Effectiveness and safety of low-dose versus standard-dose rivaroxaban and apixaban in patients with atrial fibrillation

Sylvie Perreault; Robert Côté; Alice Dragomir; Brian White-Guay; Aurélie Lenglet; Marc Dorais

doi:10.1371/journal.pone.0277744

Effectiveness and safety of low-dose versus standard-dose rivaroxaban and apixaban in patients with atrial fibrillation

PLoS One. 2022 Dec 1;17(12):e0277744. doi: 10.1371/journal.pone.0277744. eCollection 2022.

Authors

Sylvie Perreault^{1

2

3}, Robert Côté⁴, Alice Dragomir¹, Brian White-Guay⁵, Aurélie Lenglet^{6

7}, Marc Dorais⁸

Affiliations

¹ Faculty of Pharmacy, Université of Montréal, Montreal, Quebec, Canada.
² Chaire Sanofi sur l'utilisation des médicaments, Université de Montréal, Montreal, Quebec, Canada.
³ Centre de recherche en santé publique (CReSP), partenaire CIUSSS du Centre-Sud-de-l'Île-de-Montréal et l'Université de Montréal, Montreal, Quebec, Canada.
⁴ Faculty of Medicine, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁵ Faculty of Medicine, Université of Montréal, Montreal, Quebec, Canada.
⁶ Faculty of Pharmacy, EA 7517, Laboratory MP3CV, Jules Verne University of Picardie, Amiens, France.
⁷ Department of Pharmacy, Amiens Picardie University Medical Center, Amiens, France.
⁸ StatSciences Inc., Notre-Dame-de-l'Île-Perrot, Quebec, Canada.

Abstract

Background: Low-dose direct oral anticoagulant (DOAC) use is quite prevalent in clinical practice, but evidence of its effectiveness and safety compared with high-dose DOAC in patients with atrial fibrillation (AF) remains limited. We aimed to assess the effectiveness and safety of low-dose and high-dose DOACs in patients with AF with similar baseline characteristics.

Methods: We used a cohort of hospitalized patients with a primary or secondary diagnosis of AF after discharge to the community, whose data were stored in the Quebec administrative databases, from 2011 to 2017. Older adults with AF newly prescribed with rivaroxaban (15 or 20 mg) or apixaban (2.5 mg or 5 mg) were classified as under treatment (UT) and intent to treat (ITT). We used an inverse probability treatment weighting study of new users of rivaroxaban and apixaban to address confounding by indication. The primary effectiveness outcome was ischemic stroke/systemic embolism (SE), while the primary safety outcome was major bleeding (MB). We used Cox proportional models to estimate the marginal hazard ratios (HRs).

Findings: A total of 1,722 and 4,639 patients used low-dose and standard-dose rivaroxaban, respectively, while 3,833 and 6,773 patients used low-dose and standard-dose apixaban, respectively. No significant difference was observed in the incidence of comparative stroke/SE and MB between low-dose and standard-dose rivaroxaban, except for the risk of acute myocardial infarction (AMI), which was increased with the low dose in the UT analysis. For apixaban, no difference was found in the bleeding rates, but the risk of stroke/SE (HR: 1.95; 95% confidence interval (CI): 1.38-2.76) and death (HR: 1.99; 95% CI: 1.46-2.70) were greater in the low-dose group than in the standard-dose group in the UT analysis. Similar results were observed for the ITT analysis.

Conclusion: No significant differences were observed in the effectiveness or safety outcome between low-dose and standard-dose rivaroxaban, except for AMI. However, low-dose apixaban was associated with a greater risk of stroke/SE and death without a reduction in the bleeding rates.

Copyright: © 2022 Perreault et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anticoagulants
Atrial Fibrillation* / drug therapy
Humans
Myocardial Infarction*
Pyridones / adverse effects
Rivaroxaban / adverse effects
Stroke* / etiology
Stroke* / prevention & control

Substances

Rivaroxaban
apixaban
Pyridones
Anticoagulants

Grants and funding

This study was supported by the Heart and Stroke Foundation of Canada (G-17-0018326) and the Réseau Québécois de Recherche sur les Médicaments (RQRM). Please refer to the following URL: https://www.heartandstroke.ca/ and https://www.rqrm.ca/. The information contained in this manuscript has not been published previously and is not under review for publication elsewhere. The study findings were presented with posters and abstracts at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 24th Annual International Meeting (December 1–3, 2021) and 37th International Conference on Pharmacoepidemiology and Therapeutic Risk Management (ISPE) (August 21–25, 2021), both of which were funded by Heart and Stroke Foundation and RQRM. MD, the sole founder and representative of StatSciences Inc., provided us with independent biostatistics consultancy. These funders provided support in the form of salaries for author MD, '' and the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest ''. The specific roles of these authors are articulated in the ‘author contributions’ section. All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.