Without a nucleus, platelets are unable to produce more cyclooxygenase and, therefore, the effect of aspirin will last until the platelet reaches the end of its lifespan and is replaced, generally in the region of seven to 10 days. Restoration of normal haemostasis does not seem to require all platelets to be replaced, and can be assumed five to seven days after stopping aspirin according to UK guidelines.1 It should be noted that cessation of aspirin is often not necessary prior to operative procedures – it carries a risk of thrombosis; specialist advice should be sought.
Thromboxane A2 production by cyclooxygenase is only one of numerous mechanisms of platelet activation, so while aspirin can be shown to reduce aggregation in response to a number of agonists in vitro, it does not abolish all platelet function.2
Antithrombotic doses used in clinical trials3 for the reduction of cardiovascular disease have varied widely from less than 50 mg to over 1,200 mg per day, with no evidence of any difference in clinical efficacy, although standard doses now vary between 75 and 300 mg daily. The major risk of aspirin treatment is that of gastrointestinal ulceration and haemorrhage.
One subject which continues to receive much attention is the concept of so called aspirin ‘resistance’. This is defined in the laboratory as higher than expected platelet reactivity despite aspirin treatment. Causes are likely to be multifactorial and range from poor medication compliance, to genetic polymorphisms, to reduced platelet recovery time. There is some evidence that patients with responses to aspirin, which are lower than expected by laboratory testing, have a higher risk of cardiovascular events. However, there is, as yet, no consensus on which platelet function tests perform best in this setting and, perhaps more importantly, any indication of how the results of such testing should alter management.4 Certainly, increasing aspirin dose, or adding other antiplatelets, does not seem to alter outcomes.5 Tests for aspirin ‘resistance’ are therefore not yet routinely recommended outside the context of clinical trials.5
Aspirin in secondary prevention of cardiovascular disease
NICE recommends a dose of 75 mg aspirin daily as secondary prevention in all patients without a contraindication – a dose which is felt to provide the optimum balance between efficacy and gastrointestinal side effects.6
Aspirin in primary prevention of cardiovascular disease
The role of aspirin in primary prophylaxis against arterial thrombosis in those at risk is more controversial. Evidence for benefit is weak, and largely based on subgroup analyses of larger trials. On the whole, primary prophylaxis with aspirin is NOT recommended, as the small benefit is probably outweighed by the small risk of gastrointestinal bleeding. NICE guidance, drawing on position statements from the European Society for Cardiology (ESC), suggest considering primary prophylaxis only in the highest risk patients (hypertensive patients with renal impairment (eGFR <45 mls/min) and/or 10-year cardiovascular risk estimation of >20%)7. The POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial8 found no beneficial effect of aspirin in diabetic patients with asymptomatic peripheral artery disease.
Aspirin in atrial fibrillation
As discussed in module 1, thrombus formation in atrial fibrillation (AF) occurs under conditions of low shear and thus has more in common with venous thrombosis than arterial thrombosis. One might expect that aspirin would have limited efficacy in prevention of thrombosis and stroke in AF and, this does seem to be the case. Recent guidelines from NICE9 and the ESC10 do not recommend aspirin for stroke prevention in AF, as accumulating evidence suggests it is substantially less effective than anticoagulants at preventing stroke, while carrying a similar risk of bleeding.10 This will be discussed again in module 3.
Dipyridamole has a number of actions: as an inhibitor of phosphodiesterase it prevents the inactivation of cyclic adenosine monophosphate (cAMP). Hence, intra-platelet levels of cAMP are increased, resulting in reduced activation of second messengers within the cytoplasm. A second action is in the inhibition of thromboxane synthase, thus reducing platelet activation. A corollary of this is that more endoperoxides are available as a substrate for prostacyclin synthase, so that levels of prostacyclin rise, leading to vasodilation as well as platelet inhibition. Its effect is relatively short-lived and repeated dosing, or slow-release preparations are required in order to achieve 24-hour inhibition of platelet function.
Dipyridamole can be used along with aspirin in the secondary prevention of stroke and transient ischaemic attack, although recent NICE and Royal College of Physicians guidelines recommend clopidogrel monotherapy as the more cost-effective option, with aspirin plus dipyridamole reserved for patients with a contraindictation to clopidogrel.11,12
Side effects relate to its vasodilatory properties: gastrointestinal symptoms, dizziness, rash, tachycardia and worsening symptoms of coronary artery disease. Cautions include rapidly worsening angina, recent MI, heart failure, hypotension, and left ventricular outflow obstruction.