Lessons Learned and Insights Gained in the Design, Analysis, and Outcomes of the COMPANION Trial

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

Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

Indications for cardiac-resynchronization therapy (CRT) in patients with heart failure include a prolonged QRS interval (> or =120 msec), in addition to other functional criteria. Some patients with narrow QRS complexes have echocardiographic evidence of left ventricular mechanical dyssynchrony and may also benefit from CRT. We enrolled 172 patients who had a standard indication for an implantable cardioverter-defibrillator. Patients received the CRT device and were randomly assigned to the CRT group or to a control group (no CRT) for 6 months. The primary end point was the proportion of patients with an increase in peak oxygen consumption of at least 1.0 ml per kilogram of body weight per minute during cardiopulmonary exercise testing at 6 months. At 6 months, the CRT group and the control group did not differ significantly in the proportion of patients with the primary end point (46% and 41%, respectively). In a prespecified subgroup with a QRS interval of 120 msec or more, the peak oxygen consumption increased in the CRT group (P=0.02), but it was unchanged in a subgroup with a QRS interval of less than 120 msec (P=0.45). There were 24 heart-failure events requiring intravenous therapy in 14 patients in the CRT group (16.1%) and 41 events in 19 patients in the control group (22.3%), but the difference was not significant. CRT did not improve peak oxygen consumption in patients with moderate-to-severe heart failure, providing evidence that patients with heart failure and narrow QRS intervals may not benefit from CRT. (ClinicalTrials.gov number, NCT00132977 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.