The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated 
with impaired clopidogrel response and worse prognosis in clopidogrel-treated 
patients. The benefit of tailored therapy according to platelet function test 
results remains unclear, and the potential effect of genotypes on this benefit 
has not been addressed in unstable patients. The present study was designed to 
evaluate the benefit of tailored therapy with a higher maintenance dose 
according to CYP2C19 genotypes in patients identified as nonresponders who 
underwent percutaneous coronary intervention for non-ST-segment elevation acute 
coronary syndromes. Three hundred forty-six consecutive patients were enrolled 
and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes 
and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed 
with platelet reactivity index vasoactive-stimulated phosphoprotein, was 
significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 
allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was 
higher in CYP2C19*2 allele carriers (53% vs 41%, p = 0.04). All clopidogrel 
nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, 
received high 150-mg clopidogrel maintenance doses at discharge to overcome 
initial low response. After 1 month, high maintenance doses overcame clopidogrel 
low response in only 44% of the whole population and significantly less 
frequently in *2 carriers than in noncarriers (28% vs 50%, p = 0.01). In 
conclusion, higher clopidogrel maintenance doses were able to overcome 
clopidogrel low response in fewer than half of clopidogrel low responders who 
underwent percutaneous coronary intervention for non-ST-segment elevation acute 
coronary syndromes. The benefit of this tailored therapy was significantly 
reduced in CYP2C19*2 carriers. Therefore, these patients might require 
alternative strategies with new P2Y₁₂ blockers.