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ADVANCE-1: Apixaban failed to prove noninferiority to enoxaparin
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50th ASH Annual Meeting
The results of the ADVANCE-1 trial indicate that apixaban failed to meet one of two prespecified noninferiority criteria margins in reducing rates of venous thromboembolism, but showed lower major and clinically relevant non-major bleeding rates in patients undergoing total knee replacement.
“Apixaban and enoxaparin demonstrated remarkably low rates of VTE following total knee replacement,” said Michael Lassen, MD, of the University of Copenhagen, Hørsholm, Denmark. “However, noninferiority criterion was only nearly achieved for the relative risk reduction of 1.02 (95% CI, 0.78-1.32; P=.06), but achieved for the absolute difference of 0.1% (95% CI, 2.22-2.44; P=.001).”
The phase-3, randomized, double blind ADVANCE-1 trial compared the efficacy and safety of 2.5 mg oral apixaban twice daily to subcutaneous 30 mg enoxaparin for the prevention of VTE after total knee replacement. Study investigators enrolled 3,195 patients.
The primary efficacy endpoint was overall VTE, a composite of DVT by venography, symptomatic DVT or pulmonary embolism, or all-cause mortality. The primary safety endpoint was major bleeding, clinically relevant nonmajor bleeding and minor bleeding.
The primary efficacy endpoint was achieved by 8.99% of patients assigned apixaban and 8.85% of patients assigned enoxaparin (P=.06). Patients assigned to apixaban had significantly fewer bleeding events, according to Lassen.
There was no difference between the two groups regarding serious adverse events.
Dr. Lassen has indicated that he is a paid consultant for Bristol Myers-Squibb and Sanofi-Aventis.
The negative result of this trial could be viewed as an unfortunate statistical aberration. Although the predefined criteria for non-inferiority were not met, review of the primary data suggests that the two drugs were pretty equivalent in reality. The marginally lower bleeding risk with apixaban at this dose could be indicative of a wider therapeutic index compared with enoxaparin, or as a window of opportunity to increase the antithrombotic efficacy by a slight increase in dosing in a future trial. Either way, we will hopefully hear more about this potentially useful anticoagulant in the future.
– Nigel Key, MD
HemOnc Today Editorial Board member
For more information:
- Lassen MR. #31. Presented at: 50th Annual Meeting of the American Society of Hematology; Dec. 5-9, 2008; San Francisco.