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Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events

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Abstract

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute PE treatment according to the manufacturer’s labelling, beyond the contraindication in severe renal insufficiency. We designed a prospective, multicenter cohort study to investigate the impact of prescription of non-recommended DOAC doses on 6-month adverse events. The primary endpoint was a composite of all-cause death, recurrent VTE, major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). In total, among 656 patients discharged with DOACs between 09/2012 and 10/2016, 28 (4.3%) were not treated with a recommended DOAC dose. All the non-recommended DOAC dose prescriptions were under-dosed according to the drug labelling. After multivariate adjustment, age > 70 years, a history of coronary artery disease, creatinine clearance < 50 mL/min and concomitant aspirin therapy were independently associated with non-recommended DOAC dose prescription (C-statistic: 0.82; Hosmer Lemeshow test: 0.50). The primary composite endpoint occurred in 7/28 patients (25.0%) in the non-recommended dose group and in 38/628 patients (6.1%) in the recommended dose group, yielding a relative risk of 3.19 in the non-recommended dose group (95% CI 1.16–8.70; p < 0.001). The higher primary endpoint rate observed in the non-recommended dose group was driven by a significantly higher rate of major bleeding (7.1 vs. 1.4%; p = 0.008), with a non-significant trend toward a higher rate of death (7.1 vs. 2.2%; p = 0.23), recurrent VTE (3.6 vs. 1.4%; p = 0.31), and CTEPH (7.1 vs. 1.6%; p = 0.32). In conclusion, empiric dose reduction of DOACs was associated with 6-month adverse events in our real-life registry.

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Funding

This study was funded, in part, by a research grant from Bristol-Myers Squibb, Bayer, Boehringer-Ingelheim, and Daiichi Sankyo.

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Authors and Affiliations

  1. Department of Cardiology, EA3920, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Romain Chopard, Guillaume Serzian, François Schiele & Nicolas Meneveau

  2. Department of Internal Medicine, Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Sébastien Humbert

  3. Department of Internal Medicine, University Hospital, 2 Boulevard du Maréchal de Lattre de Tassigny, 21000, Dijon, France

    Nicolas Falvo

  4. Department of Cardiology, General Hospital, 2 Faubourg Saint Etienne, 25300, Pontarlier, France

    Mathilde Morel-Aleton

  5. Department of Cardiology, General Hospital of Vesoul, 2 Avenue René Heymes, 70000, Vesoul, France

    Benjamin Bonnet

  6. Department of Cardiology, Hospital Center Louis Pasteur, 73 Avenue Léon Jouhaux, 39100, Dole, France

    Gabriel Napporn

  7. Medical Oncology Unit, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Elsa Kalbacher

  8. Orthopedic, Trauma, Plastic, Reconstructive and Hand Surgery Department, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Laurent Obert

  9. Department of Physiology, EA3920, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Bruno Degano

  10. Medical Intensive Care Unit, EA3920, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France

    Gilles Cappelier

  11. Department of Cardiology, University Hospital, 2 Boulevard du Maréchal de Lattre de Tassigny, 21000, Dijon, France

    Yves Cottin

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  1. Romain Chopard
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  2. Guillaume Serzian
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  6. Benjamin Bonnet
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  7. Gabriel Napporn
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  8. Elsa Kalbacher
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  9. Laurent Obert
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  12. Yves Cottin
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  13. François Schiele
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  14. Nicolas Meneveau
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Corresponding author

Correspondence to Romain Chopard.

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Conflict of interest

Dr. Chopard has received research grant support from the French Federation of Cardiology, the Burgundy Franche-Comte region, and Edwards Lifesciences. Dr. Francois Schiele declares research grants from GlaxoSmithKline, St. Jude Medical, Sanofi-Aventis, Servier, Daiichi-Sankyo/Lilly. Dr. Nicolas Meneveau declares receipt of consultancy agreements Bayer Healthcare, BMS-Pfizer. Drs. Serzian, Humbert, Falvo, Morel-Aleton, Bonnet, Napporn, Kalbacher, Obert, Degano, Cappelier, Cottin have no relevant financial disclosures.

Ethical approval

The research involved human participants. The study was conducted in accordance with the Declaration of Helsinki. Institutional Review Board approval was obtained.

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Informed consent was obtained from each study participant.

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Chopard, R., Serzian, G., Humbert, S. et al. Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events. J Thromb Thrombolysis 46, 283–291 (2018). https://doi.org/10.1007/s11239-018-1690-6

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