Background: A total of 405 participants in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial were prospectively enrolled in an exercise sub-study designed to study the influence of cardiac resynchronization therapy (CRT) on measures of exercise capacity, functional capacity, and quality of life (QOL).Methods and Results: Substudy eligibility included New York Heart Association (NYHA) functional Class III or IV heart failure, left ventricular ejection fraction <= 0.35, QRS interval of >= 120 ms, normal sinus rhythm, a heart failure hospitalization (or equivalent) within 1 year, a peak VO2 <= 22 mL.kg.min, the ability to walk 150 to 425 meters in 6 minutes, forced expiratory volume in 1 second/forced vital capacity >= 50%, and no clinical indication for a pacemaker or implantable cardioverter-defibrillator. Patients were randomized in a 1:4 ratio to optimal medical therapy (OPT) or to OPT plus CRT. Cardiopulmonary exercise testing (peak VO2 and 6-minute walk distance [6MWD]) and assessment of NYHA functional class and QOL were assessed at baseline and at 3 and 6 months of assigned therapy. There was no significant improvement in peak VO2 at 6 months in the CRT group compared with the OPT group (+0.63 mL.kg.min) by unadjusted analysis (P = .05) or by analyses adjusted for missing data. Thus the primary end point of the study was not met. There was significantly greater improvement in the 6MWD in the CRT group compared with the OPT group at both 3 and 6 months by both statistical methods (P <= .045). Likewise, a greater proportion of CRT patients improved by 1 or more NYHA functional classes (P < .01) at 3 months and had better QOL scores (P < .01) at 3 and 6 months compared with the OPT patients. Baseline peak VO2 predicted clinical events (time to death, time to death or first hospitalization, or time to death and first heart failure hospitalization: P < .05) in CRT participants.Conclusion: CRT patients with moderate to advanced symptoms of systolic heart failure and prolonged QRS intervals benefit from the addition of CRT to OPT in terms of exercise capacity, functional status, and QOL. CRT should be considered standard therapy in this select group of heart failure patients.

OBJECTIVES:We performed a post hoc analysis to determine the influence of cardiac resynchronization therapy with a defibrillator (CRT-D) or without a defibrillator (CRT-P) on outcomes among diabetic patients with advanced heart failure (HF). BACKGROUND:In patients with systolic HF, diabetes is an independent predictor of morbidity and mortality. No data are available on its impact on CRT-D or CRT-P in advanced HF. METHODS:The database of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure trial was examined to determine the influence of CRT (CRT-D and CRT-P) on outcomes among diabetic patients. All-cause mortality or hospitalization, all-cause mortality or cardiovascular hospitalization, all-cause mortality or HF hospitalization, and all-cause mortality were analyzed among diabetic patients (n = 622). A Cox proportional hazard model, adjusting for age, gender, New York Heart Association, ischemic status, body mass index, left ventricular ejection fraction, heart rate, QRS, left or right bundle branch block, blood pressure, comorbidities (renal failure, carotid artery disease, peripheral vascular disease, hypertension, coronary artery bypass grafting, and atrial fibrillation), medications, and device (with or without defibrillator), was used to estimate hazard ratios (HRs) and significance. RESULTS:The overall outcome of diabetic patients was similar to that of nondiabetic patients in the optimal pharmacologic therapy arm. With CRT, diabetic patients experienced a substantial reduction in all-cause mortality or all-cause hospitalization (HR = 0.77, 95% confidence interval [CI] 62-0.97), all-cause mortality or cardiovascular hospitalization (HR = 0.67, 95% CI 0.53-0.85), all-cause mortality or HF hospitalization (HR = 0.52, 95% CI 0.40-0.69), and all-cause mortality (HR = 0.67, 95% CI 0.45-0.99) compared with optimal pharmacologic therapy. Procedure-related complications and length of stay were identical in diabetic and nondiabetic patients. CONCLUSION:In diabetic patients with advanced HF, there is a substantial benefit from device therapy with significant improvement in all end points.

Background - Cardiac resynchronization therapy ( CRT) alone or combined with an implantable defibrillator ( CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure ( HF) hospitalizations and mortality in patients with New York Heart Association ( NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure ( COMPANION) trial to assess the potential benefits of CRT and CRT-D.Methods and Results - The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients ( n = 217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT ( hazard ratio [ HR], 0.64; 95% CI, 0.43 to 0.94; P = 0.02) and CRT-D ( HR, 0.62; 95% CI, 0.42 to 0.90; P = 0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT ( HR, 0.57; 95% CI, 0.37 to 0.87; P = 0.01) and CRT-D ( HR, 0.49; 95% CI, 0.32 to 0.75; P = 0.001) Time to all-cause death trended to an improvement in both CRT ( HR, 0.67; 95% CI, 0.41 to 1.10; P = 0.11) and CRT-D ( HR, 0.63; 95% CI, 0.39 to 1.03; P = 0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group ( HR, 0.27; 95% CI, 0.08 to 0.90; P = 0.03). There was a nonsignificant reduction in time to HF deaths for both CRT ( HR, 0.68; 95% CI, 0.34 to 1.37; P = 0.28) and CRT-D ( HR, 0.79; 95% CI, 0.41 to 1.52; P = 0.48).Conclusions - CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.

Background— The factors that determine the risk for sudden death or implantable cardioverter defibrillator therapy in patients receiving cardiac resynchronization therapy (CRT) therapies are largely unknown. Methods and Results— We hypothesized that clinical measures of heart failure severity and the presence of comorbid conditions would predict the risk of malignant arrhythmias in the 1520 patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Outcomes in the CRT group after implantable cardioverter defibrillator therapy were also evaluated. The CRT-defibrillator device reduced the risk of sudden death by 56% compared with drug therapy (17 of 595 [2.9%] versus 18 of 308 [5.8%], P<0.02). CRT therapy was not associated with sudden death risk reduction (48 of 617 [7.8%]). Other factors associated with reduced sudden death risk were left ventricular ejection fraction >20% (HR, 0.55 [95% CI, 0.35 to 0.87]; P=0.01), QRS duration >160 ms (HR, 0.63 [95% CI, 0.40 to 0.997]; P=0.05), and female gender (HR, 0.56 [95% CI, 0.34 to 0.94]; P=0.003). The risk for sudden death was increased by advanced New York Heart Association class IV heart failure (HR, 2.62 [95% CI, 1.61 to 4.26]; P<0.011) and renal dysfunction (HR, 1.69 [95% CI, 1.06 to 2.69]; P=0.03). An appropriate shock was experienced in 88 (15%) of the 595 CTR-D patients. In the CRT-defibrillator patients, female gender (HR, 0.54 [95 % CI, 0.31 to 0.94]; P=0.03) and use of neurohormonal antagonists were associated with reduced risk. Class IV heart failure status increased risk. Appropriate implantable cardioverter defibrillator therapy was positively associated with risk of death or all-cause hospitalization (HR, 1.57; P<0.002), pump failure death or hospitalization (HR, 2.35; P<0.001), and sudden death (HR, 2.99; P=0.03), but not total mortality (HR, 1.3; P=0.28). Conclusions— In CRT candidates, sudden cardiac death risk is associated with higher New York Heart Association class and renal dysfunction. In CRT-defibrillator recipients, reduction in the risk of an appropriate shock is associated with medical therapy with neurohormonal antagonists, female gender, and New York Heart Association functional class III versus IV clinical status. Shock therapy was associated with worse outcome.

In heart failure populations receiving primary prevention ICD therapy, the risk of heart failure worsening and death appears to increase after the need for an appropriate ICD shock.

Introduction: Uncontrolled acute and chronic data indicate that there is greater benefit from cardiac resynchronization therapy (CRT) if the LV lead is placed in a more lateral vs a true anterior branch vein location. We sought to determine the influence of lead location on clinical outcome in patients (pts) enrolled in the COMPANION trial comparing optimal pharmacological therapy (OPT) for heart failure to either a CRT-P or CRT-D device. Methods: Pts were retrospectively assigned to three cohorts based on lead location as documented by the implanting physician: anterior (Ant), posterior (Pos), and lateral (Lat) for the CRT-P and CRT-D arms. Cox proportional hazards models were used to examine three outcomes with respect to OPT: 1) all-cause mortality and first all-cause hospitalization (M+ACH); 2) all-cause mortality and first HF hospitalization (M+HFH); 3) all-cause mortality (M). All analyses were adjusted for baseline differences. Lat and Pos outcomes were each directly compared to Ant. Results: COMPANION enrolled 1520 pts, characterized as 68% male, mean age 67, mean LVEF 21%, and 56% ischemic. Of 1080 pts who received a device, lead locations were Lat (63%), Ant (26%), Pos (10%), and unreported (1%). Hazard ratios for each lead position when compared to OPT are shown in the upper graph. Direct comparisons of Ant vs. Pos and Ant vs. Lat are shown in the lower graph. Conclusions: Ant and Pos lead locations appear to be associated with improvement when comparing CRT-D or CRT-P to OPT. With CRT-D, hazard ratios appear to favor Pos/Lat over Ant, but the differences were not statistically significant. These data suggest that aggressive attempts to achieve a Lat LV lead location, such as referral for thoracotomy placement, may not be required to achieve benefit from CRT.

Up to 10% of patients (pts) otherwise expected to benefit from cardiac resynchronization therapy (CRT) do not have a successful LV lead implant procedure due to a number of well-documented technical and anatomic considerations. We sought to determine the clinical factors associated with a failed implant in the COMPANION trial and to assess pt outcomes and compare these outcomes to optimal pharmacologic therapy (OPT) alone.

Introduction: Diabetes is an independent predictor of morbidity and mortality among heart failure (HF) patients. No data are available, however, on the impact of diabetes on resynchronization therapy with (CRT-D) or without (CRT-P) defibrillator in advanced HF. Methods: The database of COMPANION trial was examined retrospectively to determine the influence of diabetes on outcome. The primary end point of all cause mortality or hospitalization as well as several outcome measures were analyzed among diabetics (n=622) and non diabetics (n=897). Cox proportional hazard model adjusting for age, gender, NYHA, ischemic status, body mass index, LVEF, systolic blood pressure, heart failure medications and device (CRT with or without ICD) was used to estimate hazard ratios and significance. Results: The prevalence of diabetes was high (41%). The outcome of diabetics was similar to non-diabetic as shown in the figure. Diabetes was associated with a significant increase in all-cause mortality or HF hospitalization [44% vs. 36% HR 1.22 (95% 1.03–1.45)]. When CRT-P and CRT-D were pooled together and compared to optimal medical management (OPT), there was an overall similar response in diabetics and non-diabetics. A striking decrease in pump failure deaths was noted in diabetics (HR 0.62; 95% 0.20 – 0.86. Comparing OPT to combined CRT-P and CRT-D suggested a more pronounced benefit in diabetics (fig.). Conclusion: In diabetics with advanced HF, the benefit from device therapy is substantial. There is a need for prospective trial to determine whether diabetes should be a factor favoring the use of device therapy.