Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach

Abstract

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

Keywords: anticoagulants; safety; treatment efficacy; venous thromboembolism.

© 2013 International Society on Thrombosis and Haemostasis.

Figures

Figure 1

(a) Decision-making with two endpoints: Decision-making in bivariate space is straightforward if a new anticoagulation therapy results in reduction of both bleeding and VTE risk or if it increases risk of both events (southwest or northeast quadrants). Decision-making is difficult if results are equivocal (northwest or southeast quadrants). (b) Bivariate results from recent VTE trials of new oral anticoagulants: Primary VTE and bleeding results from recent oral anticoagulation trials plotted as a bivariate outcome, calculated from data provided in the references. Axes denote the estimated difference in risk for VTE and bleed (experimental therapy minus control; i.e., negative values indicate reduced risk with experimental). Although new anticoagulation treatments are always evaluated on both bleeding and VTE endpoints, the results are usually presented separately and the tradeoff is left to the readership.

Figure 2

(a) Superiority trial based on RECORD1: Bivariate decision rule maps the possible 2-dimensional outcomes into decisions in favor of superiority (blue shaded) or against superiority (red shaded). Points A,B,C used to define curve: A represents superiority on bleeding and non-inferiority on VTE, B represents significant reductions on both endpoints, and C represents superiority on VTE and non-inferiority on bleeding. (b) Non-inferiority trial based on Kids-DOTT: Bivariate decision rule maps the possible 2-dimensional outcomes into decisions in favor of non-inferiority (blue shaded) or against non-inferiority (red shaded). Points A,B,C define the curve: A represents highly significant benefit on bleeding with slight inferiority on VTE, B represents no effect on bleeding with a statistically significant benefit on bleeding, and C highly significant benefits on VTE with slight harm on bleeding.