Clopidogrel resistance: identifying and overcoming a barrier to effective antiplatelet treatment

Cardiovasc Ther. 2011 Dec;29(6):e100-11. doi: 10.1111/j.1755-5922.2010.00202.x. Epub 2011 Jul 31.


Clopidogrel is an inhibitor of the ADP receptor P2Y12 and platelet aggregation. It is widely used for the management of atherothrombotic disease in patients who have experienced severe vascular events such as stroke or myocardial infarction or with peripheral artery disease. However, some patients show "resistance" to clopidogrel, and show impaired inhibition of platelet aggregation. In this review, I discuss the clinical evidence of the extent of the problem, potential implications for future cardiovascular events and clinical tests to assess platelet aggregation. I also discuss the mechanisms that appear responsible for clopidogrel resistance. Clopidogrel is administered as a prodrug and the active metabolite is generated by the cytochrome P450 system. Therefore, inadequate responses to clopidogrel may be caused by polymorphisms in one or more of the cytochrome P450 enzymes and interaction/competition with other drugs metabolized by the cytochrome P450 system (e.g., statins and proton pump inhibitors). Finally, I discuss the therapeutic options available for patients with known or suspected clopidogrel resistance, including the use of drugs with alternative molecular targets (e.g., cilostazol), metabolized via different pathways (e.g., prasugrel) or administered in an active form (e.g., ticagrelor). Clopidogrel resistance is a clinically significant problem with potentially severe consequences if it is not identified or managed appropriately. The availability of point-of-care assays and novel treatments provide clinicians with an extensive array of tools that should aid in the management of atherothrombotic diseases/events, and reduce the risk of future severe events in these patients.

Publication types

  • Review

MeSH terms

  • Animals
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / drug therapy*
  • Clopidogrel
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Drug Resistance* / genetics
  • Humans
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Polymorphism, Genetic
  • Purinergic P2Y Receptor Antagonists / metabolism
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / metabolism
  • Ticlopidine / therapeutic use
  • Treatment Failure


  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Cytochrome P-450 Enzyme System
  • Clopidogrel
  • Ticlopidine