Genotyping Reduces Adverse Events with Warfarin

–But still unclear whether benefit justifies the cost.

Because its effects can be highly variable, warfarin is a notoriously difficult drug to administer. In recent years warfarin has resulted in more medication-related visits to emergency departments among older patients than any other drug.

Researchers have long hoped that genotype-guided dosing of warfarin might reduce the rate of adverse events, including venous thromboembolism (VTE) and bleeding complications. Previous studies have been inconclusive, since they were not large enough to assess the clinical effect of genotype-guided dosing.

Now the Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis, published in JAMA, delivers the most detailed look yet at the effect of genotype-guided dosing. The results suggest that genotype-guided dosing can reduce clinical events, but the study leaves questions about whether personalized warfarin dosing based on genetic testing is cost-effective.

Patients (n=1,650) undergoing hip or knee arthroplasty were genotyped for known warfarin-related polymorphisms and then randomized to genotype-guided or clinically-guided warfarin dosing for the first 11 days after surgery. Genotype-guided dosing won: rates of the primary endpoint (composite of major bleeding, INR of 4 or greater, VTE, or death) were 14.7% in the clinically-guided group versus 10.8% in the genotype-guided group (P=0.02). There were no deaths.

Most of the difference occurred in the INR endpoint, though the differences in bleeding and VTE also favored genotyping:

  • INR of 4 or greater: 77 events for clinically-guided versus 56 events for genotype-guided
  • Major bleeding: 8 events versus 2 events
  • VTE: 38 versus 33

The GIFT investigators, led by Brian Gage (Washington University), also reported that the percentage of time in the therapeutic range (PTTR) was increased by 3.4 percentage points, from 51.3% in the clinically guided group to 54.7% with genotype-guided dosing.

The authors also noted that although several tests are commercially available to obtain warfarin genotypes, “routine genotyping is not yet recommended.” CMS will use the the results of GIFT to help determine future coverage, according to the authors.

In an accompanying editorial, Jon Emery (University of Melbourne) said that “there are remaining questions about the cost-effectiveness of this strategy.” He acknowledged that the findings “could potentially be of clinical importance” but that “there is statistical uncertainty about the magnitude of this effect.” Emery pointed out that the benefit of genotyping would likely be smaller in atrial fibrillation patients, since the risk of VTE is higher in the arthroplasty population.

In the end, however, he said that “exploring the value of genotyping from the perspective of a single prescribing decision is the wrong question.” Instead, he proposed that “a single pharmacogenomic test covering many common variants relevant to multiple different prescribing decisions over time is far more likely to be cost-effective,” though, once again, he acknowledged that “the evidence for this proposition is lacking.”


  1. One word (or four!) – NOACs! This advance in pharmacology makes this an immediate, mildly interesting footnote in the history of anticoagulation with the endpoint that powered the trial a ridiculous one (buried amongst relevant clinical endpoints of efficacy and bleeding) that is irrelevant now with the advent of tested and approached NOACs. The cost of genotyping will never be less that the 35 days of therapy with a class of drugs that is inherently safer. Can’t believe that JAMA published this. The submissions must have been slow.

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