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Original Research |

Long-term anticoagulation with rivaroxaban for preventing recurrent VTE: A benefit–risk analysis of EINSTEIN EXTENSION

Philip S. Wells, MD; Martin H. Prins, MD, PhD; Bennett Levitan, MD, PhD; Jan Beyer-Westendorf, MD; Timothy A. Brighton, MD; Henri Bounameaux, MD; Alexander T. Cohen, MD, FRACP; Bruce L. Davidson, MD, MPH; Paolo Prandoni, MD, PhD; Gary E. Raskob, PhD; Zhong Yuan, MD, PhD; Eva G. Katz, PhD, MPH; Martin Gebel, PhD; Anthonie WA. Lensing, MD, PhD
Author and Funding Information

Conflict of Interest Disclosures: Dr Wells has received research support from Bristol-Myers Squibb, Pfizer; has participated on scientific advisory boards for Bayer Schering Pharma, Pfizer, and Boehringer Ingelheim; and has received honoraria from Bayer Schering Pharma, Pfizer, and Biomerieux.

Dr Prins has acted as a consultant to Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, GlaxoSmithKline, Daiichi Sankyo, LEO Pharma, ThromboGenics and Pfizer.

Drs Levitan, Yuan, and Katz. are employees of Janssen Pharmaceutical Research & Development LLC, United States and stockholders in Johnson & Johnson. Dr Levitan is also a stockholder in Baxter International, Inc., Pharmaceutical Holdrs Trust, and Zimmer Holdings, Inc and also owns stock in a variety of companies that at times include pharmaceutical and health care-related companies

Dr Beyer -Westendorf has received honoraria for lectures and advisory boards from Bayer Pharma, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Novartis, and Leo Pharma.

Dr Bounameaux has received research grant support from the Swiss National Foundation, Daiichi Sankyo, and Bayer Schering Pharma as well as honoraria for lectures or consultancy from Pfizer and Bayer Schering Pharma.

Dr Cohen. has served on advisory boards for Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer, Portola, and Sanofi, and has received consulting fees, lecture fees, support for manuscript preparation, and payment for the development of educational presentations from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb.

Dr Davidson has received consultant fees from Bayer HealthCare Pharmaceuticals.

Dr Prandoni has received consultant fees from Bayer Pharma, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, and Sanofi-Aventis.

Dr Raskob has received consulting fees or honoraria from ICTOM/ Bayer HealthCare Pharmaceuticals, Takeda R&D, and Quintiles.

Drs Lensing and Gebel are employees of Bayer Healthcare AG, Germany.

Trial registration: EINSTEIN EXTENSION (NCT00439725)

1Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ontario, Canada

2Maastricht University Medical Center, Maastricht, The Netherlands

3Janssen Pharmaceutical Research & Development LLC, Titusville, NJ, United States

4University Hospital “Carl-Gustav Carus”, Department of Vascular Medicine, Technische Universität Dresden, Germany

5Department of Haematology, Prince of Wales Hospital, Sydney, New South Wales, Australia

6Division of Angiology and Hemostasis, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland

7Department of Haematological Medicine, Guys and St Thomas’ Hospitals, King’s College Hospital, London, UK

8University of Washington School of Medicine, Seattle, WA, USA

9Department of Cardiovascular Sciences, University of Padua, Padua, Italy

10University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City, OK, USA

11Janssen Pharmaceutical Research & Development LLC, Raritan, NJ, United States

12Bayer HealthCare AG, Wuppertal, Germany

Corresponding author: Name: Philip S Wells Address: Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ontario, Canada


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.05.023
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Published online

Abstract

Background  Short-term anticoagulant treatment for acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) effectively reduces the risk of recurrent disease during the first 6 to 12 months of therapy. Continued anticoagulation is often not instituted because of the perception among physicians that the risk of major bleeding will outweigh the risk of new venous thrombotic episodes.

Methods  Benefit-risk analysis using the randomized EINSTEIN-EXTENSION trial, which compared continued rivaroxaban versus placebo in 1197 patients with symptomatic DVT or PE who had completed 6-12 months of anticoagulation and in whom physicians had equipoise with respect to the need for continued anticoagulation. One-year Kaplan-Meier rates and rate differences of recurrent venous thromboembolism (VTE) and major bleeding were calculated. Benefits and risks were assessed using rate differences scaled to a population size of 10000 patients treated for 1 year.

Results  Recurrent VTE occurred in 8 (3.0%) rivaroxaban recipients and 42 (9.6%) placebo patients. In a population of 10000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI 246-1084) fewer recurrent VTEs than placebo (number needed to treat=15). Major bleeding occurred in 4 (0.7%) and 0 patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI 2-134) more major bleeding events than placebo (number needed to harm=147). Kaplan–Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at ±100 days.

Conclusions  A clinically important benefit and a favorable benefit–risk profile of continued rivaroxaban anticoagulation was observed.


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