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Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure - MERIT-HF
Description:
Metoprolol vs. placebo for mortality in heart failure.
Hypothesis:
To determine the effects on mortality of once-daily dosing of metoprolol succinate controlled release/extended release (CR/XL) when added to standard therapy for heart failure.
Study Design
Study Design:
Patients Screened: Not given
Patients Enrolled: 3,991
NYHA Class: 41% Class II; 55% Class III, 3.5% Class IV
Mean Patient Age: 64
Female: 23%
Mean Ejection Fraction: 28%
Primary Endpoints:
Total mortality
Secondary Endpoints:
Combined endpoint of all-cause mortality/all-cause hospitalization (time to first event).
Drug/Procedures Used:
Metoprolol CR/XL (titrated from 12.5 to 25mg during the first 2 weeks to 200mg during weeks 7 and 8) or placebo.
Concomitant Medications:
ACE inhibitors (89%), diuretics (90%), digoxin (63%), angiotensin II inhibitors (7%).
Principal Findings:
Five months after the initial post-randomization analysis, the data safety and monitoring committee found that the previously defined criteria for termination of the study for mortality reduction had been met and exceeded. Preliminary data showed an approximate 35% reduction in total mortality in the metoprolol group. Mortality results were consistent across the predefined subgroups.
Findings related to the secondary endpoint were consistent with the mortality data. Discontinuation of study medication was similar in both groups and serious adverse effects were more common in the placebo group. In view of the "highly significant benefit observed," the study was terminated prematurely and all patients were offered metoprolol CR/XL.
There was a significant total mortality reduction in the metoprolol group (7.2%) compared with the placebo group (11.0%, P=0.0062) at 1 year. This represents a 34% relative risk reduction in total mortality.
The investigators also found a 38% relative risk reduction in cardiovascular death, a 41% relative risk reduction in sudden death, and a 49% relative risk reduction in congestive heart failure. When subgroup analysis was performed, the benefits of metoprolol were found in all patients, regardless of NYHA class, LVEF, gender, or presence of ischemic heart disease.
At 1 year there was a statistically nonsignificant difference in the number of patients who discontinued their medication in the metoprolol group (14%) and the placebo group (15.5%).
When the cause of death was analyzed, patients were more likely to die of CHF than sudden death in NYHA Class IV patients (56% vs 33%), in contrast to NYHA Class II patients (12% vs 64%).
Interpretation:
Metoprolol provided a 34% reduction in mortality in CHF patients with systolic dysfunction, which is a result similar in magnitude to the earlier carvedilol and bisoprolol trials. Metoprolol also had a good safety profile and there was no run-in period. However, one important limitation of the trial is that few NYHA Class IV patients were studied. It is unclear which beta-blocker is best, since there have been no comparative trials to date. With a greater understanding of the impact of neuroendocrine stimulation on the adverse outcomes of heart failure (especially lethal arrhythmias and sudden cardiac death), promising evidence continues to accumulate for beta-adrenergic blockade in these patients. Both the Metoprolol in Dilated Cardiomyopathy (MDC) trial and the Cardiac Insufficiency Bisoprolol Study (CIBIS) found beta blockade to be associated with decreased mortality rates in patients with non-ischemic heart failure. Specifically, MDC found a decrease in the combined endpoint of death and need for transplantation. CIBIS I found no significant overall effect, but retrospective subgroup analysis showed a significant decrease in patients with non-ischemic cardiomyopathy. CIBIS II found overall mortality down 32% and a significant decrease in both ischemic and non-ischemic patients.
References:
1. Circulation 1998;98(Suppl I):I-364. Preliminary results
Presented at ACC 48th Scientific Sessions, New Orleans, LA, 1999.
Keywords: Risk, Carbazoles, Heart Failure, Propanolamines, Bisoprolol, Metoprolol, Death, Sudden, Cardiac, Cardiomyopathy, Dilated
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