Dear Editors,
We read with interest the recent review article by Ay et al. [1] in the Annals of Oncology regarding the treatment of venous thromboembolism in patients with active cancer. As the authors allude to, the advent of the direct oral anticoagulants (DOACs) has the potential to transform care for these patients. Arguably, the most relevant open question is that of drug interactions between chemotherapy agents and DOACs.
There is some agreement that DOACs should not be used in patients treated with strong P-glycoprotein inhibitors/inducers and that apixaban/rivaroxaban are best avoided in patients receiving strong CYP3A4 inhibitors/inducers [2, 3]. However, many chemotherapy agents would not be considered strong inducers/inhibitors of P-glycoprotein/CYP3A4, and it remains unclear to what extent most chemotherapy agents affect DOAC plasma levels. This may vary between individuals, depending on genetic/physiological factors and concomitant medications.
We concur with Ay et al. [1] that the available evidence from clinical trials [4] and registry-based data [5] indicate that most interactions may not be clinically relevant. The wide therapeutic margin of DOACs could explain this finding. Yet, the percentage of patients receiving each of the potentially interacting chemotherapy agents in clinical trials was small. Drawing solid conclusions would require adequately sized studies, with cohorts of patients anticoagulated for the same indication, treated with the same chemotherapy regimens and exposed long enough to both anticoagulation and the agent under study. This appears unlikely.
Against this background, and with the benefit of their expertise, do the authors expect further evidence to definitively resolve these issues? If so, what type of studies may do so? In their practical recommendation, the authors suggest not using DOACs when there are drug-drug interactions but, do the authors recommend against DOACs in patients receiving mild/moderate inducers/inhibitors (any DOACs for P-glycoprotein inducers/inhibitors and apixaban/rivaroxaban for CYP3A4 inducers/inhibitors)? In patients treated with strong inducers/inhibitors, do the authors think more evidence may ultimately show that some of these agents ultimately do not interact with some DOACs to a clinically relevant extent?
Funding
None declared.
Disclosure
The authors have declared no conflicts of interest.
References
- 1. Ay C, Beyer-Westendorf J, Pabinger I.. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol 2019; 30(6): 897–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Mosarla RC, Vaduganathan M, Qamar A. et al. Anticoagulation strategies in patients with cancer. J Am Coll Cardiol 2019; 73(11): 1336–1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kraaijpoel N, Carrier M.. How I treat cancer-associated venous thromboembolism. Blood 2019; 133(4): 291–298. [DOI] [PubMed] [Google Scholar]
- 4. Raskob GE, van Es N, Verhamme P. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378(7): 615–624. [DOI] [PubMed] [Google Scholar]
- 5. Shah S, Norby FL, Datta YH. et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018; 2(3): 200–209. [DOI] [PMC free article] [PubMed] [Google Scholar]