Aspirin: how low is low dose?

- Australian Prescriber

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http://www.australianprescriber.com/magazine/19/3/79/81

Aspirin: how low is low dose?

John Lloyd, Division of Haematology, Institute of Medical and Veterinary Science, and Department of
Clinical and Experimental Pharmacology, University of Adelaide, Adelaide; and FelixBochner, Department
of Clinical and Experimental Pharmacology, University of Adelaide and Department of Clinical
Pharmacology, Royal Adelaide Hospital, Adelaide

Summary
Aspirin reduces the risk of non-fatal stroke, non-fatal myocardial infarction and vascular death in patients at high risk of
arterial thrombosis. Platelet function is inhibited by doses of 40-160 mg daily. In clinical trials performed before 1985, doses
of 500-1500 mg daily were found to be effective. Since 1985, low doses have been evaluated and a meta-analysis has shown
that daily doses of 75-150 mg are as effective as the previously used higher doses. The risk of adverse effects is
dose-dependent above 75 mg daily. The maximum benefit:risk ratio is likely to be achieved with doses of 75-150 mg daily. In
Australia, this is best achieved by either a single 100 mg tablet or half a 300 mg tablet taken daily.
Key words: formulation, clinical trials, adverse effects, platelet function.
Aust Prescr 1996;19:79-81

Introduction
For almost 100 years, aspirin (acetylsalicylic acid) has been used extensively for its effective analgesic, antipyretic and
anti-inflammatory properties. In the last 25 years, since its ability to inhibit platelet function was discovered, aspirin has been
increasingly used as an antithrombotic agent. There are now extensive data from clinical trials supporting its effectiveness in
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the prevention of thrombosis. The analyses of the Antiplatelet Trialists' Collaboration show conclusively that antiplatelet
therapy (principally aspirin) reduces the risk of non-fatal stroke, non-fatal myocardial infarction and vascular death by
25-32% in patients at high risk of arterial thrombosis. In addition, there are significant reductions in the incidence of
occlusion of grafts and native vessels after vascular surgery and of venous thromboembolism in high-risk patients.
In clinical trials before 1985, the doses of aspirin used (500 -1500 mg daily in divided doses) were considerably greater than
required for maximum inhibition of platelet function. More recent evidence has shown that lower doses (75-325 mg daily as a
single dose) are clinically effective. Furthermore, dose-ranging studies with different formulations show that the maximum
effect of aspirin on platelet function is attained by doses of 40-160 mg daily.

Mechanism of action of aspirin

In platelets, the predominant product of the pathway for synthesis of prostaglandins is thromboxane A2 which is a powerful
promoter of platelet aggregation. In a developing thrombus, thromboxane is produced by stimulated platelets and secreted
into the surrounding medium. There it acts synergistically with other platelet stimuli to enhance platelet stickiness and,
hence, platelet aggregation. Aspirin prevents the production of thromboxane by inhibiting the enzyme cyclooxygenase. This
leads to inhibition of the mechanisms of both haemostasis and thrombosis, as shown by a prolongation of the bleeding time
and by a decreased tendency to arterial thrombosis in experimental animals. As aspirin binds to platelet cyclooxygenase
irreversibly, it inhibits the function of the platelets for the rest of their 8-10 day lifespan.
Aspirin also inhibits cyclooxygenase in the endothelium of the arteries and veins, and hence blocks the production of
prostacyclin, a powerful inhibitor of platelet aggregation. This aspirin-induced loss of prostacyclin production potentially
reduces the overall antithrombotic action of aspirin, but the clinical significance is not known. The inhibition of prostacyclin
formation is reversible, because the endothelium is capable of resynthesising cyclooxygenase.
Rationale for using lower doses and different formulations of aspirin
Lower doses
It seems reasonable to use doses of aspirin which, while lower than those used previously, are still sufficient to exert a
maximum inhibitory effect on platelet function. The two main reasons for this are to minimise adverse effects, and to attempt
to spare prostacyclin production in the vessel wall.
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Adverse effects. The adverse effects of aspirin are mainly gastrointestinal. They are dose related so they are reduced at
lower doses (325 mg per day or less). Aspirin may cause gastric erosions and gastric ulcers and patients may present with
anaemia and/or haemorrhage. Longitudinal studies show that 75 mg daily causes a small but significant increase in

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gastrointestinal bleeding, and this effect doubles with 300 mg daily and increases 5-fold with 1.8-2.4 g daily.

An important, but uncommon, adverse effect is haemorrhagic stroke. The incidence was estimated to be 0.7 per 1000
patients treated in a subset of trials where the reduction in ischaemic stroke was 10 per 1000 patients treated.5 However,
unlike the risk of gastrointestinal bleeding, the risk of haemorrhagic stroke would not be expected to decrease unless very
low doses of aspirin were used, doses which do not maximally inhibit platelet function. Currently, there is little or no evidence
to indicate that such very low doses would be adequate to prevent thrombosis.
Sparing of prostacyclin production. A further advantage of lower doses of aspirin might be that inhibition of prostacyclin
formation in the vessel wall could be minimised. Preservation of prostacyclin production may be valuable in the prevention of
thrombosis. Many dosage regimens have been investigated to find one which leads to maximal inhibition of platelet
thromboxane formation while sparing inhibition of prostacyclin formation. Most recent studies suggest that any sparing of
prostacyclin production is likely to be minimal, and the resultant clinical benefit will be small and therefore difficult to
demonstrate in a clinical trial.1 Hence, the arguments for use of lower doses of aspirin continue to rest on the lesser
frequency and severity of adverse effects.
Different formulations
Adverse effects. Aspirin is available as soluble, compressed, delayed release and enteric-coated formulations. The incidence
and severity of the gastrointestinal adverse effects of increased blood loss and peptic ulceration are low when aspirin is given
in doses of about 100 mg daily. However, doses even lower than 100 mg are still associated with bleeding6, and it would
seem likely that this could be further reduced by taking delayed release or enteric-coated formulations.
Sparing of prostacyclin production. Oral aspirin has a variable but generally high presystemic (first-pass) clearance. The
bioavailability of slow release or enteric-coated formulations can be as low as 25%. For rapid release formulations (such as
solutions and compressed aspirin), it is about 50%. The product of presystemic metabolism is salicylate, which has no
antiplatelet activity. Thus, especially with slow release or enteric-coated formulations, complete inhibition of platelet
cyclooxygenase could occur during the time that platelets are in the presystemic (portal) circulation. These formulations
could better exploit the capacity of the liver and portal blood to metabolise aspirin to salicylate, so that less aspirin reaches
the systemic circulation. This will result in less inhibition of prostacyclin formation by the vessel wall. In practice, any benefit
obtained from this strategy is likely to be small.

Effects of different doses

On platelet function
Studies in normal volunteers have revealed much of the relationship between the dose of aspirin and the degree of inhibition
of platelet function.3 It is important to distinguish between the effects of a single dose of aspirin and the effects of repeated
daily doses. When given as a single dose, 325 mg of soluble aspirin is sufficient to maximally inhibit platelet function within
30 minutes. Hence, this dose of aspirin as a solution or rapid release formulation should be given as a loading dose in
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situations, such as myocardial infarction, where an immediate effect is desirable. When given as a daily dose of 40-80 mg,
soluble aspirin has a cumulative effect such that it maximally inhibits platelet thromboxane formation by >95% after 4-5
days. When given as a daily dose of 80-100mg, an enteric-coated preparation also produces cumulative and near complete
inhibition of agonist-induced platelet aggregation and thromboxane formation in 3-5 days.
In clinical trials
The evidence from clinical trials shows that all doses which maximally inhibit platelet function are effective in the prevention
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of thromboembolism. The Antiplatelet Trialists' Collaboration has published a meta-analysis of 145 randomised clinical trials
of antiplatelet therapy. Forty-six trials (some trials contributed to more than one comparison) in which aspirin alone was used
were analysed to compare 3 dosage regimens:
<160 mg (mostly 75-150 mg) (7 trials)
160-325 mg (12 trials)
500-1500 mg daily (30 trials)
Risk reductions for myocardial infarction, stroke or vascular death were not significantly different for these 3 regimens, being
26%, 28% and 21% respectively. Three trials were analysed in which a higher dose of aspirin (500-1500 mg daily) was
compared with a lower dose (75-325 mg daily). There was no significant difference in efficacy between these regimens.
These trials provide substantial evidence that doses as low as 75 mg daily are effective, but no substantial evidence about
daily doses less than 75 mg.
Soluble aspirin in doses of 75-100 mg daily almost completely inhibits cyclooxygenase in both platelets and arterial walls.
Whether lower doses have a greater or lesser therapeutic effect is unknown. Neither is it known whether slow release
formulations at doses which are just sufficient to substantially inhibit platelet function might significantly spare prostacyclin
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production to provide a probably small, but possibly significant, clinical advantage.

There remains some controversy concerning the application of the above conclusions to the prevention of ischaemic stroke. It
has been suggested that, for patients with a prior stroke or transient ischaemic attack, doses as high as 1000 mg per day
may be preferable7, although the clinical trials provide little evidence to support this.

Choice of doses of aspirin in Australia

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In Australia, aspirin is available as 100 mg tablets (3 preparations, two of which are enteric-coated). The next highest dose
available is 300 mg (at least 5 preparations). Hence, doses of 75-150 mg can be obtained by daily ingestion of either a single
100 mg tablet or half a 300 mg tablet. Alternatively, 150 mg taken on alternate days would seem reasonable, but there are
no clinical trial data to support such a regimen.
Conclusion
Low doses of aspirin of the order of 75-300 mg daily are as effective as higher doses for the prevention of arterial
thrombosis. Although in many of the clinical trials higher doses were used, there is now reasonable evidence that lower doses
are probably effective. To reduce the incidence of adverse effects, it seems reasonable to prescribe a low dose. Where cost is
not a limiting factor, an enteric-coated or slow release preparation can be used, which may reduce the incidence of
gastrointestinal blood loss and indigestion. Many patients will prefer the least expensive option which is about 150 mg of
ordinary or soluble aspirin (half a standard 300 or 325 mg tablet).
References
1 . Roth GJ, Calverley DC. Aspirin, platelets, and thrombosis: theory and practice. Blood 1994;
2 . Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - 1: Prevention of
death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J
1994;308:81-106.
3 . Bochner F, Lloyd JV. Aspirin for myocardial infarction. Clinical pharmacokinetic considerations. Clin Pharmacokinet
1995;28:433-8.
4 . Hirsh J, Dalen JE, Fuster V, Harker LB, Salzman EW. Aspirin and other platelet-active drugs. The relationship between
dose, effectiveness, and side effects. Chest 1992;102(4 Suppl):327S-336S.
5 . Dunbabin D, Sandercock P. Antiplatelet Trialists Collaboration. Platelets 1994;5:3-12.
6 . Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287 -94.
7 . Dyken ML, Barnett HJ, Easton JD, Fields WS, Fuster V, Hachinski V, et al. Low-dose aspirin and stroke. 'It ain't necessarily
so' [editorial]. Stroke 1992;23:1395-9.

Self-test questions
The following statements are either true or false (click here for the answers)
1. The lowest dose of aspirin recommended for the prevention of arterial thrombosis is 75 mg.
2. Inhibition of endothelial cyclooxygenase by aspirin potentially increases platelet aggregation.

First published online: July - 1996

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