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

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 PATIENTSThe 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 MEASURESThe 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.

Effect of Gene-Based Warfarin Dosing on Anticoagulation Control and Clinical Events in a Real-World Setting

“…Subsequently, GBWD had less of an effect on anticoagulation control, and multiple-dose titrations might have had a greater role. The finding that the TTR was shorter in the GBWD group is similar to that observed in the GIFT, EU-PACT, and COUMAGEN-II trials Wen et al, 2017) but different from that in the COAG study and other Asian-based studies Gage et al, 2017;Syn et al, 2018;Zhe et al, 2018). Our study revealed that GBWD resulted in a lower prevalence of bleeding events related to anticoagulation therapy, which may have been due to superior primary outcomes.…”

Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes

“…Using one of several existing NGS panels, including PGRNseq [7], AmpliSeq Pharmacogenomics Research Panel (thermofisher.com), or VeraCode ADME Core Panel (illumina.com), these variants indeed would be interrogated, but at the cost of requiring an additional test. Considering that every individual on average harbors six pharmacogenetically actionable variants, we identified several patients, who require significant PGx-based dosage adjustments, which has been shown to optimize treatment outcome for instance for the anticoagulants phenprocoumon or warfarin [24].…”

The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus

“…In the case of SLE, the traditionally employed drug for treating fulminant lupus nephritis-cyclophosphamide-has lower effectiveness for remission in black and Hispanic patients compared to whites and Asians [8••]. Moreover, there has been a recent rise in RCTs involving genotype-guided dosing, where genetic factors are taken into consideration when prescribing appropriate medication dosing [31]. While these genotype-guided dosing RCTs could inform future tailored interventions, a major concern is that the under-representation of racial minorities could lead to ineffective treatment, or even be detrimental to the disease course in these groups.…”