Prescriptions of CYP3A4- and P-gp inducers for patients on direct oral anticoagulants: Bridging the gap between epidemiology and patient management for optimal thromboembolic event prevention

Direct oral anticoagulants (DOACs) are frequently used for the treatment and prevention of ischaemic stroke in patients with non-valvular atrial fibrillation. Compared to vitamin K antagonists, DOACs have significant advantages, although their drug-drug interaction (DDI) profile may complicate drug efficacy and safety. This narrative review addresses the clinical challenges posed by these DDIs and the potential pharmacological alternatives and monitoring strategies available. A PubMed search was conducted (1 January 2000-31 December 2023) including human DDI studies on DOAC use and CYP3A4/P-gp inducers in adult patients, evaluating patient outcome data and recommendations for DDI management. Twenty-two studies were included. Case reports (n = 6) indicated that antiepileptic drugs such as carbamazepine, phenobarbital and phenytoin may be associated with thromboembolic events. The nested case-control studies (n = 2) and cohort studies (n = 9) found that co-administration of DOACs and CYP3A4/P-gp inducers, particularly carbamazepine and phenytoin, increased the risk of thromboembolic events. Pharmacovigilance database analyses indicated a significant association between DOAC DDIs and increased reported stroke rates. Management recommendations in systematic reviews (n = 5) highlighted monitoring when DOACs were combined with inducers. Strategies included using alternative drugs with a weaker or preferentially absent inducing profile. Limited evidence suggests that edoxaban may be an acceptable option in case of DOAC and CYP3A4/P-gp inducer interactions; however, robust clinical data confirming safety are needed. Present literature indicates a higher thromboembolic risk in patients on DOAC treatment combining CYP3A4- and/or P-gp inducers. DOAC management should be tailored to the individual patient through collaboration between expert healthcare professionals.