Vasodilator and inotropic drugs for the treatment of chronic heart failure: Distinguishing hype from hope

Abstract

During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.

Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable haemodynamic monitor: results of a 1 year multicentre feasibility study

“…Although some studies have demonstrated that acute haemodynamic changes in response to drug therapy are poor predictors of long-term clinical outcomes [1,2] , it has been suggested that serial measurements, rather than isolated 'snapshots', might provide unique insight regarding pathophysiological mechanisms and responses to treatment. Other studies of titration of vasodilator dosage according to haemodynamic end-points have demonstrated important clinical improvements that may not have been possible when simply using an empirical target dose [3,4] .…”

Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

“…A variety of therapeutic strategies have been applied to augment the depressed left ventricular function of heart failure, particularly during periods of acute decompensation (Packer, 1988;Rahimtoola, 1989;Shipley and Hess, 1995). Current clinically available inotropic agents that act via elevation of cyclic AMP, such as dobutamine and phosphodiesterase inhibitors; are associated with tachycardia, significant changes in preload or afterload or increases in myocardial O 2 consumption (MVO 2 ), and decreases in myocardial mechanical efficiency (Katz, 1986;Simaan et al, 1988).…”

“…In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO 2 was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O 2 utilization in the failing heart while providing inotropic support comparable to a ␤-receptor-mediated agonist.A variety of therapeutic strategies have been applied to augment the depressed left ventricular function of heart failure, particularly during periods of acute decompensation (Packer, 1988;Rahimtoola, 1989;Shipley and Hess, 1995). Current clinically available inotropic agents that act via elevation of cyclic AMP, such as dobutamine and phosphodiesterase inhibitors; are associated with tachycardia, significant changes in preload or afterload or increases in myocardial O 2 consumption (MVO 2 ), and decreases in myocardial mechanical efficiency (Katz, 1986;Simaan et al, 1988).…”

A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure.

“…Phases 2, 3, and 4-Efficacy periods. Phases [2][3][4] consisted of three identical double-blinded, study drug administration periods lasting for 8 weeks each. The study was designed for each patient to cross over to a different study drug treatment regimen every 8 weeks so that by the end of the study, all patients would have received all three treatment regimens in a random fashion.…”