Association Between Use of Pharmacokinetic-Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case-Control Study

Clin Pharmacol Ther. 2021 Dec;110(6):1526-1536. doi: 10.1002/cpt.2369. Epub 2021 Aug 10.


Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition/induction effect on P-gp/CYP3A might increase risk of bleeding/treatment failure, respectively. We designed a nested case-control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow-up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient-years of follow-up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P-gp/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran-verapamil, rivaroxaban-verapamil, and rivaroxaban-amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13-4.60), 2.18 (1.07-4.40), and 1.68 (1.14-2.49), respectively. There were 1,116 events of stroke/SE, in 79,302 DOAC-treated patients with AF and 118,124 patient-years of follow-up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke/SE: adjusted OR 2.18 (1.55-3.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Anticoagulants / pharmacokinetics*
  • Case-Control Studies
  • Drug Interactions / physiology*
  • Female
  • Follow-Up Studies
  • Health Maintenance Organizations*
  • Hemorrhage / chemically induced
  • Humans
  • Male
  • Pharmacokinetics
  • Treatment Outcome


  • Anticoagulants