A recent health economics study in France projected that over a four-year period, the revolutionary ACE inhibitor therapy could save 16,000 lives in France alone, and offer savings of about pounds 370m to the national health-care budget by reducing the length of time patients stayed in hospital.
ACE inhibitors are used to treat high blood pressure (hypertension) and heart failure. Although hypertension, which affects one in five adults in the United Kingdom, rarely causes symptoms, it is a big contributor to deaths from strokes and heart attacks. We do not fully understand why people become hypertensive, but we know that renin, an enzyme released from the kidneys, plays a significant part.
Renin acts on a protein in the bloodstream to form a relatively inactive substance called angiotensin I. This is transformed by an enzyme into the most potent known constrictor of blood vessels, angiotensin II.
If a drug could block the formation of angiotensin II, it might dramatically lower blood pressure. This was the premise on which the search for an inhibitor - an angiotensin converting enzyme (ACE) - began.
Dr Miguel Ondetti, an organic chemist working at the Bristol-
Myers-Squibb Pharmaceutical Institute in Princeton, New Jersey, looked at several thousand compounds before he and his co-
workers isolated the first ACE inhibitor, teprotide, from the venomous Brazilian arrowhead viper, Bothrops jararaca.
Unfortunately, it was effective only when given as an injection, and was therefore inappropriate for routine therapy.
The next advance came when the Princeton team, using new data on enzyme architecture and the latest computer graphics, set out to design a molecule with the structure needed to block the active site of the converting enzyme. This resulted in the world's first orally active ACE inhibitor, captopril, which did indeed dramatically lower blood pressure.
The drug became available in this country in 1981 for treatment of severe cases, but soon was licensed for use in mild to moderate hypertension and congestive heart failure. Initially, it was used at higher doses than it is today, and side-effects were not uncommon. However, it soon became apparent that, generally, patients felt better.
Some of the older drugs produced adverse side-effects, including fatigue, depression and impotence in men. Today, however, the ACE inhibitors, in common with several of the new anti-hypertensive drugs, are thought to improve patients' quality of life.
In little more than a decade's experience, perhaps the most exciting contribution has been in the drugs' treatment of heart failure. The symptoms of this common condition are distressing and relentless; patients accumulate fluid on the lungs and become increasingly short of breath. Life expectancy for many is worse than in most forms of cancer.
This depressing picture began to change with the report in June 1987 on a large trial, called Consensus, in Scandinavia. About 250 severe heart failure patients were randomly assigned supplies of Merck Sharp and Dohme's enalapril, the second ACE inhibitor to become available, or dummy tablets, as well as their conventional therapy. Twelve months later, results showed that the ACE inhibitor not only relieved symptoms but also reduced the death rate by about one-third.
This showed for the first time that something could be done to improve the survival rate of heart failure victims. And further large- scale trials have confirmed these benefits for patients who have less severe, and even symptomless disease. Heart failure may develop in patients after a severe heart attack. This is believed to be primarily because of damage to the heart's main pumping chamber, the left ventricle; the chamber enlarges over time and pump failure ensues.
In the Fourth International Study of Infarct Survival (ISIS-4) involving 60,000 patients, Oxford researchers will compare the use of captopril and two other agents - as well as other drugs such as aspirin - given within 24 hours of suspected acute heart attack.
The trial co-ordinator, Dr Rory Collins, believes that while benefits have been shown in heart failure, 'clear data should emerge in the next year or two' in cases of acute heart attack. Results of ISIS-4 and the Italian GISSI-3 study, which is assessing the ICI ACE inhibitor lisinopril in 20,000 patients, are expected to be presented to the American Heart Association in Atlanta in November.
Wall Street is also keeping a close eye on events. If these drugs are shown to reduce the death toll among heart attack victims, clinical practice and the market share of the ACE inhibitors will be substantially altered.
Like most sophisticated new drugs, ACE inhibitors are expensive, but Professor Philip Poole- Wilson, a cardiologist at the National Heart and Lung Institute, London, contends that they are very cost-effective. It is not often that new treatments have been shown to 'improve quality and length of life', he says. 'The treatment of heart failure in the United Kingdom should be given higher priority in the allocation of health resources.'
While the clinical and economic arguments for greater use of ACE inhibitors are persuasive, much still has to be learnt about these drugs, including optimal dosage.
Then there is the intriguing finding that the renin-angiotensin system not only circulates but can also be localised in various tissues, such as the heart, kidney and even the brain. Many researchers believe that these local 'biochemical cascades' may play important roles in health and disease.
The author works at the Royal Brompton National Heart and Lung Hospital, London.
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