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    Genetically Guided Warfarin Dosing Lowers Risk of Some Adverse Events in TJA Patients

    Using genetic testing to help personalize doses of warfarin therapy given to patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) appears to lower the risk of adverse events compared with clinically guided dosing, according to research presented at the recent annual meeting of the American College of Cardiology.

    The Genetic InFormatics Trial (GIFT) of Warfarin Therapy to Prevent DVT — the first trial to quantify the benefit of pharmacogenetic dosing of warfarin on clinical events — found that compared with clinically based dosing, genotype-guided dosing was associated with a 27% reduction in the study’s primary endpoint, a composite of death, confirmed venous thromboembolism, warfarin overdose (INR ≥ 4), and major bleeding.

    Because there were no deaths during the trial, the researchers were unable to assess whether genotype-guided dosing reduced mortality.

    Clarifying the Value of Genotype-Guided Dosing

    “The way we dose warfarin clinically is trial-and-error dosing. We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose,” said Brian F. Gage, MD, MSc, professor of medicine at Washington University School of Medicine in St. Louis, and the study’s lead author.

    Clinical dosing used in this trial was likely better than standard dosing, Dr. Gage said, because it used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

    The trial also showed a statistically significant improvement in INR control, the study’s secondary endpoint, among patients whose warfarin dose was determined based on genetic information in addition to clinical factors.

    Previous studies had shown mixed results as to whether genotype-guided dosing improved INR control. However, compared with previous studies, the GIFT trial was considerably larger, added another gene (CYP4F2), and recruited older patients (age 65 years and older) at high risk of bleeding.

    “Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr. Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”  

    27% Relative Risk Reduction of Adverse Events

    This multicenter, randomized controlled trial followed 1,597 participants 65 years or older undergoing elective THA or TKA (63.8% women, 91.1% Caucasian). Most patients were recruited at the Hospital for Special Surgery in New York City, Washington University in St. Louis, and the University of Utah and Intermountain Healthcare in Salt Lake City.

    Participants were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2). They were then randomized to receive either clinical dosing or genotype-guided dosing by the algorithms; clinical factors were also taken into account. In addition, patients were randomly assigned to a target INR of either 1.8 or 2.5.

    For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application (www.WarfarinDosing.org) that incorporated clinical factors in all patients and genotype in participants randomized to genotype-guided dosing. Most of the time, prescribers gave the dose that was recommended. After 11 days of therapy, prescribers were free to continue the current warfarin dose or adjust the dose.

    Patients were monitored using standard INR testing, and most participants underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after surgery to check for clots. Researchers followed participants for 90 days and assessed the primary outcome through day 30. DVTs and PEs detected through day 60 were also included in the primary outcome.

    The rate of adverse events was 14.7% in the clinical arm and 10.8% in the genotype-guided arm, a 27% relative risk reduction. There was a significant reduction in INR values ≥ 4, from 9.8% in the clinical arm to 6.9% with genotype-guided dosing.

    However, in looking at events by themselves, there was no significant reduction in DVT/PE or major bleeds between groups. At 30 days of follow-up, no participant died and 1 was lost to follow-up.

    Dr. Gage said that future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants. In addition, as clinical and genetic factors affecting warfarin dose requirements vary by race, there may be benefit of dosing algorithms tailored to ancestry.