Elsevier

European Journal of Cancer

Volume 148, May 2021, Pages 371-381
European Journal of Cancer

Original Research
Effects of concomitant administration of anticancer agents and apixaban or dalteparin on recurrence and bleeding in patients with cancer-associated venous thromboembolism

https://doi.org/10.1016/j.ejca.2021.02.026Get rights and content

Highlights

  • Anticancer agents did not influence rates of primary outcomes during anticoagulation.

  • No interaction between apixaban and CYP3A4 or permeability glycoprotein inducers or inhibitors was found.

  • Anticancer agents can be concomitantly administered to apixaban-treated patients with venous thromboembolism.

  • An increased risk of clinically relevant non-major bleeding was observed in apixaban-treated patients with colorectal and lung cancer.

Abstract

Background

Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE) is undefined. The pharmacological interaction between anticancer agents and direct oral anticoagulants is perceived as a concern.

Methods

We evaluated the effects of concomitant administration of anticancer agents on recurrent VTE, major bleeding and death in patients with cancer-associated VTE randomised to receive apixaban or dalteparin in the Caravaggio study.

Results

Anticancer agents were concomitantly given to 336 patients (58.3%) treated with apixaban and to 332 patients (57.3%) treated with dalteparin. In patients treated with apixaban, recurrent VTE occurred in 20 (6.0%) and 12 (5.0%) among patients treated or not treated with anticancer agents, respectively (hazard ratio [HR] = 1.14; 0.55–2.38); major bleeding occurred in 12 (3.6%) and 10 (4.2%) patients , respectively (HR = 0.79; 0.34–1.82), and death occurred in 74 (22.0%) and 61 (25.4%) patients , respectively (HR = 0.71; 0.51–1.00). In patients treated with dalteparin, recurrent VTE occurred in 24 (7.2%) and 22 (8.9%) among patients treated or not treated with anticancer agents, respectively (HR = 0.71; 0.40–1.28); major bleeding occurred in 16 (4.8%) and 7 (2.8%) patients, respectively (HR = 1.78; 0.66–4.79), and death occurred in 87 (26.2%) and 66 (26.7%) patients, respectively (HR = 0.85; 0.62–1.18). The comparative efficacy and safety of apixaban and dalteparin was not different in patients treated or not treated with anticancer agents. No effect on recurrent VTE, major bleeding or death was observed with inhibitors or inducers of P-glycoprotein and/or CYP3A4.

Conclusion

In our study, concomitant administration of anticancer agents had no effect on the risk of VTE recurrence or major bleeding in patients treated with apixaban or dalteparin for cancer-associated VTE.

Introduction

Patients with cancer-associated venous thromboembolism (VTE) have a 2- to 3-fold increase in the risk of VTE recurrence and anticoagulant treatment–emergent bleeding compared with patients without cancer [1,2]. Treatment with anticancer agents has been identified as an independent risk factor for cancer-associated VTE [3,4], but its role in recurrence and bleeding during treatment with anticoagulants is unclear. The high risk of recurrence and bleeding as well as concomitant anticancer treatment make patients with cancer-associated VTE a peculiar patient population so that specific clinical trials are required to claim for the efficacy and safety of a particular treatment in these patients.

Three direct oral anticoagulants (DOACs) have been successfully evaluated for treatment of cancer-associated VTE [[5], [6], [7]] and have been incorporated or are about to be considered by recent international guidelines [[8], [9], [10], [11], [12], [13]]. Although less commonly than vitamin K antagonists, DOACs may have several drug-to-drug interactions [14,15]. The most common interactions that involve DOACs are those mediated by either the cytochrome CP450, mainly CYP3A4, or transporter permeability glycoprotein (P-gp) [14]. Concomitant administration of an inducer of CYP3A4 or P-gp or both may result in a reduced concentration of DOACs, which may limit their efficacy. On the other hand, inhibitors of either CYP3A4 or P-gp or both may result in an increased concentration of DOACs, which may be associated with an increased risk of bleeding.

Anticancer agents and some supportive care drugs can either be inducers or inhibitors of CYP3A4 or P-gp [14,15]. The pharmacological interaction between anticancer agents, particularly inhibitors or inducers of CYP3A4 or P-gp, and DOACs is perceived as a concern in the management of cancer-associated VTE. However, no data supporting an effect of these pharmacological interactions on the efficacy and safety of anticoagulants in patients treated for cancer-associated VTE are currently available.

The Caravaggio study compared the efficacy and safety of apixaban and dalteparin in the treatment of VTE in patients with cancer [7,16]. In this study, apixaban was non-inferior to dalteparin for the treatment of cancer-associated VTE without an increased risk of major bleeding. We performed this analysis to evaluate the effects of concomitant administration of anticancer agents on VTE recurrence, major bleeding and death in patients with cancer-associated VTE randomised to receive apixaban or dalteparin in the Caravaggio study.

Section snippets

Methods

Caravaggio was a multinational, randomised, open-label, non-inferiority study with blind assessment of the study outcomes [7]. A detailed description of the study protocol has been previously published by Agenlli et al [16] and is available at ClinicalTrials.gov (NCT05406304). The study was an investigator-initiated trial funded by the Bristol Myers Squibb-Pfizer Alliance.

The Caravaggio study included patients with active cancer or cancer diagnosed within 2 years before the randomisation and

Results

Of 1155 patients included in the Caravaggio study, 336 (58.3%) in the apixaban group and 332 (57.3%) in the dalteparin group received at least one concomitant anticancer agent (Table 1). In 91 patients in each group, anticancer treatment was being given at the time of randomisation and was continued thereafter; in 245 and 241 patients treated with apixaban or dalteparin, respectively, anticancer treatment was started after randomisation. Of the apixaban-treated and dalteparin-treated patients,

Discussion

This study shows that concomitant administration of anticancer agents does not appear to influence the rates of VTE recurrence and major bleeding associated with apixaban or dalteparin when these anticoagulants are used for treatment of VTE in patients with cancer.

Treatment with anticancer agents has been reported to be an independent risk factor for VTE through several prothrombotic mechanisms [2,21]. Cytotoxic anticancer agents damage endothelial cells, cause apoptosis and consequently

Author contributions

M.V., C.B. and G.A. contributed to conception and design. All authors contributed to collection and assembly of data. All authors contributed to data analysis and interpretation. All authors contributed to manuscript writing. All authors contributed to final approval of the manuscript.

Conflict of interest statement

M.V. reports personal fees from Pfizer, Bristol Myers Squibb and Bayer Healthcare, outside the submitted work; A.M. reports personal fees from Celgene, Sanofi, Pfizer-BMS, Leo Pharma, Daiichi Sankyo, Bayer Healthcare, Halozyme, AstraZeneca, Rovi, Merck Sharp & Dohme, Roche, Eli Lilly, Servier, Merck Serono, Incyte and Amgen, outside the submitted work; R.B. reports personal fees from Bristol Myers Squibb, Bayer, Daiichi Sankyo, Leo Pharma and Pfizer, outside the submitted work; M.V.H. reports

Acknowledgements

Caravaggio was an investigator-initiated trial funded by the Bristol-Myers Squibb-Pfizer Alliance.

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