Does flucloxacillin increase the risk of stroke and systemic embolism in patients who are already using direct oral anticoagulants?

Study type
Date of Approval
Study reference ID
Lay Summary

Direct oral anticoagulants (DOACs) are a group of blood thinning agents. They are commonly used to lower the risk of stroke and blood clots in body. They were developed as alternatives to another blood-thinning agent, warfarin. DOACs are just as safe and effective as warfarin in prevention of stroke in patients with heart rhythm problems, and are more convenient than warfarin because routine blood tests are not required.
Flucloxacillin is an antibiotic that is commonly used worldwide to treat infections in the skin and soft tissues and is typically used for 7-10 days. Previous studies have shown that flucloxacillin decreases the ideal effect of warfarin when they are used together, thus leading to an increased risk of stroke. Also, laboratory studies showed that flucloxacillin might have a similar effect on DOACs effectiveness in preventing strokes and blood clots. Thus in this study, we aim to investigate if the use of flucloxacillin and DOACs together increases the risk of strokes compared to use of another antibiotic and compared to no treatment with antibiotics.
The results of our study will help with safer use of flucloxacillin, especially in patients who are already receiving blood thinning agents.

Technical Summary

This study will examine the association between concomitant use of flucloxacillin and DOACs, and the risk of stroke and systemic embolism.
This will be a retrospective cohort study using the Clinical Practice Research Datalink (CPRD). All adults above 18 years old with a prescription of DOACs between 2011-2022 will be included.
The index date will be the prescription date of flucloxacillin. The primary exposure of interest in this study is use of flucloxacillin, while the primary outcome is a stroke or systemic embolism 5-20 days after prescription fill of flucloxacillin.
We will perform a propensity score matching to balance covariates at index date. Then cox proportional hazards models will be used to conduct statistical analysis.
The main analysis will compare the risk of stroke and systemic embolism among DOAC users taking flucloxacillin versus phenoxymethylpenicillin users and versus non-antibiotic users.
In the secondary analyses, we will perform the analysis on subgroups and conduct a self-controlled case-crossover study to account for confounders that are stable over time.
In the self-controlled case-crossover study, patients experiencing either a stroke or systemic embolism will work as their own control and contribute with data for both the exposed and unexposed follow-up time. The time for experiencing an outcome is defined as day 0, and day -5 to day -20 is defined as the focal window, which determines the reason for the outcome. We will also apply a wash-out-window of 15 days after the focal window and 4 reference windows, all having a length of 15 days.

Health Outcomes to be Measured

Occurrence of stroke or systemic embolism; bleeding.


Shahab Abtahi - Chief Investigator - Utrecht University
Shahab Abtahi - Corresponding Applicant - Utrecht University
Anton PottegÄrd - Collaborator - University Of Southern Denmark
Ditte Bork Iversen - Collaborator - Utrecht University
Martin Ernst - Collaborator - Utrecht University
Olaf Klungel - Collaborator - Utrecht University
Patrick Souverein - Collaborator - Utrecht University
Tore Bjerregaard Stage - Collaborator - University Of Southern Denmark