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J Thromb Haemost. 2013 Aug;11(8):1443-8. doi: 10.1111/jth.12324.

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

Author information

1
Department of Biostatistics and Informatics, University of Colorado, Aurora, CO, USA.

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

PMID:
23773172
PMCID:
PMC4528967
DOI:
10.1111/jth.12324
[Indexed for MEDLINE]
Free PMC Article

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