Barbara S. Wiggins, PharmD, Cardiovascular Clinical Pharmacist, Clinical Lipid Specialist, Clinical Researcher, Affiliate Professor at the College of Pharmacy Medical University of South Carolina. In this video she speaks about Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week.
Millions of people in the United States require long-term anticoagulant medication. For decades, vitamin K antagonists were the only oral choice; nevertheless, they have several well-known drawbacks. The introduction of direct oral anticoagulants (DOACs) has long been seen as a significant therapeutic advance, owing to the elimination of the requirement for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can cause major and clinically significant nonmajor bleeding even when administered correctly. Drug-drug interactions (DDIs) involving the DOACs are a significant factor to the increased risk of bleeding. It is crucial to be aware of these DDIs and how to appropriately treat them in order to optimize management while minimizing bleeding risk. This paper gives an overview of DOAC metabolism, the most frequent medicines that are likely to cause DOAC DDIs, their underlying processes, and how to best manage them.
• Drug-drug interactions with DOACs might result in significant side effects.
• To evaluate for specific interactions, a thorough examination of the literature was conducted.
• Specific suggestions are provided to ensure safety and efficacy.
• Clinical management receives priority focus.
With the approval of direct oral anticoagulants (DOACs), a number of barriers connected with the vitamin K antagonist (VKA) warfarin were lifted. The therapeutic benefits include a faster and more predictable anticoagulant response, less need for frequent laboratory monitoring, and fewer drug-food and drug-drug interactions (DDIs) (1–3). Prophylaxis against stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF), as well as therapy and prevention of recurrent venous thromboembolism, are among the indications (VTE).
DOACs have been demonstrated to have equivalent or enhanced efficacy and safety when compared to warfarin in both randomized controlled trials and real-world scenarios (4–9). Despite its benefits, DOACs, like warfarin, can cause major and clinically significant nonmajor bleeding even when administered correctly (10). DOAC usage in NVAF, however, is linked with nonsignificant decreases in overall major bleeding, significantly decreased rates of cerebral hemorrhage, and greater rates of gastrointestinal bleeding, with variation in these hazards among the different agents (6). In contrast, DOAC-treated patients with VTE had comparable rates of gastrointestinal bleeding and decreased overall rates of major and cerebral hemorrhage (11–13).
In people using a DOAC, improper dose raises the risk of thrombosis and bleeding, which can reduce the efficacy of these medications (14–18). Because DDIs can represent a comparable danger, this study presents a current assessment of select drugs most likely to interact with DOACs, including the newest agent betrixaban, as well as management suggestions. The authors searched PubMed from 2009 to 2018 for select DDIs that contained DOACs and antiarrhythmic drugs, calcium-channel blockers, and well-known enzyme inducers (e.g., phenytoin). Data from clinical trials, pharmacokinetic (PK) investigations, case reports, and prescribing information were used to develop the final recommendations.
DDIs, Enzyme Systems, and Transporters: A Summary
The cytochrome P450 (CYP450) enzyme and/or the transporter permeability glycoprotein are the most prevalent DDIs involving DOACs (P-gp). However, other transport mechanisms, such as the influx transporter that regulates cellular uptake, the organic anion-transporter polyprotein (OATP), the efflux/influx organic cation transporter (OCT), and the efflux transporter breast cancer resistance protein, have been implicated in certain DDIs (BCRP). Medication can be either an inducer or an inhibitor of one or more of these enzymes or transport proteins, according to DDI. When inhibition occurs, direct competition between drugs occurs, resulting in increasing serum concentrations of one or both compounds. Induction, on the other hand, results in lower serum concentrations, which may reduce the efficacy of a medicine.