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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bass reported serving on boards for the American College of Rheumatology and the Rheumatology Research Foundation of the American College of Rheumatology. Dr Stevens reported having prior research contracts with Bristol-Myers Squibb and Iverson Genetics. Mr Rodríguez reported receiving salary support from Washington University in St Louis. Dr Barrack reported receiving grant funding and personal fees from Stryker; grant funding from Biomet, Medical Compression Systems Inc, Smith & Nephew, Wright Medical Technology, and EOS Imaging; and royalties from the McGraw-Hill Companies Inc and Wolters Kluwer Health/Lippincott Williams & Wilkins. No other disclosures were reported.

Figures

Figure 1.. Consent, Randomization, and Follow-up of Participants in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis

aThe number of patients screened for eligibility is not known. bA list of the exclusion criteria appears in the Methods section.

Figure 2.. Kaplan-Meier Plot of the Time to Supratherapeutic International Normalized Ratio of 4 or Greater

Figure 3.. Kaplan-Meier Plot of the Time to a Major or Nonmajor Clinically Relevant Bleeding Event

Figure 4.. Distribution of Percentage of Time in the Therapeutic Range (PTTR) for All Patients With an International Normalized Ratio on Day 4 or Later (N = 1588)

Plot shows the probability densities of the PTTR of the international normalized ratio values from days 4 through 28 of warfarin therapy.

Figure 5.. Distribution of Percentage of Time in the Therapeutic Range (PTTR) for Patients Stratified by the Absolute Difference in the Predicted Initial Dose of Warfarin and by Self-described Race

Plots show the probability densities of the PTTR of the international normalized ratio values from days 4 through 28 of warfarin therapy. aPatients whose clinically guided vs genotype-predicted doses of warfarin differed by 1.0 mg/d or greater (according to baseline genotype and clinical algorithms). bPatients whose clinically guided vs genotype-predicted doses of warfarin differed by less than 1.0 mg/d (according to baseline genotype and clinical algorithms).