Trials show CHF to be reversible
Clinical trials offer promise for carvedilol
Until a recent series of clinical trials on carvedilol, congestive heart failure (CHF) was believed to be an irreversible disease process. It now can be considered at least partially reversible, says Michael R. Bristow, MD, PhD, chief of cardiology at the University of Colorado School of Medicine in Denver and a member of the National Institutes of Health Task Force on Heart Failure. Bristow was an investigator on all but one of four clinical trials that examined carvedilol’s efficacy for CHF. All four were reported in a recent issue of Circulation.
The first trial, termed the Multicenter Oral Carvedilol Heart Failure Assessment trial, demonstrated dose-related improvements in heart function, mortality rates, and hospitalization rates of 345 patients with mild-to-moderate heart failure.1 The death rate was 1.1% among patients receiving the highest doses, compared to 15.5% among those getting placebos. That trial also showed a 73% drop in short-term death rates among patients treated with carvedilol during six months of treatment.
Carvedilol eclipses competition
The second clinical trial compared metoprolol to carvedilol.2 Generic metoprolol is an older, second generation receptor blocker. It is much less expensive than carvedilol is expected to be, but compares unfavorably to the newer agent.
Unlike drugs like metoprolol, carvedilol was found to exert a comprehensive antiadrenergic action, keep beta-adrenergic receptors in a lowered state of activity, and reduce norepinephrine levels.
The third trial, called the Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise, found clinical benefits for patients concurrently taking digoxin, diuretics, and ACE inhibitors current therapy for moderate-to-severe CHF.3
The importance of the fourth trial lay in the character of its participants.4 It demonstrated that, when added to standard therapy, the drug slows the progress of heart failure in those patients with heart failure due to mildly symptomatic left ventricular systolic dysfunction.
Caveat: Not for use in refractory disease
An editorial accompanying the trial reports in Circulation issues a word of caution: Patients with severe, unstable heart failure don’t tolerate this or any therapy with blocking agents.5 Patients included in the carvedilol studies had mild-to-moderate disease. "Uncontrolled studies and clinical experience suggest," reads the editorial, "that patients with clinically overt severe and unstable heart failure do not tolerate beta-adrenergic antagonists, and the survival benefit of beta-blocker therapy in such patients has not been established."
Kanu Chatterjee, MB, FRCP, a cardiologist at the University of California at San Francisco and the author of the editorial, explains further. "Carvedilol, when added to ACE inhibitors in patients with depressed left ventricular systolic function, can retard progression of heart failure and, therefore, should be considered a therapeutic agent for prevention of progressive clinical heart failure rather than for treatment for refractory heart failure."
References
1. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure Circulation 1996; 94:2,807-2,816.
2. Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996; 94:2,817-2,825.
3. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation 1996; 94:2,793-2,799.
4. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996; 94:2,800-2,806.
5. Chatterjee K. Heart failure therapy in evolution (editorial). Circulation 1996; 94:2,689-2,693.
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