Hormones, drugs, remodeling and outcome in heart failure and after myocardial infarction.

Abstract

Sustained neurohormonal activation commonly occurs after large myocardial infarctions (MI) and in chronic heart failure. This activation is thought to be a critical contributor to the progressive left ventricular structural remodeling that accompanies these syndromes and appears to shorten life expectancy [1]. The clinical efficacy of beta blockers after MI was demonstrated before the structural remodeling process was understood [2] and thus the mandate for their use in this setting is based on outcome not on mechanism. In contrast, the mandate for angiotensin convertingenzyme (ACE) inhibitors is based on both outcome and a favorable effect on remodeling after MI [3,4]. The sequence of investigation was reversed in heart failure, in which ACE inhibitors were first demonstrated to be effective on both remodeling and outcome [5,6] whereas the beta blocker efficacy on these end-points could only be studied in ACE inhibitor-treated patients [7,8]. This historical discrepancy has left evidence-based zealots without the proof that beta blockers work as well without ACE inhibitors in heart failure and without the proof that beta blockers inhibit remodeling after acute MI. And it is hard to turn back the clock to accumulate these data, since ACE inhibitors are mandated therapy in chronic heart failure and beta blocker use is a mandated guide to good clinical management after acute MI. Insightful clinical scientists recognize that the mechanisms contributing to adverse outcomes and their response to therapy are probably similar in patients with different disease entities such as myocardial infarction and heart failure. So we comfortably utilize the two drug groups together in both syndromes, with the assumption that they are contributing independently to a favorable effect on both remodeling and outcome. That independence is better demonstrated in chronic heart failure than it is in the postinfarction period. Furthermore, the therapeutic choices have recently been expanded by the availability of angiotensin receptor blockers [9] and the demonstration that spironolactone may also exert a favorable effect on outcome [10], possibly through an anti-remodeling action. So physicians are confused and conflicted. Should they use all the drugs together because of their likely independent effects? Should they accept the high cost, potential side effects and complexity of this polypharmacy? Or should they be selective by trying in the absence of persuasive data to determine who should receive an ACE inhibitor, who a beta blocker, and who both? The CARMEN trial, described in this issue of Cardiovascular Drugs and Therapy [11], should help to answer some of these questions. Furthermore, by studying the effect of an unusual beta blocker, carvedilol, with additional pharmacological properties, including alpha 1-adrenergic blockade and antioxidant properties, the protocol should provide valuable new therapeutic efficacy data. Could this single drug produce an effect as great as an ACE inhibitor-beta blocker combined? Or will the study corroborate the clinical suspicion that beta blockers exert a synergistic effect with ACE inhibitors? For those who are dedicated to reducing the use of multiple drugs in the absence of demonstrated independent efficacy, this could be an important study. The problem facing the CARMEN investigators in designing the study was that it could not easily be powered for morbid events. Thus a more sensitive marker for efficacy was both necessary and preferable. Indeed, morbid events are likely to occur in only a small fraction of the patients entering a study like CARMEN, and thus the majority of randomized patients would not contribute to the end-point. Monitoring structural changes in the left ventricle provides an end-point to which all patients should contribute and also might provide a mechanistic marker that could be used in clinical management. The problem is not simple, however. Echocardiography is notoriously unreliable in multicenter studies, and the primary end-point selected by the investigators— end systolic volume—is particularly difficult to quantitate in assymetic ventricles after MI. We have recently been using magnetic resonance imaging technology in an effort to improve the precision of quantitation. The analysis of these clinical and echo data will strain the