Two new studies, ADVANCE-1 and ADVANCE-2, shed important new and somewhat contradictory light on apixaban, a new specific factor Xa inhibitor under development by Pfizer and Bristol-Myers Squibb.
ADVANCE-1, a large study comparing apixaban to enoxaparin for thromboprophylaxis, missed its primary endpont and failed to demonstrate that apixaban was noninferior to enoxaparin.
Nearly 3,200 patients who underwent total knee replacement surgery were randomized, according to the ADVANCE-1 paper published today in the New England Journal of Medicine. The primary endpoint, a composite of asymptomatic and symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, and death from any cause during treatment, was reached in 9% of apixaban patients and 8.8% of enoxaparin patients, a result that did not demonstrate noninferiority. According to the investigators, the overall rate of events was lower than anticipated in the trial.
On the positive side, the rate of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P=0.03).
The authors wrote that “our results support the view that specific factor Xa inhibition has the potential to combine effective thromboprophylaxis with a low risk of bleeding and may have a favorable benefit-to-risk ratio as compared with that for low-molecular-weight heparins.”
The results of ADVANCE-1 may be offset by the results of ADVANCE-2, which was presented last month in Boston at ISTH. In ADVANCE-2, the benefits of apixaban were much clearer. The primary composite endpont was reached in 15.1% of the apixaban-treated patients and 24.4% of the enoxaparin-treated patients, a highly significant difference. Bleeding was also reduced from 4.8% with enoxaparin to 3.5% with apixaban.
It should be noted that in ADVANCE-1 apixaban was compared to the standard US dose of enoxaparin (30 mg twice daily). In ADVANCE-2, by contrast, apixaban was compared to the European standard for enoxaparin (40 mg/day).