EU-PACT: Genotype-Guided Dosing of Warfarin vs. Standard Dosing

Genotype-based dosing at the initiation of warfarin therapy was found to be superior to standard dosing, and "was associated with a higher percentage of time in the therapeutic international normalized ratio (INR) range," according to results of the EU-PACT study, presented Nov. 19 as part of AHA 2013, and published simultaneously in the New England Journal of Medicine.

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The EU-PACT Warfarin Study looked at 455 patients with atrial fibrillation or venous thromboembolism. A point-of-care test was used to perform genotyping for CYP2C9*2, CYP2C9*3, and VKORC1, and patients were randomly assigned to the genotype-guided dosing arm or to the standard dosing control group. In the genotype-guided group, "warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first five days." Patients in the standard dosing control group "received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to the routine clinical practice."

Results showed "the mean percentage of time in the therapeutic range was 67.4 percent in the genotype-guided group as compared with 60.3 percent in the control group (adjusted difference, 7.0 percentage points; 95 percent confidence interval, 3.3 to 10.6, P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001)."

"We found that genotyping before starting warfarin increased the time in therapeutic range by approximately 7 percent, reduced over-anticoagulation, reduced the time required to reach therapeutic range, improved the time required to reach stable dose and reduced the number of warfarin dose adjustments," said Munir Pirmohamed, MD, PhD, lead author of the study and NHS Chair of Pharmacogenetics at the University of Liverpool in the United Kingdom. "Our study very much fits in with the concept of personalized medicine, which aims to get the right drug, at the right dose to the right patient," Pirmohamed added. "There is huge potential in the cardiovascular field for personalizing therapy on the basis of genetic or non-genetic tests … for genetic testing, in some cases it may be possible to undertake the testing at the bedside or in surgery, so called point-of-care tests as we did in this trial. We need evidence from randomized controlled trials to show the utility of genetic testing."

Keywords: Warfarin, Atrial Fibrillation, Genetic Testing, Genotype, Pharmacogenetics

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