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Aspirin: how low is low dose?

Aust Prescr 1996;19:79-81 | 1 July 1996 | http://dx.doi.org/10.18773/austprescr.1996.070

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.

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 the prevention of
thrombosis.1 The analyses of the Antiplatelet Trialists' Collaboration2 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.3

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

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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.

Adverse effects. The adverse effects of aspirin are mainly gastrointestinal.4 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 gastrointestinal bleeding, and this
effect doubles with 300 mg daily and increases 5-fold with 1.8-2.4 g daily.4

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.3

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
situations, such as myocardial infarction, where an immediate effect is desirable.3 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

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The evidence from clinical trials shows that all doses which maximally inhibit platelet function are
effective in the prevention of thromboembolism. The Antiplatelet Trialists' Collaboration2 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 production to provide a
probably small, but possibly significant, clinical advantage.1

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.2

Choice of doses of aspirin in Australia

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.

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Aspirin: how low is low dose? - Australian Prescriber http://www.australianprescriber.com/magazine/19/3/79/81

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 anywhere on the panel 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 1 July 1996

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