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Thromb Haemost 2016; 116(03): 544-553
DOI: 10.1160/TH15-12-1000
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

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

John M. Kittelson
1   Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado – Anschutz Medical Campus, Aurora, Colorado, USA
,
Philippe Gabriel Steg
2   FACT (French Alliance for Cardiovascular Trials), Université Paris-Diderot, Paris, France
5   NHLI, Imperial College, Royal Brompton Hospital, London, UK
,
Jonathan L. Halperin
6   The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
,
Neil A. Goldenberg
7   Divisions of Hematology, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
8   Johns Hopkins All Children’s Hospital and All Children’s Research Institute, St. Petersburg, Florida, USA
,
Sam Schulman
9   Department of Medicine, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Ontario, Canada
,
Alex C. Spyropoulos
10   North Shore-LIJ Health System, Hofstra North Shore-LIJ School of Medicine; Manhasset, New York, USA
,
Craig M. Kessler
11   Department of Medicine and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., USA
,
Alexander G. G. Turpie
9   Department of Medicine, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Ontario, Canada
,
Neal R. Cutler
12   Worldwide Clinical Trials, Beverly Hills, California, USA
,
William R. Hiatt
13   Department of Medicine, Division of Cardiology, University of Colorado School of Medicine–Anschutz Medical Campus and CPC Clinical Research, Aurora, Colorado, USA
,
for the Antithrombotic Trials Leadership and Steering (ATLAS) Group› Institutsangaben
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Publikationsverlauf

Received: 30. Dezember 2015

Accepted after major revision: 19. Mai 2016

Publikationsdatum:
29. November 2017 (online)

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Summary

Clinical trials of antithrombotic 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 antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 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 defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing 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 antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Clinical trial - net clinical benefit - noninferiority - meta-analysis