Selection of direct-oral anticoagulants (DOACs) and risk stratification can be improved when clinicians assess both polypharmacy and potential drug interactions, especially with concomitant cardiovascular drugs and site-specific bleeding risk, suggests a study.
“Clinicians should incorporate comprehensive medication profiles into DOAC selection and risk stratification, especially for high-risk patients,” said the investigators, who extracted individual case safety reports involving apixaban, dabigatran, edoxaban, or rivaroxaban from the Food and Drug Administration Adverse Event Reporting System (FAERS).
FAERS contains at least 28 million reports and is deemed as one of the most important adverse event reporting systems. [Curr Drug Targets 2024;25:454-464]
In the study, the investigators categorized DOAC-related reports based on exposure to concomitant use of predefined drug classes of interest (ie, 10 cardiovascular drug classes, three classes of pharmacokinetic modifiers, antiplatelets, and NSAIDs) and bleeding events.
Bleeding events were defined at three levels, namely haemorrhage-related events, actual bleeding events, and major bleeding. Major bleeding was further classified according to anatomical site. The investigators then estimated the adjusted reporting odds ratios (RORs) through exact matching and logistic regression.
Interaction signals
A total of 317,583 reports were analysed. Fifteen DOAC‒drug combinations were identified as significant interaction signals across bleeding definitions, with adjusted RORs ranging from 1.06 to 2.36. [Am J Med 2026;139:1337-1347.e6]
Diuretics demonstrated consistent interaction signals across DOACs and bleeding definitions. The drugs with the most robust interaction signals were as follows: digitalis glycosides, nondihydropyridine calcium channels blockers, and amiodarone analogues.
In site-stratified major bleeding analyses, 64 significant interaction signals were identified. Rivaroxaban accounted for the largest proportion, while edoxaban had a relatively less extensive interaction signal profile.
“Among the 64 identified DOAC-cardiovascular drug-bleeding site combinations, approximately 20 percent involved renin-angiotensin system (RAS) inhibitors,” the investigators said.
“Given these agents are commonly prescribed for hypertension, heart failure, and renal comorbidity in DOAC users, this finding is clinically relevant in patients with multiple cardiovascular comorbidities who are frequently exposed to polypharmacy,” they added. [BMC Cardiovasc Disord 2022;22:141]
Literature
Earlier studies found potential associations between RAS inhibitors and bleeding risk, including recurrence of chronic subdural haematoma and genetic susceptibility to bleeding in patients treated with DOACs. [J Stroke Cerebrovasc Dis 2023;32:107291; Pharmaceutics 2022;14:231]
A previous study has found an association between RAS and the coagulation and fibrinolysis pathways, which appeared to impact bleeding risk. Animal studies have also shown a potential link between rivaroxaban and RAS, particularly angiotensin II. [J Manag Care Pharm 2007;13(8 suppl B):9-20; Sci Rep 2022; 12:9771; Sci Rep 2017;7:369]
“Building on prior studies, our findings further extend these observations by demonstrating interaction signals across multiple bleeding sites in a large-scale, real-world polypharmacy setting,” the investigators said.
“Although RAS inhibitors provide therapeutic benefits in the management of cardiovascular disorders, their potential impact on haemostatic balance and bleeding susceptibility warrants further investigation,” they added.
In real-world practice, patients treated with DOACs often have several cardiovascular disorders (eg, hypertension, heart failure, coronary artery disease, and dyslipidemia). Consequently, they are also exposed to different cardiovascular medications. [Eur J Clin Invest 2021;51:e13498]