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Abstract & Commentary
Synopsis: In selected patients, cardiac resynchronization therapy with a pacemaker or pacemaker-defibrillator improves their clinical course and the addition of a defibrillator with cardiac resynchronization therapy alone further reduces mortality.
Source: Bristow MR, et al. N Engl J Med. 2004;350:2140-2150.
Previous studies on cardiac resynchronization therapy (CRT) have used an improvement in heart failure symptoms or a decrease in hospitalization as their primary end points and have not had adequate statistical power to detect changes in mortality. In this paper, Bristow and colleagues report the results of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) Trial. This was a multicenter trial conducted in North America to evaluate the effects of CRT with and without defibrillation on both symptoms and mortality. Patients were eligiblefor inclusion if they had New York Heart Association class III or class IV heart failure due to either an ischemic or nonischemic cardiomyopathy, a left ventricular ejection fraction of 0.35 or less, and a QRS duration of at least 120 msec. All patients had sinus rhythm.
Patients could not have a documented bradycardia or tachycardia indication for a pacemaker or defibrillator and were required to have had a hospitalization for heart failure within the preceding 12 months. Patients were randomly assigned in a 1:2:2 ratio to treatment with either contemporary pharmacologic therapy for heart failure, pharmacologic therapy plus CRT with a pacemaker, or pharmacologic therapy plus CRT with a pacemaker-defibrillator. The pharmacologic therapy used in all groups was designed to include diuretics, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, beta blockers, and spironolactone. Digoxin could be used at the investigators’ discretion. Patients who underwent CRT with a pacemaker received right atrial, right ventricular and left ventricular epicardial pacing leads and were programmed in the VDD mode with a lower rate below the patient’s lowest intrinsic heart rate. Patients who received a defibrillator used similar pacing settings, but therapy for ventricular arrhythmias was programmed.
The primary end point was a composite of death from any cause or hospitalization from any cause from the time of randomization to the time of the first event. Hospitalization for implant was not included. Unscheduled intravenous administration of inotropic or vasoactive drugs from more than 4 hours in an emergency department or outpatient setting was considered to be the equivalent of a hospitalization. Death from any cause was a secondary end point.
Enrollment began in January 2000 and was stopped in November 20002 when the Data Safety Monitoring Board reported that a prespecified target of 1000 events had been reached. At that time, 1520 patients had undergone randomization.
The average age was 67 years and 67% of the patients were male. Eighty-five percent of the patients were in New York Heart Association class III at the time of randomization and heart failure had been present for a mean of 3.6 years. The mean left ventricular ejection fraction was 21%. The median QRS interval was 159 msec and 56% of the patients had an ischemic cardiomyopathy.
Of the patients who were assigned to CRT, implantation was successful in 87% of the patients in the pacemaker group and in 91% of the patients in the pacemaker-defibrillator group. There were 5 deaths in the pacemaker group and 3 in the pacemaker-defibrillator group that were thought to be related to procedural complications. However, the mortality rate during the 30 days after randomization was similar among the 3 groups: 1% in the CRT pacemaker group, 1.8% in the CRT pacemaker-defibrillator group, and 1.2% in the pharmacologic therapy group. CRT devices become available for routine clinical use during the trial. As a result, follow-up was complicated by the fact that 13% of the pharmacologic therapy group withdrew from the study, primarily to receive an out-of-study resynchronization device. Because of this, complete outcome data through the end of the study was known for only 91% of the patients in the pharmacologic therapy group vs 99% of the patients in the other groups. Mortality data, however, were complete for 96% of the pharmacologic therapy patients. A total of 1020 primary end points were analyzed. The 12-month rate of the primary composite end point of death from any cause or hospitalization from any cause was 68% in the pharmacologic therapy group as compared with 56% in the pacemaker group and 56% in the pacemaker-defibrillator group. The 1-year mortality rate in the pharmacologic therapy group was 19% and there was a total mortality during the entire study of 25%. Implantation of a pacemaker was associated with a trend toward improved survival (hazard ratio, 0.76; 95% confidence interval, 0.58-1.01) whereas the implantation of the pacemaker-defibrillator was associated with a significant 36% reduction in risk (hazard ratio, 0.64; 95% confidence interval, 0.48-0.86).
When only death or hospitalization for cardiovascular causes was considered CRT with or without defibrillation produced significant reductions in risk. The risk reductions were 25% in the pacemaker group and 28% in the pacemaker-defibrillator group. A variety of subgroups were analyzed to test the applicability of the data to select populations. Favorable trends were noted for most subgroups. In particular, CRT reduced the risk of primary end points among patients with both ischemic and nonischemic cardiomyopathy to approximately the same extent. Both CRT groups experienced an improvement in 6-minute walk distance, quality of life and New York Heart Association class symptoms. Median systolic blood pressures were increased with resynchronization therapy and were decreased with pharmacologic therapy.
Bristow et al conclude that in selected patients, cardiac CRT with a pacemaker or pacemaker-defibrillator improves their clinical course and that the addition of a defibrillator with cardiac resynchronization therapy alone further reduces mortality.
Comment by John P. DiMarco, Md, PhD
COMPANION is an important trial because it addresses several key questions about the use of biventricular pacemakers and ICDs. Although the results might have been more definitive if the trial had been allowed to run further, the results are adequate for making several clinical conclusions. First, resynchronization therapy with biventricular pacing improves a number of important outcomes in patients with prolonged QRS durations and depressed left ventricular ejection fractions. Second, the effects of CRT and ICD therapy on mortality appear to be additive. Third, there is no apparent difference between patients with ischemic vs nonischemic cardiomyopathies. These conclusions are well justified by the data and should be used for clinical decision making. They should also form the basis for a revision of current reimbursement guidelines.
However, many questions still remain. The event rates, particularly for hospitalization, in COMPANION remain quite high even with CRT. Is there some way that CRT can be optimized to further improve therapy? Why do some patients not improve? Is QRS duration a valuable predictor of response or is there at least some minimum value—130 or 140 msec—below which improvement should not be expected?
COMPANION also illustrates an interesting problem facing those who design clinical trials in patients with heart failure. Pharmacologic therapy has improved prognosis for patients with heart failure dramatically. The COMPANION investigators therefore selected a very high risk group by requiring all patients to have had a recent heart failure hospitalization. Although this resulted in a high rate of events, it also meant that the clinical release of CRT devices for general use after the trial was under way had 2 unfortunate consequences: many desperate control patients withdrew from the trial to receive an out-of-study CRT device and enrollment dramatically declined in the later phases of the study. These 2 developments almost caused the trial to stop because of the poor enrollment and the withdrawals to cross-over made data analysis much more difficult. These problems will continue in future trials if the clinical availability of the device under study changes during the course of the study.
As of June 2004 the Centers for Medicare & Medicaid Services has not yet revised there reimbursement guidelines on the basis of the COMPANION data. As clinicians, we should demand that new guidelines that allow appropriate use of CRT devices in patients likely to benefit be issued soon.
Dr. DiMarco, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, is on the Editorial Board of Clinical Cardiology Alert.