Direct oral anticoagulants in the prevention of stroke in breast cancer patients with atrial fibrillation during adjuvant endocrine therapy: A cohort study
Introduction
Atrial fibrillation (AF) is the most common cardiac arrythmia with the prevalence of 3.2% in the adult population [1]. Among patients with malignant diseases, AF is observed even in 15–19% individuals [2,3]. Anticancer treatment, in particular chemotherapy and its side effects, renders the prevention of stroke and systemic thromboembolism with the recommended strategy, i.e. life-long oral anticoagulation in that patient group might be challenging [4,5]. Breast cancer is the leading cancer in women worldwide, with the age-adjusted annual incidence of new cases in Europe of 144.9/100000 in 2018 [6]. The prevalence of AF in newly-diagnosed breast cancer patients is estimated at around 2% [7]. Optimal preventive strategies in AF patients with breast cancer like in most other types of malignancy are unknown. Given the fact that nowadays, early breast cancer is a curable disease [8], stroke prevention in AF patients with this disease is of paramount importance.
Active malignancy was an exclusion criterion in most AF clinical trials with direct oral anticoagulants (DOACs) [[9], [10], [11]]. The efficacy and safety of DOACs compared with vitamin K antagonists (VKAs) have found to be similar or better in non-cancer patients with AF [[9], [10], [11]]. However, subjects during chemotherapy are prone to unstable anticoagulation with VKA with labile international normalized ratios [12]. Moreover, in these patients potent drug-drug interactions might be anticipated, which may increase bleeding risk [13]. No randomized clinical trials comparing the use of DOACs versus VKAs in cancer patients with AF have been performed until now. In the retrospective analysis of the ENGAGE-AF TIMI 48 study 5.5% of patients (n = 1153) developed new or recurrent malignancy after randomization (including 6.5% with breast cancer). Unfortunately, edoxaban in that group was referred to the higher risk of major bleeding and all-cause mortality comparing to non-cancer individuals [14]. In turn, subgroup analysis of the ARISTOTLE trial has demonstrated that apixaban might be as effective and safe as warfarin in 1236 cancer patients (6.8% of all), including those with active disease (n = 157, 12.7%) and breast cancer (11%) [15]. On the other hand, subgroup analysis of RE-LY trial has shown two- to six-times higher risk of bleeding in cancer patients in comparison to non-cancer individuals [16]. The type of cancer was not accurately reported in the majority of reported clinical trials [14,15]. Nevertheless, DOACs have been found to be as effective and safe as low-molecular-weight heparin (LMWH) in the treatment of venous thromboembolism in cancer patients [17].
It has been demonstrated that real-life cancer patients with AF are undertreated. Malavasi et al. [18] have reported that 23.9% of patients with AF associated with active cancer, with an unspecified number of breast cancer patients, had no prescription of anticoagulants and 35.3% of them were prescribed a prophylactic dose of LMWH with suboptimal protection against stroke. On the other hand, European Society of Cardiology guidelines and expert opinions do not distinguish different treatment modalities in cancer patients with AF but recommend interdisciplinary team approach [13,19].
Little is known about the real-life efficacy and safety of DOACs in breast cancer patients with AF [12,20,21]. Most small cohort studies reported similar thromboembolic and bleeding complications in breast cancer vs. non-cancer patients with AF. In the retrospective analysis breast cancer AF patients treated with rivaroxaban had similar bleeding and stroke risk as matched warfarin users and lower risk of VTE [21]. To our knowledge, there have been no published studies on the use of DOACs in breast cancer patients receiving hormonal therapy. Therefore, in the present study we sought to prospectively evaluate clinical outcomes in breast cancer females with AF during adjuvant hormonal therapy on long-term DOACs treatment.
Section snippets
Methods
In this cohort study we recruited 48 consecutive ambulatory female patients with breast cancer during adjuvant endocrine therapy and AF who were referred to our center for further work-up between 2015 and 2020. Before enrolment the patients were treated with radical intent according to the standard procedures [22] and were receiving hormonal therapy i.e. tamoxifen, aromatase inhibitors or sequential tamoxifen 2–3 years and afterwards aromatase inhibitors 2–3 years. The study protocol was
Statistical analysis
The results were analyzed using Statistica TIBCO 13.3 software (StatSoft, Tulsa, Oklahoma, United States). Continuous variables were checked for normal distribution by the Shapiro-Wilk test. Continuous variables were reported as median and interquartile range. Categorical variables were given as number (percentage). To investigate whether the continuous or categorical variables were related to the unfavorable clinical outcomes the U Mann-Whitney, Kruskal-Wallis, log-rank, and Chi-square tests
Patient characteristics
As shown in Table 1, the enrolled women were at a median age of 63 (interquartile range 56–69) years. All had a history of surgical therapy, followed by chemotherapy and radiotherapy in 65% and 71% of cases, respectively. The patients received adjuvant hormonal therapy at enrolment i.e. tamoxifen or aromatase inhibitors (50% of participants each). Amid the patients treated with aromatase inhibitors, 6 (25%) received previously tamoxifen as part of sequential treatment. AF was diagnosed after a
Discussion
In the present study we have demonstrated that DOACs are an effective and safe option for the anticoagulant treatment of patients with AF and breast cancer during adjuvant hormonal therapy. To our knowledge, this study is the largest published report presenting follow-up data on AF patients with breast cancer on DOACs.
Use of DOACs in our cohort was associated with acceptable risk of thrombotic and bleeding complications. We recorded 2 cerebrovascular thromboembolic episodes (1.3% per year) in
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This statement is to certify that all Authors have seen and approved the manuscript being submitted. We warrant that the article is the Authors' original work. We warrant that the article has not received prior publication and is not under consideration for publication elsewhere. On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. This research has not been submitted for publication nor has it been published in whole or in part elsewhere. We
Declaration of Competing Interest
We declare no conflict of interests.
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- 1
This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Equal senior-author contribution