Abstract
Direct oral anticoagulants (DOACs), namely apixaban, dabigatran, edoxaban, and rivaroxaban are being increasingly prescribed among the general population, as they are considered to be associated to lower bleeding risk than classical anticoagulants, and do not require coagulation monitoring. Likewise, DOACs are increasingly concomitantly prescribed in patients with epilepsy taking, therefore, antiepileptic drugs (AEDs), above all among the elderly. As a result, potential interactions may cause an increased risk of DOAC-related bleeding or a reduced antithrombotic efficacy. The objective of the present review is to describe the pharmacokinetic interactions between AEDs and DOACs of clinical relevance. We observed that there are only few clinical reports in which such interactions have been described in patients. More data are available on the pharmacokinetics of both drugs classes which allow speculating on their potential interactions. Older AEDs, acting on cytochrome P450 isoenzymes, and especially on CYP3A4, such as phenobarbital, phenytoin, and carbamazepine are more likely to significantly reduce the anticoagulant effect of DOACs (especially rivaroxaban, apixaban, and edoxaban). Newer AEDs not affecting significantly CYP or P-gp, such as lamotrigine, or pregabalin are not likely to affect DOACs efficacy. Zonisamide and lacosamide, which do not affect significantly CYP activity in vitro, might have a quite safe profile, even though their effects on P-gp are not well-known, yet. Levetiracetam exerts only a potential effect on P-gp activity, and thus it might be safe, as well. In conclusion, there are only few case reports and limited evidence on interactions between DOACs and AEDs in patients. However, the overall evidence suggests that the interaction between these drug classes might be of high clinical relevance and therefore further studies in larger patients' cohorts are warranted for the future in order to better clarify their pharmacokinetic and define the most appropriate clinical behavior.
Highlights
The direct-acting oral anticoagulants (DOACs), known as non-vitamin K oral anticoagulants (NOACs), are five drugs acting on coagulation cascade, without the use of anti-thrombin as a mediator, subdivided in factor Xa inhibitors and direct thrombin inhibitors.Their indication in the clinical practice is as anticoagulants for primary and secondary prevention of ischaemic stroke, in patients suffering from non-valvular atrial fibrillation (AF) [1], and for prevention and treatment of pulmonary embolism and deep venous thrombosis [2].Strokes and cerebrovascular diseases represent the main cause (30–40%) of symptomatic epilepsy among elderly [3] and most of these patients need a chronic treatment with antiepileptic drugs (AEDs)
In 2017, Chang et al found that in a large cohort of 91.330 patients suffering from non-valvular AF and treated with dabigatran, rivaroxaban or apixaban, there was a higher risk of major bleeding when the patients were taking phenytoin (N-7158) for concomitant epilepsy, as compared with patients not assuming this drug with an adjusted incidence rate difference per 1,000 person-years of 52.31 (32.18–72.44; p < 0.01)
We summarized the clinical data available on the potential interactions existing between DOACs and AEDs
Summary
The direct-acting oral anticoagulants (DOACs), known as non-vitamin K oral anticoagulants (NOACs), are five drugs acting on coagulation cascade, without the use of anti-thrombin as a mediator, subdivided in factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin inhibitors (argatroban and dabigatran).Their indication in the clinical practice is as anticoagulants for primary and secondary prevention of ischaemic stroke, in patients suffering from non-valvular atrial fibrillation (AF) [1], and for prevention and treatment of pulmonary embolism and deep venous thrombosis [2].Strokes and cerebrovascular diseases represent the main cause (30–40%) of symptomatic epilepsy among elderly [3] and most of these patients need a chronic treatment with antiepileptic drugs (AEDs). The direct-acting oral anticoagulants (DOACs), known as non-vitamin K oral anticoagulants (NOACs), are five drugs acting on coagulation cascade, without the use of anti-thrombin as a mediator, subdivided in factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin inhibitors (argatroban and dabigatran). Their indication in the clinical practice is as anticoagulants for primary and secondary prevention of ischaemic stroke, in patients suffering from non-valvular atrial fibrillation (AF) [1], and for prevention and treatment of pulmonary embolism and deep venous thrombosis [2]. The potential interactions between DOACs and AEDs represent a field of particular clinical interest
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