11.1 Aspirin

11.1.1 DOSAGE

Aspirin is the antiplatelet agent of choice: it is of comparable efficacy to other currently-available antiplatelet agents in prevention of cardiac or arterial thromboembolic events^{7, 8, 9} and is widely available and inexpensive. The standard dose preparations available in the UK are 75 mg and 300 mg. Standard, dispersable, and enteric-coated preparations are available. For patients with clinically-suspected acute myocardial infarction or unstable angina, or CT-confirmed non-haemorrhagic acute stroke, who are not already taking regular aspirin, it is recommended that 150-300 mg of non-enteric-coated aspirin should be swallowed as soon as possible, to achieve rapid inhibition of platelet function. Doses of 30-1200 mg/day have been used in randomised controlled trials of aspirin as an antithrombotic agent in most other indications. The evidence suggests that, for most indications, 75-300 mg/day is as effective as higher doses, and appears less likely to cause gastric irritation, bleeding or constipation.^{7, 143} 75 mg/day is sufficient to suppress platelet aggregation in most persons after several days.¹⁴³ Evidence level Ib

11.1.2 ADVERSE EFFECTS

Adverse effects of aspirin include allergy (e.g. bronchospasm); gastric irritation, ulceration and bleeding; constipation; renal failure¹⁴⁴; and bleeding at other sites (bruising, subconjunctival, and intracranial). The risk of haemorrhagic stroke is about 1 in 2500 man-years.¹⁴⁵

The risk of gastrointestinal symptoms and bleeding is dose-dependent, but is still increased even at low doses.^{146, 147} There is no evidence that use of enteric-coated or buffered preparations reduces the risk of major gastrointestinal bleeding.¹⁴⁸ A review of all trials listed in the antiplatelet trialists' collaboration showed a pooled odds ratio of 2 for gastrointestinal bleeding or major bleeding, and a pooled odds ratio of 1.5 for gastrointestinal symptoms leading to withdrawal of treatment.¹⁴⁷ In secondary prophylaxis of vascular disease, these risks are considerably outweighed by the benefits,⁸ and aspirin is likely to be cost-saving or cost-neutral.⁸ In primary prophylaxis of vascular disease, the benefit:risk ratio is lower, as discussed in section ⁹. With low-dose aspirin, the absolute risk of major gastrointestinal bleeding was about 1 in 500 man-years in the Thrombosis Prevention Trial.^{14, 149}

In patients with acute major haemorrhage (e.g. gastrointestinal, intracranial, retroperitoneal) aspirin should be discontinued; and consideration given to reversal of the platelet function defect by platelet transfusion, with due regard to its complications which include viral transmission.¹⁵⁰ As noted in section 5.4, aspirin may be stopped one week prior to bypass grafting.

In patients who experience gastric intolerance to aspirin, options are to reduce the dose of aspirin to the minimum effective dose (75 mg); to change to dispersable or enteric-coated preparations; to add concomitant gastro-protective drugs such as antacids, misoprostol, proton pump inhibitors, or H2-receptor antagonists;^{143 151} or to change to another antithrombotic agent: clopidogrel, dipyridamole or warfarin if appropriate.

11.1.3 CONTRAINDICATIONS

Contraindications to aspirin include: known allergy; age under 12 years (risk of Reye's syndrome); active peptic ulceration; history of recent gastrointestinal bleeding; history of recent intracranial bleeding; and bleeding disorders including haemophilia, von Willebrand's disease, thrombocytopenia and severe liver disease.

11.1.4 CAUTIONS

Cautions with aspirin include asthma; uncontrolled hypertension (risk of intracranial bleeding); and previous peptic ulceration (risk of gastrointestinal bleeding: proton pump inhibitors or H2-receptor antagonists may be considered for prophylaxis). As noted above, combination therapy with aspirin and oral anticoagulants increases the risk of bleeding^{14, 92, 143} and should be avoided, except in situations of high thrombotic risk where the antithrombotic benefits of combination therapy are perceived to outweigh the risk of bleeding; e.g. prosthetic heart valves (see section 4.4) and recurrent arterial thromboembolism (see section 8).

11.1.5 RECURRENCE

In patients who experience recurrent thrombosis despite low-dose aspirin prophylaxis, options are to increase the dose (up to 1200 mg/day); add dipyridamole or substitute another antiplatelet agent (see below); or consider oral anticoagulants if appropriate (see section 12).

11.2 Dipyridamole

Dipyridamole is currently licensed in the UK as an adjunct to oral anticoagulation for prophylaxis of thromboembolism associated with prosthetic heart valves (see section 4.4) and as an alternative (or in addition) to aspirin in secondary prevention of ischaemic stroke (see section 7.2). In the large ESPS-2 study which gives evidence for the latter indication,¹²⁹ dipyridamole (200 mg twice daily in a sustained release preparation) was not associated with increased bleeding compared to placebo, but was associated with initial headache. Dipyridamole is contraindicated in uncontrolled angina, which it may exacerbate.

11.3 Clopidogrel

Clopidogrel is licensed in the UK as an alternative to aspirin for secondary prevention of myocardial infarction and stroke in patients with previous myocardial infarction (see section 5.1), ischaemic stroke (see section 7.2) or peripheral arterial disease (see section 6.1). Compared to aspirin, clopidogrel was associated with a lower risk of gastrointestinal bleeding, but a higher risk of skin rashes.⁹³ Ticlopidine, a related drug which is not licensed in the UK, has similar efficacy to clopidogrel but increased risk of adverse effects including neutropenia.¹⁴³