Can Beta-Blockers Prevent Anthracycline-Induced Cardiomyopathy?
Can Beta-Blockers Prevent Anthracycline-Induced Cardiomyopathy?
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Kalay N, et al. Protective Effects of Carvedilol Against Anthracycline-Induced Cardiomyopathy. J Am Coll Cardiol. 2006;48:2258-2262.
Anthracyclines may produce cardiotoxicity by apoptosis and free radical formation. Carvedilol, in addition to being a nonselective beta-blocker and alpha 1 blocker, is antioxidant and antiapoptotic. It has been shown to be effective in the treatment of anthracycline-induced cardiomyopathy, but not as a prophylactic agent. Thus, Kalay and co-workers in Turkey conducted a placebo-controlled trial of carvedilol 12.5 mg once daily vs placebo in patients undergoing anthracycline-based chemotherapy. Therapy was continued for 6 months. The primary endpoint was echocardiographic left ventricular (LV) systolic function. Each group had 25 patients who were well matched. Baseline LV ejection fraction (EF) was 70% in both groups. Total mortality was one carvedilol patient and 4 controls (p = NS). Echocardiograms at 5 months showed no change in EF in the carvedilol group and a decrease from 69% to 53% in the controls (p = .001). Also, LV volumes were significantly increased in the controls. Heart failure requiring further therapy or hospitalization occurred in one carvedilol patient and 4 controls. Only this one carvedilol patient exhibited a drop in EF below normal. The authors concluded that the prophylactic use of carvedilol in patients undergoing anthracycline-based chemotherapy may prevent the development of cardiotoxicity.
Commentary
The approach in this study is different than that taken in the ACEI study. Here carvedilol was started before chemotherapy was begun. Also, no biomarkers were used to select patients. In addition, the study terminated at 6 months. This is a potential issue because late cardiomyopathy development, even years later, has been seen with anthracyclines. Again, the issue of duration of therapy arises and dosage. Carvedilol was given only once a day at a modest dose, not at maximum doses twice a day as has been done in heart-failure trials.
The mechanisms of this protective effect of carvedilol are unknown, but if antioxidant, antiapoptotic and alpha 1 blocking are involved, then other beta-blockers without these properties may be ineffective. Not discussed is the potential for adverse effects, especially if carvedilol is given during chemotherapy when hemodynamic stability may be an issue. The biggest deficiency of this study is its small size. Nevertheless, the data are quite compelling.
So what are we to do? Give carvedilol early and check troponins, then start ACEI if TnI rises, but wait for one month? That is what these 2 trials would suggest. Will dual therapy cause unacceptable decreases in blood pressure? Should we just start both drugs in everyone prior to anthracyclines or high-dose chemotherapy? Further studies will be needed to answer these questions, but adopting this therapy also seems to have little downside and will probably be employed before definitive trials can be done.
Anthracyclines may produce cardiotoxicity by apoptosis and free radical formation. Carvedilol, in addition to being a nonselective beta-blocker and alpha 1 blocker, is antioxidant and antiapoptotic.Subscribe Now for Access
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