Safe Co-administration of Direct-acting Antivirals and Direct Oral Anticoagulants Among Patients With Hepatitis C Virus Infection

An International Multicenter Retrospective Cohort Study

Kathryn McDaniel; Alyssa E. Utz; Mikhail Akbashev; Katherine G. Fuller; Alison Boyle; Katherine Davidson; Fiona Marra; Sital Shah; Emily J. Cartwright; Aakriti A. Arora; Sarah DuPont; Lesley S. Miller


J Viral Hepat. 2022;29(12):1073-1078. 

In This Article

Abstract and Introduction


Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct-acting antivirals inhibit DOAC transport through P-glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56–2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC.


Hepatitis C virus (HCV) affects 2.4 million people in the US and over 70 million worldwide.[1] Untreated HCV leads to cirrhosis in over 18% of infected patients, with cirrhosis rates increasing over time.[2] HCV is easily curable with direct-acting antivirals (DAA), administered for 8–24 weeks, providing cure rates of >95%. While highly effective, DAA have multiple drug interactions via several drug metabolism and transport pathways.

Direct oral anticoagulants (DOAC) are commonly used to treat venous thromboembolism (VTE), and they prevent stroke and systemic embolism in patients with atrial fibrillation (AF). HCV and cirrhosis are associated with a 1.5-fold increased risk of incident atrial fibrillation,[3,4] as well as a 1.4-fold increase of VTE,[5] leading to many patients with HCV requiring DOAC therapy. All DAA inhibit P-glycoprotein (P-gp), breast cancer receptor protein (BCRP), and/or CYP3A4. All DOAC are P-gp, CYP3A4, and/or BCRP substrates leading to a theoretical increase in DOAC concentrations, and potentially increased bleeding, when co-administered with DAA. A recent systematic review evaluating drug concentrations reported that co-administration of dabigatran, a DOAC, and several DAA increased dabigatran concentrations. The authors conclude that more data is needed to evaluate the clinical impacts of DAA and DOAC co-administration to guide clinical decision making.[6]

Despite the reported increase in DOAC concentrations, there is a paucity of data addressing clinically relevant outcomes such as bleeding. One study described a patient population on concurrent DAA and DOAC and described potential anticoagulation management strategies during DOAC-DAA therapy, reporting no major bleeding events among 54 patients.[7]

We conducted a retrospective, international cohort study to evaluate the safety of concurrent DOAC use with DAA among patients with chronic HCV infection with or without cirrhosis.