Aspirin in Prevention of Myocardial Infarction

It is 25 years since the start of the first randomised controlled trial of aspirin in myocardial infarction. It showed a 24% reduction in deaths in men on aspirin (8.3% died on aspirin and 10.9% on placebo).1

Since then there have been more than 145 published randomised controlled trials of aspirin and the reduction of the risk of vascular disease. The evidence from these is remarkably consistent indicating that in all patient groups there is a relative reduction of around 30-40% in the incidence of vascular disease events, and one sixth in vascular deaths.2

The case for secondary prevention is accepted. That for primary prevention (in normal people and those at risk of cardiovascular disease but with, as yet, no signs or symptoms) is still debated. According to Professor Gerry Fowkes, Professor of Epidemiology and Head of Public Sciences, the University of Edinburgh, primary prevention may give the same proportionate reduction in cardiovascular events as secondary prevention. There is no evidence of significant heterogeneity in the proportionate reduction in old and young, male and female, people with and without diabetes, or even of different ages.

Professor Elwood suggested that ‘primary’ and ‘secondary’ were misleading terms and Professor Fowkes agreed with him. Professor Fowkes believed that the concept that aspirin may be useful in secondary but not primary prevention is misleading. Categorising people as ‘primary’ or ‘secondary’ is to do so on past events. It is more appropriate to divide people according to their risk of a future event. Having had a previous vascular event is only one item in the assessment of risk of a future event and therefore only one item in the decision whether or not to give prophylactic aspirin.

Overall balance between benefit and adverse effects in aspirin prophylaxis varies according to the patient group. Among those at high risk, 30 to 40 per thousand on aspirin will avoid a vascular event. This drops to 1 or 2 in the lowest risk group. In every 1,000 persons on aspirin, perhaps 1 or 2 may have a gastro-intestinal bleed on aspirin than on placebo (the respective figures are 8/1000 on aspirin and 6/1000 on placebo). Such bleeds rarely threaten life, unlike myocardial infarctions.

These statistics mean that only about 30 high risk patients need to be treated for one year to prevent one event at a cost of around £100. In those at lowest risk the cost of preventing an event, perhaps 3-400 subjects have to be treated for a year to prevent an event, at a cost of about £500. These costs are very much less than those for other anti-platelet drugs and less than other prophylactic drugs such as cholesterol and blood pressure lowering agents.

‘Early’ aspirin, that, is, aspirin given by a doctor or paramedic on first contact with a patient in the acute stage of infarction, is now standard practice. In this, the dose should be at least 300mg even when the patient has already been taking 100mg aspirin a day. However, even now some doctors’ bags do not contain soluble aspirin, and only a minority of patients reach hospital having had it.

Around half the early deaths in myocardial infarction occur before professional help arrives. It would therefore seem reasonable for patients who are judged to be at high risk of a vascular event are advised to carry their own aspirin, and chew and swallow at least 300mg immediately they experience sudden severe chest pain.

One in five deaths from coronary heart disease occur unexpectedly in people thought to be at low risk. Preventing these unsuspected deaths is today’s main challenge. Much coronary heart disease in the community is unrecognised. Evidence in asymptomatic people may include ECG ischaemia or intracoronary calcium on routine chest X-ray. There is a continuum of risk from lower to higher levels that eventually becomes established disease, but many events occur in people who apparently have no cardiovascular disease.

Studies in lower risk groups are continuing. In Dundee researchers are following aspirin prophylaxis in diabetes. In central Scotland the aspirin asymptomatic atherosclerosis trial (AAA) is studying apparently healthy people with some risk of atherosclerotic disease, using early, but asymptomatic, peripheral vascular disease as an entry criterion.

In AAA Professor Fowkes’ team is measuring ankle and arm systolic pressures and calculating the ankle-brachial systolic pressure index (ABPI). The normal ABPI distribution is skewed to lower levels, indicating atherosclerotic disease. At an ABPI of 0.9 or less there is a 2 to 3 fold increase in risk of heart attack or stroke regardless of smoking, hypertension or hypercholesterolaemia. It is a good predictor of future risk. The AAA team is randomly allocating people with low ABPI to aspirin or placebo to see if it makes a difference to their cardiovascular death rate.

Professor Fowkes estimates that aspirin must be taken daily by 100 people at high risk or by 700 people at low risk to save one life in each category. He sees no reason for it to be taken by the population at large, but higher risk groups without vascular symptoms may benefit, mainly by reductions in non-fatal myocardial infarctions.

Box 1. aspirin 75mg daily is effective in the secondary prevention of strokes and heart attacks in people with past myocardial infarctions. There is good reason to believe that it will also prevent them in people at high risk (smokers, with hypertension and/or hypercholesterolaemia) who have, as yet, no cardiac symptoms. Ankle-brachial systolic pressure difference is a good measure of risk