THE MERIT-HEART FAILURE TRIAL
Preliminary results of the merit-heart failure study were announced at the annual American Heart Association meeting in November 1998. A more complete report was given by Dr. Sidney Goldstein at the recent American College of Cardiology Late-Breaking Clinical Trials session. Approximately 4000 patients from Europe and the United States with class II-III congestive heart failure were randomized to long-acting metoprolol (Toprol XL) or placebo. Up-titration of the beta-blocker dose occurred weekly to achieve a target of 100-200 mg daily; the average dosage achieved was 159 mg daily. Forty-one percent of the cohort was NYHA class II and 55% NYHA class III. Left ventricular (LV) ejection fraction averaged 28%. Two-thirds of the patients had coronary artery disease, one-half had a prior myocardial infarction, and one-fourth had diabetes. Ninety percent of the patients were on an ACE inhibitor and 7% were on an angiotensin-II blocker.
The primary end point was all-cause mortality. The trial began in early 1997 and was scheduled to end in 2000; however, in late 1998 the study was stopped prematurely at an interim analysis because of a significant reduction in mortality. The beta-blocker patients had a decrease in one-year all-cause mortality of 34% (11% placebo, 7.2% metoprolol; P = 0.006) as well as a 41% reduction of sudden death and a 49% reduction in heart failure mortality. The response was similar in all NYHA classes. Heart failure etiology and LV ejection fraction strata were not factors in the outcomes.
Comment by Jonathan Abrams, MD
This is more convincing evidence that beta-blockers should become part and parcel of the treatment of symptomatic patients with heart failure with depressed systolic function. A variety of carvedilol studies and the recent CIBIS-2 (bisoprolol) trial demonstrated comparable reductions in mortality that are robust and consistent. The issue of whether a beta-one selective agent is more or less desirable than a nonselective beta-blocker remains unresolved. The COMET trial is comparing metoprolol to carvedilol, but the study has not been completed. Only 4% of the Merit-HF patients were in NYHA class IV, although a recent publication using carvedilol in such patients has been reported. In general, use of beta-blockers in very sick patients with heart failure is not indicated except by heart failure clinics or by individuals extremely experienced in the care of patients with severe heart failure. On the other hand, all class II-III patients should be given a beta-blocker unless there is a significant contradiction. Starting with very low doses with slow up-titration is essential, as such patients frequently become more symptomatic with initiation of this therapy. However, long-term data confirm reverse remodeling, with improved LV function (data not provided by the Merit-HF investigators), as well as symptomatic relief and improved clinical status.
The beta-blocker heart failure trials have all been with patients on ACE inhibitors; these drugs remain the first line of therapy for patients with decreased systolic function. In individuals who have normal to high blood pressure, no overt bradycardia, or AV conduction disturbance, a beta-blocker (either selective or nonselective) should be conventional therapy. Very low doses of metoprolol are difficult to administer given the current availability of only 100-mg strength Toprol CL and 50 mg of regular metoprolol. In this respect, carvedilol has an advantage because of the easier initiation with very low doses.
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