Clopidogrel Loading Dose Adjustment According to Platelet Reactivity Monitoring in Patients Carrying the 2C19☆2 Loss of Function Polymorphism

Objectives We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19(star)2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes. Background CYP2C19(star)2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention. Method A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of >= 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19(star)2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%. Results One hundred thirty-four patients (35.3%) carried at least one 2C19(star)2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 +/- 18.4% vs. 49.2 +/- 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 +/- 10.1% vs. 50.6 +/- 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19(star)2 carriers exhibiting HTPR to reach a VASP index <50%. Conclusions Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19(star)2 polymorphism. (J Am Coll Cardiol 2010;56:1630-6) (C) 2010 by the American College of Cardiology Foundation