Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study

Maxim Grymonprez; Andreas Capiau; Stephane Steurbaut; Koen Boussery; Els Mehuys; Annemie Somers; Mirko Petrovic; Tine L De Backer; Lies Lahousse

doi:10.1007/s10557-023-07521-5

Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study

Cardiovasc Drugs Ther. 2023 Nov 6. doi: 10.1007/s10557-023-07521-5. Online ahead of print.

Authors

Maxim Grymonprez¹, Andreas Capiau^{1

2}, Stephane Steurbaut^{3

4}, Koen Boussery¹, Els Mehuys¹, Annemie Somers^{1

2}, Mirko Petrovic⁵, Tine L De Backer⁶, Lies Lahousse^{7

8}

Affiliations

¹ Department of Bioanalysis, Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
² Department of Pharmacy, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
³ Centre for Pharmaceutical Research, Research Group of Clinical Pharmacology and Clinical Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Jette, Belgium.
⁴ Department of Hospital Pharmacy, UZ Brussel, Laarbeeklaan 101, 1090, Jette, Belgium.
⁵ Department of Geriatrics, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
⁶ Department of Cardiology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
⁷ Department of Bioanalysis, Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium. Lies.lahousse@ugent.be.
⁸ Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000, CA, the Netherlands. Lies.lahousse@ugent.be.

PMID: 37930588
DOI: 10.1007/s10557-023-07521-5

Abstract

Purpose: Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.

Methods: Using Belgian nationwide data, NOAC-treated AF patients were included between 2013-2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified.

Results: Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13-1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03-1.22)), urogenital (aHR 1.21, 95%CI (1.09-1.35)) and other bleeding (aHR 1.28, 95%CI (1.20-1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y₁₂ inhibitors (aHR 1.62, 95%CI (1.48-1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42-1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17-1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08-1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01-1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25-1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21-1.84)).

Conclusion: Concomitant use of PD interacting drugs, especially P2Y₁₂ inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids.

Keywords: Antiplatelet; Atrial fibrillation; Bleeding; NOAC; Pharmacodynamic drug-drug interaction; SSRI.

Grants and funding

11C0820N/Fonds Wetenschappelijk Onderzoek