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Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial

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Abstract

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35–42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06–5.30, p < 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38–0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64–0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p > 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41–0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36–0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis.

Trial registration: http://www.clinicaltrials.gov, Unique identifier: NCT01583218

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Abbreviations

APEX:

The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban trial

ARR:

Absolute risk reduction

CI:

Confidence interval

DVT:

Deep vein thrombosis

NNT:

Number needed to treat

OR:

Odds ratio

PE:

Pulmonary embolism

RR:

Relative risk

ULN:

Upper limit of normal

VTE:

Venous thromboembolism

WLW:

Wei, Lin, and Weissfeld method

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Funding

This study was funded by Portola Pharmaceuticals Inc.

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Authors and Affiliations

  1. PERFUSE Study Group, Cardiovascular Division, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 20 Overland Street, Boston, MA, 02215, USA

    Megan K. Yee, Tarek Nafee, Yazan Daaboul, Serge Korjian, Fahad AlKhalfan, Mathieu Kerneis, Cara Wiest & C. Michael Gibson

  2. Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Samuel Z. Goldhaber

  3. Duke University and Duke Clinical Research Institute, Durham, NC, USA

    Adrian F. Hernandez

  4. Division of Cardiology, R.A.H Faculty of Medicine, University of Calgary, Alberta, Canada

    Russell D. Hull

  5. Guy’s and St Thomas’ Hospitals, London, UK

    Alexander T. Cohen

  6. Department of Medicine, Stanford University, Stanford, CA, USA

    Robert A. Harrington

Authors
  1. Megan K. Yee
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  2. Tarek Nafee
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  3. Yazan Daaboul
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  4. Serge Korjian
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  5. Fahad AlKhalfan
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  6. Mathieu Kerneis
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  7. Cara Wiest
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  8. Samuel Z. Goldhaber
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  9. Adrian F. Hernandez
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  10. Russell D. Hull
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  11. Alexander T. Cohen
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  12. Robert A. Harrington
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  13. C. Michael Gibson
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Corresponding author

Correspondence to C. Michael Gibson.

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Conflict of interest

Dr. Goldhaber has provided consulting for Boehringer Ingelheim, Bayer, Portola, Daiichi-Sankyo, Janssen, BiO2 Medical, EKOS/ BTG, BMS, and Zafgen. Dr. Hernandez reports receipt of grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold, Merck, and Novartis; and personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Scientific, Luitpold, and Novartis outside the submitted work. Dr. Hull reports grant support from Portola Pharmaceuticals during the conduct of the study, and grant support and personal fees from Leo Pharma outside the submitted work. Dr. Cohen reports grant support, personal fees, and non-financial support from Portola Pharmaceuticals during the conduct of the study; grant support, personal fees, and non-financial support from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Janssen, and Bayer Pharmaceuticals, personal fees from Boehringer Ingelheim and Sanofi, and personal fees and non-financial support from Johnson & Johnson and Aspen Pharmaceuticals outside the submitted work. Dr. Harrington reports grant support from Portola Pharma during the conduct of the study; grant support from CSL Behring, AstraZeneca, GlaxoSmithKline, Regado, and Sanofi Aventis, grant support and personal fees from Merck and The Medicines Company, personal fees from Amgen, Gilead Sciences, MyoKardia, and WebMD, and other support from Scanadu, SignalPath, Element Science, Vida Health, and Adverse Events outside the submitted work. Dr. Gibson reports grant support from Portola Pharmaceuticals during the conduct of the study, and grant support from Johnson & Johnson and Bayer outside the submitted work. The other authors report no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Yee, M.K., Nafee, T., Daaboul, Y. et al. Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial. J Thromb Thrombolysis 45, 1–8 (2018). https://doi.org/10.1007/s11239-017-1583-0

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  • DOI: https://doi.org/10.1007/s11239-017-1583-0

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