Cardiac Resynchronization for Heart Failure
Abstract & Commentary
Synopsis: Cardiac resynchronization reduces the mortality of progressive heart failure in patients with symptomatic left ventricular dysfunction and dyssynchrony.
Source: Bradley DJ, et al. JAMA. 2003;289:730-740.
In this paper, Bradley and Associates present the results of a meta-analysis of randomized trials using cardiac resynchronization. They searched the literature for randomized clinical trials of resynchronization therapy. For inclusion, the studies had to report data on death, hospitalization for heart failure, and ventricular arrhythmias as outcomes. Crossover studies were excluded if the duration of the first crossover phase was less than 3 months. Data included in the meta-analysis were obtained from 11 reports from 4 randomized clinical trials. The clinical trials included were: CONTAK CD, INSYNC ICD, MIRACLE, and MUSTIC. The first 3 trials randomized approximately 500 patients each, whereas only 54 patients were randomized in MUSTIC. Clinical characteristics were similar in all 4 trials with a mean age of about 65 and a mean left ventricular ejection fraction (LVEF) of 0.21-0.23. CONTAK CD and INSYNC ICD included patients with New York Heart Association functional classes II and III, whereas MIRACLE and MUSTIC required patients to be at least New York Heart Association functional class III. The mean QRS duration ranged from 158 to 176 msec. Patients in CONTAK CD and INSYNC ICD had conventional indications for ICD therapy. Patients with bradycardia indications for pacing were excluded from all trials. Patients with atrial arrhythmias were also excluded. Beta blockers were used in just over half of the patients included in the meta-analysis. ACE inhibitors or angiotensin receptor blocking drugs were used in approximately 90%.
All patients received an ICD or a pacemaker capable of cardiac resynchronization and were randomized to either resynchronization on or resynchronization off. Follow-up durations in the randomized phase of each trial ranged from 3 to 6 months. In each of the 3 larger trials, there was a statistically nonsignificant trend toward death from progressive heart failure in the patients treated with cardiac resynchronization. There were no heart failure deaths in the much-smaller MUSTIC trial.
Data from all 4 randomized trials were pooled for the meta-analysis. Cardiac resynchronization was associated with statistically significant 51% reduction in death from progressive heart failure relative to control (odds ratio [OR], 0.49; 95% CI, 0.25-0.93). Pooled absolute rates of progressive heart failure mortality during 3-6 months of follow-up were 1.7% in patients treated with cardiac resynchronization and 3.5% in controls. Inclusion of cardiac transplantations with death from progressive heart failure as an end point produced similar results. Cardiac resynchronization was not associated with a statistically significant effect on mortality not related to heart failure. Pooled absolute rates of other mortality over 3-6 months of follow-up were 3.2% in patients treated with cardiac resynchronization and 2.8% in controls. When heart failure and other deaths were combined, there was a trend toward reduced all-cause mortality. The OR was 0.77 with a confidence interval of 0.51-1.8. The pooled absolute rates of all-cause mortality of 3-6 months were 4.9% in patients treated with cardiac resynchronization and 6.3% in controls. In the ICD trials, the cardiac resynchronization was not associated with a statistically significant reduction in patients who experienced ventricular tachycardia or ventricular fibrillation. The event rates for treated arrhythmias were 17.2% in those treated with resynchronization vs 18.4% in controls. Sensitivity analysis shows that these parameters were stable over a wide range of assumptions.
Bradley et al concluded that cardiac resynchronization reduces the mortality of progressive heart failure in patients with symptomatic left ventricular dysfunction and dyssynchrony.
Comment by John DiMarco, MD, PhD
Cardiac resynchronization is now an accepted therapy for patients with a QRS duration of greater than 130 msec, New York Heart Association functional class III or IV congestive heart failure, left ventricular dilatation, and systolic dysfunction. End points in the studies that established this indication were changes in New York Heart Association functional class, hemodynamic measures, and exercise tests parameters. By themselves, none of the studies showed a significant decrease in mortality with resynchronization therapy. However, the studies were not powered to test mortality, and they were of relatively short follow-up.
It should be noted that all of these studies implanted a resynchronization device in every patient before randomization. Therefore, this is not a true intention-to-treat analysis starting from baseline. The studies reported here ignore any morbidity or mortality that might be associated with the procedure. However, there is another trial, which has only been reported in a news release, the COMPANION Trial, in which significant reductions in total mortality were seen with resynchronization compared to an untreated control group using an intention-to-treat analysis. An even greater reduction in mortality was seen with the addition of ICD therapy.
Cardiac resynchronization therapy is still technically difficult in approximately a third of patients. Further progress in the design of devices for resynchronization should be forthcoming. In addition, better methods to assess patients who are likely to respond will help physicians who are considering this option for their patients.
Dr. DiMarco is Professor of Medicine Division of Cardiology University of Virginia, Charlottesville.
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