Drug Interactions Between Direct Oral Anticoagulants and Nonsteroidal Anti-inflammatory Drugs: A Clinical Risk-Benefit Analysis With Focus on Special Populations.

BACKGROUND

Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently coprescribed in this population due to comorbid musculoskeletal or inflammatory conditions. However, the combined use of DOACs and NSAIDs is associated with an increased risk of bleeding due to additive pharmacodynamic effects and potential pharmacokinetic interactions.

AREA OF UNCERTAINTY: Although the bleeding risk of this drug combination is well-recognized, evidence-based strategies to mitigate such risk remain limited. Current clinical guidelines do not offer detailed, stratified recommendations based on specific NSAID classes, individual DOAC agents, or particular high-risk populations such as elderly patients, individuals with cancer, those with chronic kidney disease, or patients with autoimmune disorders requiring prolonged NSAID therapy. In addition, the clinical relevance of pharmacokinetic interactions involving CYP3A4 and P-glycoprotein (P-gp), which may influence both DOAC and NSAID metabolism, remains insufficiently explored in real-world settings.

DATA SOURCES: We conducted a structured literature search across PubMed/MEDLINE, Scopus, and Web of Science from January 2005 to December 2024 using the terms "direct oral anticoagulants," "NSAIDs," "bleeding," "drug interactions," and related MeSH headings. We included pharmacological studies, randomized trials, real-world cohort analyses, narrative reviews, and meta-analyses. Articles were screened by title and abstract, with full-text assessment for eligibility.

THERAPEUTIC ADVANCES: The concomitant use of NSAIDs and direct oral anticoagulants (DOACs) presents a well-recognized bleeding risk due to their synergistic effects on platelet function and gastrointestinal mucosa integrity. However, the clinical message should not be a blanket prohibition of NSAID use in anticoagulated patients. However, careful and judicious use, at the lowest effective dose and for the shortest necessary duration, should be considered in select clinical situations.