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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Aspirin and clopidogrel resistance
Desmond J Fitzgerald1, Andrew Maree
1UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. des.fitzgerald@ucd.ie
Insights
Aspirin and clopidogrel offer cardiovascular benefits, but variable responses, not true resistance, explain differing therapeutic effects. Understanding these variations is key for optimizing patient treatment.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Hematology
Background:
- Aspirin and clopidogrel are crucial for managing cardiovascular disease.
- Platelet activation complexity leads to some cardiovascular events despite antiplatelet therapy.
- The concepts of aspirin and clopidogrel 'resistance' are prevalent but potentially misleading.
Purpose of the Study:
- To clarify the nature of variable responses to aspirin and clopidogrel.
- To differentiate between true drug resistance and other factors influencing therapeutic efficacy.
- To discuss the clinical significance of observed variations in antiplatelet drug response.
Main Methods:
- Review of existing literature on aspirin and clopidogrel efficacy and response variability.
- Analysis of definitions and assays used to assess antiplatelet 'resistance'.
- Examination of pharmacological and pharmacokinetic factors influencing drug response.
Main Results:
- Observed 'resistance' varies significantly based on the definition and measurement assay used.
- True aspirin resistance involves reduced cyclooxygenase-1 sensitivity, though its clinical impact is unclear.
- Clopidogrel response variability is primarily linked to active metabolite bioavailability, not receptor resistance.
Conclusions:
- The terms 'aspirin resistance' and 'clopidogrel resistance' are often misnomers for variable drug responses.
- Understanding individual drug pharmacology and pharmacokinetics is essential for interpreting response variations.
- Further research is needed to establish the clinical significance of these variable responses in cardiovascular patients.
Abstract:
Aspirin and clopidogrel provide significant clinical benefit in patients with cardiovascular disease. However, given the complexity of platelet activation, it is not surprising that aspirin or clopidogrel prevent a small proportion of cardiovascular events. Of late, the terms aspirin and clopidogrel "resistance" have entered the physicians' lexicon, and infer a lack of therapeutic response and a single underlying mechanism, which is misleading. The incidence of "resistance" detected in studies varies with the definition applied and assay used to measure response. Rather than true resistance, however, there is a variable response that reflects the unique pharmacology and pharmacokinetics of each drug, the clinical significance of which remains to be established. True "aspirin resistance" implies that cyclooxygenase-1 is less sensitive to inactivation by aspirin. Despite 95% inhibition of serum thromboxane B(2) by aspirin, residual platelet aggregation is detected in some cases, the clinical significance of which is unknown. Heritable factors directly and indirectly related to platelet cyclooxygenase may influence aspirin response. In contrast to aspirin, the response to clopidogrel is highly variable and reflects the bioavailability of the active metabolite and not "resistance" of the receptor to inhibition.
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