Carvedilol update III: Rationale for use in congestive heart failure

In February of 1995, several multicenter, double-blind, placebo-controlled clinical trials of the novel, multiple action cardiovascular drug, carvedilol, were terminated prematurely for ethical reasons due to the remarkable reduction in mortality observed in patients receiving carvedilol plus conventional therapy (i.e., angiotensin converting enzyme inhibitors, diuretics and digitalis) compared to patients receiving placebo plus conventional therapy. The dramatic reduction in mortality produced by carvedilol occurred across all studies and was observed in patients with mild, moderate and severe heart failure. The results of these dramatic clinical trials with carvedilol will be presented later this year. The purpose of this update is to describe in detail the multiple pharmacological actions of carvedilol that make this drug unique, and which provide the rationale for its use in congestive heart failure. Carvedilol is both a β-blocker and a vasodilator, and these activities produce significant reductions in myocardial work and reduce all three parameters of myocardial oxygen demand, namely heart rate, contractility and wall tension. The vasodilatory effects of carvedilol reduce afterload, and the resulting decreases in impedance to left ventricular ejection offsets the negative inotropic effect resulting from β-blockade, and as a result, stroke volume and cardiac output are maintained or even increased in patients with congestive heart failure. Carvedilol and several of its metabolites are extremely potent antioxidants, and this activity may account for the dramatic cardioprotective effects observed in animal models, and may also protect the myocardium of patients with congestive heart failure where oxidative stress is now recognized to occur. The antioxidant effects of carvedilol may inhibit both the direct cytotoxic actions of reactive oxygen radicals as well as preventing oxygen radical-induced activation of transcription factors and genes associated with inflammatory processes and cardiac remodeling. Accordingly, carvedilol inhibits the gene expression of ICAM-1, a critical adhesion molecule for polymorphonuclear leukocytes which typically infiltrate the myocardium under conditions of ischemia and exacerbate ischemic injury. These unique actions of carvedilol are not shared by any other drugs currently used in the management of congestive heart failure, or by any other β-blockers. The multiple actions of carvedilol provide the underlying pharmacologic rationale for its use in the treatment of congestive heart failure, and may play a significant role in the remarkable reduction in mortality produced by the drug in clinical trials.