Cardiology · 1987
CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study)
By the mid-1980s, heart failure management had reached something of a ceiling. Diuretics and digoxin controlled fluid retention and symptoms, but neither agent had been shown to extend survival. The neurohumoral hypothesis, which held that activation of the renin-angiotensin-aldosterone system was driving progressive ventricular dysfunction, had theoretical support but no large trial had tested whether blocking it altered mortality. The patients most likely to benefit were also the most precarious: those with NYHA class IV disease, who were dying at rates approaching 50% per year.
CONSENSUS enrolled 253 patients with NYHA class IV heart failure across Scandinavian centers and randomized them to enalapril or placebo on top of conventional diuretic and digoxin therapy. Led by John Kjekshus and co-investigator Karl Swedberg, the trial was designed to detect a survival signal in the most severe heart failure population then studied. At six months, mortality was 44% in the placebo group and 26% in the enalapril group. The difference was large enough that the trial's safety committee stopped it early, judging continued placebo assignment unethical.
The results, published in the New England Journal of Medicine in June 1987, were received with both enthusiasm and some skepticism. The trial was small, confined to the sickest patients, and enalapril's benefit could have reflected protection against the hemodynamic side effects of high-dose diuretics as much as any specific neurohormonal effect. That debate was addressed by subsequent work. The SOLVD Treatment Trial in 1991 enrolled patients with NYHA class II and III disease and ejection fractions below 35%, confirming that enalapril reduced mortality across a broader spectrum of systolic dysfunction.
The mechanism that CONSENSUS implicitly validated, neurohormonal blockade, became the organizing principle for heart failure pharmacotherapy over the following three decades. Beta-blockers, which had long been considered contraindicated in heart failure, were subsequently tested and shown to further reduce mortality; spironolactone and eplerenone extended blockade to the mineralocorticoid pathway. Each of these drug classes demonstrated incremental mortality reductions that were layered onto the ACE inhibitor foundation established by CONSENSUS.
Today, the guideline-directed medical therapy for heart failure with reduced ejection fraction includes an ACE inhibitor or ARNI, a beta-blocker, a mineralocorticoid antagonist, and an SGLT2 inhibitor. CONSENSUS did not establish that entire regimen, but it provided the first mortality evidence that made aggressive neurohormonal blockade credible. The trial was also an early example of stopping a randomized trial early on ethical grounds, a practice that has since developed its own methodology and controversy.
Key People
- John Kjekshus — Lead investigator of the CONSENSUS trial, Norwegian cardiologist
- Karl Swedberg — Co-investigator; subsequent leader in European heart failure research
N Engl J Med. 1987;316(23):1429-1435.
Related landmarks
- 1987 · FDA approval of lovastatin, the first statin (HMG-CoA reductase inhibitor) (Cardiology)
- 1986 · GISSI-1 (Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction) (Cardiology)
- 1988 · ISIS-2 (Second International Study of Infarct Survival) (Cardiology)
- 1991 · SOLVD Treatment Trial (Cardiology)