Beta Blockers for Congestive Heart Failure: Interesting New Reports
Abstracts & Commentary
Two major randomized clinical trials using beta-blocking agents for congestive heart failure (CHF) have recently been reported, with disparate results. One report, the BEST (Beta Blocker Evaluation of Survival Trial) study, suggests that there may be important racial differences in modulating responses to the therapy. The other report involves carvedilol, a drug with beta 1 and 2 receptor antagonism, alpha blocking actions, antioxidant properties, and nonadrenergic mechanisms of action. Carvedilol has been studied in a variety of smaller trials in class II and III CHF, as well as in the postinfarct patient (CAPRICORN trial, recently reported in Clinical Cardiology Alert). COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study) (Packer M, et al. N Engl J Med. 2001;344:1651-1658) enrolled patients with "severe chronic heart failure," defined by dyspnea or fatigue at rest or with minimal exertion and a left ventricular ejection fraction (EF) of < 25% on standard CHF therapy. Randomization occurred between 1997 and March 2000, at which time the study was stopped prematurely because of a "significant beneficial effect of carvedilol on survival."
All patients were stable late class III-IV, with no more than minimal peripheral edema, and "euvolemic." Carvedilol or placebo was initiated at 3.125 mg b.i.d. for 2 weeks, with an increase to 25 mg twice daily at 2-week intervals, as tolerated. The primary end point was all-cause death. Prespecified secondary end points included combined risk of death or hospitalization. Subgroup analyses included age, sex, and EF. A total of 2,289 patients were randomized to placebo or carvedilol. Mean dose at 4 months was 41 mg (placebo) and 37 mg (carvedilol).
Results: There was a 35% decrease in risk of death with the beta blocker (P = .0014), with a cumulative 1-year mortality of 18.5% placebo and 11.4% carvedilol. There was a 24% reduction in the combined end point of death or hospitalization. Benefits were seen in all subgroups. A high-risk cohort was identified by recent cardiac decompensation or an EF < 20%. Carvedilol reduced mortality by 39% and the combined end point by 29%, P = .009 and P = .003, respectively. Drug withdrawal rates were greater with placebo (18.5%) than with carvedilol at 1 year (14.8%).
Packer and associates conclude that in addition to the favorable data with carvedilol in less severe heart failure, the drug was beneficial in individuals with more advanced CHF. The 1-year mortality rate in placebo patients in COPERNICUS was higher than reported in other beta-blocker trials but similar to class IV subjects. EF was lower than in other studies; and also important, there was a significant decrease in death and hospitalization in the very high-risk group. Packer et al conclude that carvedilol was effective and well tolerated overall, even in those at the highest risk. They suggest that not all adrenergic-blocking drugs are similar, and they stress that the BEST trial (see below) was neutral to negative. Whether carvedilol’s additional properties, such as alpha-adrenergic antagonism or antioxidant activity, play a useful role is speculative.
In contrast to the results of COPERNICUS, the BEST report with bucindolol was disappointing. (N Engl J Med. 2001;344:1659-1667.) Patients in this trial had class III-IV heart failure and an EF of < 35%. Bucindolol, a nonselective adrenergic beta-blocker with mild vasodilating activity, or placebo, were administered. An initial oral dose of 3 mg b.i.d. was given for 1 week, increasing to 50-100 mg b.i.d. The planned average follow-up was 3 years. Radionuclear ventriculo grams were obtained at 3 and 12 months. The primary end point was all-cause mortality, with a variety of secondary end points. There were multiple interim analyses in this trial with a change in the monitoring boundaries. Thus, "it is difficult to calculate an adjusted P value." Randomization took place between May 1995 and December 1998, with a total of 2708 patients enrolled in the United States and Canada.
In July 1999, the study was terminated by the sponsors (NHLBI and Department of Veterans Affairs) because of a lack of significant event-curve separation between placebo and beta-blocker. The mean duration of follow-up in BEST was 2.0 years. The average dose of placebo or bucindolol was 76-79 mg b.i.d. Approximately 25% of subjects had discontinued from study medication at the time of trial termination. There was a 10% decrease in mortality with bucindolol, (P = .10; the annual mortality rate was 17% placebo and 15% bucindolol). Cardiovascular death was significantly lower with bucindolol (P = .04); there was a significant reduction in hospitalization for heart failure of 22% (P < .001). The combined end point of death or heart transplantation was slightly diminished by bucindolol (hazard ratio [HR] 0.87; P = .04). EF improved by 7.3 units at 12 months with the beta-blocker vs. 3.3% with placebo. An interesting subgroup analysis indicated that there was a "nominally significant interaction . . . for race (black vs nonblack; P = .02)," related to apparent lack of benefit in blacks, HR for mortality 1.17; P = .27, vs. a "significant survival benefit in nonblack patients, risk reduction 18%; P = 0.01." Less severe CHF patients had a trend toward improved survival with bucindolol as did those with an EF greater than 20%. Only 8% of BEST individuals were in class IV heart failure at baseline; mean EF was 23%. Thus, bucindolol was beneficial in nonblack patients, similar to other beta-blocker CHF trials.
The annual placebo mortality was 16% in BEST—higher than MERIT and CIBIS II but slightly lower than COPERNICUS. Whether there is a true difference in response in black vs. nonblack patients remains unclear, but is suggested by the BEST data. Bucindolol is a nonselective beta-blocker, well tolerated in heart failure, perhaps in part because of alpha blocking and vasodilator properties. The BEST investigators concluded that the BEST findings "raise questions about the efficacy . . . in blacks and in patients with more advanced heart failure, as well as about the equivalency of beta blockers." They call for further studies to examine the possible difference in responsiveness between black and white patients, as well as efficacy in class IV heart failure.
Comment by Jonathan Abrams, MD
COPERNICUS advances the construct of beta-blocker therapy for all patients with CHF and depressed LV function by establishing a major benefit in very ill individuals who are relatively stable and not volume overloaded or hypotensive. In nonblack patients in BEST, there was a benefit in survival and hospitalization that has been noted in all of the major beta-blocker trials; the BEST patients were almost as sick as in COPERNICUS, with similar placebo mortality rates but with different outcomes. For unclear reasons, bucindolol was ineffective in the black population, which represented 23% of the BEST study cohort, far higher than the other beta-blocker trials. Interrogation of the databases of all of the major CHF trials may help answer the question as to whether there is a differential racial response. The hypothesis that there are ethnic differences in response to beta-blockers is an important issue to be assessed in future trials.
Carvedilol is an outstanding drug for heart failure, demonstrating surprising safety and robust efficacy when administered according to the protocol in COPERNICUS and the previous carvedilol trials. Thus, slow uptitration and avoidance of patients with major fluid shifts or large diuretic requirements, hypotension, and significant fluid retention is important. The CAPRICORN trial, using carvedilol in postinfarction patients with depressed left ventricular function, extends the use of this drug to individuals with compromised systolic function who have minimal or no symptoms. Reverse remodeling, ie, an increase in EF or a decrease in left ventricular size, has been demonstrated with metoprolol, bucindolol, and carvedilol. A recent publication suggests carvedilol is more effective than metoprolol in raising EF.1 One does not know until the results of the large COMET trial (metoprolol vs carvedilol) whether carvedilol is a unique molecule and more effective than metoprolol or bucindolol. At the present time, one can conclude: 1) beta-adrenergic blockers should be used in all patients with CHF, irrespective of symptoms, who are clinically stable and have a depressed EF < 30%; 2) carvedilol, metoprolol, or bucindolol are the preferred agents. Bisoprolol appears to be appropriate for nonblack patients but should be proscribed in black patients; 3) clinicians must pay meticulous attention to dose titration and the clinical status of the patients; and 4) general internists and cardiologists should initiate this therapy. The belief in the community that only heart failure specialists are capable of starting patients on beta-blockers is outmoded (a view that harkens back to the early days of ACE inhibitor use when it was also thought that only "specialists" could only be trusted to use these drugs). Beta-blockers as well as ACE inhibitors are now essential drugs for the large majority of patients with CHF and significantly depressed left ventricular function, and they are significantly underused.2 The choice of agent and differential responses to these agents remain unresolved issues and of great importance.
References
1. Packer M, et al. Am Heart J. 2001;141:899-907.
2. Adams K. Am Heart J. 2001;141:884-889.
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