Aspirin and Vascular Disease

Myocardial infarction: The first randomised controlled trial of aspirin in the prevention of vascular events was set up in 1969 and published in 1974 (Elwood et al 1974). Over one thousand post infarction male patients were put on a daily dose of 330 mg aspirin, or matching placebo. A reduction by aspirin in all-cause mortality by aspirin of 24% was observed (95% CI -42.4% to 5.3%).

This first trial stimulated wide interest and by 1980 five other trials had been reported, the results of none of which were significant at conventional levels of probability. However the combined results of the six trials indicated a highly significant reduction in total mortality by aspirin (overall reduction: 23%: 95% CI 21.7 to 24.3).

Several major overviews of aspirin trials have since been published, the most recent being by the Antiplatelet Trialists Collaboration (1994). This combines results from 145 RCTs with a total of 102,459 patients and 10,943 outcome events. This makes aspirin, used in vascular disease, by far the most thoroughly investigated drug available in clinical practice. It establishes that aspirin reduces non-fatal myocardial infarction by 34% and all-cause mortality by about 16% with no evidence of any important differences in the proportionate benefit after a variety of previous clinical events (unstable angina, MI, stroke, peripheral vascular disease and artery and valve surgery). Nor is there any evidence of significant heterogeneity in the reduction achieved within different groups of patients (males/females, older/younger, diabetic/non-diabetic, hypertensive/non-hypertensive, older and younger). With this evidence, the current under-use of prophylactic aspirin, evidence for which is given later, is inexcusable.

An Overview Of Rct's Of Aspirin And Cardiovascular Disease.

Reduction in various groups of patients:
Prior MI 11trials 25% reduction
Acute MI 9 29%
Prior stroke or TIA 18 22%
Other high risk 104 32%
ALL PATIENT GROUPS 25% reduction

Reduction in the separate outcomes:
Non-fatal MI 122 trials 34% reduction
Non-fatal stroke 124 25%
Vascular death 144 17%
All-cause death 144 16%

There was no evidence of any difference in the reduction by aspirin in:

male and female patients patients under and over 65years of age hypertensive and normotensive patients diabetic and non-diabetic patients

Based on Antiplatelet Trialists Collaboration (1994).

Of course there are failures. Some of these failures are undoubtedly due to poor compliance. In the Physicians Health Study (Glynn et al 1994) aspirin was to be taken on alternate days, and it was possible to assess compliance. Subjects who took aspirin on every day recommended experienced a 51% reduction in vascular events, wheras those who complied poorly (took aspirin on less than half the days recommended) showed on 17% reduction.

Additional to this, platelets are not responsible for every vascular event, and aspirin does not prevent every infarction. However a number of studies have compared infarctions in patients who had been taking aspirin and in control patients who had not been on aspirin at the time of their infarction. The MI which developed appears to have been modified by aspirin, increasing the likelihood that it would be less severe and of the small, non Q-wave variety (Col et al 1995; Garcia-Dorado et al 1995).

Aspirin and Stroke : The use of aspirin in stroke prophylaxis appears to be in line with MI prevention both in the degree of protection and in the dose that is appropriate (Gijn 1999). Thus aspirin reduces the incidence of further cerebro-vascular events by about 30% (Antiplatelet Trialists Collaboration 1994; Solomon et al 1994) and long-term aspirin prophylaxis should therefore always be considered in patients at risk of an ischaemic cerebral event. The differential diagnosis between an ischaemic lesion and cerebral haemorrhage is of course impossible on clinical grounds alone. If computerised tomography (a CT scan) can be performed and if this indicates an ischaemic lesion, aspirin should be given as early as possible, but if haemorrhage is demonstrated by CT, then aspirin should be withheld during the acute phase of the lesion.

The question naturally arises as to the advisability of aspirin prophylaxis in the acute phase of a stroke if CT cannot be performed. Evidence on this has been provided by two recent large randomised trials: CAST (Chinese Acute Stroke Collaborative Group 1997) and IST (the International Stroke Trial Collaborative Group 1997). These trials together indicate that aspirin, given as early as possible on diagnosis of a stroke, leads to a further reduction of about 10 deaths or recurrent strokes per 1,000 patients, compared to the saving by aspirin prophylaxis commenced later, while the incidence of cerebral bleeding is likely to be at most 1 per 1,000 with aspirin. That is, aspirin commenced immediately after the onset of stroke symptoms, when CT is not available, will lead to a decrease in the number of deaths and disabling strokes which is `modest but worthwhile' (Kmietowicz 1997).

Mechanisms in cardio-embolic stroke are different and anticoagulation, rather than aspirin, is the treatment of choice. Nevertheless, an overview of relevant trials did show a reduction by aspirin in stoke in patients with atrial fibrillation, though the reduction of 21% by aspirin compared with a reduction of two thirds by anticoagulants (The Atrial Fibrillation Investigators 1997). If therefore facilities for monitoring are not adequate and it is decided not to use anticoagulants, aspirin should certainly be included in the management of patients with AF.

aspirin and so-called `primary' prevention : All but a very few of the major trials have been based on patients who have already experienced a major vascular event. Questions have arisen about aspirin prophylaxis in primary prevention, that is, in subjects who have not already had an MI, stroke or other vascular event. These questions arise from a misleading understanding about so-called `primary' prevention.

Relevant data come from a number of trials. 5,139 Healthy British doctors, half of whom were given 500 mg aspirin per day for six years gave no evidence of protection from aspirin (Peto et al 1988). A trial of 22,071 American physicans who were given 325 mg aspirin on alternate days, was however stopped prematurely when a monitoring committee reported a relative reduction by aspirin of 44 in the incidence of non-fatal myocardial infarction. Subsequent analyses of the complete results raised doubts however about the wisdom of extrapolations from this trial because of a cardiovascular mortality that was only15% of that expected and an MI case-fatality rate of 9.5% against an expected of around 50% (Steering Committee of the Physician's Health Study Research Group 1989). Nevertheless, the two trials taken together suggest a significant protection from non-fatal infarction by aspirin of 33% and a non-significant reduction in all vascular deaths of 10% (Steering Committee of the Physician's Health Study Research Group 1989; Antiplatelet Trialists Collaboration 1994).

The Thrombosis Prevention Trial (MRC 1998) examined this situation further. This was based on over five thousand men who had not had a vascular event but were judged to be at increased risk. The relative reduction by aspirin in incident events (32% in non-fatal and 20% in fatal events) is homogeneous with the reductions in all other trials, including those in so-called `secondary' prevention, thus confirming further the concepts illustrated in the diagram below. The Swedish Angina Pectoris aspirin Trial (Juul-Moller et al 1992) gives further evidence of protection in men who have not had a vascular event: a relative reduction of 34%, equivalent to the prevention by aspirin of one event each year in every 100 angina patients.

The terms `primary' and `secondary' relate however to past history, and not to future risk. They are therefore misleading and the concept is not in the best interests of patients. In relation to the risk of a future event subjects simply form a continuum, ranging from subjects at exceedingly low risk, such as US Physicians, to patients who have recently had an MI. Ranged between these are subjects who smoke, who have raised BP, raised cholesterol, experience angina etc. The diagram above displays the continuum of vascular risk. As the diagram indicates, it is reasonable to assume that aspirin will reduce the risk of a future vascular event by about one third, right across this continuum. On the other hand, the incidence of undesirable side effects is constant at all levels of vascular risk. Clearly, aspirin prophylaxis is mandatory at the high-risk end of the continuum, but whether or not aspirin is recommended at lower levels of risk is clearly a clinical decision, taking into account the likely risk of a future vascular event and the likely occurrence of serious side effects. The occurrence of a past event is only one element in this judgement albeit an important factor.

A relative reduction in risk of 33% translates into an absolute risk reduction equivalent to the prevention of one death and two non-fatal events per year in every thousand US Physicians, but around 40 events in every thousand post MI patients. Yet the incidence of undesirable side effects is the same in all subgroups however defined. Thus, amongst US Physicians the absolute number of subjects who experienced a major bleed was more than the number in whom a cardiovascular event was prevented. On the other hand, amongst post-MI patients about 40 events are prevented for each patient who experiences a side effect.

Overall Balance In aspirin Prophylaxis
In every 1,000 patients given low-dose aspirin, per year...

• 30 to 40 patients with a recent MI or stroke will avoid a vascular event
• perhaps 15-20 patients with angina will avoid an event
• about 15 `high risk'* patients will avoid an event
• probably only two or three `low risk'* subjects will avoid an event

AND, in every 1,000 subjects on aspirin, per year...

• one or two will suffer a major bleed
• around 8% will experience minor bleeding and GI symptoms
• High and low' risk are clearly clinical judgements based on the levels of all relevant risk factors and not just the occurrence of a prior vascular event

Note: these estimates are based on trials from which patients with contradictions for aspirin have been excluded - as in all good clinical practice.

`Early' and `immediate' aspirin: There are two special situations in which the use of aspirin would seem to be most reasonable, though both represent an extrapolation from the present available evidence. The first of these is what has become generally known as `early' aspirin: that is, aspirin given by a doctor or para-medic on first contact with a patient who has chest pain and is judged to possibly have had an MI. This is recommended by Health Authorities and other bodies (Weston et al 1994; NHS Executive 1995).

An extension of this measure would be for patients who are judged to be at high-risk of infarction, to be advised to carry their own aspirin and chew and swallow a tablet immediately they experience chest pain. This might be called `immediate' aspirin. It has been recommended (Brecker 1990; Elwood 1997; Norfolk Health 1996) and it would certainly seem to represent a very reasonable and simple extension of present practice.

While neither `early' not `immediate' aspirin have been tested in ad-hoc randomised trials, the CAST trial gave evidence suggestive of increased benefit from early aspirin (Chinese Acute Stroke Collaborative Group 1997). Both these measures - early and immediate aspirin - might therefore substantially increase the benefits of Aspirin in Cardiovascular Disease for the following reasons:

• The initial mortality after myocardial infarction is high and this rapidly decreases with time. The earlier aspirin is given after symptoms commence, the greater the savings in death and disability are likely to be.
  
• Platelet emboli have been found within the coronary circulation in subjects who have died suddenly (Haerem 1974) and it could be that aspirin, if taken early enough, would limit the growth of a developing thrombus and possibly lead to the disaggregation of the platelets in these emboli.
  
• There is a peak in the occurrence of myocardial infarction in the early morning between about 04.00 and 10.00 hours and this coincides with an increased sensitivity of platelets to aggregating agents (Tofler et al 1987). The readiness with which a patient is likely to call a doctor, and the availability of help during these hours is probably less than later in the day. Furthermore, it is of relevance that in the US Physicians trial it was found that the reduction in myocardial infarction by aspirin was significantly greater during the early morning (59%), than during the rest of the day (34%) (Ridker et al 1990).
  
• A high proportion of patients in whom an infarct is proven are likely to go on to receive thrombolytic therapy. There is a `marked' or `considerable' heightening of platelet activity after thrombolysis (Fitzgerald 1988). Prior treatment with aspirin abolishes the excess in re-infarction that otherwise follows fibrinolytic therapy (Second International Study of Infarct Survival Group 1988).

aspirin is now considered a standard part of the early management of the acute infarct as well as for the secondary long-term management of the infarct patient. (Rappaport & Gheorhoriade 1996)

The question arises however as to the subjects to whom `immediate' aspirin might be recommended. In the absence of evidence from randomised trials, this has to be decided on clinical grounds. The older the subject the greater the risk of infarction, yet even in healthy subjects of advanced years, the absolute risk of myocardial infarction is still low. If, however, a subject has raised levels of any of the known risk factors for cardiovascular disease, then the giving of advice about `immediate' aspirin should be considered.

Most patients who have been judged to be at high risk of a thrombotic event should already be on low-dose aspirin maintenance. How should they be advised? The half-life of aspirin in the circulation is only about 30 minutes and it would seem likely that if a thrombus develops despite daily exposure to aspirin, then some sensitive platelets have come into the circulation and have not been acted upon by aspirin. If this is the case, an extra `flush' of aspirin could well be beneficial. Such patients will have already been screened for intolerance to aspirin, and so a single dose of, say, 300-600 mg of aspirin, taken in addition to a daily dose of perhaps 100 mg., could be beneficial and could do no harm.

A further question about self-administered `immediate' aspirin arises with patients with angina as it would not be advisable for an aspirin tablet to be taken every time a patient experienced anginal pain. A careful explanation to such patients should however avoid this, particularly as most patients are likely to be able to distinguish the pain of infarction from exercise induced angina.