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

Authors :
Gage BF
Bass AR
Lin H
Woller SC
Stevens SM
Al-Hammadi N
Li J
Rodríguez T Jr
Miller JP
McMillin GA
Pendleton RC
Jaffer AK
King CR
Whipple BD
Porche-Sorbet R
Napoli L
Merritt K
Thompson AM
Hyun G
Anderson JL
Hollomon W
Barrack RL
Nunley RM
Moskowitz G
Dávila-Román V
Eby CS
Source :
JAMA [JAMA] 2017 Sep 26; Vol. 318 (12), pp. 1115-1124.
Publication Year :
2017

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.<br />Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation.<br />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.<br />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.<br />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.<br />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.<br />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.<br />Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

Details

Language :
English
ISSN :
1538-3598
Volume :
318
Issue :
12
Database :
MEDLINE
Journal :
JAMA
Publication Type :
Academic Journal
Accession number :
28973620
Full Text :
https://doi.org/10.1001/jama.2017.11469