The MERIT of Using Metoprolol CR/XL in Heart Failure
Abstract & commentary
Synopsis: This study convincingly demonstrates that controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) given once daily is profoundly beneficial to patients with NYHA class II-IV systolic heart failure.
Source: Hjalmarson A, et al. JAMA 2000;283:1295-1302.
During the period of 1996-97, several studies demonstrated that treatment of congestive heart failure with either carvedilol or bisoprolol (both beta-1 blockers) improved survival. On the basis of these observations, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) study was designed to further investigate the survival benefit of beta-1 blockade in chronic heart failure due to systolic dysfunction and to gain information regarding its effect on hospitalizations, symptoms, and quality of life.
The trial was a randomized, double-blind, placebo-controlled trial that recruited patients with NYHA functional class II-IV heart failure. Extended-release metoprolol (metoprolol CR/XL) was compared to placebo. A total of 3991 patients were recruited from 313 investigational sites in the United States and Europe. To qualify, patients had to have ejection fractions of 0.4 or less and be receiving optimum treatment for at least two weeks prior to entry. Optimum treatment was defined as the combination of an ACE inhibitor and a diuretic. If an ACE inhibitor could not be tolerated, hydralazine, a long-acting nitrate, or an angiotensin II blocker could be used. The patient may or may not have also been receiving digitalis. Furosemide was used as the diuretic (average dose = 65 mg/day) and either enalapril (average 15 mg/day), captopril (70 mg/day), or lisinopril (16 mg/day) was used as the ACE inhibitor.
Patients with class II heart failure were started at 25 mg of extended-release metoprolol per day. Class III-IV patients were started at 12.5 mg. It was recommended that the dose be doubled every two weeks to reach a target level of 200 mg, but the regimen could be modified upon the judgment of the investigator. Once at the target level, patients were followed every three months. Randomization was begun on Feb. 14, 1997, and the last patient was randomized on April 14, 1998. Although it was planned to continue the study for at least 2.4 years of follow-up, the study was stopped on October 31, 1998, due to the significant difference in end points between the treated and nontreated groups.
Treatment with metoprolol CR/XL significantly reduced all combined end points, which included: total mortality or all-cause hospitalization; total mortality or hospitalization due to worsening of heart failure; death or heart transplantation; cardiac death or nonfatal acute myocardial infarction; and total mortality or hosptalization or emergency department visit due to worsening of heart failure. Treatment reduced total mortality by 34% and total hospitalization by 36%. The treatment group also reported a statistically significant improvement in quality-of-life parameters (activities of daily life and sense of well-being).
Comment by michael k. Rees, MD, MPH
This study convincingly demonstrates that controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) given once daily is profoundly beneficial to patients with NYHA class II-IV systolic heart failure. This treatment is also profoundly beneficial to society because expensive hospital days were reduced by 34% by a relatively inexpensive drug. The study greatly challenges at least this practitioner, because at least in the Boston area, the vast majority of managed care plans exclude metoprolol CR/XL from their preferred formulary and request that metoprolol be used instead. The cost to the patient is much greater if the extended-release form of the drug is used.
Are the managed care companies justified in their prejudice against metoprolol CR/XL? Is the practitioner justified in asking the patient to bear a significant increase in out-of-pocket expense for the extended-release/contolled-release formulation? Sandberg and colleagues state: "This formulation leads to a more pronounced and even beta-blockage over 24 hours compared with conventional immediate-relases metoprolol tartrate tablets, 50 mg 3 times per day."1 The citation here is a paper published in a supplement of the European Journal of Clinical Pharmacology. Here it is important to note that the MERIT-HF study was funded by the manufacturer of metoprolol CR/XL.
That metoprolol CR/XL greatly benefits the appropriately selected patient with heart failure seems well established. Whether it does a better job than the much less expensive immediate release form is not established by this study. It will take a head-to-head trial to determine this. Such are the challenges the clinician faces in this era of managed care.
Reference
1. Sandberg A, et al. Eur J Clin Pharmacol 1988; 33(suppl):S3-S7.
In the MERIT-HF study, what is the recommended starting dose of Metoprolol CR/XL for the patient with NYHA class III systolic heart failure?
a. 6.25 mg/day
b. 12.5 mg/day
c. 25 mg/day
d. 37.5 mg/day
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