According to background information in the article, beta-blockers remain underused in this patient population despite their established effectiveness in improving outcome in heart failure. Concerns that the early phase of treatment produces few immediate benefits and may have important risks (such as symptomatic hypotension during the first 4 to 8 weeks of therapy) may be partly the cause for avoidance of beta-blockers by some physicians.

Henry Krum, M.B., and his Australian team reported findings from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. One of the trial’s objectives was to evaluate early effects of the beta-blocker in patients with severe heart failure. In the overall study (mean follow-up, 10.4 months), carvedilol reduced the risk of death by 35 percent compared with placebo. This trial focused on patients with severe heart failure who might be expected to have the greatest difficulty starting treatment with a beta-blocker.

The study was a randomized, double-blind, placebo-controlled trial conducted from October 1997 to March 2000 at 334 hospital centers in 21 countries: A total of 2,289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25 percent participated in the trial.

Patients were randomly assigned to receive carvedilol, started at 3.125 mg twice daily with up titration to a target dosage of 25 mg twice daily (1,156 patients), or to placebo (1,133 patients) in addition to their usual medications for heart failure.

The researchers wrote "The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 versus 25); who died or were hospitalized (134 versus 153); or who died, were hospitalized, or were permanently withdrawn from treatment (162 versus 188)."
These effects were similar in direction and magnitude to those observed during the entire study, and they were apparent particularly in patients with a very depressed left ventricular ejection fraction. "Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2 percent and was reported with similar frequency in the placebo and carvedilol groups (6.4 percent versus 5.1 percent)."

"During both initiation and up titration, patients treated with carvedilol had no increase in the risk of worsening heart failure, pulmonary edema, cardiogenic shock, or other serious adverse cardiovascular events, including death," they wrote. "If concerns about efficacy and safety during the initiation of beta-blocker therapy have caused physicians to deny or delay the use of these drugs, our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of clinical trials."

In an accompanying editorial, Sergio L. Pinski, M.D., wrote that "congestive heart failure will continue to be an increasing public health problem for the foreseeable future: The lifetime risk of developing heart failure has been recently estimated at 1 in 5. Although therapeutic progress has accelerated in the last few years, its implementation in the community has been slower."

"Both beta-blockers and cardiac resynchronization improve well-being and prolong life in patients with severe congestive heart failure due to left ventricular systolic dysfunction," Pinski wrote. "Hopefully, dissemination of the findings ... in this issue will lead to more appropriate use of these therapies. Beta-Blockade is now a mature therapy and should be prescribed to every patient without a strong contraindication."