Edoxaban Vs. Low Molecular Weight Heparin As Anticoagulant Therapy in Hospitalized Patients with Atrial Fibrillation and COVID-19 Infection

Abstract

Background During SARS-CoV-2 pandemic, the anticoagulant management in patients with atrial fibrillation (AF) was simplified to the use of low molecular weight heparin (LMWH) in different international guidelines. These recommendations were based for the possible drug interactions between oral anticoagulants and the experimental coronavirus disease 2019 (COVID-19) therapies. However, not all direct oral anticoagulants (DOACs) have the same risk of drug-drug interactions. The metabolism of edoxaban by CYP3A4 is less than 4% being one of the DOACs that poses less of drug-drug interactions risk with the therapy used against the COVID-19 (http://www.covid19-druginteractions.org/). Unfortunately, the current information about the use of DOACs in hospitalized patients with COVID-19 infection is very scarce. Objective To determine whether the effectiveness (major thromboembolic events) and safety (bleedings) of edoxaban or low molecular weight heparin (LMWH) were different among patients with AF that had been hospitalized for COVID-19 infection in Catalonia, Spain. Methods Observational and multicenter study with a retrospective analysis that consecutively included from March 5th to April 27st 2020 hospitalized patients with the diagnosis of non-valvular AF who received anticoagulant treatment with LMWH or edoxaban concomitantly with the empirical therapy used for COVID-19 infection. The initiation or continuation of anticoagulant treatment with edoxaban was performed according to medical criteria and with close monitoring for possible interactions. The use of LMWH was carried out with therapeutic and intermediate doses. The minimum follow-up was 30 days or until death. Thromboembolic events, hemorrhagic events, length of hospitalization and death from all causes were analyzed. Clinical and analytical factors were compared between both cohorts. Results A total of 232 patients (mean age 80.3±7.7 years, 50.0% men, CHA2DS2-VASc 4.1±1.4; HAS-BLED 2.6±1.0) were included. Regarding treatment for COVID-19 during hospitalization, the majority of patients were taking azithromycin (98.7%), hydroxychloroquine (89.7%) and ritonavir/lopinavir (81.5%). The biodemographic, analytical characteristics are summarized in the table 1. With regard to outcomes, mean duration of hospitalization was 14.6±7.2 days and mean total time of follow-up (since admission to last visit) was 31.6±13.4 days. 12.9% of patients required admission in the intensive care unit, 18.5% of patients died and 9.9% had a bleeding complication (34.8% major bleeding). Whereas peak mean D-dimer was higher in those patients taking LMWH (1691.7±2240.8 vs 3249.4±5146.3 µg/L; P=0.003). Except for the duration of hospitalization that was longer in those patients taking LMWH (13.3±6.5 vs 16.0±7.7 days; P=0.005), the rest of outcomes similarly occurred in patients treated with edoxaban or LMWH (Table 1). Conclusions Approximately one out of 5 hospitalized COVID-19 patients with AF anticoagulated with edoxaban or LMWH died and one out of 10 presented a bleeding complication. Mortality rates, arterial and venous thromboembolic complications and bleedings did not significantly differ between groups. However, the duration of hospitalization was significantly lower with edoxaban. In our clinical practice, edoxaban had a similar therapeutic profile to LMWH and may provide additional benefit. Further studies are needed to determine whether the possible interaction between edoxaban and the antiviral treatment used empirically for COVID-19 is clinically relevant. Disclosures Olivera: Boehringer Ingelheim: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BAYER: Consultancy; Daiichi Sankyo: Consultancy, Speakers Bureau. Campoy:boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cerezo:Daiichi Sankyo: Consultancy, Speakers Bureau.

Efficacy and Safety of Direct Oral Anticoagulants Compared With Heparin for Preventing Thromboembolism in Hospitalized Patients With COVID-19: A Systematic Review and Meta-Analysis

“…A total of 1360 hospitalized patients with COVID-19 (composing 5 trials) were enrolled in the meta-analysis, and the majority of them were in mild to moderate condition. Among the trials, 2 studies 19 , 22 were retrospectively performed, and 3 studies 20 , 21 , 23 were RCTs. They were carried out in 5 different countries, namely, Spain, India, Brazil, the USA and Egypt.…”

“…Four studies 19 , 21 – 23 consisting of 1132 patients were included, and 148 patients died during these trials. The mean mortality rates in the DOAC group and heparin group were approximately 13.0% and 13.1%, respectively.…”

“…After thoroughly reading the full text of the remaining 13 studies, 8 studies (including those with an inappropriate design, with unavailable data or without heparin as a control group) were subsequently excluded. Finally, 5 published studies [19][20][21][22][23] fulfilled the inclusion criteria for the meta-analysis. Figure 1 illustrates the strategy and algorithm for study selection.…”

“…Five studies [19][20][21][22][23] including 1360 patients were included in the analysis. Among these patients, 108 individuals experienced thromboembolic events: 41 in the DOAC group and 67 in the heparin group.…”

“…Five studies [19][20][21][22][23] reported the incidence of bleeding, including major and clinically relevant nonmajor bleeding, after preventive treatment of anticoagulation in hospitalized patients with COVID-19. The percentage of bleeding events in the DOAC group ranged from 0.9% to 8.0%, and that in the heparin group ranged from 2.0% to 52.9%.…”