The Effect of CYP2C19 Genetic Polymorphisms and the Concomitant Use of Rabeprazole or Esomeprazole on the Anti-Platelet Action of Clopidogrel

Purpose: To investigate the effect of CYP2C19 genetic polymorphisms and concomitant use of rabeprazole or esomeprazole on the anti-platelet effect of clopidogrel in vitro. Methods: Patients receiving a stable dose of clopidogrel 75 mg with or without rabeprazole or esomeprazole for > 2 weeks were recruited. Genotyping for CYP2C19 and VASP testing using flow cytometry to measure platelet reactivity index (PRI) were performed. A detailed questionnaire regarding the indication and duration of use of clopidogrel and PPI therapy was completed on all patients including a detailed concomitant drug history. Results: To date, 178 consecutive patients (132M and 46F; mean age= 66.7±12.1) were enrolled after informed consent. 79 patients were on clopidogrel without concomitant PPI therapy (C group), 64 were on clopidogrel + rabeprazole (CR group), and 35 on clopidogrel + esomeprazole (CE group). The mean number of concomitant medications in addition to clopidogrel was 5.3± 2.4. The indications for clopidogrel use were cardiac, neurologic, and peripheral vascular disease (72.5, 24.7, and 2.8 % respectively) and the mean duration of clopidogrel therapy was 31.5 ± 39.2 months. The indications for PPI use were considered appropriate in 29.4% of users. On CYP2C19 genotyping, 146 patients did not have loss of function polymorphism (LOF) while 32 had LOF (31 heterozygous and 1 homozygous mutant for CYP2C19*2).The mean PRI was 20.8±21.3 % in the clopidogrel group, 17.4±18.3 % in the CR group, and 28.5±27.6 % in the CE group (p = 0.054). Abnormal PRI, defined arbitrarily as >50%, was observed in 11 (13.9%), 8 (12.5%), and 7 (20.0%) patients on C, CR, CE respectively (p = 0.59). A PRI of >30% was noted in 19 (24.1%), 11 (17.2%), and 16 (45.7%) patients on C, CR, CE respectively (p = 0.007). Four patients with an abnormal PRI on CE had improvement in PRI after stopping E in 1 and switching to R in 3 (from a mean of 81.1% to 24.3%; p = 0.007). On multivariate logistic regression, use of esomeprazole was the only independent variable associated with an abnormal in vitro response to clopidogrel defined as PRI >30% [p = 0.021, OR = 2.75 (1.17-6.49)]. The presence of CYP2C19 LOF was not associated with an abnormal PRI. Conclusion: Up to 14% of individuals on clopidogrel monotherapy have an unsatisfactory in vitro platelet inhibition independent of CYP2C19 polymorphism. Esomeprazole appears to exhibit an inhibitory effect on the anti-platelet function of clopidogrel in vitro independent of loss of function mutations in CYP2C19. Rabeprazole, characterized by predominant non-enzymatic metabolism, does not appear to exert any measurable effect on the anti-platelet action of clopidogrel in vitro. (This study is supported by the Lebanese National Council for Scientific Research.)