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Using the Symmetry Analysis Design to Screen for Adverse Effects of Non-vitamin K Antagonist Oral Anticoagulants

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Abstract

Introduction

Knowledge on adverse effects (AEs) related to non-vitamin K antagonist oral anticoagulants (NOACs) in real-world populations is sparse.

Objective

Our objective was to identify signals of potential AEs in patients with atrial fibrillation (AF) initiating NOAC treatment using a hypothesis-free screening approach.

Methods

Using the nationwide Danish registries, we identified patients with AF initiating dabigatran, rivaroxaban, or apixaban between 2011 and 2015 (n = 50,627). Applying a symmetry analysis design, we screened for AEs of NOAC, as reflected by new drug treatments, incident diagnoses, or procedures. For signals with the lowest number needed for one additional patient to be harmed (NNTH), we evaluated whether they likely represented genuine AEs or other types of associations. Signals assessed as potential AEs were grouped into five categories for analysis of effect modification according to patient and drug characteristics.

Results

Of the identified signals, 61 were classified as potential AEs. Most signals could be categorized as the following types of AEs: bleedings, non-bleeding gastrointestinal symptoms, mental disease, urinary tract disorders, and musculoskeletal symptoms. Older age and first-ever use of anticoagulants was associated with strengthening of all “NOAC-adverse effect” associations. Conversely, use of low-dose NOAC and apixaban led to attenuation of most associations.

Conclusion

Through a symmetry analysis-based hypothesis-free screening of large-scale healthcare databases, we were able to confirm well-established AEs of NOAC therapy in clinical practice as well as potential AEs that deserve further investigation.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, 5000, Odense C, Denmark

    Maja Hellfritzsch, Lotte Rasmussen, Jesper Hallas & Anton Pottegård

Authors
  1. Maja Hellfritzsch
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  2. Lotte Rasmussen
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  3. Jesper Hallas
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  4. Anton Pottegård
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Corresponding author

Correspondence to Maja Hellfritzsch.

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Conflict of interest

Maja Hellfritzsch declares speaker honoraria from Bristol-Myers Squibb and Pfizer. Lotte Rasmussen, Jesper Hallas, and Anton Pottegård declare participation in research projects funded by Boehringer-Ingelheim, with funds paid to the institution at which they were employed (no personal fees).

Funding

This work was funded by a Grant from the Danish Council for Independent Research.

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Hellfritzsch, M., Rasmussen, L., Hallas, J. et al. Using the Symmetry Analysis Design to Screen for Adverse Effects of Non-vitamin K Antagonist Oral Anticoagulants. Drug Saf 41, 685–695 (2018). https://doi.org/10.1007/s40264-018-0650-6

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