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Genotype-guided dosing of warfarin: GIFT wrap-up

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Elizabeth Silverman

January 2018—In an ideal world, clinical research data would be applied with immediate and beneficial effect to clinical practice, especially when the data come from a well-controlled, well-run trial that meets the gold standard of being large, randomized, and blinded. However, as the Sept. 26 publication of the Genetic Informatics Trial to evaluate genotype-guided dosing of warfarin demonstrates, reality is far more complicated (Gage BF, et al. JAMA. 2017;318[12]:1115–1124).

Despite GIFT showing that genotype-guided dosing prevents more adverse outcomes than clinically guided dosing, pharmacogenetic testing to improve warfarin initiation may not become widespread practice anytime soon.

GIFT was designed to do what the earlier COAG and EU-PACT trials had failed to do: provide the definitive answer to the question of whether genotype-guided warfarin dosing provided statistically significant clinical benefit to patients undergoing anticoagulant therapy. The inconsistent results of the prior trials—the COAG study found no benefit, EU-PACT did—were all the more puzzling because the effects of allelic variation in genes related to warfarin metabolism are well known and well characterized. (The results of both were published Dec. 12, 2013 in the New England Journal of Medicine, along with the results of a third study not of warfarin but of two other vitamin K antagonists.)

GIFT, which was a study of patients undergoing elective hip or knee arthroplasty, differed from the earlier trials in important respects that led investigators to hope it would provide a clearer answer to the question. GIFT was larger (1,597 patients compared with 1,015 in COAG and 455 in EU-PACT) and differed in the length of time the dosing algorithms were used. (EU-PACT found a higher percentage of time in the therapeutic INR range but wasn’t powered to assess for differences in clinical outcomes.)

Dr. Eby

Dr. Eby

“We were optimistic that the trial could show a difference favoring pharmacogenetic testing because of some pretty important details,” says investigator Charles S. Eby, MD, professor of pathology and immunology and co-chief of the Division of Laboratory and Genomic Medicine, Washington University School of Medicine.

“One, we had, under [principal investigator] Brian Gage’s leadership, developed dosing adjustment algorithms that went all the way to day 11 of warfarin treatment [versus four or five days in COAG and EU-PACT] and allowed for additional fine-tuning of the warfarin dose using both the known genetic information for the patients randomized to that arm plus how their INR was changing in those first 11 days.”

“We basically had more detailed algorithms to make dose refinement adjustments,” Dr. Eby explains.

A second advantage is that GIFT investigators included the polymorphism CYP4F2, which has been shown to have minor impact on steady state warfarin dose, he says, because the product of that gene is a protein involved in metabolizing vitamin K. “If vitamin K metabolism is slower, it means there will be more vitamin K inside of liver cells that has to be antagonized by warfarin, and it actually predicts a slightly higher warfarin dose,” Dr. Eby says.

The third advantage was a different population. GIFT investigators enrolled patients undergoing major surgery who historically have a higher rate of deep vein thrombosis in the first 30 days than nonsurgical patients started on warfarin. “We anticipated that we would have more clinical events to further help differentiate the benefits of the pharmacogenetic-based dosing algorithm,” Dr. Eby says. “We estimated that based on preexisting risks for DVT, a sample size of 1,600 would give us the power to see a difference in the composite outcome of VTE, major bleeding since patients undergoing major surgery had higher bleeding risks, INR of four or greater, and death.”

Coauthor Gwendolyn A. McMillin, PhD, medical director of toxicology and pharmacogenetics at ARUP Laboratories, says the biggest flaw of the prior studies (she was involved in COAG also) was the short period of time the genotype-guided algorithm was applied to warfarin dosing. “It takes four or five days for someone to reach steady state with warfarin if they have normal metabolism. If they have impaired metabolism, it’s going to take even longer, and then we also have to consider the kinetics of eliminating the clotting factors,” she says, noting that these temporal relationships had largely not been incorporated into previous study designs. “Most of the early studies switched back to the clinical monitoring before the genotyping really had any time to impart its effects.”

Dr. McMillin, who is also a professor of pathology at the University of Utah School of Medicine, says the incorporation in GIFT of the additional allele was important and that 42 percent of the study population was heterozygous for it. Brian F. Gage, MD, MSc, professor of medicine at Washington University School of Medicine and medical director of the Barnes-Jewish Hospital Blood Thinner Clinic, says there is a five to eight percent increase in dose per CYP4F2 allele and that he hopes to use the GIFT data to quantify this effect more precisely.

To some extent, GIFT did what it was designed to do. The study met its primary endpoint of the four composite outcomes of major bleeding, INR of four or greater, VTE, and death. There were no deaths in the trial and the three other outcomes favored the genotype-guided algorithm group. “We were glad to see that genotype dosing worked,” Dr. Gage says of the overall results. “We also were part of the COAG trial, so some of my colleagues had grown skeptical about the potential of genome-guided dosing. However, GIFT squeezed more benefit from genotype-guided dosing by using genotype for days one through 11 of therapy and by including SNPs in another gene [CYP4F2].”

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