Clopidogrel resistance

The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. In part this tremendous variation in incidence reflects the definition of resistance (recurrent thrombosis while on antiplatelet therapy vs in vitro testing), methods by which drug response is measured, and patient compliance. Several methods for testing aspirin and clopidogrel resistance in vitro are now FDA-approved however, their utility outside of clinical trials remains controversial. 

Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004 109 166-171. 

Matetzky S, Shenkman B, Guetta V et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction, Circulation 2004 109 3171-3175. 

Wiviott SD, Antman EM (2004) Clopidogrel resistance. A new chapter in a fast-moving story. Circulation 109 3064-3067... 

Cattaneo M (2004) Aspirin and clopidogrel efficacy, safety, and the issue of drag resistance. Arterioscler Thromb Vase Biol 24 1980-1987... 

All of the data mentioned earlier strongly support insufficient metabolite generation as the primary explanation for nonresponsiveness rather than genetic polymorphisms of platelet receptors or intracellular signaling mechanisms. The latter mechanisms may be relevant in those patients who may remain resistant and with high platelet reactivity to ADP even after treatment with high doses of clopidogrel. 

Reports of high incidences of aspirin resistance may be due to laboratory measurements based on nonspecific methods that do not isolate the response of platelet COX-1 to aspirin or due to an inadequate dose required to fully inhibit the COX-1 in selected patients. Clopidogrel nonresponsiveness is a consistent phenomenon observed in research studies conducted at multiple medical centers around the world. Data from small studies support that patients with high ex vivo platelet reactivity to ADP during and after percutaneous intervention may be at greatest risk for subsequent ischemic events. 

Gurbel PA. Clopidogrel response variability and drug resistance. Haematologica 2004 897 (suppl 7) 9-l I. 

Chen W-H, Lee P-Y Ng W, et al, Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004 43 1 122-1 126. 

Gurbel PA, Bliden KR Hiatt BL, O Connor CM. Clopidogrel for coronary stenting response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003 107 2908-2913. 

Measurement of the concentration of the active metabolite can be used to assess clopidogrel efficacy for patients who have a pharmacokinetic mechanism for platelet resistance. Mega et al. showed that patients who are intermediate or slow metabolizers... 

Gurbel PA, Bliden KP, Etherington A, Tantry US. Assessment of clopidogrel responsiveness measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients. Thromb Res 2007 121 107—15. 

Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel a review of the evidence. J Am Coll Cardiol 2005 45 1157-1164. 

---