Anti-platelet effects of aspirin
Introduction
Platelets are small cells in the blood which play a key role in blood clotting. When this happens inappropriately within blood vessels the clots which are formed can be carried to the heart or the brain. Blockage in these organs leads to localised ischaemia resulting in heart attack or stroke.
How it works
Low doses of aspirin affect platelet function by primarily inhibiting platelet cyclooxygenase thereby preventing the formation of the aggregating agent thromboxane A2. This action is irreversible and the effects last for the lifetime of the platelet. New platelets are little affected unless aspirin is taken repeatedly.
Clinical Studies in Cardiovascular Disease
The first randomised controlled trial of aspirin in the prevention of vascular events was published in 1974 and it showed a non-significant reduction in all cause mortality by aspirin of 24%. Since that time many more studies have been carried out culminating in 1994 with the publication of the Anti-platelet Trialists Collaboration meta analysis. This study combined results from 145 randomised controlled trails with a total of 102,459 patients and 10,943 outcome events. It conclusively established that aspirin reduced non-fatal myocardial infarction by ca. 34% and all cause mortality by ca. 16%.
There was no evidence of any important differences in the proportionate benefit after a variety of previous clinical events, including unstable angina, myocardial infarction, stroke, transient ischaemic attack, angioplasty, valve replacement and peripheral vascular disease. Nor was there any significant heterogeneity in the reduction achieved with different groups of individuals including males/females, diabetic/non-diabetic, hypertensive/non-hypertensive and older/younger patients.
Clinical Studies in Stroke
The degree of stroke prevention by aspirin appears to be similar to that with myocardial infarct protection. Thus aspirin reduces the incidence of further cerebrovascular events by 30%. The difference, of course, between stroke and myocardial infarct is that 10-20% of strokes are haemorrhagic in nature and therefore unless an ischaemic lesion can be confirmed by computerised tomography or magnetic resonance scan, aspirin is probably best withheld during the acute phase of the lesion.
Primary prophylaxis
The evidence for so-called "primary prophylaxis" is less robust but a number of studies, taken together, do suggest that patients who have not yet had an infarct but who are at increased risk because of smoking, hypertension, raised cholesterol, obesity, family history, etc., will benefit from low dose aspirin prophylaxis. The clinical judgement of the treating physician is key in this area.
Early aspirin in acute myocardial infarction.
The early administration of aspirin in both acute myocardial infarction and ischaemic stroke is important as evidence suggests that aspirin given within approximately 4 hours of an ischaemic event has a greater effect than if given later. Recommendations exist in the UK that doctors, paramedics and ambulance staff should carry aspirin and treat patients suspected of having a myocardial infarction unless there is an absolute contraindication for its use. However, current evidence would suggest that, even in countries where these recommendations exist, not all doctors and paramedics carry aspirin. Some health authorities in the UK consider this to be an inexpensive and worthwhile practice which could save lives.
An extension of this measure has been recommended by some in the UK which advises patients at high risk of infarction to carry their own aspirin and chew and swallow a tablet immediately they feel chest pain. Evidence suggests that soluble aspirin is particularly appropriate for early use because of the rapidity of its absorption. Studies have shown complete platelet inhibition in volunteers only 15 minutes after chewing 300mg of soluble aspirin. However any aspirin as long as it is chewed and swallowed will be effective.
Aspirin dosage
The Anti-platelet Trialist Collaboration recommended that the dose of daily aspirin for prophylaxis should be in the range 75-160mg. However, a bewildering range of aspirin doses are currently available for prophylaxis globally; daily doses of 50mg, 60mg, 75mg, 81mg, 100mg, 150mg and 162mg are common but probably the most widely used are 75mg, 81mg and 100mg. The first two of these are the doses used mainly in the UK and the USA and their usage is based on the availability of children's aspirin in those countries where the dosage was historically one quarter of the strength of an adult analgesic tablet (300mg and 325mg respectively). Most countries in the rest of the world use a daily dose of 100mg which is the dose recommended by the World Health Organisation in its List of Essential Drugs.
There is little convincing evidence that the dose used in stroke prophylaxis should be any different from that used in myocardial infarct patients. Recommended doses for acute use should be greater than those for prophylaxis in order to inactivate platelets as quickly as possible and thereby potentially limit the extent of the infarct. Single doses of 150-600mg have been suggested.
Aspirin formulations
Formulations of aspirin for cardiovascular use vary widely around the world; plain, soluble, mouth dispersible, microencapsulated, buffered and enteric coated forms are all available in low dose. Recent evidence suggests however that there is little difference between formulations in terms of the likelihood of a serious of gastrointestinal bleed.
In fact it has been estimated that the risk of a bleed which would necessitate hospitalisation as a result of low dose aspirin use is very low at around one incident per 1000 patients per year. This is contrasted with the 30-40 patients with a recent myocardial infarct given low dose aspirin who will avoid a vascular event for every 1000 patients treated per year. An accurate estimate of the percentage of patients who suffer dyspeptic symptoms as a result of low dose aspirin usage is not available but many of these patients may tolerate enteric coated formulations.
For those few patients with an absolute contraindication to aspirin use, an increasing number of effective but more costly alternatives are becoming available. When treating a patient with an acute, evolving myocardial infarction, all formulations of aspirin, when chewed and swallowed, will affect platelets. However, there is good evidence that around 300mg soluble aspirin will inactivate platelets within 15 minutes of dosing because of the rapidity of absorption. When there is a choice therefore it may be advisable to administer a soluble formulation to a patient judged to be suffering an acute myocardial infarction. Clearly, swallowing an enteric coated tablet, without first chewing it, will be of little value in the acute situation.
Treatment costs
The costs of aspirin prophylaxis are minimal; in terms of the sum required to prevent one death in the first year following an infarct, aspirin usage has been estimated (1998) to cost around US$130 per life saved. In contrast, a similar calculation based on the use of a recently introduced product which antagonises ADP-induced platelet aggregation suggests that an equivalent expenditure would be around 200 times more expensive. Figures for a statin may be over US$100,000 per life saved (1998 figures).
This, of course, is not to say that statins should not be used where raised cholesterol is an issue; but in these patients aspirin use should also be considered. On this evidence there could be few who would argue against the increased usage of aspirin in both the developed and developing worlds; in terms of cost effectiveness it can have few, if any equals.