title: 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).
authors.affiliation: Department of Biostatistics and Informatics, University of Colorado, Aurora, CO, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kittelson
authors.forename: A C
authors.initials: AC
authors.lastname: Spyropoulos
authors.forename: J L
authors.initials: JL
authors.lastname: Halperin
authors.forename: C M
authors.initials: CM
authors.lastname: Kessler
authors.forename: S
authors.initials: S
authors.lastname: Schulman
authors.forename: G
authors.initials: G
authors.lastname: Steg
authors.forename: A G G
authors.initials: AG
authors.lastname: Turpie
authors.forename: N R
authors.initials: NR
authors.lastname: Cutler
authors.forename: W R
authors.initials: WR
authors.lastname: Hiatt
authors.forename: N A
authors.initials: NA
authors.lastname: Goldenberg
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000627:therapeutic use; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D009025:Morpholines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D012306:Risk; D000069552:Rivaroxaban; D013876:Thiophenes / Q000627:therapeutic use; D054556:Venous Thromboembolism / Q000628:therapy*
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban
keywords: anticoagulants; safety; treatment efficacy; venous thromboembolism