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. 2022 Dec 29;12(12):e066846.
doi: 10.1136/bmjopen-2022-066846.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C)

Olga V Kravchenko  1 , Richard D Boyce  2 , Ainhoa Gomez-Lumbreras  3 , Paul T Kocis  4 , Lorenzo Villa Zapata  5 , Malinda Tan  6 , Charles E Leonard  7 , Kathleen M Andersen  8   9 , Hemalkumar Mehta  9 , G Caleb Alexander  8   9 , Daniel C Malone  3 ; N3C consortium
Affiliations

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C)

Olga V Kravchenko et al. BMJ Open. .

Abstract

Objective: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE.

Design: We used nested case-control study design.

Setting: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA.

Participants: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days.

Primary and secondary outcome measures: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban.

Results: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18).

Conclusion: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Keywords: Anticoagulation; BIOTECHNOLOGY & BIOINFORMATICS; CLINICAL PHARMACOLOGY; COVID-19; Health informatics; Thromboembolism.

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Conflict of interest statement

Competing interests: After the completion of this work, KMA became a full-time employee of Pfizer. GCA is past Chair and a current member of Food and Drug Administration's(FDA) Peripheral and Central Nervous System Advisory Committee; is a co-founding Principal and equity holder in Monument Analytics, a healthcare consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation; and is a past member of OptumRx’s National P&T Committee. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. CEL is an Executive Committee Member of the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training. The centre receives funds from Pfizer and Sanofi to support pharmacoepidemiology education. CEL recently received honoraria from the American College of Clinical Pharmacy Foundation, the University of Florida, the University of Massachusetts, and the Scientific and Data Coordinating Center for the NIDDK-funded Chronic Renal Insufficiency Cohort Study. CEL is a Special Government Employee of the US FDA and consults for their Reagan-Udall Foundation. CEL receives travel support from John Wiley & Sons. CEL’s spouse is an employee of Merck. Neither CEL nor his spouse owns stock in the company. There are no other disclosures to report.

Figures

Figure 1
Figure 1
Schematic diagram representing retrospective observational nested case–control study design used in this study. DOAC, direct oral anticoagulant.
Figure 2
Figure 2
Schematic diagram representing the flow of data for cohort formation and selection of cases and controls. DEX, dexamethasone; DOAC direct oral anticoagulant; N3C, National COVID Cohort Collaborative; TEE, thromboembolic event.
See this image and copyright information in PMC

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