Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis - GIFT

Contribution To Literature:

The GIFT trial showed that genotype-based dosing of warfarin is superior to standard management in increasing the amount of time spent in target therapeutic range over 4 weeks and reducing clinical events up to 30 days, among patients needing anticoagulation for VTE prophylaxis following hip and knee arthroplasty.

Description:

The goal of the trial was to assess the safety and efficacy of genotype-based dosing of warfarin among patients needing venous thromboembolism (VTE) prophylaxis for hip and knee arthroplasty.

Study Design

Patients undergoing elective hip or knee surgery and requiring warfarin (goal international normalized ratio [INR], 1.8 or 2.5) were randomized in a 1:1 fashion to genotype-guided dosing of warfarin or routine management for the first 11 days. Warfarin dosing was guided by a web application (WarfarinDosing.org) that incorporated clinical variables for all patients and also incorporated single-nucleotide polymorphisms in VKORC1, CYP2C9, and CYP4F2 for patients randomized to genotype-guided dosing algorithms.

• Total number of enrollees: 1,650
• Duration of follow-up: 60 days
• Mean patient age: 72.2 years
• Percentage female: 49.7%

Inclusion criteria:

• Planning to undergo elective hip or knee arthroplasty 
• Age ≥65 years 
• Life expectancy  >6 months 

Exclusion criteria:

• Genotype or therapeutic warfarin dose known from prior therapy
• Prior nonadherence
• Contraindication to warfarin
• Treatment plan to receive an anticoagulant other than warfarin
• Known thrombophilia
• Bleeding disorder
• Serious bleeding event within past 2 years (unless caused by trauma)
• Baseline INR ≥1.35
• Additional indication for warfarin (e.g., atrial fibrillation).

Other salient features/characteristics:
 
• White race: 91%
• Knee replacement: 74%
• Target INR 1.8: 50%
• Wild-type VKORC1 genotype was noted in 37%, heterozygous in 45%, and homozygous for G-A mutation in 17% of patients; wild-type CYP2C9 genotype was noted in nearly 80% of patients, with homozygous genotype for CYP2C9 in about 1.5-2% 


Principal Findings:

The primary endpoint, major adverse cardiac events (major bleeding within 30 days, INR ≥4 within 30 days, death within 30 days, and symptomatic or asymptomatic VTE confirmed by objective testing within 60 days of arthroplasty) for genotype guided vs. routine management, was 10.8% vs. 14.7%, p = 0.02.

• Major bleeding on days 1-30: 0.2% vs. 1.0%, p = 0.06
• INR ≥4 on days 1-30: 6.9% vs. 9.8%, p = 0.04
• VTE days 1-60: 4.1% vs. 4.8%, p = 0.48

Secondary outcomes for genotype guided vs. routine management:

• Time in therapeutic range through first 4 weeks: 54.7% vs. 51.3%, p = 0.004

Interpretation:

The results of the GIFT trial indicate that genotype-based dosing of warfarin for days 1-11 (for VKOR1C, CYP2C9, and CYP4F2) was superior to standard management in increasing the amount of time spent in target therapeutic range over 4 weeks and also for reducing clinical events up to 30 days, primarily related to a high INR and bleeding, among patients needing anticoagulation for VTE prophylaxis following hip and knee arthroplasty. This indicates benefits in both safety and efficacy with such a strategy.

Genotype-guided management is not endorsed by current guidelines due to largely negative results from other randomized controlled trials, other than EU-PACT, where a similar benefit was noted. The algorithm used in the current trial is different from other trials, and needs further validation in larger studies before this strategy can be broadly implemented. It is also important to note that nearly 91% of enrolled patients were white, which may limit generalizability to other ethnic groups.

The cost-effectiveness of this strategy needs to be further assessed. Further, with the availability and widespread use of direct oral anticoagulants, it is unclear if this strategy would be incrementally beneficial from either an efficacy or cost standpoint.

References:

Gage BF, Bass AR, Lin H, et al. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA 2017;318:1115-24.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Anticoagulants, Arthroplasty, Replacement, Knee, Atrial Fibrillation, Blood Coagulation, Blood Coagulation Disorders, Genotype, Hemorrhage, International Normalized Ratio, Mutation, Polymorphism, Single Nucleotide, Primary Prevention, Surgical Procedures, Elective, Thrombophilia, Venous Thromboembolism, Venous Thrombosis, Warfarin


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