Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice

Abstract

The direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming the most commonly prescribed drugs for preventing ischemic stroke in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). Rivaroxaban was also recently approved for the treatment of patients with a recent acute coronary syndrome (ACS). Their use demonstrated to have a favorable risk-benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality compared to warfarin, but with increased gastrointestinal bleeding. Nevertheless, their safety profile is compromised in multimorbidity patients requiring contemporary administration of several drugs. Comorbidity and polypharmacy have a high prevalence in elderly patients, who are also more susceptible to bleeding events. The combination of multiple treatments can cause relevant drug–drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs. Although important differences of the pharmacokinetic (PK) properties can be observed between DOACs, all of them are substrate of P-glycoprotein (P-gp) and thus may interact with strong inducers or inhibitors of this drug transporter. On the contrary, rivaroxaban and, to a lower extent, apixaban, are also susceptible to drugs altering the cytochrome P450 isoenzyme (CYP) activities. In the present review, we summarize the potential DDI of DOACs with several classes of drugs that have been reported or have characteristics that may predict clinically significant DDIs when administered together with DOACs. Possible strategies, including dosage reduction, avoiding concomitant administration, or different time of treatment, will be also discussed to reduce the incidence of DDI with DOACs. Considering the available data from specific clinical trials or registries analysis, the use of DOACs is associated with fewer clinically relevant DDIs than warfarin, and their use represents an acceptable clinical choice. Nevertheless, DDIs can be significant in certain patient conditions so a careful evaluation should be made before prescribing a specific DOAC.

Individual Pharmacotherapy Management (IPM)—IV: Optimized Usage of Approved Antimicrobials Addressing Under-Recognized Adverse Drug Reactions and Drug-Drug Interactions in Polypharmacy

“…All currently approved DOACs are contraindicated with most macrolides (notice the metabolic properties of three different groups) and azoles because they increase the risk of hemorrhages due to the decreased DOAC degradation by inhibited P-gp and/or CYP3A4 [ 26 ]. The same applies to ticagrelor metabolism [ 27 ], which is also a substrate of P-gp and CYP3A4, a fact that is often not taken into account postinterventionally in cardiology patients and is further aggravated by concomitant hepatic dysfunction with reduced metabolic capacity, e.g., related to right-sided heart failure.…”

Superiority of Direct Oral Anticoagulants over Vitamin K Antagonists in Oncological Patients with Atrial Fibrillation: Analysis of Efficacy and Safety Outcomes

“…On the other hand, strong P-glycoprotein transporter and CYP3A4 enhancers, such as rifampin, are able to decrease the bioavailability of apixaban and rivaroxaban by half, thus, decreasing the efficacy of these drugs [ 49 ]. In particular, for active prostate cancer, no pharmacological interferences with DOACS and docetaxel have been reported [ 50 , 51 , 52 ]. On the contrary, the association with hormone therapy is not advisable due to the interactions with both the cytochrome CYP3A4 and the P-glycoprotein transport system [ 53 ].…”

Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications

“…With their rapid mode of action, especially the novel VTE drugs, DOACs are preferred over other currently used drugs. However, compared to parenteral anticoagulants, oral anticoagulants are often accompanied by the risk of undesired drug–drug interaction (DDI) [ 85 ]. DDIs are secondary to the specific effect of a therapeutic and can occur when two administered drugs share the same cell membrane transporter or metabolic pathway.…”

“…For instance, dabigatran activity could increase by up to 70% in patients that are treated with dronedarone. For this reason, to treat atrial fibrillation, the drug amiodarone, a moderate P-GP competitor, is preferred to dronedarone in patients using DOACs [ 85 ]. In cancer patients, imatinib and crizotinib, two tyrosine kinases, are contraindicated for DOAC patients, due to their strong inhibitory capacity of P-GP [ 87 ].…”

“…Enzalutamide, a prostate cancer hormonotherapy, promotes P-GP function, and this could reduce the concentration of the administered DOAC, resulting in an increased risk for recurrent VTE [ 88 ]. P450 cytochromes CYP2C9, CYP1A2, and CYP3A4 mediate the elimination of oral anticoagulants, and DOAC or VKA patients that receive P450-cytochromes-inhibiting drugs have an increased bleeding risk [ 85 ]. Drugs to treat atrial fibrillation and cancer are most often cited for their DDI with oral anticoagulants, but DDIs with statins and antibiotic, antidepressant, and antiviral drugs have also been described [ 89 , 90 , 91 ].…”