Abstract 16324: Genetic Predisposition Influences Anticoagulation Control and Major Hemorrhage Among Warfarin Users
Objective: Genetic variants in Cytochrome P450 2C9 (CYP2C9) and Vitamin K epoxide reductase complex 1 (VKORC1) are recognized predictors of warfarin dose. However, their influence on percent time in target range (PTTR; INR range 2-3), overanticoagulation (INR>4) and risk of major hemorrhage have not been extensively evaluated. Herein, categorizing warfarin users possessing CYP2C9 (*2,*3,*5,*6,*11) and/or VKORC1 (-1639C>T) variants as sensitive responders, we evaluated whether sensitive responders (vs. normal) were more likely to have lower PTTR and a higher risk of overanticoagulation and major hemorrhage.
Methods: The analysis included 1262 participants [310 sensitive responders (SR); 952 normal responders (NR)] in a warfarin pharmacogenetics inception cohort. The Rosendaal interpolation method was used to compute the PTTR, percent time above range (PTAR) and percent time below range (PTBR). Major hemorrhages included serious, life threatening and fatal bleeding events.
The influence of responder status (SR vs. NR) on PTTR, PTBR, and PBAR was evaluated using linear regression, and overanticoagulation and hemorrhage by Cox proportional hazards analysis adjusting for clinical factors.
Results: Participants were followed for an average of 1.4 (± 0.9) years; with 1799 person-years (pyr) accrued. There was no difference in PTTR between SRs (54.4% vs. 53.8%, p=0.66) compared to NRs. However SRs had higher PTAR (20.3% vs. 16.7%, p=0.005) and lower PTBR (25.2% vs. 29.5%, p=0.01) and were more likely to experience over-anticoagulation (HR: 1.38, 95% CI: 1.23-1.56, p<0.001).
SRs had higher incidence of hemorrhage compared to NRs ((IRR: 1.48, 95% CI: 1.04-2.08, p=0.03). After adjusting for clinical factors, SRs remained at a higher risk for hemorrhage (HR: 1.81, 95% CI: 1.23-2.68, p=0.003).
Conclusion: Warfarin users possessing CYP2C9 and/or VKORC1 variants are sensitive responders, spending higher percent of time above target INR range. These patients are more likely to experience overanticoagulation and major hemorrhagic events. Future research evaluating alterative treatment strategy including candidacy for the non-vitamin K antagonist oral anticoagulants is needed.
Author Disclosures: A. Shendre: None. T.M. Brown: None. N. Liu: None. T.M. Beasley: None. C.E. Hill: None. N.A. Limdi: None.
- © 2015 by American Heart Association, Inc.