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Original Investigation
September 26, 2017

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee ArthroplastyThe GIFT Randomized Clinical Trial

Author Affiliations
  • 1Washington University in St Louis, St Louis, Missouri
  • 2Hospital for Special Surgery, New York, New York
  • 3University of Massachusetts, Worcester
  • 4Intermountain Healthcare, Salt Lake City, Utah
  • 5University of Utah, Salt Lake City
  • 6New York Presbyterian Queens Hospital, New York, New York
  • 7University of Central Florida College of Medicine, Orlando
  • 8Saint Louis University, St Louis, Missouri
JAMA. 2017;318(12):1115-1124. doi:10.1001/jama.2017.11469
Key Points

Question  Does genotype-guided dosing of warfarin prevent adverse events?

Findings  In this multicenter randomized clinical trial that included 1650 patients undergoing elective hip or knee arthroplasty, genotype-guided warfarin dosing compared with clinically guided warfarin dosing reduced the rate of a composite of major bleeding, international normalized ratio of 4 or greater, venous thromboembolism, or death from 14.7% to 10.8%.

Meaning  Genotype-guided dosing may improve the safety of warfarin initiation among patients undergoing hip or knee arthroplasty.


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, and CYP4F2 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