Atrial fibrillation (AF) is common in patients with cancer, and up to one in every four persons with AF has comorbid cancer [1,2]. However, the causal relationship is still uncertain.
AF in cancer patients increases the risk of adverse cardiovascular events, including heart failure [3]. In addition, a new-onset AF in cancer patients could reflect a more advanced cancer stage and signify a poorer oncological prognosis [4].
Mechanisms for AF in cancer patients
A few mechanisms have been proposed to explain the onset of AF in cancer patients.
Cancer-related systemic inflammation could contribute to atrial remodeling. In addition, the disequilibrium of the autonomous nervous system due to pain and emotional and/or physical stress could play a role. Metabolic and electrolyte abnormalities, fluid imbalance (e.g., during chemotherapy), and infections could contribute to AF development [5].
Cancer therapies can increase the risk of AF. For example, doxorubicin impairs Ca2+ homeostasis in isolated cardiac myocytes and induces mitochondrial dysfunction through the production of mitochondrial reactive oxygen species [6,7].
Ibrutinib, a tyrosine kinase inhibitor, is another anticancer drug associated with AF. It can lead to AF in 6–16% of treated patients [8].
For all these mechanisms, cancer patients seem to be at higher risk of AF than the general population, even though no solid literature supports this relationship.
Large population studies highlighted a higher risk of AF in cancer patients. For example, patients with colorectal cancer have been found more likely to develop AF within 90 days after diagnosis than the general population (adjusted odds ratio: 12, 95% CI: 9.3–15) [9]. Furthermore, new-onset breast and colorectal cancer were especially associated with AF in the first 90 days after diagnosis (adjusted hazard ratio: 3.4, 95% CI: 2.1–5.6). However, patients with cancer are at a higher risk of AF in the long run, as suggested by a prospective study with a follow-up of 16.3 years [11].
AF and VTE in cancer patients
Patients with cancer also have an increased risk of developing venous thromboembolism (VTE) and major bleeding, especially once initiated the anticoagulation therapy. While specific scores are available to test the risk of VTE in cancer patients, the standardized risk models available for AF (CHA2DS2-VASC and HAS-BLED score) do not consider the presence of malignancy [5].
Moreover, international guidelines for AF do not include specific recommendations for risk stratification and choice of antithrombotic management in patients with AF and active cancer [5].
Interestingly, the same prothrombotic factors associated with a higher VTE risk in cancer patients are associated with a hypercoagulable state typical in patients with AF.
Patients with AF are characterized by abnormal concentrations of prothrombotic growth factors (like von Willebrand factor, tissue factor, and VEGF) in endocardial tissue and circulation. Many studies focused on the role of procoagulant microvesicles, platelet activation, and neutrophil extracellular traps too [5].
It is possible that cancer-related hypercoagulability exacerbates thrombogenesis in patients with AF as it does in patients with VTE through common pathways.
Oral anticoagulants, VTE and FA
Anticoagulant therapy is recommended to prevent the risk of VTE in cancer patients.
Oral anticoagulants (OACs; non-vitamin K antagonists and warfarin) are used to manage AF to prevent ischemic stroke. In addition, the 2021 European Heart Rhythm Association Practical Guide recommends the use of non-vitamin K antagonist in patients with AF [12].
The use of anticoagulant therapy in cancer patients is tricky for the higher risk of major bleeding.
A recent retrospective cohort study evaluated how active cancer influences the net cerebrovascular benefit and bleedings after initiation of OAC treatment in patients with AF [13]. All individuals diagnosed with AF between 1 January 2006 and 31 December 2017, were identified from the National Swedish Patient Register.
Active cancer was not associated with a statistically significant higher risk for cerebrovascular events. The cumulative incidences of patients with cerebrovascular events within the first year after OACs initiation were 2.7% (95% CI: 2.3–3.0%) and 2.3% (95% CI: 2.2–2.3%) in patients with cancer and patients without cancer, respectively.
Bleeding was instead higher in patients with cancer than patients without cancer after OAC initiation (8.6%, 95% CI: 8.0–9.2% and 4.3%, 95% CI: 4.2–4.4%, respectively) independently from the cancer site. In addition, gastrointestinal bleedings were more common among patients with gastrointestinal, urological, and hematological cancers.
Patients with brain tumors showed a higher risk of intracranial bleeding and did not benefit from OACs.
Finally, in line with the European Heart Rhythm Association Practical Guide, nonvitamin K antagonists seem to be a safer alternative than warfarin, regardless of cancer status, in cancer patients
In summary
This recent retrospective cohort study indicates that patients with AF and active cancer have a similar net cerebrovascular benefit of oral anticoagulants to patients with AF and without cancer. Patients with cancer have an increased overall risk of nonfatal bleedings, though.
Current evidence shows no reasons to deviate from current guidelines for managing AF in patients with cancer.
For patients with AF and cancer specifically, future studies can help to elucidate their long-term thromboembolic risk, considering patient-specific factors, such as cancer stage and cancer treatment. Moreover, more studies are needed to investigate the optimal anticoagulation therapy in patients with cancer and AF. It would be of great interest to develop specific risk assessment scores that include cancer.
References
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10. Saliba W, Rennert HS, Gronich N, Gruber SB, Rennert G. Association of atrial fibrillation and cancer: Analysis from two large population-based case-control studies. PLoS One. 2018;13(1):e0190324. Published 2018 Jan 11.
11. Kattelus H, Kesäniemi YA, Huikuri H, Ukkola O. Cancer increases the risk of atrial fibrillation during long-term follow-up (OPERA study). PLoS One. 2018;13(10):e0205454. Published 2018 Oct 5.
12. Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation [published online ahead of print, 2021 Apr 25]. Europace. 2021;euab065.
13. Atterman A, Friberg L, Asplund K, Engdahl J. Atrial Fibrillation, Oral Anticoagulants, and Concomitant Active Cancer: Benefits and Risks. TH Open. 2021;5(2):e176-e182.