Atrial fibrillation (AF) is the most common type of cardiac arrhythmia worldwide. It causes a significant burden to patients, physicians, and the health care system owing to its high morbidity and mortality, including heart failure, death, thromboembolism (e.g., ischemic stroke and systemic emboli), and subsequent anticoagulation-related bleeding events [1, 2, 3, 4]. AF is prevalent in patients with cancer and may be present during anticancer treatment, at the time of diagnosis, or even a period of time after cancer therapy [1]. However, the mechanisms underlying the association between cancer and AF remain unclear [5].

Cancers are associated with an increased risk of thromboembolism due to multiple risk factors, such as hypercoagulability, overproduction of inflammatory cytokines, and compression or invasion of blood vessels [6, 7]. However, patients with active cancers are also at higher risk of bleeding, possibly due to endothelial dysfunction, thrombocytopenia, or thrombocyte dysfunction, especially during anticancer therapies [5]. These opposing characteristics challenge the clinician on how to best manage the hypercoagulable state without causing major bleeding.

Currently, there is no consensus on the use of oral anticoagulants (OACs) to prevent thromboembolism in patients with active cancer and AF. Additionally, it is indicated that the popular AF risk-stratification models, namely, the CHA₂DS₂-VASc and HAS-BLED scores, may not be appropriate for cancer patients with AF to predict the risk of AF-related thromboembolism and OAC-related major bleeding events, respectively [8, 9]. Therefore, this retrospective cohort study was conducted to verify the applicability of the CHA${}_2$DS${}_2$-VASc score and to assess the efficacy and safety outcomes of OAC therapy in active-cancer patients with AF.

A total of 2429 patients with active cancer were enrolled in this study. There were 1060 patients (age, 75.2 $\pm$ 10.6 years; female, 40.8%) with AF (Table 1). Only 326 cancer patients (30.8%) with AF received OACs. The baseline characteristics of this cohort are summarized in Table 1. However, there were several significantly different variables between patients with and without OAC; therefore, propensity score matching was conducted for further analysis. Ultimately, 690 cancer patients with AF were enrolled in the analysis, comprising 225 patients taking OACs and 465 patients without OAC treatment. The top five cancer diagnoses were colorectal cancer (17%), hepatocellular cancer (15%), lung cancer (15%), genitourinary cancer (10%), and oral cancer (6%) (Table 2 and Fig. 2).

Fig. 2.

Distribution of cancer diagnoses.

The median follow-up duration was 3.2 (interquartile range, 1.6–5.1) years. Both groups had high CHA${}_2$DS${}_2$-VASc scores. Compared to cancer-and-AF patients without OAC treatment, OAC-treated cancer-and-AF patients had a better prognosis, with lower all-cause mortality (OAC-treated vs. no OAC: 24.4% vs. 37.4%, HR 1.84 [95% CI 0.43–0.78], p 0.001, Table 3). However, the incidence rate of stroke/TIA and SE between the OAC-treated group and no OAC group was not different (OAC-treated vs. no OAC: 8.4% vs. 4.7%, HR 0.58 [95% CI 0.99–3.4], p = 0.06, Table 2). Additionally, the difference in the incidence of either AMI or HF hospitalization between the 2 groups (Table 3) was not significant, either.

The risk of major bleeding composition (major GI bleeding and ICH) was similar between the two groups (OAC-treated vs. no OAC: 3.6% vs. 4.3%, HR 0.82 [95% CI 0.34–1.83], p = 0.64, Table 3). Neither major GI bleeding nor ICH risk was significantly different between the two groups (Table 3).

Finally, stroke/TIA and SE events were identified in the nontreated group. The CHA${}_2$DS${}_2$-VASc score was calculated for all patients with cancer and for AF patients without OAC treatment. Stroke/TIA and SE were most prevalent among patients with CHA${}_2$DS${}_2$-VASc scores of 3 to 5. The risks did not increase as the scores increased (Table 4).

This study revealed that compared to the active cancer and AF patients without taking OACs, those active cancer and AF patients with OAC treatment did not have lower risk of stroke/TIA and SE. However, these OAC-treated cancer patients with AF had lower all-cause mortality rate. Furthermore, OAC treatment did not increase the risk of major bleeding, such as major gastrointestinal bleeding and ICH.

Given improvements in cancer treatment, the survival rate of cancer patients has increased. The coexistence of cancer and AF is becoming increasingly prevalent, and clinicians are likely to encounter an increasing number of patients with comorbid conditions. The increased risk of thromboembolism and bleeding challenges clinicians in deciding whether to initiate anticoagulation and how to choose an anticoagulant. Nevertheless, there are no guidelines or recommendations for the treatment of this high-risk population. The 2020 European Society of Cardiology guidelines for AF recommended a multidisciplinary team to make decisions regarding thromboprophylaxis in cancer patients because these patients may have multiple comorbidities, such as renal failure, hepatic failure, thrombocytopenia, obesity, or cachexia, and drug–drug interactions between OACs and cancer therapy regimens [4]. Several observational studies investigated the efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonist (warfarin) in patients with active cancer and AF and showed the efficacy and safety of OACs [10, 11, 12, 13]. Major trials regarding stroke prevention for patients with atrial fibrillation carried subgroup analyses. In ARISTOLTE, ROCKET AF, and ENGAGE AF-TIMI 48 trials, the relative efficacy and safety of DOACs compared with warfarin were not significantly different in patients with and without active cancer [10, 11, 14]. However, current existing data have focused on efficacy and safety in the comparison of different OAC treatments in patients with active cancer and AF [11]. The efficacy and safety of using OAC treatment are left to be explored. Moreover, the prescription of OACs is often hindered by the fear of bleeding in our current practice.

Regarding bleeding tendency, the OAC subgroup did not show a significant increase in the risk of GI bleeding and ICH compared to that in AF cancer patients without OAC. The results may be associated with a lack of data to stratify indications and dosage of OACs, site(s) or complexity of cancer, and most importantly, a previous history of bleeding events. The OAC subgroup may have been in better condition, regardless of the comorbidities.

OAC treatment may significantly reduce the risk of death, without safety concerns, in active-cancer patients with AF. Further studies are required to determine the optimal use of anticoagulation therapy in this high-risk population.

Conceptualization—LYY, YWL and PYL; methodology—LYY, YWL and PYL; software—YCL and TYC; validation—YWL, PFS and PYL; formal analysis—LYY, YCL and PFS; investigation—YWL; resources—PYL; data curation—YWL and PYL; writing—original draft preparation—LYY; writing—review and editing—YWL and PYL; visualization—YWL; supervision—PYL; project administration—PYL; funding acquisition—PYL. All authors have read and agreed to the published version of the manuscript.

This study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the NCKUH Human Research and Ethics Committee (IRB: B-ER-111-052). Because this was a retrospective study and all data were fully anonymized, the Human Research and Ethics Committee of the National Cheng Kung University Hospital waived the requirement for informed consent.

Not applicable.

This study was supported by a research grant from the National Health Research Institutes (NHRI-111A1-CACO-02222211).

The authors declare no conflict of interest. Yen-Wen Liu is serving as one of the Guest Editors of this journal. We declare that Yen-Wen Liu had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Buddhadeb Dawn.