Aspirin is an inhibitor of the enzyme cyclo-oxygenase, the action being considered to be due to an irreversible acetylation process.
In blood platelets such enzyme inhibition prevents the synthesis of thromboxane A2, a compound which is a vasoconstrictor, causes platelet aggregation, and is thus potentially thrombotic.
In blood vessel walls the enzyme inhibition prevents the synthesis of prostacyclin, which is a vasodilator, has anti-aggregating properties, and is thus potentially anti-thrombotic.
Aspirin therefore appears to have paradoxical biological effects. The duration of these effects, however, may differ, with the effects on the vascular tissue generally being shorter than the effects on the platelets (although the animal species studied, the type of blood vessel used, and the prevailing experimental conditions may alter the results). The difference may be explained by the fact that vascular cells regain the ability to regenerate prostacyclin in a few hours but platelets are unable to re-synthesise cyclo-oxygenase, which results in no new thromboxane A2 being produced for about 24 hours until more platelets are released by the bone marrow; as platelet activity in bone marrow may also be affected by aspirin it is generally considered that aspirin only needs to be given once daily for inhibition of platelet aggregation to occur. The inhibitory effect on thromboxane is rapid and unrelated to serum concentrations of aspirin, probably because of the inactivation of cyclo-oxygenase in platelets in the presystemic circulation. Since the effect is unrelated to systemic bioavailability, modified-release and dermal delivery preparations which do not achieve high systemic concentrations of aspirin are being developed to limit extraplatelet effects of aspirin. Inhibition is cumulative on repeated dosage, and it has been estimated that a daily dose of 20 to 50¬†mg will result in virtually complete suppression of platelet thromboxane synthesis within a few days. Large doses of 150 to 300¬†mg can produce maximum suppression almost instantaneously.
Uses. Aspirin’s antiplatelet activity has led to its use or investigation in a variety of disorders.1-4
It is used as part of the initial treatment of unstable angina and is given in the early treatment of myocardial infarction; it is also of benefit in the initial treatment of acute ischaemic stroke.
Aspirin is used for its combination of anti-inflammatory, antipyretic, and antiplatelet activity in the treatment of Kawasaki disease. It is also used to treat thrombotic symptoms associated with antiphospholipid syndrome, such as occurs in patients with systemic lupus erythematosus, and has been recommended for prophylactic use in pregnant patients with antiphospholipid antibodies who are at risk of fetal loss. Aspirin has also been tried in pregnancy-induced hypertension for the prevention of pre-eclampsia and intra-uterine growth retardation but it appears that its use may be justified only in women at high risk.
It is of value for the prevention of cardiovascular events in patients at high risk, including those with stable or unstable angina, current or previous myocardial infarction, ischaemic stroke, or transient ischaemic attack. It has also been used in the long-term management of atrial fibrillation for the prevention of stroke in patients with contra-indications to warfarin or if there are no other risk factors for stroke.
The value of aspirin for primary prevention of cardiovascular events, particularly myocardial infarction and stroke depends upon the accurate estimation of overall cardiovascular risk but is probably not justified in healthy individuals.
Although aspirin may prevent venous thromboembolism after surgery, other treatments have been preferred. However, it is recommended for use in preventing thrombotic complications associated with procedures such as angioplasty and coronary bypass grafting. Aspirin is often given as an adjunct to patients with peripheral arterial thromboembolism to prevent propagation of the clot and also to prevent postoperative complications. It may have some effect in delaying disease progression and reducing vascular events in patients with peripheral arterial disease but an analysis8 concluded that there was insufficient evidence to support its prophylactic use in patients with intermittent claudication but no additional cardiovascular risk factors.
The benefit of aspirin for the primary prevention of cardiovascular events in patients with diabetes mellitus (see under Diabetic Complications, ) and who have no other cardiovascular risk factors remains to be determined.6 Use is recommended in all those at increased risk, which includes (in the USA) all diabetics over 40 years of age,9 or those aged 50 and over or with existing atherosclerosis or hypertension or a history of diabetes for over 10 years (in the UK).10
The value of adding aspirin to anticoagulants for the prophylaxis of thromboembolism in patients with artificial heart valves (see ) is also still to be firmly established. It is usually recommended as an adjunct in patients with other risk factors. Aspirin alone may be considered in patients with bioprosthetic valves who do not require anticoagulation.
Several pharmacological studies have attempted to find a dose of aspirin that would inhibit synthesis of platelet thromboxane A2 while sparing the effect on prostacyclin production11-13 but it has been pointed out4 that in patients with vascular disease accompanying or caused by endothelial dysfunction, such as in atherosclerosis, a selective sparing of vascular prostacyclin production may not be obtained at any effective antiplatelet dose. However, the clinical relevance of inhibiting the synthesis of prostacyclin may have been exaggerated.14 Experimental evidence indicates that aspirin is thrombogenic only at extremely high doses (200¬†mg/kg), far exceeding the minimum dose required to inhibit prostacyclin production. Also aspirin is clinically effective as an antithrombotic drug at doses that inhibit the synthesis of prostacyclin. Further support for the lack of importance of inhibition of prostacyclin synthesis comes from epidemiological studies in patients with arthritis given large doses of aspirin and patients with congenital cyclo-oxygenase deficiency; neither of these groups of patients have experienced an excess of thrombotic episodes.
In a meta-analysis conducted by the Antithrombotic Trialists’ Collaboration6 daily doses of 75 to 325¬†mg appeared to be equally effective for their antiplatelet effect; doses greater than 500¬†mg did not appear to be superior and caused more gastrointestinal adverse effects. Whether doses less than 75¬†mg offer the same efficacy with reduced gastrointestinal toxicity remains to be determined (see Effects on the Gastrointestinal Tract, ). The meta-analysis concluded that for the long-term prevention of serious vascular events in high-risk patients, a daily dose of aspirin in the range of 75 to 150¬†mg should be effective; if an immediate effect is required as in the initial treatment of acute myocardial infarction, acute ischaemic stroke, or unstable angina, a loading dose of 150 to 300¬†mg may be given. Another analysis8 has made similar dose recommendations. Aspirin should be chewed or dispersed in water; chewing a tablet of aspirin ensures that some buccal absorption occurs.
The use of aspirin in children is limited because of the risk of Reye’s syndrome (see under Adverse Effects, ); however, it may be specifically indicated in those at risk of clot formation after cardiac surgery or for the prophylaxis of stroke in high-risk children. The BNFC has suggested an oral dose of 5¬†mg/kg once daily in neonates; children aged 1 month to 18 years may be given 3 to 5¬†mg/kg (to a usual maximum of 75¬†mg) once daily.