Aspirin Resistance: An Evaluation of Current Evidence and Measurement Methods

Christopher P. Martin, Pharm.D.; Robert L. Talbert, Pharm.D., FCCP


Pharmacotherapy. 2005;25(7):942-953. 

In This Article

Abstract and Introduction

Aspirin resistance is a poorly characterized phenomenon, whereby certain patients do not benefit from the antithrombotic effect of aspirin. The frequency of aspirin resistance is unknown, but estimates range from 5-60%. The mechanism of aspirin resistance also is unknown; proposed mechanisms are poor patient compliance, poor aspirin absorption, increased isoprostane activity, platelet hypersensitivity to agonists, increased cyclooxygenase-2 activity, a cyclooxygenase-1 polymorphism, and the platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa. Aspirin resistance appears to be dose related in some patients and therefore may be overcome with high doses. Evidence indicates that aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. To date, a sensitive and specific assay of aspirin effect that reliably predicts treatment failure has not emerged. However, several commercially available products are being marketed for this purpose without convincing clinical data. Despite a wealth of literature on the topic, aspirin resistance remains an enigma. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.

Aspirin is perhaps the world's oldest known drug therapy, dating back to the time of Hippocrates, when the bark of the willow tree was consumed for its analgesic and antipyretic properties. The antiplatelet properties of aspirin were first recognized in 1967, and its mechanism of action was elucidated in 1971.[1,2] Since then, aspirin has possibly been used more for its antiplatelet properties than its analgesic or antipyretic action. The Antithrombotic Trialists' Collaboration reported that aspirin reduced the risk of serious vascular events by an average of 25% in patients with acute or previous myocardial infarction, ischemic stroke, unstable or stable angina, peripheral arterial disease, or atrial fibrillation.[3] Despite its impressive efficacy, many patients receiving aspirin therapy still experience vascular events. Aspirin resistance has been proposed as a possible reason for these break-through vascular events.

Aspirin resistance has been defined in both clinical and pharmacodynamic contexts. The proposed clinical definition is the occurrence of a vascular event despite appropriate thrombo-prophylaxis with aspirin. Extrapolating from event rates despite aspirin therapy, reported by the Antithrombotic Trialists' Collaboration,[3] the frequency of aspirin resistance according to the clinical definition can be estimated at 12.9% (range 10.9-17.3%) depending on aspirin dosage. No clear relationship exists between dosage and failure rate.

In pharmacodynamic terms, aspirin resistance has been defined as the failure of aspirin to reduce platelet aggregation as measured by various in vitro and in vivo assays. The frequency of aspirin resistance according to the pharmacodynamic definition is estimated to range from 5.2-60%, depending on the population studied and platelet function assay used.[4,5]

The true definition and frequency of aspirin resistance remain to be established. Only a small number of studies have attempted to quantify aspirin resistance in both clinical and pharmacodynamic terms, and these were hampered by internal and external validity concerns. The lack of an operational definition of aspirin resistance is directly related to the lack of a sensitive and specific measure of platelet aggregation under the influence of aspirin. To date, none of the platelet aggregation assays have been convincing in predicting clinical events, and interassay results have been discordant. Despite the absence of an operational definition and the known frequency of aspirin resistance, response to aspirin is clearly variable, which could be due to resistance.