008) was further randomized into 2 subgroups to identify (group 1) and validate an optimal threshold (group 2). Patients with >40% reduced SAL had a significantly increased 77-day short-term cumulative incidence of death (P = .0006), HFE/death (P < .0001), or VTA/death (P = .0248). After adjustment for clinical covariates, these patients remained at an increased risk for death (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .001), HFE/death (HR, 2.7; 95% CI, 1.8-3.9; P≤ .001) and VTA/death (HR, 1.9; 95% CI, 1.31-2.6; P = .001). A decline in SAL following a nonfatal VTA and HFE was also associated with an increased probability of death. Decline in activity level is a short-term predictor for adverse cardiovascular events in patients with mild to moderate heart failure undergoing cardiac resynchronization.

Incremental Value of Speckle Tracking Echocardiography to Predict Cardiac Resynchronization Therapy (CRT) Responders.

BackgroundSpeckle tracking echocardiography (STE) is reported as a useful method to predict cardiac resynchronization therapy (CRT) responders. This study aimed to identify the incremental value of a STE parameter to predict CRT responders.Methods and ResultsWe enrolled 171 patients from the Speckle Tracking imaging for the Assessment of cardiac Resynchronization Therapy (START) study. CRT responders were defined as patients with ≥15% reduction of left ventricular (LV) end‐systolic volume at 6 months post‐CRT. Based on multivariable logistic regression analysis, incremental values of STE were assessed by c‐statistics, net reclassification improvement (NRI)/integrated discrimination improvement (IDI), and decision curve analysis. Six parameters (left bundle branch block or right ventricular pacing, use of beta‐blocker, blood urea nitrogen ≤3.0 mg/dL, LV end‐systolic diameter ≤50 mm, mitral regurgitation index ≤40%, and STE parameter standard deviation of time from QRS onset to first peak on the circumferential strain curves [TSD] ≥116 ms) were identified as the determinants. Compared to the multivariable logistic regression model without TSD (model 1), that with TSD (model 2) showed significant improvement to predict CRT responders: c‐statistic (0.86 vs 0.77; P<0.001), NRI=0.19, P<0.001, and IDI=0.17, P<0.001. The decision curve of model 2 was higher than that of model 1 at threshold probabilities ≥0.2. Based on model 2, a START score was constructed. Compared to the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT‐CRT) score, the decision curve of the START score was higher than that of the MADIT‐CRT score at threshold probabilities ≥0.2.ConclusionsBased on various statistical methods, this study revealed that STE had an incremental value to predict CRT responders.

Clinical Implications of Complete Left-Sided Reverse Remodeling With Cardiac Resynchronization Therapy: A MADIT-CRT Substudy

BackgroundClinical implications of complete left-sided reverse remodeling due to cardiac resynchronization therapy with a defibrillator (CRT-D), defined as reduction in both left ventricular end-systolic volume (LVESV) and left atrial volume (LAV), are unknown. ObjectivesThis study aimed to evaluate the rate and predictive value of complete left-sided reverse remodeling on heart failure (HF) and death events in CRT-D patients with left bundle branch block (LBBB) enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). MethodsThe study population comprised 533 CRT-D patients with LBBB, 212 (40%) with complete left-sided reverse remodeling (above-median change in both LAV and LVESV), 115 (22%) with discordant reverse remodeling (above-median change in only LAV or LVESV), and 206 (38%) with lesser reverse remodeling (below-median LAV and LVESV change). The primary endpoint was HF or death; secondary endpoints included HF alone and death alone during long-term follow-up. ResultsPatients with complete left-sided reverse remodeling had a significantly lower rate of HF or death than those with discordant reverse remodeling or lesser reverse remodeling (p < 0.001). Multivariate Cox proportional hazard models consistently showed a decreased risk for HF and death in patients with complete reverse remodeling compared with discordant reverse remodeling or lesser reverse remodeling (hazard ratio: 0.66 per each group; 95% CI: 0.50 to 0.85; p = 0.002). This finding was similar for HF alone and death alone. ConclusionsIn MADIT-CRT, >20% of CRT-D patients exhibited discordant reverse remodeling in the left ventricle and the left atrium. CRT-D patients with LBBB and complete left-sided reverse remodeling had a significantly lower risk of HF and death, HF alone, and death alone during long-term follow-up than patients with discordant or lesser reverse remodeling. (MADIT-CRT: Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)

Metabolic syndrome is associated with different clinical outcome after cardiac resynchronization therapy in patients with ischemic and non-ischemic cardiomyopathy

Although association of metabolic syndrome (MS) and ischemic heart disease is strongly established, it is not known whether presence of MS may differently influence clinical responses to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the associations between obesity and metabolic features and the clinical outcome after cardiac resynchronization with defibrillator therapy (CRT-D), compared to an implantable cardioverter defibrillator (ICD). The risk of heart failure (HF) or death and death alone was evaluated in 829 non-obese patients, 156 obese patients without MS, and 277 obese patients with MS (all with left bundle branch block), who were enrolled in the Multicenter Automatic Defibrillator Implanta-tion Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Obese patients with MS (HR 0.50, 95% CI 0.32-0.77, p = 0.002), obese patients without MS (HR 0.57, 95% CI 0.30-1.06, p = 0.077), and non-obese patients (HR 0.48, 95% CI 0.37-0.62, p < 0.001) had a similar risk reduction of HF/death in response to CRT-D therapy when compared to ICD patients. However, among those with non-ischemic cardiomyo-pathy, obese patients with MS experienced a 90% reduction for HF/death (HR 0.11, 95% CI 0.04-0.32, p < 0.001), whereas obese patients without MS had no reduction (HR 0.98, 95% CI 0.48-1.98, p = 0.951; interaction p < 0.001). The reverse was observed in ischemic car-diomyopathy patients: obese patients with MS had no reduction in the risk of HF/death (HR 0.80, 95% CI 0.48-1.34, p = 0.402), while obese patients without MS showed a significant reduction in the risk of events (HR 0.15, 95% CI 0.04-0.65, p = 0.011; interaction p = 0.036). Similar trends were observed for the endpoint of death. Presence of MS differentiates the response to CRT in obese patients with is-chemic and non-ischemic etiology for HF.

Bipolar left ventricular pacing is associated with significant reduction in heart failure or death in CRT-D patients with LBBB

There are limited data on the significance of left ventricular (LV) lead pacing polarity to predict clinical outcomes. We aimed to determine the association between the LV lead pacing polarity for heart failure (HF) or death and ventricular tachyarrhythmias (VTA) in patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), receiving a cardiac resynchronization therapy device with implanted cardioverter-defibrillator (CRT-D). We retrospectively analyzed LV pacing polarity. Patients with LV bipolar leads paced between LV ring and LV tip were identified as True Bipolar, while those with LV bipolar leads paced between LV tip or LV ring and right ventricular coil or unipolar leads were identified as Unipolar/Extended Bipolar. Kaplan-Meier survival analyses and multivariate Cox proportional hazards regression models were used. Of the 969 patients, 421 had True Bipolar pacing while the remainder (n = 548) had Unipolar/Extended Bipolar pacing. Among patients with left bundle branch block (LBBB), True Bipolar pacing was associated with lower cumulative incidence of death (P = .022) and HF/death (P = .046) compared to those with Unipolar/Extended Bipolar LV pacing. After adjustment for clinical covariates, bipolar LV pacing in LBBB patients was associated with 54% lower risk for death (HR: 0.46; 95% CI: 0.24-0.88; P = .020) and 32% lower risk for HF/death (HR: 0.68; 95% CI: 0.46-1.00; P = .048) compared to Unipolar/Extended Bipolar LV pacing, but not in those with non-LBBB. No association was seen with risk of ventricular tachyarrhythmia. True Bipolar LV pacing configuration is associated with a significantly lower risk of HF/death and all-cause mortality in CRT-D patients with LBBB.

Relative Wall Thickness and the Risk for Ventricular Tachyarrhythmias in Patients With Left Ventricular Dysfunction

BackgroundRelative 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. ObjectivesThe 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. MethodsThe study population comprised 1,260 patients with mild heart failure and left bundle branch block. ResultsIn 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. ConclusionsIn 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)

Abstract 17167: Risk Stratification for Long-term Survival Benefit With Cardiac Resynchronization Therapy in Mild Heart Failure Patients

Background: Cardiac resynchronization therapy (CRT) has been shown to reduce heart failure (HF) events or death in mild HF patients with left bundle branch block (LBBB) ECG pattern. However, risk stratification for long-term mortality benefit with CRT in this cohort is currently lacking. Methods: The study population comprised 1266 patients with LBBB enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). A clinical risk score was developed using best-subset proportional hazards regression analysis in patients randomized to CRT with defibrillator (CRT-D) to predict survival benefit. Cox proportional hazards regression analysis was used to evaluate risk reduction of death by CRT-D versus an implantable cardioverter defibrillator (ICD)-only among the risk score groups. Results: We identified four clinical variables predicting outcome in CRT-D patients: age≥65, creatinine≥1.4 mg/dl, coronary artery bypass graft [CABG] in the patient history, and left ventricular ejection fraction [LVEF] &lt; 26%. Five-year risk of mortality was 4% with no risk factor (low risk, n=357), 6% with 1 risk factor (n=500), 12% with 2 risk factors, and 27% with 3 risk factors (n=123); there were no patients with 4 risk factors. The mortality benefit from CRT-D vs. an ICD-only showed a U-shaped pattern with no significant benefit in patients with no risk factor (HR=0.77, CI 0.32-1.85, p=0.553), 46% reduction with 1 risk factor (HR=0.54, CI 0.32-0.89, p=0.017), 45% reduction with 2 risk factors (HR=0.55, CI 0.34-0.90, p=0.018), and no benefit with 3 risk factors (HR=0.77, CI 0.32-1.85, p=0.553). Conclusions: In MADIT-CRT, mild HF patients with LBBB with an intermediate mortality risk derived long-term survival benefit from CRT-D vs. an ICD-only. However, no survival benefit was observed in patients with low risk or a very-high risk.

Abstract 12677: Long-Term Survival of Patients With Left Bundle Branch Block who are Clinical or Echocardiographic Hypo-Responders to Cardiac Resynchronization Therapy

Introduction: Guidelines support cardiac resynchronization therapy with a defibrillator (CRT-D) in heart failure (HF) patients with left bundle branch block (LBBB). However, not all patients demonstrate clinical or echocardiographic (ECHO) response to CRT-D. We aimed to compare the long-term outcomes of clinical hypo-responders and ECHO hypo-responders with LBBB who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Methods: Five-hundred thirty-four patients with LBBB in the CRT-D arm were followed for 5.6 years (median). Clinical hypo-response was defined as presence of defibrillator treated ventricular arrhythmia or HF event in the first year after CRT-D implantation. ECHO hypo-response was defined as less than or equal to 35% reduction (median) in left ventricular end-systolic volume (LVESV) 1 year after CRT-D implantation; we also tested 15% and 25% reduction in LVESV. Results: Clinical and ECHO response was observed in 246 (46%) patients. Two-hundred twenty-six (42%) patients were ECHO hypo-responders and 62 (12%) patients were clinical hypo-responders. Fifty (9%) patients died during long-term follow-up. ECHO hypo-responders had an increased risk of all-cause mortality compared to clinical + ECHO responders (hazard ratio [HR] 3.02, 95% CI 1.45-6.31, p=0.003). Clinical hypo-responders had an increased risk of mortality compared to clinical + ECHO responders (HR 3.67, 95% CI 1.45-9.33, p=0.006), but not compared to ECHO hypo-responders. There was no significant difference between outcomes for clinical hypo-responders and ECHO hypo-responders when using an ECHO cutoff of 15% or 25% reduction in LVESV. Conclusion: During long-term follow-up, heart failure patients with LBBB who have clinical or echocardiographic hypo-response to CRT-D have comparable increased risk of mortality relative to patients who demonstrate good clinical and echocardiographic responses.

Abstract 14932: Effects of Cardiac Resynchronization Therapy in Ischemic Cardiomyopathy Patients by Revascularization Procedures in MADIT-CRT

Background: The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that patients with ischemic cardiomyopathy (ICM) had similar reductions in clinical events with implanted CRT-D vs. ICD-only when compared to patients with non-ischemic cardiomyopathy (NICM). Frequency of revascularizations may serve as a surrogate for severity of coronary artery disease in patients with ICM and severely reduced left ventricular ejection fraction. However, it is unknown whether the number of revascularizations plays a role in clinical outcomes in ICM patients implanted with CRT-D vs. ICD-only. Methods: Using a multivariable analysis of MADIT-CRT data, we evaluated the effect of CRT-D vs. ICD-only on combined heart failure (HF) or death and combined ventricular tachycardia (VT), ventricular fibrillation (VF) or death in ICM patients by the number of pre-enrollment revascularizations (1 or ≥ 2 revascularizations) compared to those with no need for revascularization. Follow-up over a median period of 5.6 years for HF/death and 4.0 years for VT/VF/death was assessed among 1374 ICM patients with a Left Bundle Branch Block (LBBB). Results: There was a significant and similar risk reduction with CRT-D vs. ICD-only in HF/death in all three sub-groups: ICM with no need for revascularization (HR 0.45 [0.26-0.80]; p &lt; 0.006), ICM with one revascularization (HR 0.46 [0.31-0.69]; p &lt;0.001), and ICM with 2 or more revascularization (HR 0.50 [0.30-0.84]; p = 0.008). However, significant risk reduction of VT/VF/death with CRT-D vs. ICD-only was only observed in patients with no need for revascularization (HR 0.52 [0.30-0.89]; p = 0.017), less so in those with ICM with one revascularization (HR 0.72 [0.49-1.06]; p = 0.10), and no reduction was seen in those with ICM with 2 or more revascularization (HR 0.94 [0.54-1.62]; p = 0.81). Conclusions: In ischemic cardiomyopathy patients, CRT-D vs. ICD-only is associated with a significant risk reduction in heart failure events or death irrespective of the frequency of pre-enrollment revascularization procedures; however, the benefit of CRT-D vs. ICD-only to reduce ventricular tachyarrhythmias is attenuated with the increasing number of revascularization procedures.

Inverse Relationship of Blood Pressure to Long-Term Outcomes and Benefit of Cardiac Resynchronization Therapy in Patients With Mild Heart Failure: A Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Long-Term Follow-Up Substudy.

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. 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). 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.