Physicians are rapidly adopting beta-blockers for treating chronic heart failure. However, some physicians are still hesitant to use these drugs in patients with very advanced cardiac dysfunction. They may believe that these patients may not benefit, or that they may be more susceptible to early adverse effects.

Few clinical trials have enrolled meaningful numbers of patients with extremely depressed left ventricular ejection fraction. Investigators recently completed the CarvedilOl ProspEctive RaNdomiIzed CUmulative Survival (COPERNICUS) trial. Data from this study provide an opportunity to evaluate the effects of beta-blockers in patients with extremely depressed cardiac function.

The COPERNICUS trial included 2,289 patients with symptoms of heart failure and a left ventricular ejection fraction less than 25%. About one sixth of patients in this trial (371 patients) had an ejection fraction of 15% or less.

Investigators stopped the trial early because carvedilol provided a meaningful reduction in risk of death. The overall risk reduction was 35% vs. placebo (P = 0.00013).

This new analysis shows that COPERNICUS patients with extremely depressed cardiac function (15% or less) have the same apparent benefit in mortality. The magnitude of the effect was similar to the effect in patients with less severe cardiac depression.


Major Clinical Events by Ejection Fraction Subgroup

	Left ventricular ejection fraction 16% to 24%		Left ventricular ejection fraction 15% or less
	Placebo	Calvedilol	Placebo	Calvedilol
Death	17.4%	9.7%	23.8%	18.9%
Death or hospitalization	50.7%	40.4%	59.9%	47.2%

Hazard ratios indicated the favorable effect of carvedilol on both groups. This was true across a host of prespecified outcome variables. The effect was as large in the very advanced cardiac dysfunction patients, if not larger.

Investigators also evaluated the effect of carvedilol on patient sense of well being after 6 months of maintenance therapy. Patients on the beta-blocker were more likely to feel improved. This occurred both in the group with extreme ejection fraction depression, and in the patient with somewhat higher ejection fraction.

The COPERNICUS patients on carvedilol were more likely to experience hypotension, dizziness and bradycardia during the initiation of treatment. They were also less likely to report worsening heart failure during the trial. The pattern and magnitude of these responses were also similar for both ejection fraction subgroups.

Finally, patients taking carvedilol were less likely to discontinue therapy or report a serious adverse event. This was true again for both ejection fraction subgroups.

Together, the findings suggest that in chronic heart failure, carvedilol is effective and well tolerated, even in patients who have left ventricular ejection fraction that is extremely depressed.