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Knowing a patient’s genetic background could increase the safety of warfarin, an anticoagulant prone to cause bleeding and other serious complications in the event of improper dosage.
A study of more than 1,600 patients published in the Journal of the American Medical Association found that tailoring the dose of this therapy based on clinical and genetic variants led to fewer adverse health events. Specifically, genotyping of CYP2C9 and VKORC1 variants “can help optimize warfarin dose, when used in combination with clinical decision support, in the first few days of therapy,” study co-author Gwendolyn McMillin, PhD, DABCC, told CLN Stat.
Dosing requirements for warfarin vary from patient to patient. There’s a delicate balance in finding a correct dosage: Too low a dose may fail to stop blood clots while too high a dose may lead to internal bleeding. “Because knowledge of a patient’s genotype should lead to more accurate warfarin initiation and a concomitant reduction in adverse events, the product label for warfarin … has encouraged genotype-guided dosing since 2007,” according to the study’s authors.
Prior multicenter studies on genotype-guided dosing of oral vitamin K antagonists have not yielded consistent results. Investigators of the multicenter Genetic Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis (GIFT) decided to push this approach further, to see if genotype-guided dosing of warfarin would lead to fewer health complications. The trial included 1,650 individuals age 65 and older at six U.S. medical centers who were initiating warfarin for elective hip or knee replacement surgery. All patients were initially genotyped for polymorphisms CYP2C9*2 and CYP2C9*3, VKORC1-1639G>A, and CYP4F2 V433M, then randomized to genotype-guided or clinically guided doses and to a target international normalized ratio (INR) of 1.8 or 2.5 during the first 11 days of therapy.
“By genotyping everyone prior to randomization, we were able to maintain double blinding and to ensure that all participants randomized to genotype-based dosing had their genotype available beginning with their first warfarin dose,” lead study author Brian F. Gage, MD, MSc, explained to CLN Stat.
The clinically guided group received dosages based on age, race, gender, body mass index, health history, and other medications that might interact with warfarin. The genotype-guided group’s dose was adjusted based on these clinical factors, plus genetic variants. Investigators monitored patients for signs of major bleeding, an INR ≥4, venous thromboembolism, and warfarin overdose. All patients a month after hip or knee surgery underwent lower-extremity duplex ultrasound.
Genotype-guided therapy appeared to prevent side effects of warfarin. Among the genotype-guided group, 10.8% experienced at least 1 adverse effect, compared with 14.7% of the patients in the clinically guided group. No deaths took place during the trial. According to Gage, genotyping was most effective at preventing warfarin overdose. Its impact on reducing other events such as major bleeding wasn’t as statistically significant.
Based on the GIFT trial results, labs should be prepared to offer genotype testing in certain instances—such as with pre-operative planning for elective arthroplasty patients, said McMillin, a professor of pathology at the University of Utah School of Medicine and medical director for toxicology and pharmacogenomics at ARUP Laboratories in Salt Lake City. A good resource labs can refer clinicians to is www.WarfarinDosing.org, a public website that assists doctors in beginning warfarin therapy. The website’s electronic dosing algorithm helps improve the safety of dosing, she advised.
Other patients taking warfarin—not just joint replacement patients—could benefit from the findings in this study, said co-author Anne R. Bass, MD, a rheumatologist at Hospital for Special Surgery (HSS) in New York, New York, in a statement. “This was really a study addressing warfarin management and warfarin safety, so I think you can extrapolate the results to other patients taking this blood thinner, such as those with atrial fibrillation,” she said.
Study authors acknowledged that certain factors might influence the widespread application of genotype-guided dosing. “Although several commercial platforms for warfarin-related genes have been approved by the U.S. [Food and Drug Administration] and the European Medicines Agency, routine genotyping is not yet recommended,” they wrote.
Cost is an important factor to consider with this approach, Jon D. Emery, MBBCh, MA, MRCGP, FRACGP, DPhil, wrote in a related editorial. One study, the European Pharmacogenetics of Anticoagulant Therapy trial, suggests that pharmacogenomics testing is cost-effective, at least in atrial fibrillation patients on warfarin, Emery noted. Despite this finding, and the fact that genotyping has gotten less expensive, “health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy worthy of investment,” he wrote. “Ideally an updated meta-analysis of trial data should be applied to cost-effectiveness modeling to inform new policy.”
In future research, Gage said he and his colleagues would like to conduct a meta-analysis of all trials of pharmacogenetic dosing and plan to use the GIFT data to develop a new set of dosing algorithms for WarfarinDosing.org.