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


Despite numerous studies, aspirin resistance is an enigma. The mechanism of aspirin resistance remains unknown, it is poorly defined, and its true frequency is not established. To equate the occurrence of clinical events despite appropriate aspirin therapy with aspirin resistance ignores the multifactorial etiology of vascular events, and a validated definition based on platelet aggregation assays has yet to emerge. However, the topic of aspirin resistance evokes much interest because of the enormous impact it poses regarding treatment of a variety of vascular maladies. Considering that an estimated 26 million patients in the United States alone currently take aspirin for thromboprophylaxis, and assuming a conservative aspirin resistance rate of 15%, almost 4 million patients are at risk of a breakthrough thrombotic event because they do not receive an antiplatelet benefit from aspirin. The potential impact on public health is substantial.

Although many aspects remain to be elucidated, a few details about aspirin resistance can be deduced from the current literature. Aspirin resistance is likely dose related in many patients, as studies have demonstrated,[5,31,33] and seems to change over time; thus, it is probably influenced by dynamic factors yet to be identified. One explanation could be related to the diurnal variation in platelet activity described by one group of investigators.[56] This could be a possible confounder in studies of aspirin resistance in that the variability in aspirin effect could be overestimated if measurements are taken at different times of the day. Most studies have used a one-time-only measurement of aspirin sensitivity, which may misrepresent the true nature of the phenomenon. More studies involving several measurements are necessary to provide a clearer picture of aspirin resistance.

Given the temporal and dose-related nature of aspirin resistance and the complex nature of platelet physiology, numerous factors probably are involved in the development of aspirin resistance. The theories thus far proposed for aspirin resistance are all plausible but lack convincing evidence to favor one over the other. Considering the complexity of platelet aggregation—specifically the physiologic redundancy of multiple platelet agonists—it would be exceedingly difficult to maximize the signal:noise ratio experimentally to tease out a true etiology. As such, the mechanism of aspirin resistance is likely to remain elusive for some time.

Of greater importance than establishing the etiology of aspirin resistance is determining whether aspirin resistance translates into an increased risk of clinical events. To determine whether a phenomenon has a particular effect, a reliable method must be used to measure the phenomenon in question. Establishing aspirin resistance as a risk factor for breakthrough vascular events is inexorably tied to the quest for a reliable measurement of aspirin effect. This is the biggest challenge in aspirin resistance research.

Methods proposed for use in routine clinical practice have yet to be satisfactorily evaluated. The risk of clinical events from aspirin resistance based on proposed measures is unknown, or possibly overestimated, due to significant limitations in the clinical studies of these assays. The ideal test should be not only convenient for the practitioner and patient to use, but also correlated with relevant clinical outcomes, such as vascular events and death. The study of the urinary 11-dehydro-TXB2 assay (AspirinWorks) showed a progressive increase in event rates with increased metabolite levels.[35] However, extrapolating these study results to clinical practice is impractical considering the disparity in vascular disease risk factors and comorbidities in the case group versus controls. The PFA-100 is a convenient tool for assessing platelet function but lacks meaningful clinical data. Aspirin resistance measured by the VerifyNow has been associated with a significant increase in cardiac enzymes after PCI in a prospective cohort study.[29] Although increases in CK-MB and troponin I levels are undesirable, no antiplatelet agent has achieved approval from the Food and Drug Administration based on any surrogate measure, such as cardiac enzymes or other biomarkers.[68]

Further study of these tests with clinical end points is needed to justify their use for monitoring and adjusting antiplatelet therapy. In addition, a method to distinguish between aspirin unresponsiveness secondary to a bio-availability issue (poor compliance or absorption) and pharmacodynamic aspirin resistance should be considered in future investigations. Consideration should also be given to other potential confounders, such as lipid levels[69] and interactions with nonsteroidal antiinflammatory agents.[70,71] Assessment of aspirin response should also be part of any investigation of new therapies for atherosclerotic disease.