Cardiology

Edited by: James Kling M. Packer, M.R. Bristow, J.N. Cohn, W.S. Colucci, M.B. Fowler, E.M. Gilbert, N.H. Shusterman, "The effect of carvedilol on morbidity and mortality in patients with chronic heart failure," New England Journal of Medicine, 334:1349-55, 1996. (Cited in more than 160 publications to date) Comments by Edward M. Gilbert, division of cardiology, University of Utah School of Medicine, Salt Lake City STANDARD OF CARE: Research by Utah's Edward Gilbert suggests that blocking norepinephrine could be beneficial for heart failure patients. The mechanistic causes of cancer are becoming more clear as research progresses, and most agree that AIDS stems from the action of a single type of virus. But the roots of heart failure-probably shaded by the complexity of the pathways that regulate blood pressure, heart rate, and physiological responses to exercise-are much more difficult to discern. That's one of the reasons why there hasn't been a novel heart failure drug introduced in more than 10 years. But evidence suggests that beta-blockers-so named because they block the action of norepinephrine and related molecules that stimulate the circulatory system-may bring relief to heart patients. High levels of circulating norepinephrine indicate a poor prognosis and may be toxic to the myocytes that compose the heart's muscle tissue. In search of better treatments for heart failure, researchers are now considering carvedilol, a nonspecific beta-blocker made by Philadelphia-based SmithKline Beecham Corp. and Indianapolis-based Boehringer Mannheim Biochemicals Inc. The compound is currently prescribed for hypertension. "Carvedilol has been shown to improve left ventricular function and the pathologic remodeling that occurs in a failing heart, [bringing it] back to a more normal shape and geometry," says Edward M. Gilbert, an associate professor of medicine in the division of cardiology at the University of Utah School of Medicine in Salt Lake City. But the Food and Drug Administration (FDA) is not always impressed with improved physiologic remodeling because such seeming benefits don't always translate into clinical approval, notes Gilbert. SmithKline Beecham enlisted Gilbert and his colleagues to design a trial to test the safety and efficacy of the drug. Although carvedilol is already prescribed for heart failure, SmithKline Beecham wanted FDA to let the company include heart failure in the drug's indications. For its part, the team wanted "to show physicians that this is the standard of care you must provide" for heart patients, says Gilbert. This paper announced the results of that trial, including the surprising finding that patients taking carvedilol had a 65 percent lower risk of death than did controls. Gilbert reports that "95 percent of these patients were on ACE [angiotensin converting enzyme] inhibitors, and over 90 percent were on digoxin and diuretics . . . so they were getting aggressive therapy, and yet we were able to see an advantage by adding carvedilol." He speculates that the paper has been highly cited because it is "the first suggestion that the hypothesis that blocking norepinephrine could be beneficial is in fact true." Beyond improving the condition of the heart, the therapy may actually reduce the rate of death and hospitalization among heart failure patients. The paper certainly isn't the last word on carvedilol, however. When they began the trial, the investigators decided to mea sure the effectiveness of the treatment by evaluating increases in patients' ability to exercise, rather than focusing on the number of hospital stays or risk of death. Only after the trial had been completed did the team realize the surprising effect on mortality. But in order to get FDA consideration, the study would have had to be expressly defined as an investigat ion of mortality from the outset. Therefore, additional trials designed to assess mortality will have to be completed in order for the company to get FDA approval, according to Gilbert. These studies are under way, and Gilbert is optimistic about carvedilol's-and patients'-chances. "Hopefully by the time the Olympics come to Salt Lake City [in 2002], we'll have really solid proof" that carvedilol extends the length and quality of heart patients' lives.

Cardiology

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