Cancer and cardiovascular disease (CVD) have shared risk factors and frequently occur together, particularly in elderly patients. Furthermore, individuals with cancer who are undergoing active treatment are exposed to numerous potentially cardiotoxic medications. This exposure can lead to various cardiovascular events, including left ventricular systolic dysfunction, heart failure, arrhythmias, and venous thromboembolism (VTE), with the latter two necessitating the administration of anticoagulants [1-3].
During the webinar “Insights and Challenges in Cardio-Oncology,” professor Antonella Tufano addressed the topic of the management of anticoagulants in cancer patients in her presentation titled “Managing anticoagulants in Cardio-Oncology.” You can watch Antonella Tufano’s lecture in the video below and the full webinar recording here.
Arrhythmias and cancer
Cancer patients may experience various cardiac arrhythmias, with approximately 25% of atrial fibrillation (AF) cases occurring alongside cancer. The prevalence of AF in cancer patients is expected to rise due to improved cancer detection and treatment [3, 4].
AF can be caused by tumors or can arise after surgery or anticancer therapies like chemotherapy or radiotherapy. Managing anticoagulation in cancer patients with AF is challenging due to the need to balance thromboembolism and bleeding risks, both of which are increased in this population. Limited evidence and clinical trial data exist to guide optimal anticoagulation strategies in these patients.
Cancer and thrombosis
Cancer is a well-recognized risk factor for VTE, a condition that poses significant morbidity and mortality risks in cancer patients. The incidence of cancer-associated thrombosis (CAT) has been increasing, influenced by factors such as improved cancer treatments leading to longer survival, aggressive treatment protocols with prothrombotic effects, an aging population, advanced imaging techniques, and frequent imaging procedures.[5, 6].
Systemic chemotherapy significantly raises the risk of VTE, with thrombotic complications being the second leading cause of death among cancer patients .
Anticoagulation in the setting of cancer
Venous thromboembolism (VTE)
The ESC Cardio-oncology guidelines recommend two classes of anticoagulants, direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH), for managing VTE in cancer patients . A recent clinical trial meta-analysis showed comparable efficacy between DOACs and LMWH in cancer patients, although DOACs have a higher risk of minor and gastrointestinal bleeding . Therefore, LMWH is recommended for certain patients with specific conditions such as unresected upper gastrointestinal or urothelial cancer, mucositis-related bleeding risk, drug interactions, obesity, or thrombocytopenia .
The guidelines also propose a structured approach called TBIP for VTE management, considering the risk of thrombosis, bleeding, drug-drug interactions, and patient preferences. In cases of high bleeding risk, the guidelines suggest periodic reassessment rather than anticoagulant use.
Atrial fibrillation (AF)
The ESC guidelines for AF do not specify the choice of anticoagulant for patients with or without cancer. Cancer itself increases the risk of thromboembolic events in AF patients, and certain anticancer therapies can further contribute to this risk. Risk stratification for anticoagulation in cancer patients with new-onset AF is a complex issue. The use of ibrutinib as a cardioprotective medication is also associated with an increased risk of AF.
Existing literature supports the notion that AF patients with cancer have higher rates of bleeding and thrombotic events compared to those without cancer. An observational study involving 10,000 patients showed that active cancer significantly raises the risk of bleeding. Interestingly, cancer patients in the study were more commonly treated with LMWH and less frequently with DOACs compared to non-cancer patients. However, the use of DOACs did not increase the bleeding risk .
In the absence of specific guidelines, the selection of anticoagulants for patients with AF becomes a challenging decision. There is currently limited data available on the use of anticoagulants in patients with active cancer and AF across all three classes of anticoagulants. Therefore, decisions regarding the choice of anticoagulant should be made on an individual basis, considering the specific circumstances of each patient.
DOACs are generally considered the preferred therapy for AF. However, there is limited evidence available regarding their specific use in patients who have both AF and cancer. LMWHs have not been extensively studied or approved for the treatment of AF. They are rarely used as a primary treatment option for AF, except in specific cases such as peri-operative bridging, where temporary anticoagulation is needed, when patients have metastatic cancer and are at a high risk of bleeding or when oral anticoagulants are not well-tolerated by the patient.
DOACs for patients with AF and cancer
Although there is a lack of specific clinical trials focusing on anticoagulant use in patients with both AF and cancer, some data have been collected through a meta-analysis, indicating that DOACs are equally effective as vitamin K antagonists in both cancer and non-cancer patients with AF. The study also showed no significant differences in bleeding risk . Additionally, a recent retrospective study found similar bleeding risks between warfarin and DOACs in AF patients with cancer .
While the use of DOACs in cancer patients with AF shows promise, caution should be exercised. Several concerns exist regarding DOAC use in this population, including unpredictable absorption, increased risk of gastrointestinal bleeding in patients with mucositis or other gastrointestinal complications, potential changes in drug metabolism in patients with liver or kidney impairment, drug interactions with hormonal and chemotherapeutic agents, and the risk of thrombocytopenia.
DOACs have fewer drug interactions compared to vitamin K antagonists, but the specific interactions between DOACs and certain chemotherapeutic agents are not well understood. Most of the information regarding DOAC interactions is based on theoretical considerations or small studies conducted on healthy individuals.
Risk stratification based on individual patient and tumor characteristics is vital for personalized therapy in AF and cancer patients . Recent recommendations highlight the importance of considering these factors in selecting anticoagulation regimens . The TBIP approach, used in VTE treatment, is also recommended for AF management.
Limited data exist on the use of ibrutinib in high-risk bleeding patients or those on anticoagulant or antiplatelet therapy. The cardiovascular protective effects of ibrutinib in vascular disease risk are uncertain. Caution should be exercised with certain medications, and alternative treatments should be considered if dual antiplatelet therapy is required. Concurrent use of ibrutinib and vitamin K antagonists should be avoided, while DOACs may be suitable for extended anticoagulation .
Future prospects include the development of novel anticoagulants like factor XI inhibitors, potentially offering alternative options for AF and cancer patients.
To summarize Prof. Tufano’s talk, the coexistence of CAT and AF poses challenges in managing antithrombotic therapy and can impact the prognosis of cancer patients. While LMWH and DOACs are approved for treating VTE in cancer patients, LMWH is not approved for AF, and managing vitamin k antagonists therapy in AF patients with cancer can be challenging. DOACs are a preferred option due to their practicality and lower bleeding risk. Personalized therapies and regular reassessment of patients’ conditions are crucial in optimizing treatment outcomes.
- Lyon, A.R., et al., 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). European Heart Journal, 2022. 43(41): p. 4229-4361.
- von Kemp, B., S. Halvorsen, and A. Nohria, The new 2022 ESC Guidelines on Cardio-oncology and their impact on the Acute Cardiovascular Care Society. Eur Heart J Acute Cardiovasc Care, 2022. 11(11): p. 844-849.
- Zamorano, J.L., et al., 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). European journal of heart failure, 2017. 19(1): p. 9-42.
- Siegal, D.M. and D.P. Leong, Evaluating Anticoagulant Strategies for Atrial Fibrillation in Patients With Cancer: Challenges and Opportunities. Cardio Oncology, 2022. 4(3): p. 351-353.
- Khorana, A.A., N. Mackman, and A. Falanga, Cancer-associated venous thromboembolism. 2022. 8(1): p. 11.
- Connors, J.M., Antidote for factor Xa anticoagulants. N Engl J Med, 2015. 373(25): p. 2471-2.
- Sabatino, J., et al., Direct oral anticoagulants in patients with active cancer: a systematic review and meta-analysis. Cardio Oncology, 2020. 2(3): p. 428-440.
- Falanga, A., et al., Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol, 2023. 34(5): p. 452-467.
- Malavasi, V.L., et al., Impact of malignancy on outcomes in European patients with atrial fibrillation: A report from the ESC‐EHRA EURObservational research programme in atrial fibrillation general long‐term registry. European journal of clinical investigation, 2022. 52(7): p. e13773.
- Cavallari, I., et al., Efficacy and Safety of Nonvitamin K Oral Anticoagulants in Patients with Atrial Fibrillation and Cancer: A Study-Level Meta-Analysis. Thromb Haemost, 2020. 120(2): p. 314-321.
- Potter, A.S., et al., Outcomes by Class of Anticoagulant Use for Nonvalvular Atrial Fibrillation in Patients With Active Cancer. JACC: CardioOncology, 2022. 4(3): p. 341-350.
- Delluc, A. and T.F. Wang, Anticoagulation of cancer patients with non-valvular atrial fibrillation receiving chemotherapy: Guidance from the SSC of the ISTH. 2019. 17(8): p. 1247-1252.
- Shatzel, J.J., et al., Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost, 2017. 15(5): p. 835-847.