Influence of CYP2C9 and VKORC1 on Warfarin Dose and Complications in Kazakhstani Patients with Left Ventricular Assist Device

Abstract

Purpose The use of anti-platelet and anti-thrombotic therapy is a main stay in left ventricular assist devises (LVAD) to mitigate complicationssuch as pump thrombosis or systemic thromboembolism. Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance is limited. The purpose of this study is to evaluate the influence of CYP2C9 and VKORC1 polymorphisms on warfarin response and dosing algorithms in LVAD patients. Methods 100 patients implanted the HW, HM2, HM3 LVAD, irrespective of intended goal of therapy (either bridge to transplantation or destination therapy) after December 2011 at a single clinic - National Research Center for Cardiac Surgery, Astana, Kazakhstan with genotype data available for CYP2C9 (*1, *2, and *3 [rs1799853 and rs1057910]) and VKORC1 (-1639 G>A [rs9923231]) variants were included into study after institutional ethics committee approved the protocol. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). Results 32.0% of patients with implanted LVADs had at least one polymorphism: VKORC1 (14.0%), CYP2C9*2 (15.0%), CYP2C9*2 and VKORC1 (3.0%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.2±1.5 vs. 5.5±3.7 mg, p = 0.015) and achieved a similar mean INR (2.20±0.67 vs. 2.19±0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first days of therapy. Conclusion This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in LVAD patients and demonstrates an impact of genetic factors on clinical outcomes and proof of concept that genotype data could be incorporated into Warfarin dosing algorithm in LVAD patients.