In the early 1980s, hypertension conferences were routinely enlivened by the poisonous Brazilian viper, Bothrops jararaca. With its striking zig-zag markings and aggressively protruding tongue, images of the snake were a welcome break from graphs and tables in presentations about captopril — the first of the angiotensin-converting enzyme (ACE) inhibitors, whose effects on blood pressure mechanisms mimicked those of the snake’s venom. When the cardiovascular juggernaut alighted in Sao Paulo, Brazil, for a major congress in 1984, there was even an opportunity for delegates to visit a snake farm and see the beast in all its glory.
“The discovery of the ACE inhibitors and the creation of captopril was one of the really great advances in cardiovascular medicine, alongside beta blockers, calcium channel blockers and statins. When captopril arrived, there was a lot of excitement and a feeling that acting on the renin-angiotensin system was going to be a very important step forward,” recalls Philip Poole-Wilson, emeritus professor of cardiology at the National Heart and Lung Institute, Imperial College, London.
ACE was identified as the enzyme responsible for the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II, in the mid 1950s.1 In 1968, studies carried out in the Royal College of Surgeons laboratories of Nobel prize winner, John Vane, showed that peptides from the Brazilian viper’s venom inhibited the activity of ACE from dog lung.2 When Vane proposed an ACE inhibitor research programme to US pharmaceutical company, ER Squibb and Sons (now part of Bristol Myers Squibb), clinical advisers were wary because, at that time, the renin-angiotensin system was thought to play a role only in the most serious “malignant” hypertension.3,4 However, it was decided that there was enough clinical interest to proceed with trying to develop synthetic ACE inhibitors that were orally active.3,4
Between 1970 and 1973, Squibb scientists randomly tested about 2,000 chemical structures for ACE inhibitor activity4 but could not find what they wanted. Their luck changed on Wednesday, 13 March 1974, when they decided to follow up some newly published research on an inhibitor of carboxypeptidase A — an exopeptidase thought to have a similar active site to ACE.4 Then, 60 compounds and 18 months later, they had captopril, and early clinical studies confirmed its antihypertensive effects.5
The 1981 launch of captopril brought fresh headaches for Squibb as a battery of papers and letters started to appear reporting serious hypotensive effects of the high doses of captopril that were initially recommended.
Reporting four-year data on their first 200 patients treated with captopril, the US group, which did some of the first clinical trials on captopril, concluded that the initial doses used of 400mg–1,000mg/day were “excessive” and reported that it was managing most patients with normal renal function on doses of 50mg–150mg/day.6 It explained that the original dose-ranging studies for captopril were carried out during the rebound phase of drug resistance seen in many patients after the first dose, unrecognised at the time of the studies.6 As a result, the recommended doses, based on these studies, were far higher than necessary. The British National Formulary currently recommends a captopril starting dose of 25mg/day when the drug is used alone in hypertension, with a usual maintenance dose of 50mg/day.
Even when the doses of captopril that were used in the 1980s started to come down, some patients experienced a first-dose hypotension and, when it became clear that ACE inhibitors had a role to play in heart failure, the need to resolve the issue of dosing and hypotension took on a new urgency. “There is greater activation of the renin-angiotensin system in heart failure patients because of the use of diuretics, and so the same dose of ACE inhibitor produces a much greater effect than in hypertensive patients,” Professor Poole-Wilson explains.
“While most hypertensive patients could cope with feeling a little dizzy, the combination of low blood pressure, deteriorating renal function and increased plasma potassium could result in arrhythmias and deaths in heart failure patients,” he adds.
By the mid-80s, captopril had a rival in the longer-acting Merck ACE inhibitor enalapril, which initially appeared to have a better side effect profile as well as an easier dosing schedule. However, as with captopril, the launch dose of enalapril appears to have been too high, and reports of severe hypotension after the first dose in heart failure patients led to recommendations that initiation of all ACE inhibitor treatment should be carried out under strict medical supervision.7 A serious question mark hung over the future of ACE inhibitors, at least in heart failure.
CONSENSUS to the rescue
The outlook for ACE inhibitors changed dramatically in 1987 with the publication of the Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS).8 This showed a 31 per cent reduction in mortality at one year in patients with severe heart failure who were treated with enalapril. Dropping the dose of enalapril as low as 2.5mg daily in high risk patients reduced the problem of hypotension to acceptable levels.
“The trial was stopped early by the data and safety monitoring board of the study and the triallists were called to a meeting. They were pretty furious but, when the results were presented to them, there was spellbound silence. There had never been such a significant reduction in heart failure mortality in a major trial,” explains Professor Poole-Wilson.
Further trials produced equally impressive results in less severe disease. In a September 1992 issue of the New England Journal of Medicine, the Survival and Ventricular Enlargement (SAVE) trial reported a 20 per cent reduction in mortality in heart attack patients with left ventricular dysfunction treated with captopril,9 and the Studies of Left Ventricular Dysfunction (SOLVD) trial showed a 29 per cent reduction in heart failure and deaths in patients with asymptomatic left ventricular dysfunction.10
As it became clear that ACE inhibitors saved lives, there was renewed effort to find a way of administering them safely to heart failure patients. Admitting every patient to hospital for a test dose was impractical and expensive. On the basis of a comparison of large fixed doses of captopril and enalapril, which showed that the longer acting drug produced more prolonged hypotensive effects,11 a system was introduced for administering a small test dose of the short-acting captopril and, if all went well, increasing the dose or switching to enalapril.
“It was all a nonsense because we now take the opposite view, that the longer acting ACE inhibitors, such as lisinopril and perindopril, which we use today, have a slower onset of action and are therefore less likely to cause problems than a fast onset, shorter acting drug. What really mattered was the dose, and the need to start on a reasonable dose and move up gradually rather than starting high and reducing the dose, as tended to happen in the US,” says Professor Poole-Wilson.
In 1999, the Assessment of Treatment with Lisinopril and Survival (ATLAS) study provided the evidence needed to support this approach, showing that maintaining patients on low doses of ACE inhibitor was unlikely to achieve the survival benefits seen in the earlier outcomes studies, but that there was little advantage of using high doses over intermediate doses.12
Outmoded but not forgotten
Captopril is rarely used today. As Professor Poole-Wilson explains, better once-daily ACE inhibitors have come along that are easier for patients to use within the cocktail of drugs they may need to control their blood pressure or heart failure. But, he concludes that captopril did herald major changes in approach to treatment of hypertension and heart failure.
“When I was at medical school, heart failure patients were treated with bed rest, digoxin and diuretics. Now, we put them on an exercise programme and treat them with diuretics, ACE inhibitors and beta blockers. As a result, patients have better control of symptoms, there are fewer admissions to hospital, and we have seen a 15 per cent reduction in mortality at a year. The gloomy side is that heart failure is becoming more common as patients get older and more survive heart attacks. The prognosis still remains poor, with 50 per cent of patients dead within three years. ACE inhibitors contributed to the improvement in outlook, but they haven’t provided a cure.”
- Erdös EG. The ACE and I: how ACE inhibitors came to be. The FASEB Journal 2006;20:1034–38.
- Bakhle YS. Conversion of angiotensin I to angiotensin II by cell-free extracts of dog lung. Nature 1968;220:919–21.
- Smith CG, Vane JR. The discovery of captopril. The FASEB Jounal 2003;17:788–9.
- Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991;17;589–92.
- Gavras H, Brunner HR, Turini GA, Kershaw GR, Tifft CP, Cuttelod S et al. Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. New England Journal of Medicine 1978;298,991–5.
- Hoorntje SJ, Donker AJ. Clinical use of captopril. Hypertension 1981;3:507–8.
- Cleland JGF, Dargie HJ, McAlpine H, Ball SG, Morton JJ, Robertson JIS et al. Severe hypotension after first dose of enalapril in heart failure. BMJ 1985;291:1309–12.
- The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS).New England Journal of Medicine 1987;316:1429–35.
- Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction — results of the survival and ventricular enlargement trial. The SAVE Investigators. New England Journal of Medicine 1992;327:669–77.
- The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. New England Journal of Medicine 1992;327:685–91.
- Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. New England Journal of Medicine 1986;315:847–53.
- Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312–8.
Professor Poole-Wilson was interviewed for this article shortly before his sudden death on 4 March 2009. A distinguished former President of the European Society of Cardiology and of the World Heart Federation, Professor Poole-Wilson made an important contribution to understanding and treatment of heart failure, challenging dogma, encouraging young cardiologists, and supporting international research collaborations. He was on his way to give a lecture to medical students when he died.