Carvedilol for Severe Heart Failure

Abstracts & Commentary

Synopsis: In euvolemic Class IV heart failure patients due to systolic dysfunction, carvedilol, added to conventional therapy, reduces the risk of clinical deterioration, hospitalization, and other severe adverse events.

Sources: Packer M, et al. Circulation. 2002;106:2194-2199. Wollert KC, Drexler H. Circulation. 2002;106: 2164-2166.

Beta-blockers are contraindicated in patients with decompensated heart failure, but physicians are often reluctant to prescribe them for class IV heart failure, even when the patient has been stabilized on diuretics, angiotensin converting enzyme inhibitors (ACEI), and other agents. Thus, this report of the morbidity outcomes in the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) is of interest. The beneficial effects on survival have already been reported (N Engl J Med. 2001;344:1651). Patients with class IV symptoms for 2 months, and left ventricular ejection fraction (LVEF) of < 25% were eligible. All 2289 participants were on diuretics and either an ACE1 or an angiotensin receptor blocker (ARB) unless they were not tolerated. Other oral agents were allowed but not required, and no intravenous medications could have been given within 4 days. The patients were randomized to placebo or carvedilol up titration to the target dose of 25 mg b.i.d. The secondary end points of risk of death or hospitalization, and the patient’s subjective assessment of clinical status are the subject of this report. Carvedilol reduced the combined risk of death or hospitalization for cardiovascular reasons by 27% (30% vs 42%; P < .001) and for heart failure by 31% (26% vs 38%; P < .001). These favorable effects persisted when death was excluded and across all subgroups including the highest- risk patients. After 6 months, more patients considered themselves improved, and less considered themselves worse on carvedilol vs placebo. Also, carvedilol treated patients were less likely to experience serious adverse events. Packer and colleagues concluded that in euvolemic Class IV heart failure patients due to systolic dysfunction carvedilol, added to conventional therapy, reduces the risk of clinical deterioration, hospitalization, and other severe adverse events.

Comment by Michael H. Crawford, MD

The results of this analysis of the COPERNICUS study suggest that once a class IV patient is stabilized on diuretics, ACEI, or ARB and other agents, even if they recently needed IV medications, a beta-blocker should be started and titrated to recommend doses. Interestingly, fewer patients developed worsening heart failure on carvedilol as compared to placebo (17% vs 24%), and no early increase in heart failure was observed. It must be pointed out that patients with volume overload, or who were on intravenous vasodilators or positive inotropic agents were not enrolled. Beta-blockers are still contraindicated in such patients. Also of interest, hospital lengths of stay was less in the carvedilol patients (11.2 vs 13.5 days), and carvedilol patients spent 40% fewer days in the hospital, despite their increased longevity. These results are similar to those observed in patients with mild-to-moderate heart failure (J Am Coll Cardiol. 2001;37:1692) and suggest that beta-blockers should be started as soon as patients are stabilized on diuretics, ACEI or ARB, and perhaps digoxin. Also, since beta-blockers are useful in asymptomatic patients with LV dysfunction due to coronary artery disease, these results extend the use of beta-blockers to all clinical classes of heart failure (I-IV). Whether class I patients with nonischemic LV dysfunction will benefit from beta-blockers is not known.

The accompanying editorial by Wollert and Drexler raises the issue of whether all beta-blockers are the same with regard to heart failure treatment. Metoprolol, bisoprolol, and carvedilol have all demonstrated a one third reduction in mortality and morbidity in randomized trials, yet they have different receptor blocking characteristics. Inexplicably, bucindolol was not effective in the BEST trial, reducing mortality and morbidity by only about 10%. Is carvedilol superior to metoprolol as small studies have suggested? We will have to await the results of COMET, a head-to-head trial. However, even then COMET did not use the new long-acting version of metoprolol, which some think is better. Clinical research is always a moving target.

Dr. Crawford is Professor of Medicine, Mayo Medical School; Consultant in Cardiovascular Diseases, and Director of Research, Mayo Clinic, Scottsdale, AZ.