Low-intensity international normalized ratio (INR) did not meet the primary outcome of noninferiority for venous thromboembolism (VTE) or death in the phase 3, randomized Genetic Informatics Trial (GIFT; ClinicalTrials.gov Identifier: NCT01006733). The trial studied clinically and genetically guided prophylactic warfarin dosing to a target INR of low compared with standard intensity in older patients undergoing hip or knee arthroplasty. Results from this study were published in JAMA.
This study assessed the safety and efficacy of a target INR of 1.8 compared with 2.5 for VTE prophylaxis with warfarin in patients 65 years or older undergoing elective arthroplasty. This trial randomly assigned patients in a 2-by-2 factorial design to a target INR of 1.8 (823 patients) or 2.5 (827 patients) and to either genetically guided or clinically guided thromboprophylactic dosing.
The average age of the 1650 total patients enrolled was 72.1 years, 63.6% were women, 91.0% were white, and 96.8% received at least 1 dose and were included in the primary analysis. The primary end point was a composite of VTE within 60 days or death within 30 days.
The rate of composite VTE or death was 5.1% in the low-intensity-warfarin group and 3.8% in the standard-intensity-warfarin group; this difference of 1.3% was less than the prespecified 3% margin needed for noninferiority (P =.06 for noninferiority). Still, the authors suggested additional research is warranted to identify patients who are at high risk for bleeding and should therefore receive a less intense dose of warfarin.
Major bleeding, a secondary end point, occurred in 0.4% of the low-intensity-warfarin arm and 0.9% of the standard-intensity-warfarin arm, for a difference of -0.5% (95% CI, -1.6% to 0.4%).
INR values of 4 or greater were another secondary end point, occurring in 4.5% of low-intensity-warfarin patients and 12.2% of standard-intensity-warfarin patients, for a difference of -7.8% (95% CI, -10.5% to -5.1%).
Though the GIFT trial did not meet its primary end point of noninferiority for a composite of VTE or death for a less intense INR of 1.8 compared with 2.5 in older patients receiving warfarin-based thromboprophylaxis undergoing arthroplasty, the authors concluded, “The trial may have been underpowered to meet this criterion, and further research may be warranted.”
1. Gage BF, Bass AR, Lin H, et al. Effect of low-intensity vs standard-intensity warfarin prophylaxis on venous thromboembolism or death among patients undergoing hip or knee arthroplasty: a randomized clinical trial [published online September 3, 2019]. JAMA. doi:10.1001/jama.2019.12085