TY - JOUR
T1 - Effect of genotype-guided warfarin dosing on clinical events and anticoagulation control among patients undergoing hip or knee arthroplasty
T2 - The GIFT randomized clinical trial
AU - Gage, Brian F.
AU - Bass, Anne R.
AU - Lin, Hannah
AU - Woller, Scott C.
AU - Stevens, Scott M.
AU - Al-Hammadi, Noor
AU - Li, Juan
AU - Rodríguez, Tomás
AU - Miller, J. Philip
AU - McMillin, Gwendolyn A.
AU - Pendleton, Robert C.
AU - Jaffer, Amir K.
AU - King, Cristi R.
AU - Whipple, Brandi De Vore
AU - Porche-Sorbet, Rhonda
AU - Napoli, Lynnae
AU - Merritt, Kerri
AU - Thompson, Anna M.
AU - Hyun, Gina
AU - Anderson, Jeffrey L.
AU - Hollomon, Wesley
AU - Barrack, Robert L.
AU - Nunley, Ryan M.
AU - Moskowitz, Gerard
AU - Dávila-Román, Victor
AU - Eby, Charles S.
N1 - Funding Information:
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.
Funding Information:
Funding/Support: The research was supported by grant R01 HL097036 from the National Heart, Lung, and Blood Institute. The statistical analyses were supported by clinical and translational sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (awarded to the Washington University Institute of Clinical and Translational Sciences). The genotyping and most of the duplex ultrasound imaging using the coverage with evidence development mechanism (CAG-00400N) was funded by the Centers for Medicare & Medicaid Services. GenMarkDx loaned the eSensor genotyping platform to the central genotyping laboratory.
Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2017/9/26
Y1 - 2017/9/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029935351&partnerID=8YFLogxK
U2 - 10.1001/jama.2017.11469
DO - 10.1001/jama.2017.11469
M3 - Article
C2 - 28973620
AN - SCOPUS:85029935351
VL - 318
SP - 1115
EP - 1124
JO - Journal of the American Medical Association
JF - Journal of the American Medical Association
SN - 0098-7484
IS - 12
ER -