From CONSENSUS to SAVE: The Early Development of Inhibition of the Renin-Angiotensin System in the Treatment of Chronic Heart Failure

Abstract

In the 1970s the concept of vasodilation for the treatment of systolic heart failure was launched by Ross and Cohn. Several studies documented the potential importance of this approach, especially in acute heart failure. V-HeFT I (Vasodilator Heart Failure Trial I) finally documented the effect on outcomes in chronic heart failure with the use of the combination of hydralazine and isosorbide-dinitrate (ISDN) compared with placebo. About the same time a new class of agents had been produced based on peptides from the Brazilian snake Bothrops jararaca. These agents inhibited an enzyme, angiotensinconverting enzyme (ACE), which converts the peptide angiotensin I to the potent vasoconstrictor peptide angiotensin II. The first ACE inhibitor was teprotide, a nanopeptide and not orally available, which was shown to induce vasodilation. Captopril was the first oral agent with such potential. As a vasodilating agent it was developed primarily to treat hypertension. Early on it was realized that the vasodilating properties could be used in the treatment of heart failure.Acute hemodynamic studies were also reported. The concept of neurohormonal antagonism was not discussed at that time. By the end of the 1970s, we published studies on the beneficial effects of long-term beta-blockade in patients with dilated cardiomyopathy. To explain the effects, we postulated that chronic sympathetic activation was harmful and that counteraction of this stimulation could induce improvement in myocardial performance. Chronic stimulation by other neurohumoral hormones might induce similar chronic damage. This approach to treating chronic systolic heart failure was proven 20 years later to be the most effective treatment of this syndrome. In July 1981 I joined Professors Kanu Chatterjee and William Parmley at Moffitt Hospital, University of California, San Francisco. They were studying myocardial function by various hemodynamic techniques. It was a most inspiring milieu with leading researchers in various areas, eg, Nelson Schiller in echocardiography, Eli Botvinick in nuclear imaging, Melvin Scheinman in electrophysiology, and Bruce Brundage in cardiac tomography. In addition, there were a number of very impressive fellows, eg, Eric Topol, Ralph Brindis, and Larry DiCarlo. As Chatterjee et al had just investigated the acute hemodynamic effects of captopril, another ACE inhibitor, MK421 (enalapril) fromMerck, was planned for investigation. I became involved in the evaluation of this agent. We found in an open study that an oral dose of 10 mg twice daily produced hemodynamic changes that were maintained for ≥4 weeks. In another study, we found that there was intense myocardial norepinephrine release from failing myocardium. This finding was in contrast to the myocardial norepinephrine depletion found in such hearts. The chronic neuroendocrine activation and the results of our study triggered some thoughts about neurohumoral activation in other neuroendocrine systems eg, the renin-angiotensin-aldosterone system (RAAS). The potential of new RAAS antagonists to provide more interesting effects above and beyond those which could be achieved by means of vasodilation per se would be most interesting. After my return to Sweden in the autumn of 1982, I became much involved in studies of beta-blockers in acute myocardial infarction. Studies with ACE inhibitors in chronic heart failure started to appear over the next few years with both captopril and enalapril. I remember particularly a placebocontrolled study by Norman Sharpe et al in New Zealand. In 1984 he visited us as part of a sabbatical. In 1984 we also started to discuss with Merck an outcome trial in chronic heart failure (CHF). John Kjekshus from Oslo, Norway, had very good contacts with Merck. Together with experienced people from Gothenburg (LarsWilhelmsen, Anders Vedin, and Claes Wilhelmsen), we were able to negotiate funding for a study on the effect of enalapril on mortality in CHF. Up to then, From the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom. Manuscript received November 5, 2015; revised manuscript accepted November 17, 2015. Reprint requests: Karl Swedberg, MD, PhD, Department of Medicine, Sahlgrenska University Hospital/Ostra, 41685 Gothenburg, Sweden. Tel: +46313421000. E-mail: karl.swedberg@gu.se. See page 397 for disclosure information. 1071-9164/$ see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2015.11.007