GIFT

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Clinical Question

In patients undergoing elective hip or knee arthroplasty, does using genotype-guided warfarin dosing as opposed to clinically guided warfarin dosing prevent adverse effects while maximizing benefit?

Bottom Line

The purpose of this study is to examine the safety and effectiveness of genotype-guided warfarin dosing to determine if there is a difference between this method and clinically guided warfarin dosing in terms of adverse effects and results such as INR, major bleeding, venous thromboembolism, or death.

Genotype-guided management resulted in improvements for the composite outcome of major bleeding, death, venous thrombotic events and INR >4 (NNT=25). However, the only individual outcome that was significant was the disease-oriented outcome of INR >4, while the patient-oriented outcomes of major bleeding, symptomatic DVT or PE were not significantly different.


Major Points

Among older patients, warfarin is a major contributor to medication-related emergency department visits. Dose requirements of warfarin are not standard among patients due to common single nucleotide polymorphisms (SNPs). There is conflicting data about the impact of genotype-guided dosing. One of the largest trials for warfarin genotype-guided dosing, COAG, found no improvement in international normalized ratio (INR) control, while the EU-PACT trial found improved INR control with genotype-guided dosing.The goal of this trial was to determine if adverse events caused by warfarin could be reduced by genotype-guided dosing.

The Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis was a multicenter randomized clinical trial. At 6 US medical centers, warfarin was started for hip or knee arthroplasty in patients aged 65 years or older. A 2 x 2 factorial design was used to randomize patients to genotype-guided or clinically guided dosing of warfarin on days 1 through 11 of therapy and to a target INR of 1.8 or 2.5. Patients were randomized 1:1 using a computer program which stratified the type of arthroplasty and race. Patients and study personnel were blind to group assignment and genotype. The warfarin dosing was open label. Warfarin was initiated the night prior to arthroplasty or the night of arthroplasty depending on the hospital’s standard practice. Clinicians used their clinical judgement after day 11 of therapy whether to continue the recommended warfarin dose or change it. The main outcomes measured included major bleeding, INR of 4 or greater, venous thromboembolism, or death within 30 days.

It was found that genotype-guided warfarin dosing reduced the combined risk of these outcomes in comparison with clinically guided dosing. INR was the only component that was significantly reduced alone. The outcomes of major bleeding, symptomatic deep vein thrombosis, and pulmonary embolism were not significantly different.

Guidelines

The ACCP Guidelines for Thromboprophylaxis in Total Hip and Knee Arthroplasty

  • Antithrombotic prophylaxis recommended for minimum of 10-14 days, but extension of thromboprophylaxis in outpatient period for up to 35 days from day of surgery suggested rather than for only 10-14 days (ACCP Grade 2B)

Design

  • Multicenter Randomized Control Trial
  • N=1650
    • Experimental arm (n=831)
    • Standard (n=819)
  • Setting: 6 US medical centers
  • Enrollment: Began April 2011
  • Mean follow-up: Ended October 2016
  • Analysis: Intention-to-treat
  • Primary outcome: In 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

Population

Inclusion Criteria

  • Patients planning to undergo hip or knee arthroplasty
  • Age >65 years
  • Life expectancy of >6 months


Exclusion Criteria

  • A genotype or therapeutic warfarin dose known from prior therapy
  • Prior non-adherence
  • Contraindication to warfarin
  • A treatment plan to receive an anticoagulant other than warfarin
  • Known thrombophilia
  • A bleeding disorder
  • A serious bleeding event within the last 2 years (unless caused by trauma)
  • A baseline INR of 1.35 or greater
  • An additional indication for warfarin (eg. atrial fibrillation)


Baseline Characteristics

  • Age: 72.1 years
  • Body mass index: 29.2 kg/m^2
  • Baseline INR: 1.01 (Clinically Significant)
  • Indication
    • Hip Replacement: 25.4%
    • Knee Replacement: 74.6%
  • Randomization Arm
    • Genotype-guided: 50.6%
    • Clinically-guided: 49.4%
  • Target INR
    • 1.8: 50.3%
    • 2.5: 49.4%
  • Female: 63.7%
  • Race
    • African American: 6.4%
    • Caucasian: 91.1%
    • Asian or Indian Subcontinent: 1.8%
    • Other or unknown: 0.8%
  • Hispanic: 2.6%
  • Smoker: 3.4% (Clinically Significant)
  • Diabetes: 13.8%
  • Liver Disease: 0.75%

Interventions

Genetic testing for warfarin sensitivity helps determine if a patient requires lower or higher doses of the drug. There are common genetic variations in three genes, CYP2C9 , VKORC1, and CYP4F2. Patients were genotyped for the VKORC1-1639G>A, CYP2CP*2, CYP2C9*3, and CYP4F2 V433M polymorphisms. Patients were randomized to genotype-guided or clinically guided warfarin dosing. An online website (WarfarinDosing.org) was used to guide warfarin dosing.

Outcomes

Presented as genotype-guided vs clinically-guided.

Primary Outcomes

Composite of major bleeding, death, an INR of 4 or greater within 30 days, and a venous thrombotic event within 60 days.

Experienced 1 composite end point
10.8% vs 14.7% (RR 0.73; 95% CI 0.56-0.95; P=0.02; NNT=25)
Major bleeding
0.2% vs 1.0% (RR 0.73; 95% CI 0.05-1.15; P=0.06)
INR of 4 or greater
6.9% vs 9.8% (RR 0.71; 95% CI 0.51-0.99; P=0.04)
VTE
4.1% vs 4.8% (RR 0.85; 95% CI 0.54-1.34; P=0.48)
Death
0 vs 0


Secondary Outcomes

Non-major bleeding
7.1% vs 9.4% (95% Cl, -0.4% to 5.1%, P= 0.09)
PTTR
Genotype-guided improved PTTR by 3.4% (95% CI 1.1%-5.8%; P=0.004)
High-risk subgroup (95% CI 3.4%-10.6%)


Subgroup Analysis

Kaplan-Meier analysis showing that there was no major difference between major and nonmajor clinically relevant bleeding risk.

A post hoc analysis demonstrated that the low risk of adverse events was statistically significant. Major adverse events, such as symptomatic DVTs and pulmonary embolisms, presented in 1.5% of patients in the treatment group (genotypic testing) as per the post hoc analysis. This was less than the clinically guided group with 2.9%. The difference between these two groups was determined to have a confidence interval of 0% to 3% with a p value of 0.051.


Adverse Events

  • Adverse Events: 15.2% genotypic group, 15.2% clinical group, p=0.99
  • Non-major Bleed: 10.3% genotypic group, 10.5% clinical group, p=0.87
  • Cardiovascular Event: 10% genotypic group, 13% clinical group, p=0.49
  • Infection: 6.2% genotypic group, 6.1% clinical group, p=0.93
  • Infection by location (knee or surgical site): 6.2% genotypic group, 6.1% clinical group, p=0.93

Criticisms

  • The study was double blinded, but the Warfarin dosing was open label. The personnel conducting the study might have been able to infer the study groups based on these.
  • There was no statistical significance in reduction of symptomatic clinical adverse events (symptomatic DVT, PE, major bleeding). The absolute reduction in the primary outcome was more due to differences in INRs being greater than or equal to 4.
  • There was no statistical significance in the participants having a goal INR of less than 1.5 in the first 90 days.
  • The study can be hard to generalize because most participants became involved through large academic associated medical sites.
  • The study only included participants ages 65 and older, also making it hard to generalize.
  • The study did not include comparisons of cost between the two therapies. This could have a significant impact on determining a therapy for a patient if the differences were significant.


Funding

  • Grant R01 HL097036 from the National Heart, Lung, and Blood Institute
  • Clinical and Translational Sciences Grant UL1 TR000448 from the National Center for Advancing 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


Further Reading

(1) Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013;369(24):2283-2293.PubMed [1]

(2) Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369(24):2294-2303.PubMed [2]