Brian F. Gage

Based on data from 58 US emergency departments during the years 2013 and 2014, warfarin accounted for more medication-related emergency visits among older patients than any other drug.¹ However, direct oral anticoagulants, with their rapid onset of action, also cause hemorrhage requiring emergency care,¹ especially after orthopedic surgery.^2-4 Thus, warfarin continues to be prescribed after hip and knee arthroplasty, particularly among high-risk orthopedic patients.⁵

In Reply Mr Han-You asks about subgroup analyses by type of arthroplasty (hip vs knee), site, and race in the Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Venous Thrombosis. Randomization was stratified by medical center, type of arthroplasty (knee or hip), and race (black vs other races). The primary end point, a composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death occurred in 14.7% of participants randomized to clinical warfarin dosing and in 10.8% randomized to genotype-guided dosing (P = .02). We repeated our primary analysis using a generalized linear mixed model with medical center as a random effect and the results were corroborated in that genotype-guided warfarin dosing significantly reduced the primary end point.

Importance Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions Patients were genotyped for the following polymorphisms:VKORC1-1639G>A,CYP2C9*2, CYP2C9*3, andCYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%],P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration clinicaltrials.gov Identifier:NCT01006733