Screening for Clinically Relevant Drug-drug Interactions Between Direct Oral Anticoagulants and Antineoplastic Agents: a Pharmacovigilance Approach

Background: Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due to the concern regarding 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 1/1/2004 to 12/31/2021. AE reports containing DOACs and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity suggested by published pharmacokinetic studies were included (n = 36,066). The outcomes of interest were bleeding or stroke, identified by MedDRA dictionary version 25.0. We used disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) algorithms to identify the safety signal of DDIs.

Results: The highest bleeding reporting rates for 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). In the primary analysis, no signal of DDIs by the antineoplastic therapeutic class was detected by MGPS, DPA, and LR approaches. By individual antineoplastic drug, DOACs-neratinib was the only signal detected [EBGM (EB05-EB95) = 2.71 (2.03-3.54)].

Conclusion: No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Most DDIs between DOACs and antineoplastic agents may not be clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.