Carvedilol

Heart failure patients benefit from the addition of a [beta]-blocker to the standard heart failure regimen. (1) The question of which [beta]-blocker yields the greatest effect is still the subject of current research. I would like to provide additional information on [beta]-blockers that was mentioned in "Using Carvedilol to Treat Heart Failure" (April 2002:36-58). The author explained the use of carvedilol in heart failure; however, it is important to mention that there are only 3 [beta]-blockers approved by the Food and Drug Administration (FDA) for use in heart failure: carvedilol (Coreg), metoprolol succinate (Toprol-XL), and bisoprolol (Zebeta).

Like the author suggests, not all [beta]-blockers are the same. Nor is it clear that [beta]-blockers of the same generation are the same. Like carvedilol, bucindolol, a third-generation [beta]-blocker, also sought FDA approval for treatment in heart failure. The BEST trial studied the effects of bucindolol in 2708 New York Heart Association Class III (92%) and IV (8%) heart failure patients. (2) Unfortunately, the study was terminated early because there was no difference in the survival rate between the placebo group and the bucindolol group. The most interesting finding of this study was that not all [beta]-blockers are alike. Bucindolol, a nonselective [beta]-blocker that had strong [[beta].sub.2] and weak [[alpha].sub.1] blocking properties, failed to reproduce the success over placebo that has been reported using carvedilol, metoprolol, and bisoprolol in heart failure patients. (3-5)

An important factor concerning metoprolol is that there was a difference in the clinical trials between metoprolol tartrate and metoprolol succinate. The Metoprolol in Dilated Cardiomyopathy (MDC) trial (6) used metoprolol dosing 2 or 3 times a day and the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (4) (MERIT-HF) used once a day dosing. The mean dose achieved in the MDC trial was 108 mg/day and 159 mg/day in the MERIT-HF trial. The importance of frequency and dosage was established with the MDC trial and MERIT-HF. The MDC trial could only demonstrate an improvement in the morbidity of heart failure patients. (6) The improvement in mortality was only achieved with higher dosing (150 mg) and the extended release form. (4) Carvediol is the only FDA-approved [beta]-blocker to show reduction in both mortality and morbidity from the intermediate to target doses (6.25 mg and 25 mg) within 6 months. (7) The clinical significance is tremendous because patients with heart failure begin to receive mortality benefits much earlier with carvedilol than with metoprolol succinate.

The difference in morbidity and mortality between carvedilol and metoprolol succinate in patients with heart failure was demonstrated by randomized controlled clinical trials. These findings lead to the current and ongoing question: Is selective blockade ([[beta].sub.1]) of the sympathetic nervous system more effective than nonselective ([[beta].sub.1], [[beta].sub.2], [[alpha].sub.1])? The trial that the author presented to compare the effects between carvedilol with metoprolol succinate was a brief (6 months), small (67 patients), not double-blinded study. (8) The trial was not designed to study mortality between the 2 groups. Furthermore, the extended release metoprolol was not used and the target dose of metoprolol was significantly less than previous trials (50 mg vs 150 mg). The findings of this study showed no statistical difference at 6 months between the 2 [beta]-blockers in terms of symptoms, exercise, ejection fraction, and oxidative stress.

Because heart failure is a chronic condition, a longer, larger, double-blinded study designed to investigate mortality is needed to yield the results that clinicians could apply in treating these patients. Such a study is currently underway in Europe. The Carvedilol or Metoprolol European Trial will compare the effects of metoprolol and carvedilol on all cause mortality and all cause hospitalizations and is expected to follow 3000 heart failure patients from 24 months to 44 months. (9) Until the results of this trial are published, the best answer of the question to date, in my opinion, is given in a meta-analysis by Dr Milton Packer and colleagues. (10) The meta-analysis compared all 19 randomized controlled trials with carvedilol and metoprolol, including the trials that directly compared carvedilol to metoprolol. These investigators' findings support the view that nonselective blockade of the sympathetic nervous system in addition to the antioxidant effects of carvedilol has better outcomes for patients w ith heart failure.

Rodel V. Bobadila, MSN, APRN, BC, CCRN, NP-C, FNP

References

(1.) Hunt SA, Baker DW, Chin MH, et al. ACC/ AMA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:2101-2113.

(2.) Beta Blocker Evaluation of Survival Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659-1667.

(3.) CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9-13.

(4.) Hjalmarson A, Goldstein S, Fagerberg B, et al. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001-2007.

(5.) Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure, US Carvedilol Heart Failure study Group. N Engl J Med. 1996:334: 1349-1355.

(6.) Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated Cardiomyopathy. Lancet. 1993;342:1441-1446.

(7.) Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;94:2807-2816.

(8.) Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction and oxidative stress in heart failure. Circulation. 1999;99:2645-2651.

(9.) Poole-Wilson P, Camerini F, Cleland J, et al. Carvedilol or metoprolol (poster].

(10.) Packer M, Antonopoulos GV, Berlin JA, et al. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J. 2001;141:899-907.

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