Bleeding risk among cancer patients receiving concurrent CYP-interacting tyrosine kinase inhibitors with direct oral anticoagulants versus alternative anticoagulation therapies

Abstract

Introduction

Cancer-associated stroke and venous thromboembolism (VTE) are common, life-threatening conditions in patients with cancer. Low-molecular-weight heparin was the standard of care for cancer-associated VTE, until recent evidence supported the efficacy of direct oral anticoagulants (DOAC). However, some tyrosine kinase inhibitors (TKI) inhibit the cytochrome P450 (CYP) enzymes responsible for metabolizing DOACs, potentially increasing the risk of bleeding. Therefore, the aim of this study was to evaluate concomitant use of DOACs and TKIs compared to alternative anticoagulation (AAC) and TKIs in order to guide clinicians in selecting therapy based on bleeding risk.

Methods

This study was a retrospective chart review of patient records from multiple centers within a healthcare system. It was approved by the system's Institutional Review Board prior to study initiation. Records of patients that received 3-months or longer of concomitant CYP-interacting TKI with a DOAC versus those with AAC therapies (enoxaparin and warfarin) from January 1, 2017 to March 31, 2023, and followed through June 30, 2023, were included. The primary outcome was reported as occurrence of any major bleeds, utilizing the International Society on Thrombosis and Haemostasis definition, requiring an emergency department visit or hospitalization, or which occurred during a hospital stay within three months of initiation of concurrent therapy. The secondary outcomes consisted of the following: minor bleeding events requiring an emergency department visit or hospitalization or occurred during hospital stay, VTE events, recurrence of VTE events, stroke, recurrence of stroke, and all-cause mortality – all within three months of initiation of concurrent therapy.

Results

Of the 456 screened patient records, a total of 280, with 140 in each cohort, met study inclusion criteria. The rate of major bleeding events in the DOAC group was 5.7% compared to 4.3% in the AAC group (p = 0.583). The rate of minor bleeding was more common in the DOAC group (35%) compared to the AAC group (22.9%) (p = 0.025). During the study, only two patients, one in each group, presented with any kind of VTE event (p = 1.000), both of which were a recurrent VTE event. No stroke events were observed, and one patient from each group died from complications of their malignancy (p = 1.000).

Conclusion

This study demonstrated that there was no significant difference in major bleeding between the two groups. However, concomitant use of DOACs and CYP-interacting TKIs was associated with a higher incidence of minor bleeds compared to AAC and CYP-interacting TKIs. Other secondary outcomes showed that there was no statistically significant difference in the percentage of patients in terms of incidence of VTE, stroke, or all-cause mortality between the two groups.