Drug Resistance and Pseudoresistance: An Unintended Consequence of Enteric Coating Aspirin

Study Questions:

Drug resistance to aspirin might result in treatment failure. Is there a 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 aspirin’s molecular target, cyclooxygenase-1. 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 upon repeated exposure, extension of the post-dosing interval, or addition of aspirin to their platelets ex vivo.


Pharmacological resistance to aspirin is rare; this study failed to identify a single case of true drug resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric-coated, but not immediate-release aspirin administration.


The result should not influence standard practice of coated aspirin for long-term use. The acute platelet response showing no aspirin resistance with uncoated aspirin may not reflect clinical practice. There are studies (Pulcinelli, et al. J Am Coll Cardiol 2004;43:979) demonstrating a decrease in aspirin inhibition of platelet aggregation over time. The study supports that 325 mg of uncoated aspirin should be taken by mouth, possibly chewed and swallowed, in the setting of a suspected acute ischemic event in patients who are or are not on enteric aspirin. Also, using coated aspirin for prevention less than daily should be avoided.

Keywords: Platelet Aggregation Inhibitors, Cyclooxygenase 1, Drug Resistance

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