Research Activities, May 2011: Outcomes/Effectiveness Research: Genotype information can make the predicted therapeutic dose of warfarin more accurate

Outcomes/Effectiveness Research
Genotype information can make the predicted therapeutic dose of warfarin more accurate

When treating patients with the anticoagulant warfarin, it is important that the dose is therapeutic, that is, enough to prevent abnormal blood clotting, but not so much that it causes bleeding. Including genotype information along with clinical information for patients requiring warfarin treatment may produce a more accurate estimated therapeutic dose of the drug than clinical information alone, but may not appreciably change patient outcomes, according to a new study. Until very recently, warfarin had been the only oral drug available for anticoagulation therapy. However, its optimal dosage can vary widely among patients.

Previous studies show that 35 percent of the variation among patients in therapeutic warfarin dose is due to differences in three drug-metabolizing enzyme genes (CYP2C9, CYP4F2, and VKORC1). Calculations that took into account the presence of these gene variants—the intervention arm of the trial—gave estimates closer to the actual therapeutic dose twice as often as did estimates in the control arm that relied on clinical information only (65.3 percent vs. 34.7 percent). Using genotype information did not improve the patient's time in the therapeutic target range during the first 14 days of treatment (a median of 28.6 percent for patients in both trial arms) or the risk of adverse events (8 in each trial arm) compared with clinical information alone.

The researchers collected blood samples at enrollment in the trial from 230 new patients who needed anticoagulant therapy. The patients randomly assigned to the intervention arm had their blood sample immediately genotyped for the three gene variants. Those randomized to the control arm had their blood samples frozen for later use. Primary endpoints were the absolute prediction error relative to the therapeutic dose and the time the drug dose was in the therapeutic range during the first 14 days of therapy. Secondary endpoints included time to a stable therapeutic dose, time to the first out-of-range International Normalized Ratio (INR)—a measure of clotting speed—and the number of warfarin-related adverse events. The study was funded in part by the Agency for Healthcare Research and Quality (HS16335).

More details are in "A randomized controlled trial of genotype-based Coumadin initiation," by James K. Burmester, Ph.D., Richard L. Berg, M.S., Stephen H. Yale, M.D., and others in the March 16, 2011, Genetics in Medicine.


Research Activities, May 2011: Outcomes/Effectiveness Research: Genotype information can make the predicted therapeutic dose of warfarin more accurate