Abstract 5007: Variability in the Response to Aspirin
Low dose aspirin is efficacious in the secondary prevention of stroke and myocardial infarction. It has been suggested that a syndrome of “aspirin resistance” constrains its efficacy. Despite this concern, no clear definition of aspirin resistance or a segregation of its elements has emerged and estimates of its frequency have varied up to 50% of aspirin users. We aimed to determine the incidence of an internally consistent, stable and specific “aspirin resistant” phenotype. Healthy volunteers (n=314; targeted enrollment n=400) were screened for their platelet aggregation response before and 4 or 8 hours after a single oral dose of 325 mg enteric coated aspirin testing four stimuli of platelet activation including arachidonic acid (AA). Individuals who showed a less than 60% inhibition upon AA stimulation underwent repeat testing. Individuals who failed to respond to aspirin twice were exposed to low dose aspirin (81 mg) and clopidogrel (75 mg) for one week each in a cross over design. Inhibition of the cyclooxygenases was assessed in ex vivo whole blood assays and by mass spectrometric quantitation of urinary prostaglandin metabolites. On the first occasion, 102 (32.5%) subjects responded with a reduction of the AA induced aggregation by less than 60%. However, only 23 subjects (7.3%) remained non-responsive when aspirin was added to the assay in vitro. Six individuals (1.9%) remained non-responsive when tested a second time. Currently, only one individual remains non-responsive upon exposure to low dose aspirin (81 mg daily for one week) on the third replicate measurement. There was a striking inverse relationship between “exposure” and “non-responsiveness”: Both, prolonging the post dosing interval and adding increasing concentrations of aspirin in vitro reduced the number of non-responsive individuals. Variable pharmacokinetics caused a high frequency of apparent non-responsiveness to a single dose of 325 mg enteric coated aspirin. The majority of individuals responded to aspirin upon repeated exposure, extension the post dosing interval or addition of aspirin in vitro. The incidence of internally consistent, stable and specific “aspirin resistance” - which might be explained by genetic causes - is lower than 1% in healthy individuals.