Drug Resistance and Pseudoresistance: An Unintended Consequence of Enteric Coating Aspirin
What is the commonality of a mechanistically consistent, stable, and specific phenotype of true pharmacological resistance to aspirin—such as might be explained by genetic causes?
Healthy volunteers (n = 400) were screened for their response to a single oral dose of 325 mg immediate release or enteric coated aspirin. Response parameters reflected the activity of the molecular target of aspirin, cyclooxygenase-1 (COX-1). For outcome measures (maximal aggregation, maximal slope of aggregation, absolute serum TxB2 concentration, urinary TxM excretion), a data driven classification threshold for responder versus nonresponder status was identified using a modified receiver operating characteristics analysis with the inhibition of serum TxB2 formation as the gold standard.
Individuals who appeared aspirin resistant on one occasion underwent repeat testing, and if still resistant, were exposed to low-dose enteric coated aspirin (81 mg) and clopidogrel (75 mg) for 1 week each. Variable absorption caused a high frequency of apparent resistance to a single dose of 325 mg enteric coated aspirin (up to 49%), but not to immediate release aspirin (0%). All individuals responded to aspirin on repeated exposure, extension of the postdosing interval, or addition of aspirin to their platelets ex vivo.
The authors concluded that pharmacological resistance to aspirin is rare.
Using a mechanistically consistent, temporally stable, and specific phenotype of true aspirin resistance, such as might be attributable to genomic variation in aspirin metabolism or in the platelet COX-1/TxA2 synthesis response pathway, the authors failed to find a single person who satisfied the criteria of aspirin resistance in their study. By contrast, pseudoresistance, resulting from delayed and reduced drug absorption, was common after ingestion of enteric coated aspirin. These observations question the diagnosis of aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition after enteric coated preparations of aspirin. The study further supports the use of regular as opposed to enteric coated aspirin for cardiovascular risk reduction.
Keywords: Healthy Volunteers, Platelet Aggregation Inhibitors, Thromboxane A2, Platelet Function Tests, Thromboxane B2, Risk Reduction Behavior, Cyclooxygenase 1, Cardiovascular Diseases, Ticlopidine, ROC Curve, Drug Resistance
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