Bivariate evaluation of thromboembolism and bleeding in clinical trials of anticoagulants in patients with atrial fibrillation

Clinical trials of anti thrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of anti thrombotic drugs is de-scribed and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totaling 71,683 patients for prevention of thromboembolic events(TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis de-fines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence inter-vals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treat-ment effect is measured by the distance from the null curve to the op-posing corners of the confidence rectangle (termed “corner distance (CD)”). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI:–0.56 % to–0.05 %) and reduced major bleeding by 0.88 % (95 % CI:–1.26 % to–0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = –0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = –2.07 % to –0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of anti thrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.