OBJECTIVES: Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due partly to concerns with their potential drug-drug interactions (DDIs) with antineoplastic treatments. However, the clinical relevance of these DDIs is unknown.

METHODS: We conducted a pharmacovigilance study of adverse event (AE) reports from the US Food and Drug Administration Adverse Event Reporting System from 01/01/2004 to 12/31/2021. AE reports containing both DOAC and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity (i.e., kinase inhibitors (KIs), hormonal therapy, chemotherapeutic agents, immunomodulating agents (IMAs)) were included (n=36,066). The corresponding outcomes were bleeding or stroke, identified by MedDRA dictionary version 25.0. We employed disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) algorithms (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) to identify safety signals of DDIs by antineoplastic therapeutic class and by individual drugs.

RESULTS: The highest bleeding rates in each drug class were the combination of DOACs with neratinib (39.08%, n=34), tamoxifen (21.22%, n=104), irinotecan (20.54%, n=83), and cyclosporine (19.17%, n=227). The highest rate of stroke was found for prednisolone (2.43%, n=113). No signal of DDIs by antineoplastic therapeutic class was detected using MGPS algorithms [EBGM (EB05-EB95)=1.02 (0.97-1.08) for DOACs-KIs, 1.22 (1.15-1.30) for DOACs-hormone, 1.22 (1.16-1.27) for DOACs-chemotherapy, 0.66 (0.63-0.69) for DOACs-IMAs, and 1.05 (0.90-1.21) for DOACs-inducers]. Findings from DPA and LR approaches agreed with MGPS. DOACs-neratinib was the only DDI signal detected [EBGM (EB05-EB95) = 2.71 (2.03-3.54)] for an individual antineoplastic drug.

CONCLUSIONS: No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Our findings support the hypothesis that most DDIs were not clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.