Elsevier

International Journal of Cardiology

Volume 324, 1 February 2021, Pages 78-83
International Journal of Cardiology

Direct oral anticoagulants in the prevention of stroke in breast cancer patients with atrial fibrillation during adjuvant endocrine therapy: A cohort study

https://doi.org/10.1016/j.ijcard.2020.09.037Get rights and content

Highlights

  • A•

    There have been no published studies on the use of direct oral anticoagulants in breast cancer patients receiving hormonal therapy.

  • In our study the frequency of unfavorable clinical events was similar to those reported in large clinical trials.

  • Direct oral anticoagulants are safe and effective in long-term therapy of breast cancer women with atrial fibrillation during adjuvant hormonal therapy.

Abstract

Background

Atrial fibrillation (AF) is a frequent comorbidity in malignant patients. Anticancer therapies complicate anticoagulant strategy. We evaluated the safety and efficacy of long-term use of direct oral anticoagulants (DOACs) in breast cancer women.

Methods

In a prospective cohort study we enrolled 48 consecutive radically treated breast cancer women with AF (median age 63 [interquartile range 56–69] years, CHA2DS2–VASc 2 [2,3]) score) and adjuvant hormonal therapy. Thromboembolic complications (stroke, transient ischemic attack [TIA], venous thromboembolism [VTE]) and bleeding events (major and clinically relevant non-major bleeding [CRNMB]) were recorded in follow-up.

Results

During a median follow-up of 40 (interquartile range 28–50.5) months 13 (27%) patients received apixaban, 22 (46%) rivaroxaban, and 13 (27%) dabigatran. One stroke (2.3%/year) and two CRNMBs (4.6%/year) were observed on apixaban. One TIA (1.3%/year), three major bleedings and two CRNMBs (6.7%/year, combined) were reported on rivaroxaban. Three VTE were documented in dabigatran treated individuals (7.8%/year), without any bleeding or cerebrovascular events. Women with thromboembolic events had higher body mass index (32 [29–33]) vs. 26 [24–29]) kg/m2, p = 0.02) and CHA2DS2–VASc score (3 [3]) vs. 2 [1–3]), p = 0.02). Most thromboembolic complications (n = 4, 80%) and all three major bleedings were observed in tamoxifen users, while three of four CRNMBs occurred on aromatase inhibitors. Mortality rates were low (apixaban, n = 1 [2.3%/year], rivaroxaban, n = 3 [5.22%/ year], and dabigatran, n = 2 [4%/ year]). No death was related to bleeding.

Conclusions

This study suggests that DOACs are an effective and safe therapeutic option in breast cancer patients with AF during adjuvant hormonal therapy.

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

Author agreement form

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.

References (45)

  • G. Chu et al.

    Atrial fibrillation and cancer – An unexplored field in cardiovascular oncology

    Blood Rev.

    (2019)
  • M.C. Vedovati et al.

    Patients with cancer and atrial fibrillation treated with doacs: a prospective cohort study

    Int. J. Cardiol.

    (2018)
  • F. Cardoso et al.

    Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up

    Ann. Oncol.

    (2019)
  • V.P. Shah et al.

    Tamoxifen promotes superoxide production in platelets by activation of PI3-Kinase and NADPH oxidase pathways

    Thromb. Res.

    (2012)
  • S. Björck et al.

    Atrial fibrillation, stroke risk, and warfarin therapy revisited

    Stroke.

    (2013)
  • H. Huikuri et al.

    Cancer increases the risk of atrial fibrillation during long-term follow-up (OPERA study)

    PLoS One

    (2018)
  • W.T.O. Neal et al.

    Relation between cancer and atrial fibrillation (from the REasons for geographic and racial differences in stroke study)

    Am. J. Cardiol.

    (2015)
  • A. Undas et al.

    Bleeding in anticoagulated patients with atrial fibrillation : practical considerations

    Pol Arch Intern Med.

    (2020)
  • Https://ecis.jrc.ec.europa., ECIS—European Cancer Information System,...
  • S. Guzzetti et al.

    First diagnosis of colorectal or breast cancer and prevalence of atrial fibrillation

    Intern. Emerg. Med.

    (2008)
  • C.G.M. Malvezzi et al.

    Trends and predictions to 2020 in breast cancer mortality in Europe

    (2017)
  • C.B. Granger et al.

    Apixaban versus warfarin in patients with atrial fibrillation

    N. Engl. J. Med.

    (2011)
  • Cited by (9)

    View all citing articles on Scopus
    1

    This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation

    2

    Equal senior-author contribution

    View full text