More Good News About Carvedilol
More Good News About Carvedilol
ABSTRACT & COMMENTARY
Synopsis: Carvedilol is safe to use after acute myocardial infarction with or without associated heart failure.
Source: Basu S, et al. Circulation 1997;96:183-191.
A single hospital study from the excellent cardiac unit at Northwick Park Hospital in England evaluated the role of carvedilol in acute myocardial infarction (MI), administering the drug intravenously within the first 24 hours and converting subjects to oral treatment. This was a placebo-controlled, double-blind trial in MI that randomized 146 patients to carvedilol or placebo. The target oral dose was 25 mg bid for the six-month study, but the large majority of individuals only reached a peak dose of 12.5 mg bid. End points were all major cardiovascular events. Use of ACE- inhibitor therapy was not allowed. Patients were followed with serial exercise tests, echocardiograms, and Holter recordings obtained before discharge and at days 84 and 168. Following the six-month study termination, patients were followed until the last enrolled patient was completed. Primary analysis involved the time from randomization to the development of any major cardiovascular end point on an intention-to-treat basis. Patient characteristics were well-matched; approximately half were anterior MI patients and half inferior MI patients. A small percentage were non-Q infarcts. More than two-thirds of the patients received thrombolysis. All were given aspirin and SQ heparin, and 80% received nitrates.
The results indicated a significant decrease in serious cardiac events in the carvedilol group, with a 42% risk reduction. Hard end points, such as death or infarction, were reduced by 45% (NS). Carvedilol reduced average 24-hour heart rate, but cardiac arrhythmias were not affected by the drug. No differences in ejection fraction (EF) were noted, although stroke volume was higher in the carvedilol patients. The Doppler mitral inflow velocity E/A ratio was higher on carvedilol than placebo, suggesting improved left ventricular filling. Approximately one-third of the overall population had significant left ventricular dysfunction with an EF less than 45%. At three months, individuals on the beta blocker had smaller cardiac chamber size, a trend toward a better EF, and improved wall motion score (P = 0.02). Serious cardiac events in this group were significantly reduced. The major clinical efficacy of carvedilol was a reduction of ischemic events such as reinfarction, unstable angina, and need for urgent revascularization. Of importance, patients with heart failure at entry did well and suffered no adverse effects with carvedilol while achieving a remodeling benefit. Basu and associates conclude that carvedilol is safe to use after AMI with or without associated heart failure. They call for larger trials with this drug to assess the potential for a reduction in ischemic events and mortality.
COMMENT BY JONATHAN ABRAMS, MD
Considerable excitement has been generated by the published clinical trial data (Clin Cardiol Alert 1997;16:30-31) and recent FDA approval of carvedilol for mild congestive heart failure. This interesting compound is a non-selective beta blocker with alpha-one mediated vasodilator properties as well as antioxidant activity. The role of beta blockers in the thrombolytic era has not been well assessed, and as yet, a survival benefit has not been demonstrated in patients who receive lytic agents. This small study, while not settling the issue, suggests that carvedilol is a safe and effective beta blocker but does not prove that it is different from other available beta blockers. A recent meta-analysis of beta blockers in congestive heart failure (Heidenrich, et al. J Am Coll Cardiol 1997;30:27) shows a substantial reduction in all-cause mortality with beta blockers; analysis of the carvedilol data suggests a survival benefit for those trials employing carvedilol was greater than for other beta blockers. The current study suggests that this drug may be better than or at least as good as other beta blockers on the market for the acute MI population. This may be the first clinical trial demonstrating a post-MI remodeling benefit with beta blockers, which heretofore has only been shown for ACE inhibitors and nitrates. Clearly, much larger and longer trials are necessary to assess this issue as the numbers in the Northwick Park study are small. Nevertheless, the fact that patients with depressed LV function, clinical congestive heart failure, or both tolerated the drug well with intravenous first-day therapy bodes well for the careful administration of this interesting compound. It may be that the vasodilator actions as well as free radical scavenging effects of carvedilol offer additional benefits, potentially making this agent safer and more efficacious than other beta blockers. However, the jury remains out. Carvedilol appears to be an appropriate choice for beta-blocker treatment in acute infarction that, in the United States, remains underused in spite of a large clinical database and the latest practice guidelines.
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