Desenho de Estudo de um Estudo Observacional Brasileiro sobre o uso de Edoxabana em Pacientes com Fibrilação Atrial (EdoBRA) / Study Design of a Brazilian Observational Study of Edoxaban in Patients with Atrial Fibrillation (EdoBRA)

Resumo Fundamento: Os ensaios clínicos demonstraram a segurança da Edoxabana, um anticoagulante oral não dependente de vitamina K (NOAC), e a sua eficácia na prevenção de acidente vascular cerebral e embolia sistémica em pacientes com fibrilação atrial não valvar (FANV) e também na prevenção e tratamento de tromboembolismo venoso. No entanto, pesquisas adicionais são necessárias para avaliar a segurança e a eficácia da Edoxabana em um cenário real na população brasileira. Objetivo: A fim de compreender os riscos e benefícios do uso da Edoxabana em cenários clínicos de rotina, o estudo EdoBRA está sendo conduzido para obter informações sobre a segurança e eficácia do uso da Edoxabana em pacientes não pré-selecionados com FANV no Brasil. Métodos: O estudo EdoBRA é um estudo multicêntrico, prospectivo e observacional, realizado em 36 centros no Brasil. São elegíveis para este estudo pacientes com FANV, ≥ 18 anos de idade, tratados com Edoxabana disponível comercialmente, que iniciaram o tratamento por pelo menos 14 dias e não mais do que 90 dias antes da data de inclusão no estudo, e que não estão participando de nenhum outro estudo de intervenção. Ao todo, 700 pacientes devem ser inscritos e acompanhados por um ano, com coletas de dados programadas para o período basal e 3, 6 e 12 meses após a inscrição no estudo. O objetivo primário de segurança é o sangramento clinicamente relevante (de acordo com critérios da Sociedade Internacional de Trombose e Hemostasia - ISTH), e o objetivo secundário de eficácia são desfechos cardiovasculares relevantes relacionados à FANV. Conclusão: O estudo observacional EdoBRA gerará informações adicionais relevantes sobre a Edoxabana enquanto NOAC em diversos aspectos do manejo de pacientes no atendimento clínico de rotina, como perfil de segurança e efetividade em pacientes com FANV no Brasil.

Abstract Background: Clinical trials showed the safety of Edoxaban, a non-vitamin K-dependent oral anticoagulant (NOAC), and its efficacy to prevent stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients and also to prevent and treat venous thromboembolism. However, additional research is needed to evaluate the safety and effectiveness of Edoxaban in a real-world scenario in the Brazilian population. Objective: In order to understand the risks and benefits of Edoxaban use in routine clinical settings, the EdoBRA study is being conducted to gain insight into the safety and effectiveness of Edoxaban use in non-preselected patients with NVAF in Brazil. Methods: The EdoBRA study is a multicenter, prospective, observational study conducted in 36 sites in Brazil. NVAF patients ≥ 18 years treated with commercially available Edoxaban who initiated treatment for at least 14 days and no longer than 90 days prior to enrollment, and who are not simultaneously participating in any interventional study are eligible for this study. Seven hundred patients are planned to be enrolled and one-year of follow up, with data collections expected at baseline and 3, 6, and 12 months after the study enrollment. The primary safety objective is ISTH Clinically Relevant Bleeding, and the secondary effectiveness objective focuses on relevant cardiovascular outcomes related to NVAF. Conclusion: EdoBRA observational study will generate relevant additional information about NOAC Edoxaban on various aspects of patient management in routine care, such as its safety and effectiveness profile in patients with NVAF in Brazil.

Direct Oral FXa Inhibitors Binding to Human Serum Albumin: Spectroscopic, Calorimetric, and Computational Studies.

Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research area and provides crucial information about drugs' pharmacokinetics and pharmacodynamic properties. This research focuses on the study of the interactions between HSA and four commercially available direct oral FXa inhibitors, applying methodologies including steady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and molecular dynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and the complex formation in the ground states affects the fluorescence of HSA, with a moderate binding constant of 104 M-1. However, the ITC studies reported significantly different binding constants (103 M-1) compared with the results obtained through spectrophotometric methods. The suspected binding mode is supported by molecular dynamics simulations, where the predominant interactions were hydrogen bonds and hydrophobic interactions (mainly π-π stacking interactions between the phenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications of the obtained results regarding pathologies such as hypoalbuminemia are briefly discussed.

Development and validation of capillary zone electrophoresis and high-performance liquid chromatography methods for the determination of oral anticoagulant edoxaban in pharmaceutical tablets.

The incidence of thrombotic complications in SARS-CoV-2 infections has become a global concern; thus, anticoagulants are an integral part of the treatment. Edoxaban (EDX) is an oral anticoagulant suitable for pharmacologic thromboprophylaxis. Herein, two novel analytical methods for EDX determination in tablets are developed and validated using capillary zone electrophoresis (CZE) and high-performance liquid chromatography (HPLC). Operating conditions such as the electrolyte's concentration and pH value, injection time, volume, and the capillary temperature, were optimized. The methods were successfully validated by establishing the linearity, intra- and inter-day precisions (relative standard deviation [%]), accuracy, and robustness. Adequate separation of excipients and degradation products of EDX generated by stress degradation conditions demonstrated the stability-indicating capability of the methods. The analytical procedures were linear in the range of 25-125 µg/ml (r > 0.999), with the limits of detection and quantification of 3.26 and 10.87 µg/ml for CZE and 0.740 and 2.78 µg/ml for HPLC. Although both methodologies are suitable for determining EDX in tablets, CZE provides a greener alternative due to low-cost analysis using less organic solvents and minimizing waste generation.

Obesity Paradox in Atrial Fibrillation and its Relation with the New Oral Anticoagulants.

Obesity, a chronic disease established as a global epidemic by the World Health Organization, is considered a risk factor for atrial fibrillation (AF), the most common sustained cardiac arrhythmia, which has high morbidity and mortality. Although both obesity and AF are diseases associated with negative outcomes, studies have shown the presence of an obesity paradox, in which patients with a high body mass index (BMI) and AF have a better prognosis than patients with a normal BMI. Despite the fact that the mechanisms that lead to this paradox are still uncertain, adequate anticoagulation in obese patients seems to play an important role in reducing adverse events in this group. In this perspective article, the authors discuss the relationship between new oral anticoagulants (NOACs), namely, apixaban, edoxaban and rivaroxaban (factor Xa inhibitors) and dabigatran (direct inhibitor of thrombin), and the obesity paradox, seeking to deepen the understanding of the mechanism that leads to this paradox.

Biopharmaceutics considerations for direct oral anticoagulants.

Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) have been clinically used in the treatment of coagulation disorders. There are four DOACs approved since 2010 (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban), and they were designed to overcome the practical limitations of VKA. This review summarized biopharmaceutics considerations about DOACs, which are critically discussed, applying risk analyses to subside the further classification of these drugs according to the Biopharmaceutics Classification System (BCS). These discussions included data compiled about physicochemical properties, equilibrium solubility, permeability, and drug dissolution of DOACs. From the biopharmaceutics characteristics is possible to identify critical variables related to the absorption process, which can help in the design of new formulations. The data were compared with the criteria recommended by regulatory agencies for the biopharmaceutics classification according to the BCS. From that, these data may be used to discuss the approval of generic medicines by the BCS-based biowaiver, and the clinical risks arising from novel formulations with DOACs. However, although there are indications of biopharmaceutics classifications for DOACs, conclusive information to classify these compounds according to the BCS is lacking, requiring more experimental studies to achieve this aim. Conclusive information is essential for a safe decision about the biowaiver, as well as to guide the development of new formulations containing the DOACs.

Problemas Relacionados à Trombocitopenia em Pacientes com Fibrilação Atrial Concomitante que Necessitam de Prevenção Antitrombótica: Um Estudo de Coorte Retrospectivo / Thrombocytopenia-Related Problems in Patients with Concomitant Atrial Fibrillation Requiring Antithrombotic Prevention: A Retrospective Cohort Study

Resumo Baixas doses de edoxabana e enoxaparina sódica foram objeto de uma comparação retrospectiva implementada com a técnica do escore de propensão a fim de mitigar os efeitos das diferenças nas características clínicas basais de duas coortes e minimizar o risco de viés. Posteriormente, usando um modelo de riscos proporcionais de Cox, avaliou-se a associação de cada tipo de terapia com o risco do composto de morte por todas as causas, acidente vascular cerebral/ataque isquêmico transitório, hospitalizações e ocorrência de sangramentos maiores. Para essa análise, um valor de p < 0,05 foi considerado estatisticamente significante. A terapia com enoxaparina e cirrose hepática como causadora de trombocitopenia estiveram associadas ao aumento do risco do endpoint composto (enoxaparina: hazard ratio (HR): 3,31; IC 95%: 1,54 a 7,13; p = 0,0023; cirrose hepática, HR: 1,04; 95% CI: 1,002 a 1,089; p = 0,0410). Por outro lado, a terapia com edoxabana mostrou-se significativamente associada à diminuição do risco do endpoint composto (HR: 0,071; 95% CI: 0,013 a 0,373; p = 0,0019). Com base nessa análise retrospectiva, o edoxaban em doses baixas seria uma ferramenta farmacológica segura e eficaz para a profilaxia de eventos cardioembólicos em pacientes com FA e trombocitopenia.

Abstract Low-dose edoxaban and enoxaparin sodium have been the subject of a retrospective comparison implemented with the propensity score technique in order to mitigate the effects of the differences in the basal clinical features of two cohorts and minimize the risk of bias. Subsequently, using a Cox proportional-hazards model, the association of each type of therapy with the risk of the composite of all-cause death, stroke/transient ischemic attack, hospitalizations and major bleeding events was assessed. For this analysis, a p-value < 0.05 was considered statistically significant. Therapy with enoxaparin and liver cirrhosis as causing thrombocytopenia were associated with increased risk of the composite endpoint (enoxaparin: hazard ratio (HR): 3.31; 95% CI: 1.54 to 7.13; p = 0.0023; liver cirrhosis, HR: 1.04; 95% CI: 1.002 to 1.089; p = 0.0410). Conversely, edoxaban therapy was significantly associated with decreased risk of the composite endpoint (HR: 0.071; 95% CI: 0.013 to 0.373; p = 0.0019). Based on this retrospective analysis, edoxaban at low doses would appear as an effective and safe pharmacological tool for the prophylaxis of cardioembolic events in patients with AF and thrombocytopenia.

Cost-effectiveness of edoxaban vs low-molecular-weight heparin and warfarin for cancer-associated thrombosis in Brazil.

BACKGROUND: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. In Brazil, even though low-molecular-weight heparin (LMWH) is the gold standard of care for the management of cancer-associated thrombosis (CAT), its cost limits its use and therefore warfarin is commonly prescribed. Direct oral anticoagulants (DOACs), such as edoxaban, have been introduced as an alternative in this setting. OBJECTIVE: The aim of this study was to compare the cost-effectiveness of edoxaban with LMWH (Model 1) and warfarin (Model 2) to support clinicians and hospitals when choosing an anticoagulant to manage CAT. MATERIALS AND METHODS: Cost-effectiveness analyses were performed using Markov state-transition models over a timeframe of 5 years, in a hypothetical, 64 years-old patients cancer population with an index VTE event. Transition probabilities, costs, quality-adjusted life years (QALYs) and risk reductions were either derived from the literature, estimated or calculated. A willingness-to-pay limit of 3 Gross Domestic Product (GDP) per head was used. Deterministic and probabilistic sensitivity analyses were performed for robustness. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained. RESULTS: Model 1 base case analysis demonstrated dominance of edoxaban compared to LMWH, with an ICER of $5204.46, representing cost saved per QALY lost. In Model 2, edoxaban was associated with a $736.90 cost increase vs. warfarin, with an ICER of $2541.03. Sensitivity analyses confirmed base-case results. CONCLUSION: Edoxaban represents a cost-saving alternative to LMWH for the management of CAT and is cost-effective vs. warfarin.

Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology position statement on the use of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS).

BACKGROUND: The term Direct Oral Anticoagulants (DOACs) refers to a group of drugs that inhibit factor Xa or thrombin. Even though their use for treating different thrombotic or prothrombotic conditions is increasing recently, there is no compelling evidence indicating that those medications are safe in all antiphospholipid syndrome (APS) patients. METHODOLOGY: To address this issue, specialists from the Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology performed a comprehensive review of the literature regarding DOACs use in APS to answer the three following questions: (1) potential mechanisms of action of these drugs that could be relevant to APS pathogenesis, (2) DOACs interference on lupus anticoagulant testing, and (3) the efficacy of DOACs in APS. POSITION STATEMENT: After critically reviewing the relevant evidence, the authors formulated 8 Position Statements about DOACs use in APS. CONCLUSION: DOACs should not be routinely used in APS patients, especially in those with a high-risk profile (triple positivity to aPL, arterial thrombosis, and recurrent thrombotic events). In addition, DOACs interferes with LA testing, leading to false-positive results in patients investigating APS.

Efficacy and safety of edoxaban compared with warfarin according to the burden of diseases in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 trial.

AIMS: Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs. METHODS AND RESULTS: In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen, or warfarin. We used the updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI = 0, 1, 2, 3, and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories. There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI = 0 (P < 0.05 for each). The annualized rates of the primary net clinical outcome (stroke/systemic embolism, major bleeding, or death) for CCI = 0, 1, 2, 3, or ≥4 were 5.9%, 8.7%, 6.6%, 10.3%, and 13.6% (Ptrend < 0.001). There were no significant interactions between treatment with HDER vs. warfarin and efficacy, safety, and net outcomes across the CCI groups (P-interaction > 0.10 for each). CONCLUSION: Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs. warfarin were independent of the degree of comorbidity present.

Edoxaban for Venous Thromboembolism Treatment-The New Kid on The Block for Latin America. A Practical Guide.

Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use in the treatment of venous thromboembolism (VTE) in Latin America, following global approvals for this indication. Edoxaban features some particular characteristics when compared to the previously approved DOACs. This review summarizes the main properties of edoxaban, the outcomes results of its pivotal global clinical trials and the peculiar clinical features of this compound. This practical guide aims to help Latin America clinicians understand edoxaban, its proper indication and its use for the appropriate patients with VTE.

Avaliação da efetividade e segurança dos novos anticoagulantes orais comparados à enoxaparina na prevenção de tromboembolismo venoso em pacientes submetidos à cirurgia eletiva de artroplastia de joelho ou quadril / Avaliação da efetividade e segurança dos novos anticoagulantes orais comparados à enoxaparina na prevenção de tromboembolismo venoso em pacientes submetidos à cirurgia eletiva de artroplastia de joelho ou quadril

Novos anticoagulantes orais (NACOs) surgiram no mercado com indicação para prevenção do tromboembolismo venoso em pacientes submetidos à cirurgia de artroplastia de joelho ou quadril. Os NACOs atuam na cascata de coagulação como inibidores do fator Xa e como inibidores diretos da trombina. O objetivo do presente trabalho foi avaliar a efetividade e segurança dos NACOs (apixabana, dabigatrana, edoxabana e rivaroxabana) para prevenção do tromboembolismo venoso em cirurgias de artroplastia de joelho ou de quadril. A comparação foi baseada em tratamento convencional utilizando a enoxaparina, uma heparina de baixo peso molecular. O estudo foi realizado através de revisão sistemática com metanálise, considerando estudos de fases 2 e 3 que se referiram à eficácia e a segurança dos NACOs, avaliando-se os desfechos embolia pulmonar (EP), trombose venosa profunda sintomática (TVPS), trombose venosa profunda assintomática (TVPA), sangramento maior e sangramento menor clinicamente relevante. Os resultados obtidos indicaram que não houve diferença estatística significativa entre a prevenção realizada com os NACOs e a enoxaparina para os desfechos EP, TVPS, sangramento maior e sangramento menor clinicamente relevante. Por outro lado, para o desfecho TVPA houve diferença significativa entre o grupo intervenção e o grupo controle, favorecendo o tratamento com os NACOs, embora este resultado pareça ter sido motivado pelo resultado favorável para a edoxabana. Sendo assim, os NACOs parecem pelo menos igualmente eficazes em relação ao tratamento convencional com enoxaparina para prevenção de tromboembolismo venoso em pacientes submetidos à artroplastia de quadril e de joelho, para os desfechos analisados. Esses resultados apoiam o uso dos NACOs por serem menos invasivos na forma de administração em relação à enoxaparina, aplicada por via subcutânea, mas não são decisivos para sua indicação.

New oral anticoagulants (NOACs) have appeared in the market with indication for the prevention of venous thromboembolism in patients submitted to knee or hip arthroplasty surgery. NOACs act in the coagulation cascade as factor Xa inhibitors and as direct thrombin inhibitors. The aim of the present study was to evaluate the effectiveness and safety of NOACs (apixaban, dabigatran, edoxaban and rivaroxaban) for the prevention of venous thromboembolism in knee or hip arthroplasty surgeries. The comparison was based on standard treatment using enoxaparin, a low molecular weight heparin. The study was performed through a systematic review with meta-analysis, considering phase 2 and 3 studies that referred to the efficacy and safety of NOACs, evaluating the outcomes pulmonary embolism (PE), symptomatic deep vein thrombosis (SDVT), asymptomatic venous thrombosis (AVT), major bleeding, and clinically relevant minor bleeding. The results indicated that there was no statistically significant difference between the prevention of NOACs and enoxaparin for the outcomes PE, SDVT, major bleeding and clinically relevant minor bleeding. On the other hand, for the AVT outcome there was a significant difference between the intervention group and the control group, favoring the treatment with the NOACs, although this result seems to have been motivated by the favorable outcome for the edoxaban. Thus, NOACs appear at least as effective compared to conventional enoxaparin treatment for the prevention of venous thromboembolism in patients undergoing hip and knee arthroplasty for the outcomes analyzed. These results support the use of NOACs because they are less invasive in the form of administration with respect to enoxaparin, applied subcutaneously, but are not decisive for their indication.