Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials

作者：Laporte S; Chapelle C; Bertoletti L; Ollier E; Zufferey P; Lega J C; Merah A; Decousus H; Schulman S; Meyer G; Cucherat M; Mismetti P

来源：Journal of Thrombosis and Haemostasis, 2017, 15(8): 1547-1558.

DOI：10.1111/jth.13740

• anticoagulants
• atrial fibrillation
• clinical trial
• major bleeding
• venous thromboembolism

Background: Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant nonmajor bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods: We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R-trial(2) and its 95% confidence interval (CI). Results: In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R-trial(2) was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R-trial(2) values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R-trial(2) was 0.59 (95% CI 0.15-0.82). Conclusion: Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

• 出版日期2017-8