More News on Carvedilol
ABSTRACT & COMMENTARY
Synopsis: While carvedilol is a positive addition to our drugs for heart failure, the total number of patients studied with the drug in the world’s literature is rather small.
Source: Australia/New Zealand Heart Failure Research Collaborative Group. Lancet 1997;349:375-380.
On february 27, 1997, the food and drug Administration Cardio-renal Panel approved the use of carvedilol for heart failure after previously denying approval. Presumably, the results of the Australian/New Zealand heart failure trial of this drug, as well as the reanalysis of the U.S. experience, were influential. This trial enrolled 415 patients, mostly with class 2-3 heart failure all due to ischemic heart disease with 86% on an ACE inhibitor, who were randomized to placebo or carvedilol and followed for minimum of 15 months (mean, 19 months). In brief, the results demonstrated no change in clinical status or exercise time, but the combined end point of mortality or admission for heart failure was significantly reduced (relative risk, 0.74). Worsening heart failure and NYHA class were not different between placebo and carvedilol. Furthermore, at six months there was a trend toward an increase in symptoms in the beta-blocker group, which disappeared by 12 months.When death or hospitalization for heart failure were evaluated separately, there was a trend only in favor of carvedilol, although the combined end point was statistically significant. Overall mortality in this study was 11% over an average 19-month follow-up; half the patients were admitted to the hospital during the trial. Reduction of the combined end point of death or admission was 26%.
Favorable alterations of left ventricular size and function were documented with carvedilol. Left ventricular ejection fraction increased by approximately 5% (1 year), baseline 28.4%, 33.5% at 12 months. There were modest reductions in left ventricular end diastolic and systolic dimensions, as assessed by M-mode echo, with carvedilol that were not seen with placebo.
The investigators comment on the "apparent disassociation of changes in left ventricular function from changes in exercise capacity and symptoms of heart failure." In that carvedilol is a complex drug, with beta blocking activity as well as alpha 1 blocking vasodilating properties and anti-oxidant and anti-ischemic actions, the mechanisms of the improvement in LV size and function and the combined end point in these patients are unclear.
The authors conclude that this trial, when analyzed in conjunction with the four small trials from the United States previously published (N Engl J Med 1996;334:1349 and Clin Cardiol Alert 1996;15:49-50), the total number of patients studied with carvedilol in the world’s literature is too small "for this treatment to be widely recommended for the management of patients with heart failure." They call for larger trials to evaluate the effect of this drug on survival.
COMMENT BY JONATHAN ABRAMS, MD
Beta-blockers for heart failure have been the subject of intense scrutiny for many years. Carvedilol has generated considerable enthusiasm and excitement, and in the United States’ composite trial of four studies, there appeared to be a robust decrease in mortality rate approaching 65% at 6-7 months. However, as has been pointed out, the total duration of time that patients have been on this drug, as well as the number of subjects studied, is too small to be certain that this is a real or sustained effect. The experience with heart failure trials and new drugs, particularly the inotropes, has been very disappointing. For instance, vesnarinone and flosequinan both exhibited a mortality advantage in small, early studies, which turned out to be an unhappy error when longer follow-up and greater experience was achieved.What is clear is that carvedilol does not appear to worsen heart failure over a long period of time, and when carefully administered, most patients are able to tolerate the drug. Symptomatic improvement has been variable, which is troubling. However, left ventricular systolic function and size are improved with the drug. This suggests that carvedilol is beneficial in preventing the adverse remodeling of the left ventricle and may induce favorable changes in structure and function of the myocardium over time. This aspect of beta-blockers has been suggested by others.
Carvedilol is not easy to use. The target dose of 25 mg twice daily is reached only after slow titration beginning with 3.5 mg bid, progressing to 6.25 mg bid over a period of weeks with patients under constant observation. Close observation of the patient and involvement with physicians experienced in heart failure management is mandatory. The majority of subjects in the Australia/New Zealand trial were in NYHA class II and were stable on an ACE inhibitor. These criteria should allow the careful institution of this drug by physicians particularly interested in maximizing the therapeutic approach to heart failure. Experience with carvedilol over the next few years and, hopefully, larger trials powered for survival should ultimately resolve many unanswered questions.
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