The effect of carvedilol on morbidity and mortality in patients with chronic heart failure

Summary

Multiple lines of evidence point to activation of the adrenergic nervous system as a concomitent and aggravating factor in congestive heart failure. Adrenergic blockade is thus a plausible approach to therapy, but the reliance of the failing heart on sympathetic tone to maintain function leads to a risk of dramatic decompensation if adrenergic support is abruptly withdrawn. Thus, trials of beta-blockade in heart failure have been carried out very slowly and with caution. Initial results have been positive but have shown mainly symptomatic benefit rather than reduced morbidity and mortality. This randomized, placebo-controlled trial, multi-institutional in the US, was designed specifically to look at morbidity and mortality. The agent investigated was carvedilol, a non-selective beta-blocker with alpha-1 blocking (vasodilating) and anti-oxidant properties.

Methods

• Subjects: Patients with ischemic and non-ischemic dilated cardiomyopathies, EF <: 35%. of at least three months duration. Exclusion criteria were designed to eliminate recent acute cardiac events, patients with major arrhythmias, very high or low BP, hepatic, renal or other life-shortening illnesses and treatment with calcium blockers, beta agonists or blockers and the class IC and III anti-arrhythmic agents.
   
• Intervention: Patients were screened during a three-week period and stratified according to the results of a 6-minute corridor walk test. All patients then underwent an initial two-week open-label trial of 6.25 mg carvedilol twice daily. Those who were able to tolerate the drug went on to randomization. The figure below shows the numbers of patients randomized in the various groups. Patients randomized to carvedilol were titrated up towards 50 mg bid, except for a subgroup randomized to a dose-ranging study, where the maximum doses were as shown in the figure. Stratification was according to the distance in meters the patient was able to walk during 6 minutes.




 

• Analysis: The plan was to enroll 1101 patients; the primary endpoint was mortality, the secondary endpoint was hospitalization for CHF or other cardiovascular disorder. Follow-up was to be for 6 months (12 months in the mild CHF group). A monitoring committee was to terminate the study early if a "clinically important treatment effect" (not specified ahead of time) was observed.
   
• Enrollment began April 29, 1993; the trial was halted on February 3, 1995 after randomization of 1094 patients because of a significant effect of carvedilol on survival.
   
• 1197 patients entered the two-week open label phase, 103 did not complete it (including 7 deaths = 0.6%, 17 with worsening CHF = 1.4%). Thus, 696 patients were randomized to carvedilol (mean dose 45 mg), 398 to placebo. Median duration of therapy was 6.5 months.
   
• Main characteristics of both groups were similar. For carvedilol, these included:
• Age: 58
• Male: 77%
• NYHA class IV: 3% (the remainder were class II and class III). Average EF: 23%.
• Ischemia as cause of CHF: 48%
• BP at baseline 116/72; HR 84.
• Rx: Digoxin 91%; diuretic 95%; ACE inhibitor 95%; other vasodilator 32%

(since the carvedilol group was larger than the placebo group, percentages are more meaningful here)

• Mortality: In the placebo group, there were 7.8% deaths (31), vs. 3.2% in the carvedilol group (22) (p<0.001), which represented a 65% decrease in the risk of dying (95% CI 39-80%). Most of the deaths were due to sudden death or progressive CHF. These results held across most subgroups, although the numbers were not always sufficient to reach statistical significance. Of interest, the hazard ratio was 0.61 (95% CI 0.25-1.49) for patients with baseline HR less than 82, and 0.26 (0.12-0.55) for those with HR > 82.
   
• Combined morbidity and mortality: Hospitalization for cardiovascular causes was 14.1% in the carvedilol group and 19.6% in the placebo group. Combined risk of dying or being hospitalized (taking into account that a patient who died could not subsequently be hospitalized), was 24.6% placebo, 15.8% carvedilol.
   
• Side-effects and discontinuation: The most common side-effect, more frequent in the carvedilol group than the placebo group, was dizziness, which seldom led to discontinuation of the study drug. The study drug was discontinued for adverse effects in 7.8% of the placebo group and 5.7% of the carvedilol group. The only reason for discontinuation that seems to have been more frequent in the carvedilol group was bradycardia (6 vs 0).

Comment

• Methodologic issues: In an accompanying editorial, Pfeffer and Stevenson point out that seven deaths occurred during the two-week run-in phase, when patients were being treated with 6.25 mg of carvedilol in open label fashion. Had these deaths been attributed to carvedilol, they would have accounted for 25% of carvedilol deaths and would have greatly diminished the calculated benefit of the drug. The authors, in their discussion, state that this 0.6% death rate during the two weeks is not excessive; they attribute it to the natural history of the disease, and note that the death rate during the prior three week screening period was 1.7%, in the absence of carvedilol treatment

The editorial also comments on the relatively small number of deaths (53) and short follow-up time, compared to trials that looked at the benefits of ACE inhibitors in CHF.

Finally, both the authors and the editorial point out that these results only apply to patients with mild and "moderate" CHF, as defined by this study, since too few patients were in the severe CHF group.
 

• Bottom line: In patients with mild or moderate CHF, 6-month treatment with carvedilol reduced mortality from 7.8% to 3.2%. This corresponds to an absolute risk reduction of 4.6% which yields a NNT of 22 (need to treat 22 patients for 6 months to prevent one death).
   
• Whether or not these results will apply to other beta-blockers remains unclear, and is an important issue, since newer agents such as carvedilol and bucindolol will be much more expensive than older ones like metoprolol. Trials are ongoing looking at some of these agents. This is just another example of the problem posed by trials looking at newer agents of an established class. The manufacturer of the product can say "only me" with some scientific justification, while common sense, economics and the manufacturers of rival, same-class drugs will say "me too". What is needed are more trials looking at head-on comparisons of drugs within the same class, once efficacy has been established for one of them.
   
• The patients to whom these results apply, and the exact manner of initiating therapy remain to be elucidated. Patients with severe CHF were not adequately represented. The results of the study seem to indicate that higher baseline heart rate implies greater benefit. Beta-blockers are not yet FDA approved for the treatment of congestive heart failure. Nevertheless, this is the first study to clearly indicate a mortality benefit of a beta-blocker in the treatment of congestive heart failure and represents an important advance.

Reader comments

Letters to the Editor about this article from the NEJM website.

Journal Club on the Web main screen

Submit a comment about this article