Genotyping Lowers Warfarin Risk in Hip or Knee Replacement

Ricki Lewis, PhD

September 26, 2017

A pharmacogenomics approach to tailoring warfarin dose for patients undergoing hip or knee replacement was associated with fewer adverse outcomes than solely clinically guided dosing, a study found.

"Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, [international normalized ratio (INR)] of 4 or greater, venous thromboembolism, or death," the researchers write.

Brian F. Gage, MD, from Washington University, St. Louis, Missouri, and colleagues report their findings in an article published in the September 26 issue of JAMA.

Warfarin is the most-prescribed anticoagulant globally because of the ease of administration, low cost, and reversible effects. However, the narrow therapeutic index coupled with multifactorial differences in response among patients complicate achieving optimal dosing that minimizes risk for excessive bleeding or clotting. During the last decade, use of warfarin among older patients has caused more medication-related emergency department visits than any other drug.

Monitoring response to warfarin uses the INR, but for the last 20 years, genotyping of a few common genes with associations to drug response has crept into the prescribing equation.

The Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis randomly assigned patients aged 65 years or older undergoing elective hip or knee replacement to genotype-guided (831 patients) or clinically guided (819 patients) warfarin dosing on days 1 through 11, as well as to a target INR of 1.8 or 2.5. The participants received treatment at six US medical centers. Patients and clinicians were blinded to study group assignment, but warfarin doses were open label.

The primary outcome was a composite of adverse events: major bleeding within 30 days, INR of 4 or greater within 30 days, death within 30 days, and symptomatic or asymptomatic venous thromboembolism within 60 days. The rate of major adverse events (substantial bleeding, symptomatic deep vein thrombosis, or pulmonary embolism) was 1.5% (12 events) in the genotype-guided group and 2.9% (23 events) in the clinically guided group, with a between-group difference of 1.4% (95% confidence interval, 0% - 3.0%, P = .051). No deaths occurred.

Among the genotype-guided patients, 808 completed the trial; among the clinically guided patients, 789 did so. Of the genotype-guided patients, 87 (10.8%) met one or more endpoints compared with 116 (14.7%) patients in the clinically guided group. At 90 days, the difference was similar (11.1% vs 15.1%) for a composite of the outcomes.

Subgroup analysis (black race, gene variants with the strongest associations, target INR of 1.8 vs 2.5, and hip vs knee arthroplasty) revealed a consistent benefit of genotyping.

GIFT genotyped more individuals, used more gene variants, and monitored responses longer than previous trials. However, limitations of the study include comparison of patients undergoing elective hip or knee arthroplasty (who were more likely to have been genotyped before surgery) with past studies whose participants had atrial fibrillation or venous thromboembolism and were not as likely to have had genotype-guided treatment.

The study also excluded certain gene variants more common among people of African ancestry, as these individuals comprised a small percentage of participants. In addition, conducting GIFT at academic medical centers might not translate to other settings and to younger patients.

Genetic Variants Affect Warfarin Metabolism, Sensitivity

Warfarin dosing can consider variants (single nucleotide polymorphisms) of the genes CYP2C9, VKORC1, and CYP4F2:

  • CYP2C9 encodes a liver enzyme that metabolizes one form of warfarin, and 18 variants, some more common among Europeans and some more common among Africans, are associated with reduced enzyme activity, and therefore require a lower warfarin dose.

  • VKORC1 encodes the enzyme that warfarin targets, and affects warfarin sensitivity.

  • CYP4F2 affects vitamin K metabolism, and one variant indicates need for a higher warfarin dose.

Product labels have mentioned the use of genotyping in determining warfarin dose, but three large clinical trials, which tested a total of 2018 patients for variants of CYP2C9 and VKORC1 at the start of warfarin therapy and used a primary outcome of percentage of time in the therapeutic range, had conflicting results. Two trials that used a clinical algorithm did not find a difference in using genotyping, but a third trial that compared genotyping to a standard loading dose regimen did, Jon D. Emery, MBBCh, from the University of Melbourne, Australia, writes in an accompanying editorial. Most of the patients in those trials had atrial fibrillation or venous thromboembolism.

Cost-effectiveness Key Issue

Cost-effectiveness is a key issue in implementation of genotype-guided warfarin dosing, Dr Emery writes.

Dr Emery calculated that genotyping 26 patients using current test panels could prevent one warfarin-dosing-related event. He suggests expanding the panels to improve their power. "A single pharmacogenomic test covering many common variants relevant to multiple different prescribing decisions over time is far more likely to be cost-effective; however, the evidence for this proposition is lacking. In the meantime, genotype-guided warfarin dosing probably has some clinical utility but it might be simpler and less expensive to implement wider use of clinical dosing algorithms to reduce the harms of anticoagulation," Dr Emery explains.

He also suggests that patients with certain combinations of high-risk gene variants use an anticoagulant other than warfarin.

The researchers agree that practical matters will influence how common use of genotype-guidance in determining warfarin dosing becomes. "Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics," they write. They suggest incorporating more single nucleotide polymorphisms into testing panels and integrating warfarin dosing algorithms into electronic medical records.

One coauthor reports grant funding and personal fees from Stryker and grant funding from Biomet, Medical Compression Systems Inc, Smith & Nephew, Wright Medical Technology, and EOS Imaging. The other authors and the editorial writer have disclosed no relevant financial relationships.

JAMA. 2017;318:1110-1112, 1115-1124.

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