The Way Ahead

In relation to vascular disease aspirin has really become the victim of its own success and further placebo-controlled trials in vascular disease are likely to be unacceptable _ if indeed they are necessary, the benefit of aspirin prophylaxis being so well proven.

At the same time, there are a number of ways ahead:

• the promotion of aspirin prophylaxis, and the achieving of high compliance
• the possible `targeting' of aspirin on subjects most at risk
• the development of `super aspirins'
• other possible Uses of Aspirin
• the promotion of aspirin prophylaxis: Sir Richard Peto concluded a meeting in Oxford in 1997 with the words:

`...in aspirin we have something that really works and we should make sure that it is as widely used as possible...'

Concern has repeatedly been expressed that, despite convincing evidence of its effectiveness, the knowledge of the benefits of aspirin and its use by doctors is much less than desirable. In 1992 the Regional Heart Study found that only 44% of men with a history of myocardial infarction, 39% with a history of stroke and 26% with angina, were taking daily aspirin (McCallum et al 1997). In an examination in 1993-7 of the Caerphilly Cohort of older men, it was found that only around half the men who had had a myocardial infarction or stroke were taking aspirin

While there is very little recent evidence as to the frequency of the use of aspirin it would appear that the situation is generally not good and it would appear that prophylactic, low-dose, daily aspirin is generally very seriously underused at present

With regard to the giving of aspirin early in the acute phase of a suspected infarct (and the recommendation that subjects take their own aspirin) one group has commented: `A rigid approach that restricts aspirin use to patients who are admitted with the strongest evidence of acute myocardial infarction deprives many others of the benefits of early aspirin therapy' (Prasad et al 1998).

Reports of Aspirin Use

• UK 1994: only one fith of MI patients received aspirin before admission
• UK 1994: only 70% of GP's carry aspirin
• UK 1994: only half the patients in South Wales who should be on long-term aspirin were taking it
• USA 1996: nearly 50% of patients with a history of MI did not take aspirin
• USA 1997: only 45% of MI patients received aspirin in hospital

Another aspect of aspirin prophylaxis is the promotion and maintenance of good compliance in subjects advised to take aspirin. In the Physicians Health Study (Glynn et al 1994) the subjects who were judged to have taken the medication well (over 95% of the time) showed a 51% reduction in MI risk, while those who took aspirin less than 50% of the time showed only a 17% reduction.

EFFECT OF COMPLIANCE Subjects who took aspirin (on alternate days): - 95% or more of the time 51% reduction in MI - less than 50% of the time 17% reduction in MI standardised for differences in risk factors between the groups Based on The Physicians' Health Study (Glyn et al 1994)

A test of platelet sensitivity: One of the remarkable things about aspirin prophylaxis is the size of the benefit it confers when given to patients, the selection of whom has involved no reference to platelet function. This contrasts with almost every other drug. Anti-hypertensives are given only to patients found to have raised blood pressures; cholesterol lowering drugs are given only to those with UK 1994: only one fith of MI patients received aspirin before admission UK 1994: only 70% of GP's carry aspirin UK 1994: only half the patients in South Wales who should be on long-term aspirin were taking it USA 1996: nearly 50% of patients with a history of MI did not take aspirin USA 1997: only 45% of MI patients received aspirin in hospital raised cholesterol levels. Yet aspirin, given to patients, with no reference to the sensitivity of their platelets or of any other risk factor likely to be affected by aspirin, leads to a proportionate reduction in risk of a vascular event that is at least as large as that of drugs which have been carefully targeted.

It would undoubtedly be a great advantage if the patients who are likely to benefit from aspirin prophylaxis could be identified. This would require the development of a screening test that would evaluate an aspect of platelet function that is relevant both to aspirin and to vascular risk.

Two limited studies, based upon very small numbers, have suggested that conventional tests of platelet aggregation may be predictive of vascular events (Trip et al 1990; Thaulow et al 1991). However in the Caerphilly Cohort Study, a very large study of older men, one of the aims of which had been to evaluate platelets, no measure of platelet aggregation was found to be significantly predictive of incident IHD (Elwood et al 1998).

The development of `super aspirins': Although it substantially reduces rates of myocardial infarction, stroke and vascular death, aspirin should not be seen as the ultimate anti-platelet drug. It only partially inhibits platelet aggregation to certain agonists, and leaves the responses to thrombin and serotonin virtually unaffected. Due to these limitations more potent platelet specific drugs are being sought. These are sometimes somewhat optimistically being referred to as `super-aspirins'. Certainly, the hope is that new preparations can be found that will be significantly superior to aspirin, yet the certainty is that any that are will be vastly more expensive than aspirin.

At the same time, the mechanism of action on platelets of the new drugs is likely to be different to aspirin and so their effects could well be additional to that of aspirin. With hindsight, it is regrettable that CAPRIE (1996) did not test clopidogrel and aspirin together. More recently a number of `designer' drugs have been developed which act on the receptor on the platelet to which fibrin binds: the so-called glycoprotein IIb/IIIa receptor inhibitors. Many trials have been set up, including those with the acronyms: CACHET; RAPPORT; PRISM; PRISM-PLUS; PURSUIT; EPISTENT; RESPORE; PARAGON; EPILOG and PRISM (see White et al. 1998; The Platelet Receptor Inhibition Investigators 1998).

A number of questions arise about these new drugs, and their role in the acute and the long-term management of cardiovascular events has yet to be worked out (Choussat and Montalescot 1998). Therefore, until safety and other issues are cleared `the gold standard for antiplatelet therapy in ischaemic heart disease' is aspirin (Verheugt 1997).

Other possible Uses of Aspirin: Salicylates occur widely throughout nature and have a wide variety of essential functions in plants (Pierpoint 1976). It is perhaps not surprising therefore that new Uses of Aspirin other than cardiovascular are being found.

Perhaps the most important of these possible new Uses of Aspirin is in colon and other cancers. Three major cohort studies (Thun et al 1991;.Greenberg et al 1993;.Giovannucci et al 1995) and over twenty smaller studies have been reported and overall these suggest a substantial reduction of colon, and possibly other gastro-intestinal cancers in habitual aspirin takers (reviewed in Morgan 1998; 1999). In fact, it has even been suggested that diets rich in fruit and vegetables may lower the risk of cancer and cardiovascular disease, in part, by their salicylate content ( Paterson 1998). If true, this almost certainly has nothing to do with any anti-thrombotic effect and it has been suggested that aspirin may enhance the apoptosis mechanism in early cancer.

On present evidence perhaps the most hopeful new use of aspirin is in cognitive decline and dementia. Clearly numerous factors are involved in cognitive decline, and as yet few of these are understood. The most obvious cause is of course a stroke, but it is now accepted that a less dramatic, and often unrecognised process of small repeated infarcts can contribute to cognitive decline in the elderly. This has become known as `vascular dementia' or, `multi-infarct dementia', and the fact that aspirin reduces the risk of stroke makes a reduction of cognitive decline through the prevention of mult-infarct lesions by aspirin a most reasonable expectation. Only two trials of aspirin and cognitive decline have been reported to date, and though both are encouraging, both trials are limited (Meyer et al 1989; Richards 1997).

An anti-inflammatory effect of low-dose aspirin has been reported (Ridker et al 1997) and this gives a possible biological basis for claims that anti-inflamatory drugs, including aspirin, may reduce progression in Altzheimer's disease (Stewart et al 1997; Nridner et al 1994;). Clearly, more trials are urgently needed in this most important area.

Other Possible Uses of Aspirin

• in cancer (see review in Morgan 19990
• vascular dementia (see Richards et al 1997)
• Alzheimer's disease (see review by McGeer et al 1996)
• cataract (see Gupta 1991)