Dose and formulation

The appropriate dose of aspirin for prophylaxis: There is little evidence that the degree of cardiovascular protection is related to the dose of aspirin and overviews give no evidence of any significant differences between the long-term protection with doses between about 75 and 300 mg. There is therefore no reason to dissent from the WHO recommendation of 100 mg daily for long-term prophylaxis.

It seems to be widely believed that the dose of aspirin in stroke prevention should be larger than that which is adequate for MI prevention, and 200 mg per day is often quoted. A number of trials have randomised patients to two doses and these have yielded evidence that favoured the lower dose. Evidence from recent trials is reviewed in Gijn (1999), who reached the same conclusion. Again therefore it should be emphasised that…

there is no valid reason to dissent from the WHO recommended dose of around 100 mg aspirin per day for vascular disease protection

While the formulation of aspirin would not seem to matter in most cases, there is some evidence that absorption of enteric coated tablets may be compromised if taken with food (Bogentoft et al 1978). Furthermore, absorption from enteric coated tablets is not only greatly delayed (Muir et al 1997a) but some elderly subjects may absorb very little of the drug from such preparations (Aihie et al 1994). However, as some large and successful trials have been based on enteric coated tablets these formulations are clearly effective in long-term prophylaxis in the majority of subjects.

The aim of `early' and `immediate' aspirin is to get the drug into the circulation as quickly as possible. Soluble aspirin should therefore be used if available, and if not, standard aspirin should be used and the patient instructed to chew and swallow one or two tablets. Clearly, coated tablets are unsuitable if swallowed whole. Significant quantities of aspirin have been detected in the plasma within a few minutes of the ingestion of soluble aspirin, together with a total inhibition of aggregation, again within minutes (Clark et al 1991; Dabaghi et al 1994; Muir et al 1997b). Regarding dose, it would seem to be advisable to use a relatively high dose as there is evidence that absorption can be impaired in patients during the acute phase of infarction (Zhang et al 1994). Based on studies of platelet aggregation, Berglund and Wallentin (1991) recommend that the `loading dose in unstable conditions should exceed 300 mg'… and one can reasonably add, soluble aspirin if possible.

Side-effects of low-dose aspirin: aspirin, in whatever formulation, and even at low doses, can cause gastric irritation, increased occult blood loss and occasionally, serious gastric bleeding (Anon 1997). These effects are dose related and while evidence from trials suggests that the relative risks of gastric irritation and intestinal bleeding are increased by 50 to 100%, the absolute risk for gastric irritation with continuing low-dose aspirin is only a little higher than that which occurs with placebo tablets, and for clinically significant blood loss the excess incidence is probably at most 1% (Steering Committee of the Physician's Health Study Research Group. 1989).

Risks and Benefits in aspirin Prophylaxis

Prior Prior Acute Other
per 1,000 patients/year MI stroke stroke high-risk - saving of events 38 35 8 22 - excess major bleeds 1.0 0.8 0.7 0.5 - excess intra-cranial 0.5* 2.0* 0.1* 0.1* bleed

These estimates are based on Antiplatelet Trialists (1994) and other data The figures marked* are upper 99% confidence limits.

Concerns have been expressed regarding the increased risk of cerebral haemorrhage, and in particular, during aspirin prophylaxis in stroke. The summary statistics in the above table give reassurance. Clearly, the number of bleeding events that might be attributable to aspirin is small (and technically non-significant, despite huge numbers). Furthermore, the absolute numbers of bleeds are very considerably exceeded by the numbers of events prevented by aspirin _ even in the acute phase of a stroke. It is this balance that led to the judgement that the use of aspirin prophylaxis during the acute phase of stroke is `modest but worthwhile' (Kmietowicz 1997).

In another approach to the evaluation of the risk of cerebral haemorrhage, a case-control study of 331 consecutive admissions of haemorrhagic stroke was conducted in thirteen major hospitals in Melbourne. Retrospective enquiries were made about aspirin use immediately prior to the stroke that had led to admission. No increase in aspirin taking was found among aspirin users, and the authors concluded: `the doses of aspirin that are usually used for prophylaxis against vascular disease produce no substantial increase in risk of intracerebral haemorrhage' (Thrift et al 1999).

Alternatives to Aspirin: In most trials it has been found that aspirin is inappropriate for about 8-10% of subjects. In some cases, aspirin causes abdominal discomfort or other symptoms and for these, enteric-coated tablets should be tried. In others, aspirin is definitely contra-indicated because of sensitivity, a history of peptic ulceration etc. There are Alternatives to Aspirin which should be considered in such patients.

Dipyridamole may give a small additional benefit if given along with aspirin, but is an inadequate substitute for aspirin.

Ticlopidine: A reduction in vascular events has been demonstrated (Balsano et al. 1990), but the drug appears to also cause severe neutropenia in almost 1% of patients (Moloney 1993). This drug should therefore only be used if the facilities for white cell monitoring are adequate.

Clopidogrel (Plavix): This derivative of Ticlopidine was directly compared with aspirin in the CAPRIE trial. This was conducted over a three year period, in 20,000 patients with recent MI, stroke or peripheral arterial disease (CAPRIE Steering Committee 1996). When all vascular events were considered together there was a small excess benefit in favour of clopidogrel (5.8% vascular events in patients on aspirin; 5.3% in those on clopidogrel P < 0.05). No other outcome measure showed a significant difference. Re-analyses of the data from CAPRIE has led to the conclusion that clopidogrel is no better than aspirin after MI but may be much more effective than aspirin in peripheral arterial disease (Chussat et al 1998; Verheugt 1997). It is therefore best reserved for use as an alternative to aspirin in the few patients who cannot tolerate aspirin in any formulation (Minerva 1999; DTB 1999).

Cost/effectiveness of aspirin and other prophylactics: When used in the reduction of cardiovascular risk, aspirin is certainly the most cost-effective of all drugs available at present. During the year or two after a myocardial infarction or a stroke, only about 40 patients have to be prescribed low-dose aspirin to prevent one cardiovascular event each year. This means that the cost of prophylaxis in the UK is about £80 ($110) per vascular event prevented. This contrasts somewhat with other possible prophylactic measures!.

Cost to prevent one death
By aspirin(about $3 per patient per year)

1st yr after MI: 40 persons to be treated: cost $130 (based on 1994 overview)

later, after MI: ?100 persons to be treated: cost $350 (my estimate) high risk: 150 persons to be treated: cost $500 (based on Thrombosis Prevention trial)

low risk patients 300 persons to be treated: cost $900 (based on US Physicians study)

by PLAVIX (about $700 per patient per year) high risk: 150 persons to be treated: cost $27,000 (based on CAPRIE)

by a STATIN (about $500 per patient per year)

low risk: 311 persons to be treated: cost $155,000 (based on the AFCAPS trial)

high risk: 263 persons to be treated: cost $131,000 (based on the WOSCOPS trial)

by FATTY FISH (about 50c per patient per day) 1st year after MI: 40 persons to be treated: cost $10! Based on various sources


It must be emphasised that aspirin is not in competition with other drugs, nor is it an alternative to other therapies. Thus if a patient has hypertension, this should be treated. If it is judged that the cholesterol level is high, this should be treated. But in both these and other situations in which there is evidence of an increased risk of a vascular event, long-term, low-dose aspirin prophylaxis should also be considered.