Medical therapy and prognosis in chronic heart failure. Lessons from clinical trials.

The past two decades have witnessed tremendous advances in the pharmacologic therapy of patients with left ventricular dysfunction and chronic heart failure. The pharmacologic repertoire has been and continues to be expanded with newer agents carefully subjected to the rigor of well-designed clinical trials. Treatment has consequently evolved from pathophysiologically guided therapy predicated on older concepts to evidence-guided therapy supported by results of major clinical trials that continue to expand the understanding of the pathophysiology of this complex syndrome. The goals of therapy have ambitiously evolved from the immediate symptomatic relief offered by diuretics; to the short-term hemodynamic improvement in the circulation produced by direct vasodilators; to the intermediate-term improvement in functional capacity and exercise tolerance associated with vasodilators, nitrates, and digoxin; and to the final frontier of long-term improvement in morbidity and survival associated with ACE inhibitor therapy. In addition to the expansion of the understanding of the epidemiology, natural history, and pathophysiology of chronic heart failure, several important lessons in clinical pharmacology have been learned from the clinical trials of the last decade. Many other questions, however, remain unanswered. The role of diuretics, although uncontested in the acute stabilization of congested patients, has yet to be rigorously evaluated in stable patients with chronic left ventricular dysfunction on ACE inhibitors. The long-term effects of nitrates on morbidity and mortality have not yet been established in patients with either ischemic or nonischemic ventricular dysfunction. Vasodilators as a class, and perhaps because they are not a homogeneous class, have had a mixture of successes and failures. There is no evidence that pure vasodilation in and by itself improves survival. There is ample evidence, however, that it improves the circulation and consequently the response to diuretics. This improvement may translate into intermediate-term improvement in functional capacity, but this benefit is seldom sustained. Hemodynamic improvement in the circulation may not always translate into longer-term improvement in morbidity and reduction in mortality. The syndrome of chronic heart failure from systolic left ventricular dysfunction has emerged as a disease of mechanical dysfunction and maladaptation. The maladaptation is a consequence of deleterious effects of compensatory neurohormonal mechanisms: the sympathetic nervous system, renin-angiotensin-aldosterone system, arginine vasopressin, and most likely a host of other mechanisms. The degree of activation of these mechanisms has been established as a marker of prognosis, and the effects of pharmacologic agents on these mechanisms may well determine their long-term effect.(ABSTRACT TRUNCATED AT 400 WORDS)