The timing of pericardial drainage catheter removal and restart of the anticoagulation in patients suffered from perioperative pericardial tamponade during atrial fibrillation catheter ablation and uninterrupted dabigatran: Experiences from 20 cases / 中华心血管病杂志

Objective: To investigate the timing of pericardial drainage catheter removal and restart of the anticoagulation in patients with atrial fibrillation (AF) suffered from perioperative pericardial tamponade during atrial fibrillation catheter ablation and uninterrupted dabigatran. Methods: A total of 20 patients with pericardial tamponade, who underwent AF catheter ablation with uninterrupted dabigatran in Beijing Anzhen Hospital from January 2019 to August 2021, were included in this retrospective analysis. The clinical characteristics of enrolled patients, information of catheter ablation procedures, pericardial tamponade management, perioperative complications, the timing of pericardial drainage catheter removal and restart of anticoagulation were analyzed. Results: All patients underwent pericardiocentesis and pericardial effusion drainage was successful in all patients. The average drainage volume was (427.8±527.4) ml. Seven cases were treated with idarucizumab, of which 1 patient received surgical repair. The average timing of pericardial drainage catheter removal and restart of anticoagulation in 19 patients without surgical repair was (1.4±0.7) and (0.8±0.4) days, respectively. No new bleeding, embolism and death were reported during hospitalization and within 30 days following hospital discharge. Time of removal of pericardial drainage catheter, restart of anticoagulation and hospital stay were similar between patients treated with idarucizumab or not. Conclusion: It is safe and reasonable to remove pericardial drainage catheter and restart anticoagulation as soon as possible during catheter ablation of atrial fibrillation with uninterrupted dabigatran independent of the idarucizumab use or not in case of confirmed hemostasis.

Estudio retrospectivo comparativo entre aspirina y dabigatrán en la incidencia de efectos tromboembólicos en pacientes con artroplastia de cadera y rodilla / Comparative retrospective study between aspirin and dabigatran in the incidence of thromboembolic events in hip and knee arthroplasty

Objetivo: Analizar la incidencia de eventos tromboembólicos extrahospitalarios luego de un reemplazo total de rodilla o cadera primario en los primeros 90 días posoperatorios, utilizando como tromboprofilaxis ácido acetilsalicílico o dabigatrán. El objetivo secundario fue evaluar el costo de la terapia antiagregante y de la anticoagulante. Materiales y Métodos: Se realizó un estudio observacional retrospectivo en el posoperatorio de reemplazos totales de cadera y rodilla primarios sobre la incidencia de eventos tromboembólicos extrahospitalarios, durante los primeros 90 días posteriores a la cirugía, en dos grupos. Se administró ácido acetilsalicílico (325 mg/día) o dabigatrán (150-220 mg/día) por 35 días. Resultados: La serie incluyó a 224 pacientes (media de la edad 68.5 años), el 44,2% eran hombres. El 51,3% era un reemplazo total de cadera. El 64,3% continuó la tromboprofilaxis con dabigatrán y el 35,7%, con aspirina. La incidencia total de eventos tromboembólicos fue del 1,3%; 1,4% con dabigatrán y 1,3% con aspirina (p = 0,9). El costo de la tromboprofilaxis fue de USD 3,6 con aspirina 325 mg y USD 130 o 175 con dabigatrán, según la presentación de 75 y 110 mg. Conclusiones:La aspirina como tromboprofilaxis tras un reemplazo total de cadera o rodilla en pacientes con bajo riesgo de sufrir eventos tromboembólicos ha logrado resultados clínicos similares a los del dabigatrán. Se puede recomendar un protocolo multimodal basado en el uso de aspirina. Este mejora el cumplimiento de la terapia antitrombótica por parte de los pacientes, debido al bajo costo de la profilaxis con aspirina. Nivel de Evidencia: III

Objective: To analyze the incidence of out-of-hospital thromboembolic events after a primary total knee or hip replacement in the first 90 postoperative days, using acetylsalicylic acid or dabigatran as thromboprophylaxis. As a secondary objective, to evaluate the cost of antiplatelet therapy compared to anticoagulants. Materials and Methods: A retrospective observational study was carried out in the postoperative period of primary total hip and knee replacement on the incidence of out-of-hospital thromboembolic events during the first 90 postoperative days in two groups of patients. Acetylsalicylic acid (325 mg per day) or dabigatran (150 to 220 mg per day) were used as thromboprophylaxis for 35 days. Results: The series consisted of 224 patients aged 68.5 years (38-95 years), 44.2% male. 51.3% corresponded to total hip replacement. 64.3% continued thromboprophylaxis with dabigatran and 35.7% with aspirin. The total incidence of thromboembolic events was 1.3%. In the patients who received dabigatran it was 1.4% and in those who received aspirin, 1.3% (p = 0.9). The cost of thromboprophylaxis with aspirin 325 mg was US $ 3.6 while with dabigatran it was US $ 130 or $ 175, according to its presentation, 75 and 110 mg. Conclusion: Aspirin as thromboprophylaxis after total hip or knee replacement in individuals at low risk of thromboembolic events has shown similar clinical outcomes as dabigatran, and a multimodal protocol based on the use of aspirin can be recommended. This improves patient adherence to antithrombotic therapy, due to the low cost of aspirin prophylaxis. Level of Evidence: III

Experiencia con idarucizumab como agente reversor de dabigatran / Experience with idarucizumab as a reverse agent of dabigatran

Resumen Los anticoagulantes orales directos (AOD), entre ellos dabigatrán, poseen un perfil riesgo-beneficio favorable comparados con warfarina y además no requieren monitoreo del efecto anticoagulante. Sin embargo, en ocasiones de sangrado con amenaza de vida o requerimiento de procedimiento quirúrgico de emergencia, es de gran utilidad revertir inmediatamente el efecto anticoagulante. Idarucizumab, fragmento de un anticuerpo monoclonal humanizado, revierte inmediatamente el efecto de dabigatrán y es actualmente el único agente reversor de un AOD disponible en Argentina. Presentamos una serie de 8 pacientes a los que se les administró idarucizumab para revertir el efecto de dabigatrán. Todos eran mayores de 65 años, recibían 110 o 150 mg cada 12 horas de dabigatrán y 7/8 estaban anticoagulados por fibrilación auricular; tres tenían indicación discutida para AOD y otro, una dosis mayor a la recomendada. Dos requirieron reversión debido a una cirugía de urgencia, y 6 tuvieron sangrado con amenaza de vida: tres hemorragias digestivas y tres sangrados intra-craneanos (en dos ocasiones traumático). En todos los casos se observó normalización de la hemostasia quirúrgica o control de sangrado crítico. No se observaron complicaciones trombóticas posteriores a la administración del antídoto. Dos fallecieron dentro de los 30 días de la administración por causas no relacionadas con la reversión. Ninguno de nuestros pacientes requirió administración de una segunda dosis de idarucizumab. Nuestro resultado es similar a lo informado en la literatura internacional.

Abstract Direct oral anticoagulants (DOACs), among them dabigatran, have a favorable benefit-risk profile compared with warfarin, and no monitoring of the anticoagulant effect is required. However, reversing the anticoagulant effect immediately is very useful in cases of life-threatening bleeding and emergency surgical procedure requirement. Idarucizumab, a humanized monoclonal antibody fragment, is currently the only reversal agent of a DOAC available in Argentina. Idarucizumab immediately reverse the effect of dabigatran. We present a series of 8 real-life clinical cases who received idarucizumab to reverse the effect of dabigatran. All of the patients were older than 65 years, were receiving 110 or 150 mg every 12 hours of dabigatran and 7/8 were anticoagulated because of atrial fibrillation. Three had a debatable indication for DOACs and another, a higher dose than recommended. Two required reversal due to emergency surgery, and 6 cases had life-threatening bleeding: three gastrointestinal hemorrhages and three intracranial bleeding (Two had a head trauma). In all cases normalization of surgical hemostasis or control of critical bleeding was observed. No hemorrhagic or thrombotic complications were observed after antidote administration. Two died within 30 days of administration of idarucizumab, due to causes unrelated to the reversal. None of our patients required administration of a second dose of idarucizumab. Our result is similar to that reported in international literature.

Eficácia, segurança e custo-efetividade dos anticoagulantes orais diretos para prevenção de eventos tromboembólicos nos casos de Fibrilação Atrial não Valvar, anticoagulados com varfarina e eventos adversos graves: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of direct oral anticoagulants for prevention of thromboembolic events in cases of Non-Valvar Atrial Fibrillation, anticoagulated with varfarine and serious adverse events: rapid review of evidence

Tecnologia: Os medicamentos Rivaroxabana, Apixabana, Edoxabana e Dabigatrana são anticoagulantes orais diretos (DOACs). Indicação: Prevenção e tratamento de fenômenos tromboembólicos, em pacientes portadores de Fibrilação Atrial Não Valvar (FANV). Pergunta: Os DOACs são eficazes, seguros e custo-efetivos para prevenção de eventos tromboembólicos em portadores de FANV (CHA2DS2VASC >= 2 pontos) e que apresentaram eventos adversos graves, incluindo sangramento maior, ou falha terapêutica em uso de varfarina? Métodos: Levantamento bibliográfico foi realizado nas bases eletrônicas Pubmed e Google seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas, ensaios clínicos e dos estudos econômicos com as ferramentas Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List e Quality of Health Economic Studies (QHES) checklist, respectivamente. Resultados: Foram selecionadas e incluídas 4 revisões sistemáticas, 4 ensaios clínicos e 2 estudos econômicos. Conclusão: As evidências apontam que apixabana e dabigatrana são mais eficazes e seguros que varfarina para prevenção de eventos tromboembólicos em portadores de FANV, previamente anticoagulados com varfarina, que apresentaram eventos adversos graves. Não há estudos econômicos nacionais ou internacionais que avaliem DOACs especificamente para esses casos. Os estudos econômicos disponíveis indicam que, na maioria dos contextos internacionais, os DOACs são custo-efetivos para tratamento de FANV em casos nunca anticoagulados como primeira-linha terapêutica, mas no contexto brasileiro concluem que dabigatrana e rivaroxabana não são custo-efetivos. No SUS, a varfarina é a única opção terapêutica de anticoagulantes para FANV, mesmo para os casos de falha terapêutica ou com eventos adversos graves. Outras opções terapêuticas para esses casos deveriam ser fornecidas pelo SUS, visto que as evidências disponíveis sugerem que pode ser vantajoso migrar de varfarina para apixabana ou dabigatrana (AU)

Technology: The drugs Rivaroxaban, Apixaban, Edoxaban and Dabigatran are direct oral anticoagulants (DOACs). Indication: Prevention and treatment of thromboembolic phenomena, in patients with Non-Valvar Atrial Fibrillation (NVAF). Question: Are DOACs effective, safe and cost-effective for preventing thromboembolic events in patients with NVAF (CHA2DS2VASC> = 2 points) and who have had serious adverse events, including major bleeding, or therapeutic failure using warfarin? Methods: Bibliographic search was performed on Pubmed and Google, following predefined search strategies. Evaluation of the methodological quality of systematic reviews, clinical trials and economic studies was carried out using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List and Quality of Health Economic Studies (QHES) checklist tools, respectively. Results: 4 systematic reviews, 4 clinical trials and 2 economic studies were selected and included. Conclusion: Evidence indicates that apixaban and dabigatran are more effective and safer than warfarin for preventing thromboembolic events in patients with NVAF, previously anticoagulated with warfarin, who had serious adverse events. There are no national or international economic studies that evaluate DOACs specifically for these cases. The available economic studies indicate that, in most international contexts, DOACs are costeffective for treating NVAF in cases never anticoagulated, but in the Brazilian context they conclude that dabigatran and rivaroxaban are not cost-effective. In Brazilian Public Health System, warfarin is the only therapeutic option for anticoagulants for NVAF, even in cases of therapeutic failure or with serious adverse events. Other therapeutic options for these cases should be provided by Brazilian Public Health System, as the available evidence suggests that it may be advantageous to switch from warfarin to apixaban or dabigatran (AU)

Eficácia e segurança de anticoagulantes orais diretos comparados à anticoagulação tradicional com heparina e varfarina para tratamento de tromboembolismo pulmonar e trombose venosa profunda / Effectiveness and safety of direct oral anticoagulants compared to traditional anticoagulation with heparin and varfarine to treat pulmonary thromboembolism and deep venous thrombosis

Tecnologia: Inibidores Diretos do Fator Xa (IDFXa) ­ Rivaroxabana, Apixabana, Edoxabana ­ e Inibidores Diretos da Trombina (IDT) ­ Dabigatrana ­ todos são anticoagulantes orais diretos (DOAC). Indicação: tratamento e prevenção de fenômenos tromboembólicos. Pergunta: Para tratamento de tromboembolismo pulmonar (TEP) e trombose venosa profunda (TVP), os DOAC são mais eficazes e seguros que a anticoagulação tradicional com heparina e varfarina? Métodos: Levantamento bibliográfico na base de dados Pubmed seguindo estratégias de buscas predefinidas. Avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Resultados: Foram selecionadas e incluídas 4 revisões sistemáticas. Conclusão: Na maioria dos estudos incluídos, os DOAC demonstraram eficácia e segurança similar à anticoagulação tradicional com heparina e varfarina para tratamento de TEP e TVP. Em um estudo, o risco de TVP recorrente foi menor no tratamento de IDFXa (por menos 3 meses de tratamento) e de episódios de sangramento maior foi menor no tratamento de IDT e IDFXa (por mais 3 meses de tratamento)

Technology: Direct Factor Xa Inhibitors (DFXaI) - Rivaroxaban, Apixaban, Edoxaban ­ and Direct Thrombin Inhibitors (DTI) - Dabigatran - all are direct oral anticoagulants (DOAC). Indication: treatment and prevention of thromboembolic phenomena. Question: For treatment of pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT), are DOACs more effective and safer than traditional anticoagulation with heparin and warfarin? Methods: Bibliographic survey in the Pubmed database following predefined search strategies. Evaluation of the methodological quality of systematic reviews with the tool Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Results: 4 systematic reviews were selected and included. Conclusion: In most of the included studies, DOAC demonstrated similar efficacy and safety to traditional anticoagulation with heparina and warfarin for the treatment of PTE and DVT. In one study, the risk of recurrent DVT was lower in the treatment of DFXaI (for at least 3 months of treatment) and of major bleeding episodes was lower in the treatment of DTI and DFXaI (for another 3 months of treatment)

Pharmacogenomic Research in Direct Oral Anticoagulants / 中国医学科学院学报

Oral anticoagulants play an important role in the prevention and treatment of thromboembolic diseases.Warfarin,a traditional oral anticoagulant,is limited in clinical use due to its limitations such as narrow therapeutic window and requirements on frequent monitoring and dose adjustment.Direct oral anticoagulants(DOACs)such as dabigatran,rivaroxaban,apixaban,and edoxaban are increasingly used to prevent and treat venous thrombosis or thrombus formation.However,recent studies have documented inter-individual variability in plasma drug levels of DOACs.This article summarizes the recent advances in the pharmacogenomics of DOACs.

Predictive value of four score systems on the bleeding risk in atrial fibrillation patients treated with dabigatran / 中华心血管病杂志

Objective: To compare the predictive value of HAS-BLED, HEMORR2HAGES, ATRIA and ORBIT scores on the bleeding risk in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran. Methods: Data of 942 NVAF patients participating a non-interventional prospective study of anticoagulant therapy with dabigatran, which was conducted in 12 centers from February 2015 to December 2017 in China, were analyzed. Complete HAS-BLED HEMORR2HAGES, ATRIA and ORBIT bleeding risk scores data and follow-up data were available in the enrolled patients. The endpoint of the study was bleeding events occurred during a 6 months follow-up. Cox proportional hazards models were constructed to analyze the associations between HAS-BLED, HEMORR2HAGES, ATRIA and ORBIT scores and risk of bleeding, and the area under the curve (AUC) of receiver operating characteristics curves (ROC) of each score was used to set the predictive value for bleeding risk. Results: Among the 942 patients, the mean age was (65.3±11.2) years old, 542 (57.5%) were males. A total of 93 (9.9%) bleeding events occurred during follow up, 89 (9.4%) events were minor bleeding, and 4 (0.4%) events were major bleeding. Patients with a high-risk HAS-BLED score had a 1.87-fold increased risk of bleeding compared with low-risk patients (HR = 2.87, 95% CI:1.26-6.51, P = 0.012). There was no statistically significant difference between low-medium-high-risk grading in other scoring systems and bleeding risk (all P>0.05). The AUC (95%CI) of HAS-BLED, HEMORR2HAGES, ATRIA and ORBIT bleeding risk scores were 0.558 (0.525-0.590), 0.520 (0.487-0.553), 0.513(0.480-0.545), 0.523(0.490-0.555), respectively. The AUC of all bleeding score systems were of ≤ 0.700. Conclusion: Among the NVAF patients taking dabigatran in China, the HAS-BLED bleeding risk score is superior to other 3 bleeding risk score on predicting the bleeding risk in these patients, but its predictive value is still relatively low.

Cost-effectiveness of new oral anticoagulants and warfarin in atrial fibrillation from adverse events perspective / Análisis de costo-efectividad de los nuevos anticoagulantes orales y la warfarina en fibrilación auricular desde la perspectiva de los eventos adversos

Abstract Objective: new oral anticoagulants (apixaban, dabigatran and rivaroxaban) are the newest advance for stroke's risk reduction in atrial fibrillation. These are as effective as warfarin in preventing stroke/systemic embolism, but exists heterogenic outcomes as gastrointestinal hemorrhage, mortality reduction, minor and major haemorrhage (adverse events). Despite of this, there is a lack of cost-effectiveness models focused on adverse events. Methods: a cost-effectiveness analysis with a third payer perspective, interventions included were apixaban, dabigatran, warfarin and rivaroxaban. Discount rate of 3%, and 10 years of temporal horizon. The Markov model is an international, validated, and modified to assess better adverse events. Major assumptions, patients with mild and moderate stroke returns to oral anticoagulation, patients with moderate and severe hemorrhage do not returns to oral anticoagulation. Probabilities and QALYs, taken from a cost-effectiveness analysis published. Costs, information from a cohort of stroke patients. Software, TreeAge pro( and Excel(. Results: overall results, 1.48 QALYs, $17 916 USD for apixaban, 1.49 QALYs, $18 122 USD for dabigatran, 1.32 QALYs, $21 966 USD for warfarin and 1.24 QALYs, $24 547 USD for rivaroxaban. The ICER for apixaban compared to dabigatran was $12 988 USD. Negative ICER for warfarin and rivaroxaban, shows that are dominated alternatives (less benefits and more costs). Apixaban is cost-effective at 70% and dabigatran at 30% of iterations in the probabilistic sensitivity analysis. Conclusions: apixaban and dabigatran are cost-effective alternatives, apixaban is the most cost-effective alternative from adverse events perspective. Warfarin shows better results than rivaroxaban to prevent stroke in atrial fibrillation from adverse events perspective.

Resumen Introducción: los nuevos anticoagulantes orales (apixabán, dabigatrán y rivaroxabán) son el avance más reciente para la reducción del riesgo de accidente cerebrovascular en la fibrilación auricular. Estos son tan efectivos como la warfarina en la prevención del accidente cerebrovascular/embolia sistémica, pero existen resultados heterogéneos como hemorragia gastrointestinal, reducción de la mortalidad y hemorragia menor y mayor (eventos adversos). Pese a ello, se carece de modelos de costo-efectividad enfocados en eventos adversos. Materiales y métodos: se hizo un análisis de costo-efectividad con una perspectiva de tercer pagador, en el que se incluyeron intervenciones como apixabán, dabigatrán, warfarina y rivaroxabán. La tasa de descuento fue del 3% y 10 años de horizonte temporal. El modelo de Markov es internacional, validado y modificado para evaluar mejor eventos adversos. Las principales suposiciones, los pacientes con accidente cerebrovascular leve y moderado vuelven a la anticoagulación oral, los pacientes con hemorragia moderada y grave no regresan a la anticoagulación oral. Probabilidades y AVAC, tomados de un análisis de costo-efectividad publicado. Los costos, información de una cohorte de pacientes con accidente cerebrovascular. Software, TreeAge pro y Excel. Resultados: resultados generales, 1.48 QALYs, $ 17 916 USD para apixabán, 1.49 QALYs, $ 18 122USD para dabigatrán, 1.32 QALYs, $ 21 966 USD para warfarina y 1.24 QALYs, $ 24 547 USD para rivaroxabán. El ICER para apixabán en comparación con dabigatrán fue de $ 12 988 USD. El ICER negativo para warfarina y rivaroxabán muestra que son alternativas dominadas (menos beneficios y más costos). Apixabán es rentable en 70% y dabigatrán en 30% de las iteraciones en el análisis de sensibilidad probabilístico. Conclusión: apixabán y dabigatrán son costo-efectivos; apixabán es la alternativa más costo-efectiva desde la perspectiva de los eventos adversos. Warfarina mostró mejores resultados que rivaroxabán para prevenir accidentes cerebrovasculares en fibrilación auricular desde la perspectiva de los eventos adversos.

Dabigatran and warfarin in nonvalvular atrial fibrillation or atrial flutter in outpatient clinic practice in Brazil / Dabigatrana e varfarina em pacientes com fibrilação atrial não valvar ou flutter em ambulatório especializado no Brasil

ABSTRACT Objectives: To compare warfarin and dabigatran for thromboembolic event prevention in patients with nonvalvular atrial fibrillation or atrial flutter. Methods: This was a retrospective cohort of participants with nonvalvular atrial fibrillation or atrial flutter using either warfarin or dabigatran in a reference center in Brazil. Results: There were 112 patients (mean age 65.5 years), with 55.3% using warfarin. The median duration of follow-up was 1.9 years for warfarin and 1.6 years for dabigatran (p = 0.167). Warfarin patients had a higher median of medical appointments per year (8.3 [6.8-10.4] vs 3.1 [2.3-4.2], p < 0.001) and the frequency of minor bleeding was more than four times higher (17.7% vs 4.0%, p = 0.035). Among patients with prior stroke, those using warfarin had 2.6 times more medical appointments for person-years of follow-up (8.5 vs 3.3). There was no major bleeding or embolic event during follow-up period. Conclusion: The dabigatran group had a lower frequency of minor bleeding and number of medical appointments than the warfarin group, without more embolic events or major bleeding.

RESUMO Objetivos: Comparar varfarina e dabigatrana para prevenção de eventos tromboembólicos em pacientes com fibrilação atrial não valvar ou flutter (FA). Métodos: Coorte retrospectiva de pacientes com FA em uso de varfarina ou dabigatrana em serviço especializado no Brasil. Resultados: Foram avaliados 112 pacientes (média idade 65,5), com 55,3% no grupo varfarina. A mediana do tempo de seguimento foi de 1,9 anos para o grupo varfarina e 1,6 para dabigatrana (p = 0,167). No grupo varfarina houve maior mediana de consultas médicas (CM) por ano (8,3[6,8-10,4] vs. 3,1[2,3-4,2], p < 0,001), com frequência de sangramento menor quatro vezes maior (17,7% vs. 4,0%, p = 0,035). Nos pacientes com acidente vascular cerebral isquêmico prévio, o grupo varfarina teve 2,6 vezes mais CM por pessoas-ano de seguimento (8,5 vs. 3,3). Não houve sangramento maior ou eventos embólicos no período de seguimento. Conclusão: Pacientes em uso de dabigatrana tiveram menor número de sangramento menor e CM que aqueles em uso de varfarina, sem aumentar eventos embólicos ou sangramentos maiores.

Terapia anticoagulante oral: complicações hemorrágicas em indivíduos submeticos à cirurgia oral menor e avaliação in vitro do efeito sobre células ósseas / Oral anticoagulant therapy: Bleeding complications in individuals submitted to dental surgery and in vitro effects on bone cells

Os objetivos deste trabalho foram 1) avaliar o impacto da terapia anticoagulante oral no sangramento associado à exodontias durante os períodos intraoperatório e pósoperatório; 2) investigar os efeitos do etexilato de dabigatrana, um inibidor direto da trombina, sobre as células ósseas. Para atender o objetivo 1, foram recrutados indivíduos em uso de anticoagulantes orais do tipo antagonista de vitamina K (AVK) e alvo-específico (DOAC, do inglês direct oral anticoagulant) e indivíduos sem terapia anticoagulante com indicação de exodontia. As exodontias foram realizadas sem a suspensão da terapia anticoagulante e parâmetros associados a desfechos hemorrágicos foram avaliados. A avaliação quantitativa do sangramento intraoperatório foi realizada por meio da mensuração do volume e análise dos fluidos aspirados durante o procedimento e normalizada por um escore. Obtivemos como resultados que as complicações hemorrágicas pós-operatórias bem como o escore de sangramento intraoperatório foi similar entre os grupos, sendo que nenhum evento hemorrágico foi observado no grupo DOAC. A história prévia de complicações hemorrágicas em procedimentos odontológicos (p=0,001) e uso de medidas hemostáticas locais (p=0,017) foram estatisticamente maiores no grupo AVK. Para atender o objetivo 2, experimentos foram conduzidos a partir de modelo in vitro, no qual o efeito da terapia anticoagulante foi avaliado diretamente sobre as células ósseas e em modelo animal ex-vivo. Neste modelo ex-vivo, células de animais previamente tratados com etexilato de dabigatrana foram diferenciadas em osteoclastos. Culturas primárias de células-tronco de camundongos e ratos foram diferenciadas em osteoclastos e osteoblastos e tratadas com o fármaco disponível comercialmente, etexilato de dabigatrana (Pradaxa® 1-6 µg/mL) bem como seu princípio ativo, dabigatrana (0,1, 0,3, 3 e 6 µg/mL). Células não expostas aos medicamentos foram utilizadas como controle. A diferenciação de osteoclastos foi inibida pelo tratamento em ambos os modelos, in vitro e ex-vivo. Paralelamente, observou-se a redução da expressão gênica e proteica do marcador Catepsina K e da atividade reabsortiva destas células. Nas culturas de osteoblastos, o tratamento inibiu a expressão gênica dos marcadores fosfatase alcalina (ALP) e osteocalcina, reduziu a atividade in situ de ALP e a deposição de matriz extracelular, indicando um efeito negativo na diferenciação dos osteoblastos. Concluiu-se que o uso de anticoagulantes orais não aumentou a ocorrência de desfechos hemorrágicos na população estudada, o que reforça a manutenção da terapia para a realização de exodontias. O tratamento sobre culturas celulares utilizando etexilato de dabigatrana impactou negativamente a diferenciação e atividade de osteoclastos e osteoblastos.(AU)

The objectives of this study were 1) to evaluate the impact of oral anticoagulant therapy on the pattern of intraoperative and postoperative bleeding in dental surgery; 2) to investigate the effects of dabigatran etexilate, a direct thrombin inhibitor, on bone cells. To fulfill objective 1, individuals undergoing oral anticoagulant therapy with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) and individuals without anticoagulant therapy, who had indication of dental extraction were included. Dental surgery procedures were performed without interruption of anticoagulant therapy and parameters associated with hemorrhagic outcomes were evaluated. Intraoperative bleeding was evaluated by means of the measurement of the total amount of blood collected during the procedure corrected by absorbance reading and normalized by score. The results showed that the occurrence of bleeding events and the intraoperative blood loss were similar among groups and hemorrhagic episodes were not observed amongst the individuals taking DOACs. The previous history of complications in dental procedures (p=0.001) and the use of additional hemostatic measures (p=0.017) were significantly higher in the VKA group. To fulfill objective 2, experiments were conducted by means of an in vitro model in which the direct effect of anticoagulant therapy on bone cells was evaluated. An ex-vivo animal model in which cells of animals previously treated with dabigatran etexilate were differentiated was also carried out into osteoclasts. Primary cultures of mice and rats cells were differentiated into osteoclasts and osteoblasts and treated with dabigatran etexilate solution (Pradaxa® 1-6 µg/mL) and its active principle dabigatran (0.1, 0.3, 3 and 6 µg/mL). Untreated cells were used as controls and the effects of the treatment on cell viability and differentiation were evaluated. Both dabigatran etexilate and its active principle, dabigatran inhibited osteoclast differentiation and activity in vitro and in the ex-vivo model, as demonstrated by the reduction of resorption pits and cathepsin K gene and protein expression. In osteoblast cultures, dabigatran etexilate reduced the in situ alkaline phosphatase (ALP) activity, matrix mineralization and gene expression of ALP and osteocalcin. These findings indicated osteoblast inhibition. In conclusion, oral anticoagulant therapy did not result in increased bleeding outcomes in this sample, which strengthen the advocacy of the maintenance of the therapy during dental surgery. Dabigatran etexilate treatment impaired the activity and differentiation of osteoclasts and osteoblasts.(AU)

Manejo práctico de los nuevos anticoagulantes orales en fibrilación auricular no valvular / Practical use of new oral anticoagulants in non-valvular atrial fibrillation / Manejo prático dos novos anticoagulantes orais na fibrilação atrial não valvar

Introducción. La fibrilación auricular es la arritmia más frecuente en la práctica clínica, cuya incidencia viene en ascenso alcanzando el 8 % en edades que superan los 80 años, con un impacto importante en la morbimortalidad relacionado con las complicaciones cerebrovasculares. El objetivo es identificar los aspectos farmacológicos y de manejo práctico de los nuevos anticoagulantes orales en paciente con fibrilación auricular no valvular. División de los temas tratados. Se realizó una revisión bibliográfica no sistemática en bases de datos y bibliotecas electrónicas (PubMed, Cochrane, Lilacs) incluyendo artículos desde 2008 hasta 2019, en idioma inglés y español que contuvieran los tópicos de interés. Se realizó una descripción detallada de las generalidades de los anticoagulantes orales en fibrilación auricular, incluyendo dabigatrán, rivaroxabán, apixabán y edoxabán; monitorización de la actividad anticoagulante; descripción del manejo perioperatorio de los nuevos anticoagulantes orales y reversión de la anticoagulación para los nuevos anticoagulantes orales. Conclusiones. El uso de nuevos anticoagulantes orales en paciente con fibrilación auricular no valvular es una buena alternativa, con facilidad de administración oral, sin aumento significativo del riesgo de sangrado, comparado con warfarina, con la ventaja de no requerir monitoría continua con paraclínicos. [Laguado-Nieto MA, Ardila-Acuña LC, Mayorga-Quintero JA, Rangel-Vera JA. Manejo práctico de los nuevos anticoagulantes orales en fibrilación auricular no valvular. MedUNAB. 2019;22(1):38-50 . doi: 10.29375/01237047.2823]

Introduction. Atrial fibrillation is the most common arrhythmia in clinical practice. Its incidence has been on the rise, reaching 8 % among those patients over the age of 80, with a significant impact on morbimortality related to cerebrovascular complications. The objective is to identify aspects of pharmacology and practical use of the new oral anticoagulants in patients with non-valvular atrial fibrillation. Division of topics covered. A non-systematic literature research was conducted in databases and digital libraries (PubMed, Cochrane, Lilacs), including articles from 2008 to 2019, both in English and in Spanish that included the topics of interest. A detailed description of the generalities of oral anticoagulants for atrial fibrillation was made, including dabigatran, rivaroxaban, apixaban and edoxaban; monitoring anticoagulant activity; description of the perioperative use of new oral anticoagulants and reversal of anticoagulation for the new oral anticoagulants. Conclusions. The use of new oral anticoagulants in patients with non-valvular atrial fibrillation is a good alternative, with easy oral administration, without significant increase in the risk of bleeding, compared to warfarin, and with the advantage of not requiring continuous paraclinical monitoring. [Laguado-Nieto MA, Ardila-Acuña LC, Mayorga-Quintero JA, Rangel-Vera JA. Practical use of new oral anticoagulants in non-valvular atrial fibrillation. MedUNAB. 2019;22(1):38-50 . doi: 10.29375/01237047.2823].

Introdução. A fibrilação atrial é o tipo de arritmia mais frequente na prática clínica, cuja incidência está em ascensão, atingindo 8 % nas idades acima de 80 anos, com impacto importante na morbimortalidade relacionada às complicações cerebrovasculares. O objetivo é identificar os aspectos farmacológicos e de manejo prático dos novos anticoagulantes orais em pacientes com fibrilação atrial não valvar. Divisão dos tópicos abordados. Foi realizada uma revisão bibliográfica não sistemática nas bases de dados e bibliotecas eletrônicas (PubMed, Cochrane, Lilacs), incluindo artigos de 2008 até 2016, em inglês e espanhol, que continham os tópicos de nosso interesse. Foi feita uma descrição detalhada das generalidades dos anticoagulantes orais na fibrilação atrial, incluindo dabigatrana, rivaroxabana, apixabana e edoxabana; monitorização da atividade anticoagulante; descrição do manejo perioperatório dos novos anticoagulantes orais e reversão da anticoagulação para os novos anticoagulantes orais. Conclusões. O uso de novos anticoagulantes orais em pacientes com fibrilação atrial não valvar é uma boa alternativa, com facilidade de administração por via oral, sem aumento significativo do risco de sangramento, comparado à varfarina, com a vantagem de não necessitar de monitoramento contínuo com paraclínicos. [Laguado-Nieto MA, Ardila-Acuña LC, Mayorga-Quintero JA, Rangel-Vera JA. Manejo prático dos novos anticoagulantes orais na fibrilação atrial não valvar. MedUNAB. 2019;22(1):38-50 . doi: 10.29375/01237047.2823].

O que mudou nas últimas décadas na profilaxia do tromboembolismo venoso em pacientes internados: artigo de revisão / What has changed in venous thromboembolism prophylaxis for hospitalized patients over recent decades: review article

O tromboembolismo venoso (TEV) é uma doença frequente e de alta morbimortalidade, sendo considerada a maior causa evitável de mortalidade em pacientes hospitalizados. Apesar da incidência altíssima de TEV em todos os países e das evidências de que a tromboprofilaxia reduz as complicações tromboembólicas em pacientes clínicos e cirúrgicos, e a custo baixo, persistem grandes dúvidas quanto à segurança desse tipo de intervenção nos pacientes e quanto à tromboprofilaxia ideal. Inúmeros estudos e recomendações baseadas em evidências comprovam a eficácia da profilaxia na prevenção do TEV e/ou da morte dos pacientes, mas ainda hoje ela é subutilizada. Neste artigo, apresentamos uma ampla revisão dos métodos de profilaxia existentes até os dias atuais, publicados em diretrizes e estudos nacionais e internacionais sobre tromboprofilaxia

Venous thromboembolism (VTE) is a common disease with high rates of morbidity and mortality and is considered the number one cause of avoidable mortality among hospitalized patients. Although VTE incidence is extremely high in all countries and there is ample evidence that thromboprophylaxis inexpensively reduces the rate of thromboembolic complications in both clinical and surgical patients, a great deal of doubt remains with respect to patient safety with this type of intervention and in relation to the ideal thromboprophylaxis methods. Countless studies and evidence-based recommendations confirm the efficacy of prophylaxis for prevention of VTE and/or patient deaths, but it remains underutilized to this day. This article presents a wide-ranging review of existing prophylaxis methods up to the present, from guidelines and national and international studies of thromboprophylaxis

Manejo de hemorragia asociada a anticoagulantes orales directos: estado actual de las estrategias de reversión / Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Non-Vitamin K Antagonist Oral Anticoagulants in Medical Conditions at High Risk of Thromboembolism beyond Atrial Fibrillation / 대한뇌졸중학회지

Non-Vitamin K antagonist oral anticoagulants (NOACs) have been extensively investigated in medical conditions at high risk of venous or arterial thrombosis other than atrial fibrillation (AF), including hip or knee arthroplasty, acute venous thromboembolism (VTE), cancer-associated VTE, acute coronary syndrome (ACS), stable atherosclerotic vascular disease, chronic heart failure, and embolic stroke of undetermined source (ESUS). Two large ESUS trials failed to show the benefit of rivaroxaban or dabigatran, and large randomized controlled trial (RCT) data of NOACs are lacking for another potential candidates of patent foramen ovale-related stroke, acute ischemic stroke, and cerebral venous thrombosis. On the other hand, high quality evidences of NOACs have been compiled for VTE prophylaxis after hip or knee arthroplasty, acute VTE, cancer-associated VTE, and concomitant ACS and AF, which have been reflected in clinical practice guidelines. In addition, RCTs showed the benefit of very low dose rivaroxaban in combination with antiplatelet therapy in patients with ACS and in those with stable cardiovascular disease. This article summarizes the accumulated evidences of NOACs in cardiovascular diseases beyond AF, and aims to inform healthcare providers of optimal regimens tailored to individual medical conditions and help investigators design future clinical trials.

Anticoagulantes orais diretos para o tratamento da trombose venosa profunda: revisão de revisões sistemáticas / Direct oral anticoagulants for treatment of deep vein thrombosis: overview of systematic reviews

A number of limitations of standard therapy with warfarin for deep vein thrombosis (DVT) have been established. This overview of systematic reviews presents the baseline results for efficacy and safety of the new direct oral anticoagulants (DOACs) thrombin inhibitors, and activated factor X (Xa) inhibitors in patients with DVT. Searches were run on PubMed and the Cochrane Database of Systematic Reviews. Twenty-three studies were retrieved, and one systematic review was judged eligible. This review scored maximum according to AMSTAR criteria and included 7,596 patients for analysis of thrombin inhibitors and 16,356 patients for analysis of factor Xa inhibitors. The results of the meta-analysis indicate that DOACs are similar for DVT treatment when compared to standard treatment with warfarin. The incidence of major bleeding is somewhat lower in patients treated with factor Xa inhibitors and similar to standard therapy when treated with direct thrombin inhibitors

A terapia padrão com varfarina para a trombose venosa profunda (TVP) tem uma série de limitações já estabelecidas. Essa revisão de revisões sistemáticas elenca os principais resultados de eficácia e segurança dos anticoagulantes orais diretos (DOACs), inibidores da trombina e do fator X ativado (Xa), em pacientes com TVP. A pesquisa foi realizada nas bases PubMed e Cochrane Database of Systematic Reviews. Foram recuperados 23 estudos, e uma revisão sistemática foi considerada elegível. Essa revisão atingiu escore máximo no AMSTAR e incluiu 7.596 pacientes para análise dos inibidores da trombina e 16.356 pacientes para a análise dos inibidores do fator Xa. Os resultados da metanálise indicam que os DOACs apresentam eficácia similar à terapia padrão no tratamento da TVP. A incidência de sangramento maior é um pouco menor nos pacientes tratados com os inibidores do fator Xa e similar à terapia padrão no tratamento com inibidores diretos da trombina

Evaluation of the Bleeding Intensity of Patients Anticoagulated with Warfarin or Dabigatran Undergoing Dental Procedures / Avaliação da Intensidade de Sangramento de Procedimentos Odontológicos em Pacientes Anticoagulados com Varfarina ou Dabigatrana

Abstract Background: Thrombotic disorders remain one of the leading causes of death in the Western world. Dabigatran appeared as an alternative to warfarin for anticoagulation in the treatment of atrial fibrillation (AF). The risk associated with bleeding due to its use has been documented in several randomized clinical trials, but no large study has examined in detail the risk of bleeding during dental extraction and other dental procedures involving bleeding. Objective: To compare the intensity of bleeding in individuals taking dabigatran or vitamin K antagonist (warfarin) and undergoing dental procedures. Methods: Prospective, single-center, controlled study with one single observer. Patients diagnosed with nonvalvular AF, on warfarin or dabigatran, cared for at a cardiology referral center, and requiring single or multiple dental extractions, were evaluated up to seven days post-extraction. The following outcomes were assessed: bleeding time between the beginning and the end of suture and complete hemostasis; bleeding before the procedure, after 24 hours, 48 hours, 7 days, during and after suture removal (late); p<0.05 was defined as of statistical relevance. Results: We evaluated 37 individuals, 25 in the warfarin group and 12 in the dabigatran group. Age, sex, weight, height, blood pressure, color, schooling, family income and comorbidities were similar between the two groups. Regarding bleeding after 24 hours of the procedure, no one in the dabigatran group had bleeding, whereas 32% in the warfarin group had documented bleeding (p = 0.028). The other variables analyzed did not differ between the groups. Conclusions: This study suggests that, regarding dental extraction, there is no statistically significant difference in the intensity of bleeding of patients taking dabigatran as compared to those taking warfarin. Bleeding 24 hours after the procedure was less frequent among patients on dabigatran.

Resumo Fundamento: Distúrbios trombóticos permanecem como uma das principais causas de morte no mundo ocidental. A dabigatrana surgiu como alternativa à varfarina para a anticoagulação no tratamento da fibrilação atrial (FA). O risco associado a eventos hemorrágicos com a sua utilização foi documentado em vários ensaios clínicos randomizados, mas nenhum grande estudo analisou detalhadamente o risco de hemorragia durante a extração dentária e em outros procedimentos odontológicos que envolvam sangramentos. Objetivo: Em indivíduos submetidos a procedimentos odontológicos, avaliar a intensidade de sangramento com o uso de dabigatrana em comparação ao uso de anticoagulante oral antagonista da vitamina K (varfarina). Métodos: Estudo prospectivo, controlado, unicêntrico, observador único. Pacientes com diagnóstico de FA não valvar atendidos em um centro de referência em cardiologia e com indicação de anticoagulação que necessitavam de tratamento odontológico para exodontia única ou múltipla, estando em uso de varfarina ou dabigatrana e avaliados até sete dias pós-exodontia. Foram avaliados os efeitos sobre: tempo de sangramento entre o início e o fim da sutura e hemostasia completa; sangramento antes do procedimento, após 24 e 48 horas, 7 dias, durante e após a remoção da sutura (tardio), sendo considerado como estatisticamente significativo valor de p < 0,05. Resultados: Foram avaliados 37 indivíduos, sendo 25 no grupo varfarina e 12 no dabigatrana. Idade, sexo, peso, altura, pressão arterial, cor, escolaridade, renda familiar e comorbidades foram semelhantes nos dois grupos. Em relação ao sangramento 24 horas após o procedimento, ninguém do grupo dabigatrana apresentou sangramento, que esteve presente em 32% do grupo varfarina (p = 0,028). Não houve diferenças entre os grupos em relação às outras variáveis analisadas. Conclusões: Os dados deste estudo permitem sugerir que, em indivíduos submetidos a procedimento odontológico de exodontia, não há diferença estatisticamente significante na intensidade de sangramento em uso de dabigatrana em comparação ao uso de varfarina. Há uma menor frequência de sangramento 24 horas após o procedimento nos indivíduos em uso de dabigatrana.

Segunda publicación nuevos anticoagulantes orales: guía práctica para los médicos / Second publication new oral anticoagulants: a practical guide for doctors

Resumen Los nuevos anticoagulantes orales suponen una atractiva alternativa para los clásicos antagonistas de la vitamina K (AVKs) en la prevención de ictus en pacientes con fibrilación auricular no valvular. A diferencia de los AVKs, estos anticoagulantes no requieren monitorización ni ajuste de dosis y poseen propiedades farmacológicas favorables. La falta de antídoto efi caz, su coste, o dudas en cuanto a la seguridad en los pacientes con enfermedad renal avanzada pueden explicar su lento ritmo de expansión. El uso seguro y eficaz de estos nuevos medicamentos depende en gran medida de la experiencia clínica entre la comunidad médica. Esta revisión discute las peculiaridades de los nuevos anticoagulantes orales, propor cionando algoritmos prácticos y fáciles de usar para su aplicación en la práctica clínica diaria.

Abstract New oral anticoagulants suppose an attractive alternative for classical vitamin K antagonists (AVKs) in stroke prevention for patients with non-valvular atrial fibrillation. Unlike AVKs, these anticoagulants do not require monitoring or dose adjustment and have favourable pharmacological properties. The lack of an effective antidote, its cost, or doubts regarding the safety of patients with advanced kidney disease may explain its slow rate of expansion. The safe and effective use of these new medications depends largely on clinical experience among the medical community. This review discusses the peculiarities of the new oral anticoagulants, providing practical and easy-to-use algorithms for their application in daily clinical practice.

Anticoagulation in patients with cardiac manifestations of Chagas disease and cardioembolic ischemic stroke / Anticoagulação nas manifestações cardíacas da doença de Chagas e acidente vascular cerebral isquêmico cardioembólico

ABSTRACT Objectives To describe anticoagulation characteristics in patients with cardiac complications from Chagas disease and compare participants with and without cardioembolic ischemic stroke (CIS). Methods A retrospective cohort of patients with Chagas disease, using anticoagulation, conducted from January 2011 to December 2014. Results Forty-two patients with Chagas disease who were using anticoagulation were studied (age 62.9±12.4 years), 59.5% female and 47.6% with previous CIS, 78.6% with non-valvular atrial fibrillation and 69.7% with dilated cardiomyopathy. Warfarin was used in 78.6% of patients and dabigatran (at different times) in 38%. In the warfarin group, those with CIS had more medical appointments per person-years of follow-up (11.7 vs 7.9), a higher proportion of international normalized ratios within the therapeutic range (57% vs 42% medical appointments, p = 0.025) and an eight times higher frequency of minor bleeding (0.64 vs 0.07 medical appointments). Conclusion Patients with Chagas disease and previous CIS had better control of INR with a higher frequency of minor bleeding.

RESUMO Objetivos descrever as características da anticoagulação em pacientes com manifestações cardíacas da doença de Chagas (MCDC) e comparar os participantes com sem acidente vascular cerebral isquêmico cardioembólico (AVCIC). Resultados 42 pacientes com MCDC em anticoagulação foram estudados (62,9 ± 12,4 anos), 59,5% do sexo feminino e 47,6% com AVCIC prévio, 78,6% portadores de fibrilação atrial não valvar e 69,7% com cardiomiopatia dilatada. Varfarina foi utilizada em 78,6% dos pacientes e dabigatrana em 38% (em momentos diferentes). No grupo da varfarina, aqueles com AVCIC tiveram mais consultas médicas por pessoas-ano de seguimento (11,7 vs 7,9), maior taxa de RNI na faixa terapêutica (57% vs 42% consultas médicas, p = 0,025) e uma frequência oito vezes maior de sangramento menor (0,64 vs. 0,07 consultas médicas). Conclusão pacientes com MCDC e AVCIC prévio têm melhor controle de RNI com maior frequência de sangramento menor.