New Evidence Shows Genotype-Guided Warfarin Dosing Beneficial

Genotype-guided warfarin dosing reduced a combination of adverse events, compared to clinically guided dosing among older patients treated with warfarin before elective hip or knee arthroplasty, according to a study published Sept. 26 in the Journal of the American Medical Association (JAMA). While single clinical outcomes, like major bleeding events, were not statistically improved with genotype-guided dosing, the study provides evidence of the overall reduction in adverse events from a genotype-guided dosing regimen at initiation of warfarin that may inform future coverage decisions, the authors say.

Previous studies show that warfarin accounts for more medication- related emergency department visits among older patients than any other drug. While the product label for warfarin encourages genotype-guided dosing, evidence has been mixed as to whether or not genotype-guided dosing meaningfully improves the safety of warfarin initiation. In addition to concerns about clinical utility, adoption of clinical pharmacogenomic testing has been hampered by lack of payer coverage and logistical constraints in returning results fast enough to impact decision making in non-elective situations.

The present study, the Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis, included 1,650 patients (mean age, 72.1 years; 63.6 percent women) initiating warfarin before elective hip or knee arthroplasty at six U.S. medical centers from April 2011 through October 2016. Patients were genotyped (for VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M polymorphisms) and randomized to genotype-guided (n = 831) or clinically guided (n = 819) dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. Dosing was guided by a web application (WarfarinDosing.org) that incorporated clinical variables for all patients and variant information for patients randomized to genotype-guided dosing algorithms.

The researchers found that significantly fewer patients in the genotype-guided group had one of the adverse effects (a composite of major bleeding, INR of 4 or more, venous thromboembolism, or death), compared to the clinically guided warfarin dosing group (10.8 percent versus 14.7 percent). For major bleeding or non-major clinically relevant the groups were similar, but trended towards a benefit for genotype-guided dosing. The authors say the benefit of genotype-guided dosing was consistent across the subgroups, including those at high-risk, black race, or having the CYP2C9 genotype.

"Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm," write the authors led by Brian F. Gage, M.D., from Washington University in St. Louis, Mo. Additionally, the authors say the large size enabled the effect of genotype-guided dosing to be quantified for clinical outcomes rather than for percentage of time in the therapeutic range alone.

Cost Effectiveness Still Debated
Yet, other factors, aside from clinical utility, will dictate the adoption of genotype- guided dosing, including reimbursement, practice recommendations, and logistics. The authors say that the Centers for Medicare & Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and the center will review the results to determine future coverage.

"There are remaining questions about the cost-effectiveness of this strategy," writes Jon Emery, M.B.B.Ch., from the Centre for Cancer Research in Australia, in an accompanying JAMA editorial. "Based on the GIFT trial composite primary outcome, 26 patients would need to be genotyped to prevent one 'event' (most commonly an INR ≥4). Although the cost of genotyping continues to decline, health insurers and publically funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy worthy of investment."

Emery also highlights that the logistical constraints of implementing genotyping before prescribing warfarin were removed in the GIFT trial because of the "elective nature" of arthroplasty.

"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," Emery explains. "Ideally an updated meta-analysis of trial data should be applied to cost-effectiveness modeling to inform new policy."

Takeaway: New evidence builds the case that genome-guided warfarin dosing improves safety following drug initiation for elective procedures. However, the cost-effectiveness of the strategy remains to be seen.