The Role of Genetic Factors on the Effect of Additional Doses of Clopidogrel to Improve Personalized Effectiveness in Patients. Summary of the Doctoral Thesis

Abstract

Introduction. Hyporesponsiveness to clopidogrel has been associated with increased risk of cardiovascular events for patients undergoing percutaneous coronary intervention (PCI). Low response to clopidogrel (hyporesponsivevess) may be overcome by additional loading doses (LD) and higher maintenance doses (MD). The influence of genetic polymorphisms on efficacy of personalized clopidogrel dosing remains unclear. The aim of this study was to investigate whether genetic polymorphisms of two cytochromes (CYP2C19, CYP2C9) and ABCB1 modify effect of additional LDs (600 mg) and higher MD (150 mg) used to overcome hyporesponsiveness of clopidogrel and to evaluate long-term safety of higher platelet reactivity index (PRI) cutoff value of <60% during one year period after PCI. Methods. In a prospective single-center study we enrolled 118 patients undergoing PCI with drugeluting stent (DES). PRI was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP). Genetic polymorphisms of CYP2C19, CYP2C9 and ABCB1 were determined. In patients hyporesponsive to the initial LD the doseadjustment was performed using up to 3 additional 600 mg LDs in order to achieve PRI <60%, and both 150 mg and 75 mg MD were tested at the follow-up. Long-term clinical follow up was obtained in all patients. Results. Patients with at least one CYP2C19*2 allele had higher baseline PRI after the initial LD (78.2±13.1 vs 65.3±19.5, p=0.005). The PRI reduction with additional LD was significantly smaller in carriers of the CYP2C19*2 (25.2±15.6 vs 35.5±16.8, p=0.025) and similar trend was observed with additional LDs. Both MDs were less effective in presence of CYP2C19*2: 53.3±12.1 vs 40.3±13.5, respectively; p=0.001 on day 10 while on MD of 150 mg, and 65.5±10.4 vs 56.3±14.5, respectively; p=0.020 on day 40 on MD of 75 mg. No such differences were observed for other polymorphisms. Low responders to clopidogrel had higher body mass index (BMI) (32.8±3.9 vs 29.6±4.9; p=0.007). More patients in hyporesponders group had concomitantly proton pump inhibitor (PPI) therapy compared to responders (16 vs 7; p=0.381). Conclusions. The patients carrying at least one loss-of-function CYP2C19*2 allele have significantly higher PRI following an initial LD and additional LDs. In the presence of CYP2C19*2 higher MD of clopidogrel (150 mg) was more effective but still remains insufficient in 29% of cases. Higher BMI and use of PPIs were associated with a trend to decreased efficiency of clopidogrel.