Resistance to clopidogrel: a review of the evidence

J Am Coll Cardiol. 2005 Apr 19;45(8):1157-64. doi: 10.1016/j.jacc.2005.01.034.


Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y(12) receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel's antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.

Publication types

  • Review

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Clopidogrel
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / pharmacology
  • Drug Interactions
  • Drug Resistance
  • Humans
  • Individuality
  • Membrane Proteins / genetics
  • Platelet Activation
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / pharmacology*
  • Polymorphism, Genetic
  • Receptors, Purinergic P2 / genetics
  • Receptors, Purinergic P2Y12
  • Ticlopidine / administration & dosage
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology*
  • Up-Regulation


  • Membrane Proteins
  • P2RY12 protein, human
  • Platelet Aggregation Inhibitors
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y12
  • Adenosine Diphosphate
  • Cytochrome P-450 Enzyme System
  • Clopidogrel
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ticlopidine