Less intensive warfarin therapy less effective at preventing VTE after arthroplasty

Rates of major bleeding were similar whether patients were treated to an international normalized ratio target of 1.8 or 2.5 to prevent venous thromboembolism (VTE) after hip or knee arthroplasty, a randomized trial found.


A lower-than-standard target international normalized ratio (INR) was not as effective at preventing venous thromboembolism (VTE) or death among patients taking warfarin after a hip or knee arthroplasty, a recent study found.

The trial included patients ages 65 years or older who initiated warfarin for elective hip or knee arthroplasty at six U.S. medical centers. The patients were randomized in a two-by-two factorial design to a target INR of either 1.8 (low target) or 2.5 (standard target) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, warfarin dosing was guided by a web application. Results were published in the Sept. 3 JAMA.

A total of 1,650 patients were randomized (mean age, 72.1 years; 63.6% women; 91.0% white), 96.8% of whom received at least one dose of warfarin and were included in the analysis. The study's primary outcome was a composite of VTE within 60 days and death within 30 days. Rates were 5.1% in the low-target group versus 3.8% in the standard-target group, a difference of 1.3% (one-sided 95% CI, −∞ to 3.05%, P=0.06 for noninferiority). This difference did not meet the study's prespecified noninferiority margin of 3% for the absolute risk of VTE.

The secondary endpoint of major bleeding occurred in 0.4% of the low-target group and 0.9% of the standard-target group, a difference of −0.5% (95% CI, −1.6% to 0.4%). The other secondary endpoint of an INR value of 4 or more occurred in 4.5% and 12.2% of the patients, respectively, a difference of −7.8% (95% CI, −10.5% to −5.1%).

The study authors concluded that an INR target of 1.8 did not meet the criterion for noninferiority or significantly reduce clinically relevant bleeding compared to the standard target of 2.5. However, they noted that the rate of the primary outcome was lower than anticipated, so the trial may have been underpowered. Practices in the study that may have enhanced safety included the use of the web application and genotype guidance for warfarin dosing.

The trial's results were similar to those of several previous studies, which also found that INR targets of 2 and above were associated with fewer VTEs after surgery, but more research might be helpful to identify whether some patients at high risk of bleeding could benefit from a lower INR target, the authors said. They noted that limitations of this study include its open-label design and its small proportion of minority patients.