Carvedilol update .4. Prevention of oxidative stress, cardiac remodeling and progression of congestive heart failure

On May 29, 1997, the United States Food and Drug Administration granted final approval for the use of carvedilol in the treatment of mild to moderate congestive heart failure. In this action, the United States joined 20 countries worldwide that have approved carvedilol (Coreg(R)/Kredex(R)) for treatment of hypertension and congestive heart failure. Carvedilol is also approved for the treatment of angina in several countries. Carvedilol (Fig. 1) is a chemically distinct and pharmacologically unique agent that possesses multiple pharmacological actions, including: 1) nonselective B-adrenoceptor blockade, 2) alpha(1)-adrenoceptor blockade, 3) potent antioxidant activity, and 4) regulation of genes involved in cardiovascular organ remodeling and apoptosis. Based on this pharmacological profile, carvedilol is uniquely positioned to inhibit several of the major congestive heart failure, including: 1) hemodynamics: reduction of preload, afterload and heart rate; 2) neurohormonal: inhibition of the sympathetic nervous system, renin-angiotensin system and endothelin; 3) oxidative stress: scavenging potentially toxic oxygen radicals and restoring endogenous antioxidants; 4) genomic reformatting: suppression of several genes associated with pathological organ remodeling. Thus, carvedilol, through its multiple actions, has the capacity to provide broad cardiovascular organ protection. As a result of these multiple actions, carvedilol, when used in conjunction with standard therapy for heart failure (i.e., diuretics, digoxin, and angiotensin-converting enzyme inhibitors), significantly reduced morbidity, mortality and hospitalization in patients with congestive heart failure of either ischemic or nonischemic (i.e., idiopathic dilated cardiomyopathy) origin, independent of disease severity (mild to moderate) or left ventricular function (ejection fraction). The highly favorable clinical outcomes from the large multicenter clinical trials conducted with carvedilol in the United States and Australia/New Zealand merits a detailed update of the unique mechanisms of action of carvedilol, and a thorough review of the clinical trial results. Accordingly, we will highlight in this update our previous experimental findings with carvedilol as well as more recent data that shed light on the mechanisms by which this drug produces its effects in congestive heart failure. In addition, an update of the results from the large multicenter clinical trials, which formed the basis for the approval of the drug for the treatment of heart failure, will be presented.