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GIFT: Genetics-based dosing improves warfarin safety

WASHINGTON — Pharmacogenetics-based warfarin dosing decreased adverse events compared with clinical-based dosing, investigators from the GIFT study reported at the American College of Cardiology Scientific Session.

While warfarin prevents stroke and venous thromboembolism effectively, it causes more ED visits among older patients than any other drug, mainly because of bleeding, Brian F. Gage, MD, MS, professor of Medicine, Washington University School of Medicine in St. Louis, said during a presentation.

On the warfarin label, “you’ll see information that says knowledge of genotype can inform dose selection,” Gage said. “That was the focus of our study. … Our hypothesis was that pharmacogenetic dosing of warfarin therapy decreases the rate of clinical events vs. clinical dosing in patients initiating warfarin therapy.” Brian F. Gage

Gage and colleagues designed a pharmacogenetics-based dosing strategy based on factors such as CYP2C9 single nucleotide polymorphisms slowing S-warfarin metabolism, VKORC1-1639 G > A vitamin K epoxide reductase increasing warfarin sensitivity and CYP4F2 V433M reducing vitamin K clearance.

The researchers randomly assigned 1,650 patients (mean age, 72 years; 64% women) receiving warfarin to prevent deep vein thrombosis as a result of hip-replacement or knee-replacement surgery to receive pharmacogenetics-based dosing or clinical-based dosing.

Within each group, patients were further randomized to a target international normalized ratio (INR) of 2.5 or 1.8.

The primary outcome was a composite of major bleeding at 30 days, an INR of 4 or greater at 30 days, death within 30 days and VTE confirmed within 60 days of surgery.

The genetics group had a lower rate of the primary outcome than the clinical group (10.8% vs. 14.7%; RR = 0.73; 95% CI, 0.56-0.95), Gage said.

The genetics group had less major bleeding (0.25% vs. 1.01%; P = .062) and fewer INR values of 4 or greater (6.9% vs. 9.8%; P = .041) than the clinical group. There were no deaths and no difference between the groups in VTE (genetics, 4.1%; clinical, 4.8%; P = .48), he said.

The benefits of the pharmacogenetics-dosing strategy were consistent, with no interaction by race, CYP2C9 genotype, INR target or type of surgery, according to the researchers.

Percentage of time in therapeutic range was higher in the genetic group in the overall cohort (P = .004), a prespecified high-risk subgroup with divergent clinical and genetic predicted doses (P = .0002) and those with an INR target of 2.5 (P = .0006), but not in those with an INR target of 1.8 (P = .51), Gage and colleagues found.

“The algorithm-assisted warfarin dosing is safe in both arms, clinical and genetic dosing, and therefore dosing algorithms from warfarindosing.org should be incorporated into the electronic medical record,” Gage said. “Genotype dosing reduced the relative risk of adverse events in elderly participants beginning warfarin by 27%, and the INR improved, especially among the high-risk subgroup.” – by Erik Swain

Reference:

Gage BF, et al. Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.

Disclosure: The study was funded by the NIH and the genotyping was funded by the CMS. Gage reports no relevant financial disclosures.