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

Abstract

ObjectiveThe 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.DesignWe used nested case–control study design.SettingThis study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA.ParticipantsStudy 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 measuresOur 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 Χ2test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban.ResultsMcNemar’s Χ2test 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).ConclusionThis 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.

Drug–Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

“…The possible occurrence of clinically relevant DDI in the context of COVID-19 has been a major concern, as most hospitalized patients received high doses dexamethasone, concomitant with oral anticoagulants in some patients. In a recent study, no change in the peak and trough plasma concentrations of 26 patients treated with anticoagulants (apixaban, rivaroxaban and edoxaban) was observed when measured 48 to 72 h after the initiation of dexamethasone and 14 to 21 days after cessation [102] A nested case-control study from the National COVID Cohort Collaborative on 172 patients who received dexamethasone and rivaroxaban or apixaban and 344 controls without dexamethasone, found no increase in thromboembolic events under treatment with dexamethasone [103].…”

Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients

“…Dexamethasone is a strong inducer of both P‐gp and CYP3A4 and thus can interact with DOACs. Reassuringly, a real‐world study did not find increased thromboembolism in patients receiving dexamethasone and DOACs concurrently 35 …”

“…Reassuringly, a real-world study did not find increased thromboembolism in patients receiving dexamethasone and DOACs concurrently. 35 Table 2 outlines interactions between DOACS and common anticancer agents in neuro-oncology. A review of medications and drug-drug interactions along with other factors such as age, weight, renal, and liver function, must be performed before prescribing DOACs.…”