Why an aspirin a day no longer keeps the doctor away …

Abstract

Aspirin, which has just celebrated its 111th anniversary, remains one of the most widely used antiplatelet agents worldwide (1). Its high efficacy has made aspirin the cornerstone of treatment in patients suffering from cardiovascular diseases; indeed, daily aspirin therapy reduces the risk of stroke, myocardial infarction and death by approximately 25% (2). Early investigation into aspirin’s pharmacology revealed an asymmetry between its pharmacokinetics and pharmacodynamics (3). Despite aspirin’s short half-life in blood of approximately 30 minutes, once daily aspirin administration in doses as low as 40 mg per day has been shown to induce cumulative, profound and sustained inhibition of platelet function (4). Moreover, there is no clear evidence to suggest that doses higher than 100 mg daily increase aspirin’s antithrombotic efficacy, whereas the bleeding risk associated with taking aspirin appears to be dose-dependent (2). For this reason, a fixed regimen of once daily low-dose aspirin has been adopted into all relevant treatment guidelines. While it is true in most cases that an aspirin a day keeps the doctor away, it would also appear that not all patients benefit from the drug to the same extent as others (5). In this issue of Thrombosis and Haemostasis, Henry et al. have explored whether once daily low-dose aspirin provides sustained inhibition of platelet function throughout the 24-hour dosing interval in 150 stable coronary artery disease (CAD) patients (6). The major finding of the study is that in up to 25% of patients, platelets recover their ability to aggregate within 24 hours of the last aspirin dose, thus potentially leaving patients unprotected against thrombotic events at the end of the dosing interval (6). The study leaves the reader with a number of unanswered questions: (a) what are the underlying mechanisms leading to this uncharacteristically fast recovery of platelet function in some CAD patients taking aspirin daily; and (b) what can be done about it? To answer the first question, one must first consider whether this phenomenon is substantiated. In this regard, it is interesting to note that this is not the first report of significant recovery of platelet function within 24 hours of aspirin administration. Perneby et al. have shown in healthy volunteers that platelets can recover their ability to aggregate within 24 hours of various doses of aspirin ranging from 37.5 mg to 960 mg (7). Recovery of platelet function was also shown in stable CAD patients in a small series of 11 patients on daily aspirin therapy (8). Thus, the study by Henry et al. confirms and extends these findings to a larger CAD population. Taken together, these studies suggest that while aspirin is effective in inhibiting platelet aggregation within one hour of administration (thus eliminating the most common causes of a lack of platelet inhibition by aspirin, such as non compliance, reduced aspirin bioavailability, and drug interactions), this inhibition is not sustained for the whole dosing interval in certain individuals. This of course begs the question why. Aspirin inhibits platelet aggregation by irreversibly acetylating a key enzyme in the conversion of arachidonic acid into thromboxane (Tx) A2, namely cyclooxygenase (COX)-1 (9). As a result, TxA2 formation and consequent platelet aggregation is almost completely abolished throughout the platelet lifespan of 7–10 days, and platelet function is regained by Correspondence to: Dr. Marie Lordkipanidze Centre for Cardiovascular Sciences Institute of Biomedical Research College of Medical and Dental Sciences University of Birmingham Edgbaston, Birmingham B15 2TT, UK Tel: +44 121 415 8680, Fax: +44 121 415 8817 E-mail: m.lordkipanidze@bham.ac.uk