Beneficial Effects of Carvedilol on Angiotensin-Converting Enzyme and Renin Escapes in Patients with Chronic Heart Failure Alain Cohen-Solal Hopital Beaujon, Clichy, France Heart failure is now understood to be a disorder involving chronic abnormal activation of multiple neurohormonal pathways. Although the ability of carvedilol to block several components of the adrenergic system is well understood, this interesting study demonstrates a potent mechanism of action via the renin-angiotensin system as well. Carvedilol, a nonselective beta-blocker, provides blockade of multiple adrenergic pathways in the failing heart. Angiotensin-converting enzyme (ACE) inhibitors, which are clearly effective for patients with all degrees of heart failure, have been a component of standard heart failure therapy for several years. However, the phenomenon of "escape" from ACE inhibition has been reported in some patients receiving long-term therapy. This could be due to pharmacologic tolerance, progression of disease, or possibly the complexity of the renin-angiotensin-aldosterone system, such that blockade of the conversion of angiotensin I to angiotensin II may not be sufficient to prevent all of the pathophysiologic consequences of renin activation. The clinical expression of this phenomenon may be linked to certain distinct phenotypes of the ACE protein. Today, Dr. Cohen-Solal reported on a specific subset of results from a trial that evaluated the anti-oxidant properties of carvedilol, the primary results of which were reported elsewhere at this meeting and also at the American Heart Association meeting last year. The current results focus on the beneficial effects of carvedilol on renin "escapes" among patients with chronic heart failure. The 6-month study included 50 patients with stable New York Heart Association Class II or III failure, with a left ventricular ejection fraction below 40%, and with treatment using diuretics and ACE inhibitors, as well as digoxin if indicated. Patients were randomized in a double-blind manner to receive carvedilol or a placebo. Carvedilol reduced renin levels and ACE activity, whereas both increased in patients in the placebo group. Therefore, "escape" was occurring in patients receiving placebo because renin and ACE activity rose while they were on ACE inhibitor therapy. However, carvedilol reduced this escape phenomenon. Aldosterone levels were unchanged in both groups, suggesting that aldosterone escape remains unaltered by beta-blockade. In addition, despite significant improvements in ejection fraction and New York Heart Association functional class, the other neurohormones that were measured were unaffected by carvedilol. Dr. Cohen-Solal concluded: "Therefore, the marked beneficial effect of carvedilol in heart failure may be partly related to more complete and sustained chronic blockade of the renin-angiotensin system. It is difficult to tell at this point how much of the observed beneficial clinical effect of carvedilol in heart failure may be attributable to this alternate pathway. As we develop this information further, and as we find ourselves with more choices in the future for neurohormonal blockade in heart failure patients, we may use this additional potent effect of carvedilol as a means to help us provide the greatest therapeutic effect with the fewest drugs possible." Reporter: Andre Weinberger, MD Copyright 2000-2013 by HESCO International, Ltd. All rights reserved.