Table 4.

Potential Drug Interactions Between Anticoagulants^∗ and Investigational Therapies for COVID-19

Investigational COVID-19 Therapies	Vitamin K Antagonists	Dabigatran	Apixaban	Betrixaban	Edoxaban	Rivaroxaban
Lopinavir/ritonavir	CYP2C9 induction: May decrease plasma concentration. Adjust dose based on INR.	P-gp inhibition: May increase plasma concentration. No dose adjustment recommended.	CYP3A4 and P-gp inhibition: Administer at 50% of dose (do not administer if initial dose is 2.5 mg twice daily).†	P-gp and ABCB1 inhibition: Decrease dose to 80 mg once followed by 40 mg once daily.	P-gp inhibition: Do not coadminister.	CYP3A4 and P-gp inhibition: Do not coadminister.
Tocilizumab	—	—	Reported increase in expression of 3A4 (major pathway): No dose adjustment recommended.	—	—	Reported increase in expression of 3A4 (major pathway): No dose adjustment recommended.
Interferon‡,‖	Unknown mechanism: Decreased dose may be needed.	—	—	—	—	—
Ribavirin	Mechanism not well known: Possibly decreased absorption of warfarin in the presence of ribavirin (156); increased dose may be needed.	—	—	—	—	—
Methylprednisolone	Unknown mechanism: Decreased dose may be needed.	—	—	—	—	—
Sarilumab§			Reported increase in expression of CYP3A4 (major pathway): No dose adjustment recommended.			Reported increase in expression of CYP3A4 (major pathway): No dose adjustment recommended.
Azithromycin	Unknown mechanism: Decreased dose may be needed.	P-gp inhibition: May increase plasma concentration. No dose adjustment recommended.		P-gp inhibition: Decrease dose to 80 mg once followed by 40 mg daily.	P-gp inhibition: VTE: Limit dose to 30 mg daily. Nonvalvular AF: No dose recommendation.
Hydroxychloroquine and chloroquine	—	—	—	—	—	—

Other drugs being studied to treat COVID-19 include bevacizumab, chloroquine/hydroxychloroquine, eculizumab, fingolimod, losartan, and pirfenidone. Drug-drug interactions between these medications and oral anticoagulants have yet to be identified. Bevacizumab has been reported to cause deep vein thrombosis (9%), arterial thrombosis (5%), and pulmonary embolism (1%). It is also reported to cause thrombocytopenia (58%).

CYP = cytochrome P system; INR = international normalized ratio; P-gp = P-glycoprotein; other abbreviations as in Table 1.

^∗Parenteral anticoagulants (including unfractionated or low-molecular-weight heparins, bivalirudin, argatroban, and fondaparinux) are non–CYP-metabolized and do not interact with any of the investigational agents.

^†These recommendations are based on the U.S. package insert. The Canadian package insert considers the combination of these agents to be contraindicated.

^‡Interferon has been reported to cause pulmonary embolism (<5%), thrombosis (<5%), decreased platelet count (1%–15% with Alfa-2b formulation), and ischemic stroke (<5%).

^§Sarilumab has been reported to cause decreased platelet count, with decreases to <100,000 mm³ in 1% and 0.7% of patients on 200-mg and 150-mg doses, respectively.

^‖Reported with interferon alpha.