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

J. M. Kittelson, A. C. Spyropoulos, J. L. Halperin, C. M. Kessler, S. Schulman, G. Steg, A. G.G. Turpie, N. R. Cutler, W. R. Hiatt, N. A. Goldenberg

Research output: Contribution to journalReview article

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).

Original languageEnglish (US)
Pages (from-to)1443-1448
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume11
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Anticoagulants
  • Safety
  • Treatment efficacy
  • Venous thromboembolism

ASJC Scopus subject areas

  • Hematology

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    Kittelson, J. M., Spyropoulos, A. C., Halperin, J. L., Kessler, C. M., Schulman, S., Steg, G., Turpie, A. G. G., Cutler, N. R., Hiatt, W. R., & Goldenberg, N. A. (2013). Balancing risk and benefit in venous thromboembolism trials: Concept for a bivariate endpoint trial design and analytic approach. Journal of Thrombosis and Haemostasis, 11(8), 1443-1448. https://doi.org/10.1111/jth.12324