RESUMO
OBJECTIVE: We aimed to evaluate the safety and efficacy of antithrombotic strategies by age in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention in AUGUSTUS. METHODS: Patients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were major or clinically relevant non-major bleeding, major bleeding, death or rehospitalization, and ischemic events. Treatment effects of apixaban vs. vitamin K antagonist (VKA) and aspirin vs. placebo were assessed across age groups using Cox models. RESULTS: Of 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. Apixaban was associated with lower rates of major or clinically relevant non-major bleeding than VKA (<65: HR 0.69 [0.47-1.00]; 65-74: HR 0.57 [0.43-0.75]; ≥75: HR 0.81 [0.63-1.04]). Death or hospitalization occurred less often with apixaban, regardless of age. No differences were observed in rates of ischemic events between apixaban and VKA according to age. Aspirin was associated with higher rates of bleeding than placebo (<65: HR 1.67 [1.15-2.43]; 65-74: HR 2.32 [1.73-3.10]; ≥75: HR 1.69 [1.31-2.19]). Rates of death or rehospitalization and ischemic events were similar among patients receiving aspirin or placebo across age groups. CONCLUSIONS: Apixaban was associated with greater absolute reduction in bleeding than VKA in older age groups, reflecting their higher hemorrhagic risk. Aspirin increased bleeding in all age groups vs. placebo. Our findings support the use of apixaban plus a purinergic receptor P2Y12(P2Y12) inhibitor without aspirin in patients with atrial fibrillation and recent acute coronary syndrome/percutaneous coronary intervention, regardless of age.
Assuntos
Síndrome Coronariana Aguda , Aspirina , Fibrilação Atrial , Fibrinolíticos , Hemorragia , Intervenção Coronária Percutânea , Pirazóis , Piridonas , Humanos , Idoso , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Masculino , Feminino , Aspirina/uso terapêutico , Aspirina/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Síndrome Coronariana Aguda/tratamento farmacológico , Fatores Etários , Hemorragia/induzido quimicamente , Pessoa de Meia-Idade , Fibrinolíticos/uso terapêutico , Fibrinolíticos/efeitos adversos , Vitamina K/antagonistas & inibidores , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Idoso de 80 Anos ou maisRESUMO
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Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia in patients with heart failure (HF), regardless of ejection fraction, leading to a greater risk of thromboembolic complications. Anticoagulation is one of the fundamental pillars in the treatment of AF, and prior to this, it is recommended to evaluate the embolic risk using the CHA2DS2-VASc score and the bleeding risk with the HAS-BLED score. There are two pharmacological groups of oral anticoagulants (OACs), vitamin K antagonists (VKAs), and direct oral anticoagulants (DOACs). Both groups have advantages and disadvantages in their use. VKAs require frequent monitoring to achieve INR levels within range, a greater number of drug and dietary interactions, leading to lower adherence, satisfaction, and quality of life. Likewise, scientific evidence supports the non-inferiority of DOACs versus VKAs, being recommended in recent clinical practice guidelines for the prevention of thrombotic events in all patients with AF except in cases where moderate to severe mitral stenosis or mechanical valve replacement coexist. To date, there are no published studies that assess adherence and impact on quality of life with the use of DOACs in HF with AF. Therefore, the objective of this research is to observe changes in adherence and quality of life of patients who were switched from VKA to DOAC, describing the occurrence of thrombotic or hemorrhagic events. Methodology: Quasi-experimental, prospective, longitudinal study. All patients over 18 years of age with AF without mechanical valve prosthesis or moderate/severe mitral stenosis, anticoagulated with warfarin with therapeutic range time (TTR) ≤65% and SAMe-T2R ≥2 were included. The Morisky questionnaire was administered to evaluate adherence, and the Anti-Clot Treatment Scale was used to evaluate satisfaction and quality of life. Thrombotic and hemorrhagic risk was evaluated by CHA2DS2-VASc and HAS-BLED. The questionnaires were applied using warfarin and the same questionnaires were repeated after replacing with DOAC for convenience, specifically apixaban. Statistical analysis was performed using the Kolmogorov-Smirnov test, Cochrane Q test, ANOVA, and STATAv.15.0. Results: 43 patients, 31 of whom were male, 100% had CHA2DS2-VASC >2, 37% had HAS-BLED >3, and 62.8% had SAMe-TT2R2 >2. There was a statistically significant difference (p<0.001) in relation to the use of apixaban in quality of life, disease burden, and positive impact. No thrombotic or hemorrhagic events were observed with the use of apixaban. Conclusions: A statistically significant difference was observed in adherence, satisfaction, and quality of life with the use of apixaban, without thrombotic or hemorrhagic events.
Introdução: A fibrilação atrial (FA) é a arritmia cardíaca mais comum em pacientes com insuficiência cardíaca (IC), independentemente da fração de ejeção, o que leva a um maior risco de complicações tromboembólicas. A anticoagulação é um dos pilares fundamentais no tratamento da FA e, antes disso, é recomendado avaliar o risco embólico usando o escore CHA2DS2-VASc e o risco de sangramento com o escore HAS-BLED. Existem dois grupos farmacológicos de anticoagulantes orais (AOs): os antagonistas da vitamina K (AVKs) e os anticoagulantes orais diretos (DOACs). Ambos os grupos têm vantagens e desvantagens em seu uso. Os AVKs exigem monitoramento frequente para alcançar níveis de RNI dentro da faixa, um maior número de interações medicamentosas e alimentares, levando a menor adesão, satisfação e qualidade de vida. Da mesma forma, a evidência científica suporta a não inferioridade dos DOACs em relação aos AVKs, sendo recomendados nas diretrizes recentes de prática clínica para a prevenção de eventos trombóticos em todos os pacientes com FA, exceto nos casos em que coexistem estenose mitral moderada a grave ou substituição valvar mecânica. Até o momento, não há estudos publicados que avaliem a aderência e o impacto na qualidade de vida com o uso de DOACs em IC com FA. Portanto, o objetivo desta pesquisa é observar mudanças na adesão e qualidade de vida de pacientes que mudaram de AVK para DOAC, descrevendo a ocorrência de eventos trombóticos ou hemorrágicos. Metodologia: Estudo quase-experimental, prospectivo e longitudinal. Foram incluídos todos os pacientes com mais de 18 anos de idade com FA sem prótese valvar mecânica ou estenose mitral moderada/grave, anticoagulados com varfarina com tempo de alcance terapêutico (TTR) ≤65% e SAMe-T2R ≥2. O questionário Morisky foi administrado para avaliar a adesão, e a Escala de Tratamento Anticoagulante foi usada para avaliar a satisfação e qualidade de vida. O risco trombótico e hemorrágico foi avaliado pelo escore CHA2DS2-VASc e HAS-BLED. Os questionários foram aplicados usando varfarina e os mesmos questionários foram repetidos após a substituição por DOAC por conveniência, especificamente apixabana. A análise estatística foi realizada usando o teste de Kolmogorov-Smirnov, teste Q de Cochrane, ANOVA e STATAv.15.0. Resultados: Foram incluídos 43 pacientes, sendo 31 do sexo masculino. Todos os pacientes apresentavam CHA2DS2-VASC >2, 37% tinham HAS-BLED >3 e 62,8% tinham SAMe-TT2R2 >2. Foi observada uma diferença estatisticamente significativa (p<0,001) no que diz respeito ao uso de apixabana na qualidade de vida, carga da doença e impacto positivo. Não foram observados eventos tromboembólicos ou hemorrágicos com o uso de apixabana. Conclusões: Foi observada uma diferença estatisticamente significativa na adesão, satisfação e qualidade de vida em relação ao uso de apixabana, sem eventos tromboembólicos ou hemorrágicos.
RESUMO
Background and Objectives: Venous thromboembolism (VTE) is common in cancer patients. Anticoagulant therapy with low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs), such as dalteparin and apixaban, have demonstrated efficacy and safety. However, more comparative research of these drugs is still needed. This study aimed to synthesize evidence on the efficacy of apixaban compared to dalteparin in reducing recurrent VTE, major bleeding, and clinically relevant non-major bleeding associated with cancer. Materials and Methods: We systematically searched the PubMed, Scopus, Web of Science, Embase, Cochrane Library, and ClinicalTrials databases up to 5 January 2023, for randomized controlled trials comparing apixaban versus dalteparin as treatment for cancer-associated VTE. Five studies were included. Effects according to meta-analyses were reported as relative risks (RRs) and their 95% confidence intervals (CIs). Results: It was found that 33 of 734 (4.5%) patients treated with apixaban and 56 of 767 (7.3%) with dalteparin had recurrent VTE as the efficacy outcome (RR 0.49, 95% CI 0.15-1.58, I2 38%). Major bleeding occurred in 25 of 734 patients treated with apixaban (3.4%) and 27 of 767 with dalteparin (3.5%) (RR 1.29, 95% CI 0.31-5.27, I2 59%). Likewise, clinically relevant non-major bleeding occurred in 64 of 734 patients treated with apixaban (8.7%) and 46 of 767 (5.9%) with dalteparin (RR 1.52, 95% CI 1.05-2.19, I2 0%). Conclusions: Apixaban showed a lower risk of recurrent VTE than dalteparin in patients with cancer-associated VTE, albeit with no statistical difference. Statistical significance was observed for no major clinically relevant bleeding but not for major bleeding.
Assuntos
Neoplasias , Tromboembolia Venosa , Humanos , Dalteparina/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/complicações , Neoplasias/complicações , Neoplasias/tratamento farmacológicoRESUMO
Background Intracerebral hemorrhage is the most serious complication of anticoagulant therapy but the effects of different types of oral anticoagulants on the expansion of these hemorrhages are still unclear. Clinical studies have revealed controversial results; more robust and long-term clinical evaluations are necessary to define their outcomes. An alternative is to test the effect of these drugs in experimental models of intracerebral bleeding induced in animals. Aims To test new oral anticoagulants (dabigatran etexilate, rivaroxaban, and apixaban) in an experimental model of intracerebral hemorrhage induced by collagenase injection into the brain striatum of rats. Warfarin was used for comparison. Methods Ex vivo anticoagulant assays and an experimental model of venous thrombosis were employed to determine the doses and periods of time required for the anticoagulants to achieve their maximum effects. Subsequently, volumes of brain hematoma were evaluated after administration of the anticoagulants, using these same parameters. Volumes of brain hematoma were evaluated by magnetic resonance imaging, H&E (hematoxylin and eosin) staining, and Evans blue extravasation. Neuromotor function was assessed by the elevated body swing test. Results and Conclusions The new oral anticoagulants did not increase intracranial bleeding compared with control animals, while warfarin markedly favored expansion of the hematomas, as revealed by magnetic resonance imaging and H&E staining. Dabigatran etexilate caused a modest but statistically significant increase in Evans blue extravasation. We did not observe significant differences in elevated body swing tests among the experimental groups. The new oral anticoagulants may provide a better control over a brain hemorrhage than warfarin.
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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.
Assuntos
Fator X , Albumina Sérica Humana , Tromboembolia Venosa , Humanos , Anticoagulantes , Sítios de Ligação , Calorimetria/métodos , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Termodinâmica , Fator X/antagonistas & inibidoresRESUMO
OBJECTIVES: Venous thromboembolism (VTE) is a serious national and international public health issue. Major orthopedic surgeries, such as a total hip (THA) and knee (TKA) arthroplasties, are associated with an increased risk of VTE, long-term complications, functional disability, and death resulting from hypercoagulability by surgical trauma. This pharmacoeconomic analysis aimed to identify the most cost-effective anticoagulant alternative in preventing VTE in patients undergoing THA and TKA. METHODS: A decision tree model was developed, comparing direct oral anticoagulants (rivaroxaban, apixaban, and dabigatran) with enoxaparin, with separate THA and TKA models a 3-month time horizon from the perspective of the Brazilian National Health System. The results were presented as incremental cost-effectiveness ratio (ICER), and the outcomes analyzed were avoided complications (ACs) after thromboprophylaxis. Comparative effectiveness was obtained from a published meta-analysis. A willingness to pay value of approximately R$ 15 000.00 was used per AC, and a probabilistic sensitivity analysis with the Monte Carlo simulation was conducted. RESULTS: Apixaban was the anticoagulant that presented the best ICER for patients undergoing THA (R$ 207.52/AC) and TKA (R$ 133.59/AC), followed by rivaroxaban (R$ 347.21/AC), dabigatran (R$ 372.56/AC), and enoxaparin (R$ 711.44/AC) for THA and by dabigatran (R$ 194.07/AC), rivaroxaban (R$ 221.12/AC), and enoxaparin (R$ 747.25/AC) for TKA. After ICER analysis, apixaban prevails over the other technologies analyzed for both surgical procedures, confirmed after sensitivity analysis. CONCLUSION: Our model suggests that, in the Brazilian National Health System, apixaban is the most cost-effective alternative in preventing VTE after THA and TKA.
Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Brasil , Análise Custo-Benefício , Dabigatrana/uso terapêutico , Enoxaparina/efeitos adversos , Humanos , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleRESUMO
Resumen Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas pro piedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.
Abstract Direct oral anticoagulants have emerged as the drugs that have changed the man agement of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagu lants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.
RESUMO
Direct oral anticoagulants have emerged as the drugs that have changed the management of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagulants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.
Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas propiedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.
Assuntos
Fibrilação Atrial , Tromboembolia , Anticoagulantes/uso terapêutico , Argentina , Fibrilação Atrial/tratamento farmacológico , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , HumanosRESUMO
OBJECTIVE: The first aim of this study was to investigate the effect of apixaban on endometrial receptivity via immunohistochemical investigation of integrin ß3 expression in pregnant rats. The second aim was to compare the endometrial effects of both subcutaneous and oral anticoagulant drugs in terms of integrin ß3 expressions. METHODS: A total of 24 rats were selected for this study and divided into three equal groups as control, enoxaparin and apixaban groups. Subcutaneous enoxaparin and oral apixaban were applied for 15 days starting on the first day of pregnancy. On the 15th day of pregnancy, all rats were killed by cervical dislocation, and uterine horns, including pregnancy materials, were investigated for pregnancy success and endometrial receptivity by using immunohistochemical integrin ß3 staining. RESULTS: Living, viable fetuses were higher in the apixaban group compared to the control group (p=0.037). Intensity and universality of immunohistochemical staining of integrin ß3 for endometrial stroma were detected statistically higher in the apixaban group than the other groups. (p=0.009 for intensity, p=0.014 for universality). Endometrial epithelial and myometrial integrin ß3 expression were detected to be identical between the groups (p=0.3). CONCLUSIONS: Apixaban enhances endometrial receptivity via increasing integrin ß3 expression in rats. This result can lead to further studies to be done in the future.
Assuntos
Enoxaparina , Integrina beta3 , Gravidez , Feminino , Ratos , Animais , Integrina beta3/metabolismo , Projetos Piloto , Enoxaparina/farmacologia , Implantação do Embrião , Anticoagulantes/farmacologiaRESUMO
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.
Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Humanos , Obesidade/complicações , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Trombina/uso terapêuticoAssuntos
Fibrilação Atrial , Coração Auxiliar , Acidente Vascular Cerebral , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Humanos , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Varfarina/efeitos adversosRESUMO
Resumen El objetivo de este trabajo fue comparar los niveles de fibrinógeno (FBG) obtenidos por el método de Clauss con los obtenidos por el método de fibrinógeno derivado del tiempo de protrombina (FBG PT-d), con dos tromboplastinas, en pacientes anticoagulados con distintas drogas. Se estudiaron pacientes anticoagulados consecutivos: 105 con antagonistas de la vitamina K (AVK), 55 con heparina no fraccionada (HNF), 58 con heparina de bajo peso molecular (HBPM), 60 con rivaroxabán, 45 con apixabán, 60 con dabigatrán y 100 controles normales (CN). El FBG se determinó por el método de Clauss y FBG PT-d utilizando tromboplastina de cerebro de conejo o recombinante humana; los niveles de heparina, rivaroxabán y apixabán por método cromogénico anti Xa; el dabigatrán con el ensayo de tiempo de trombina diluido. Existió un sesgo positivo (p<0,001) al comparar el FBG PT-d vs. FBG por Clauss: CN: 13,7%, AVK: 31,8%, rivaroxabán: 34,8% y apixabán: 20,0% cuando se utilizó tromboplastina de conejo. En el caso de las muestras que contenían HBPM se observó este desvío con ambas tromboplastinas. El sesgo porcentual en presencia de dabigatrán y heparina no fraccionada no fue estadísticamente distinto del obtenido en el grupo control. El ensayo de FBG PT-d no debe utilizarse en pacientes anticoagulados con rivaroxabán, apixabán, HBPM o AVK, ya que sobreestima los niveles de FBG. El porcentaje de sesgo depende del tipo de tromboplastina utilizado y fue mayor con la de cerebro de conejo en el sistema de detección utilizado.
Abstract The aim of this study was to compare fibrinogen (FBG) results obtained by Clauss method (FBG-C) and by the prothrombin time-derived fibrinogen assay (FBG PT-d) with two thromboplastins in patients under anticoagulation. Consecutive anticoagulated patients were studied: 105 vitamin-K antagonist (VKA), 55 unfractioned heparin, 58 LMWH, 60 rivaroxaban, 45 apixaban and 60 dabigatran, and 100 healthy controls (NC). FBG-C was performed by Clauss and FIB PT-d with rabbit brain and human recombinant thromboplastins, respectively. Heparins, rivaroxaban and apixaban levels were measured by antiXa; dabigatran by thrombin diluted assay. A positive bias of FBG PT-d vs. FBG-C with both thromboplastins were seen in NC (13.7 and 19.0 % for HS and RP, respectively), but bias with HS in rivaroxaban, apixaban and VKA patients were significantly higher compared to NC: 34.8%, 20.0 % and 31.8 %, respectively. LMWH presented higher BIAS compared to NC with both thromboplastins. Samples with unfraction heparin and dabigatran presented similar bias to NC. FBG PT-d should not be used in patients under anticoagulant treatment because of an important overestimation of FBG could be obtained in these patients. The percentage of bias depends on the type of thromboplastin used; it was higher with rabbit brain thromboplastin in the detection system used.
Resumo O objetivo deste trabalho foi comparar os níveis de fibrinogênio (FBG) obtidos pelo método de Clauss com aqueles obtidos pelo método do fibrinogênio derivado do tempo de protrombina (FBG PT-d), com duas tromboplastinas, em pacientes anticoagulados com diferentes drogas. Pacientes anticoagulados consecutivos foram estudados: 105 com antagonista da vitamina K (AVK); 55 com heparina não fracionada (UFH); 58 com heparina de baixo peso molecular (HBPM), 60 com rivaroxabana, 45 com apixabana, 60 com dabigatrana e 100 controles normais (CN). FBG foi determinado pelo método de Clauss e FBG PT-d usando tromboplastina de cérebro de coelho ou tromboplastina humana recombinante; níveis de heparina, rivaroxabana e apixabana pelo método cromogênico anti-Xa; dabigatrana com ensaio de tempo de trombina diluída. Há um viés positivo (p<0,001) ao comparar o FBG PT-d vs FBG de Clauss: CN: 13,7%; AVK: 31,8%, rivaroxabana: 34,8% e apixabana 20,0% quando foi utilizada tromboplastina de coelho. No caso das amostras contendo HBPM, esse desvio foi observado com ambas as tromboplastinas. O viés percentual na presença de dabigatrana e heparina não fracionada não foi estatisticamente diferente daquela obtida no grupo controle. O ensaio de FBG PT-d não deve ser usado em pacientes anticoagulados com rivaroxabana, apixabana, LMWH ou VKA, pois superestima os níveis de FBG. A porcentagem de viés depende do tipo de tromboplastina utilizado e foi maior com a de cérebro de coelho, no sistema de detecção utilizado.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Fibrinogênio/análise , Protrombina/administração & dosagem , Coagulação Sanguínea , Tromboplastina , Preparações Farmacêuticas/administração & dosagemRESUMO
Abstract Background: patients who take long-term oral anticoagulants and also have CKD have a greater probability of bleeding. Methods: a retrospective, descriptive cohort study reviewing the clinical charts of anticoagulated patients with Stage 3 CKD or above seen at an anticoagulation clinic, in order to evaluate hemorrhagic events and baseline characteristics of the population over a two-year period. Results: 238 patients were included. The anticoagulants used were warfarin (45%), rivaroxaban (31.5%), apixaban (14.3%) and dabigatran (3.4%). According to the KDIGO classification, 78% of the patients had CKD G3 (37.3% G3a and 40.7% G3b), 15.9% G4 and 5.8% G5 with renal replace ment therapy (RRT). During the study period, only 20 patients (8.4%) had hemorrhagic events; of these, seven (35%) were major (four associated with warfarin, two with rivaroxaban and one with apixaban). The other 13 bleeds were minor and associated with warfarin in 46.1% of the cases. Gastrointestinal bleeding was the most common (35%), followed by soft tissues (30%). There was only one fatal bleed, which occurred in the central nervous system (CNS) in a patient with CKD G4. Conclusion: a low rate of bleeding was found, which could be related to close follow up by an anticoagulation clinic. The anticoagulant most frequently associated with bleeding was warfarin, which could be related to a low time in therapeutic range (48.8%). Due to the low rate of events, comparisons could not be made. (Acta Med Colomb 2021; 46. DOI: https://doi.org/10.36104/amc.2021.1945).
Resumen Antecedentes: los pacientes que toman anticoagulantes orales a largo plazo y además cursan con enfermedad renal crónica (ERC), tienen mayor probabilidad de tener sangrados. Métodos: estudio de cohorte descriptivo retrospectivo en el cual se revisaron historias clínicas de pacientes anticoagulados y con ERC 3 en adelante, atendidos en una clínica de anticoagulación con el fin de evaluar eventos hemorrágicos y características básales de la población en un periodo de dos años Resultados: se incluyeron 238 pacientes. Los anticoagulantes usados fueron warfarina (45%), rivaroxabán (31.5%), apixabán (14.3%) y dabigatrán (3.4%). Según la clasificación KDIGO 78% de los pacientes tenían ERC G3 (37.3% G3a y 40.7% G3b), 15.9% G4 y 5.8% G5 con terapia de reemplazo renal (TRR). En el periodo de estudio solo 20 pacientes (8.4%) tuvieron eventos hemo rrágicos, de estos, 7 (35%) fueron mayores (cuatro asociados a warfarina, dos rivaroxabán y uno apixabán). Los otros 13 sangrados fueron menores y asociados a warfarina en 46.1% de los casos. El sangrado digestivo fue el más frecuente (35%), seguido por tejidos blandos (30%). Sólo hubo un sangrado fatal el cual se dio en sistema nervioso central (SNC) en un paciente con ERC G4. Conclusión: se apreció una baja tasa de sangrado, lo que podría estar relacionado con el estrecho seguimiento de una clínica de anticoagulación. El anticoagulante que más frecuentemente se asoció con sangrado fue warfarina, lo cual puede estar relacionado con un bajo tiempo en rango terapéutico (48.8%). Por la baja tasa de eventos, no fue posible la realización de comparaciones. (Acta Med Colomb 2021; 46. DOI: https://doi.org/10.36104/amc.2021.1945).
RESUMO
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.
Assuntos
Anticoagulantes , Biofarmácia , Administração Oral , Dabigatrana , RivaroxabanaRESUMO
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.
Assuntos
Comitês Consultivos , Síndrome Antifosfolipídica/tratamento farmacológico , Antitrombinas/uso terapêutico , Consenso , Administração Oral , Antitrombinas/efeitos adversos , Antitrombinas/farmacologia , Brasil , Contraindicações de Medicamentos , Interações Medicamentosas , Substituição de Medicamentos , Humanos , Inibidor de Coagulação do Lúpus/análise , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Reumatologia , Sociedades Médicas , Trombose/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Variation in patient characteristics and practice patterns may influence outcomes at a regional level. METHODS: We assessed differences in demographics, practice patterns, outcomes, and the effect of apixaban compared with warfarin in ARISTOTLE (n = 18,201) by prespecified regions: North America, Latin America, Europe, and Asia Pacific. The primary outcomes were stroke/systemic embolism and major bleeding. RESULTS: Compared with other regions, patients from Asia Pacific were younger, more women were enrolled in Latin America. Coronary artery disease was more prevalent in Europe and Asia Pacific had the highest rate of prior stroke and renal impairment. Over 50% of patients in North America were taking ≥9 drugs at randomization, compared with 10% in Latin America. North America had the highest rates of temporary study drug discontinuation and procedures. Time in therapeutic range (INR 2.0-3.0) on warfarin was highest in North America and lowest in Asia Pacific. After adjustment and compared with Europe, patients in Asia Pacific had 2-fold higher risk of stroke/systemic embolism and 3-fold higher risk of intracranial hemorrhage. Patients in Latin America had 2-fold increased risk of all-cause death compared with Europe. The benefits of apixaban compared with warfarin were consistent across regions; there was a pronounced reduction in major bleeding in patients from Asia Pacific compared with other regions (p-interaction = 0.03). CONCLUSIONS: Patients with AF enrolled in prespecified regions in ARISTOTLE had differences in clinical baseline characteristics and practice patterns. After adjustment, patients in Asia Pacific and Latin America had worse outcomes than patients from other regions. The relative benefits of apixaban compared with warfarin were consistent across regions with an even greater treatment effect in the reduction of bleeding in patients from Asia Pacific.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Medição de Risco/métodos , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Saúde Global , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
We report the case of a 61-year-old man who presented at the Emergency Department (ED), complaining of sudden-onset dyspnea and chest pain after a long flight from Tokyo to Houston. Considering his clinical stability and sPESI 0, enoxaparin 1â¯mg/kg BID was started for 24â¯h, and the patient was then considered for early discharge with apixaban 10â¯mg BID. Direct-factor Xa inhibition did not improve extensive thrombus burden and right ventricular dysfunction despite D-dimer measurement reduction. Because of the treatment failure, we considered thrombolysis. Currently, recommendations to use thrombolysis in patients under non-vitamin K antagonist oral anticoagulants (NOACs) do not exist. Hence, the one dose of apixaban was stopped, and 12â¯h later, we performed successful thrombolysis. A systematic review from 2007 to 2017 did not identify any cases related to NOACs failure to reduce thrombus burdens in patients with PE and persistent right ventricular dysfunction. We also did not find any evidence of cases that reported strategies for urgent thrombolysis in PE patients on NOACs. To the best of our knowledge, apixaban's failure to reduce thrombus burden, persistent right ventricular dysfunction, and a NOACs-thrombolysis bridge in patients with PE on apixaban has not been previously described. Both the bedside risk stratification and the therapeutic failures should alert clinicians in the ED to the potential limitations of low-molecular-weight heparin, NOACs therapy, and sPESI in the setting of intermediate-high-risk PE.
Assuntos
Dor no Peito/etiologia , Dispneia/etiologia , Inibidores do Fator Xa/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Terapia Trombolítica/métodos , Viagem Aérea , Anticoagulantes/farmacologia , Quimioterapia Combinada , Inibidores do Fator Xa/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/fisiopatologia , Pirazóis/farmacologia , Piridonas/farmacologia , Medição de Risco , Resultado do TratamentoRESUMO
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.
Assuntos
Humanos , Procedimentos Cirúrgicos Eletivos , Artroplastia de Quadril , Artroplastia do Joelho , Tromboembolia Venosa , AnticoagulantesRESUMO
Resumen: Conociendo el impacto real de la fibrilación auricular en el evento vascular cerebral, la Sociedad Mexicana de Electrofisiología y Estimulación Cardiaca (SOMEEC) contempló la iniciativa de desarrollar una reunión multidisciplinaria de expertos con la finalidad de actualizar la evidencia científica disponible a partir de guías de práctica clínica, metaanálisis y ensayos clínicos controlados, y complementarla con la experiencia y los puntos de vista de un grupo de expertos. Para cumplir con este objetivo, se reunió a un grupo de especialistas en el área de cardiología, electrofisiología, neurología y hematología que, dada su experiencia en ciertas áreas, compartieron la evidencia científica disponible ante el panel de expertos para dejar abierta una discusión sobre la información que se presentaría en el presente artículo. Este documento reúne la mejor evidencia científica disponible y pretende ser una herramienta útil que agilice la toma de decisiones para uso de los nuevos anticoagulantes orales en fibrilación auricular no valvular y cardiopatía isquémica, o referente al manejo de pacientes que presentan evento vascular cerebral, o insuficiencia renal, e incluso en aquellos que serán sometidos a procedimientos invasivos y cirugía electiva. En la misma se manejan esquemas comparativos de seguimiento y tratamiento que simplifica la toma de decisión por los especialistas participantes.
Abstract: Knowing the real impact of atrial fibrillation in the stroke, the Sociedad Mexicana of Electrofisiología y Estimulación Cardiaca (SOMEEC) had the initiative to develop a multidisciplinary meeting of experts the with the purpose to update the available scientific evidence from clinical practice guidelines, meta-analyses, controlled clinical trials, and complementing with the experience and views of a group of experts. To meet this goal, SOMEEC gathered a group of specialists in the area of cardiology, electrophysiology, neurology and hematology that given their experience in certain areas, they share the scientific evidence with the panel of experts to leave open a discussion about the information presented in this article. This document brings together the best scientific evidence available and aims to be a useful tool in the decision to use of new oral anticoagulants in nonvalvular atrial fibrillation and ischemic heart disease, or relating to the management of patients with stroke or renal failure, and even those that will be submitted to elective surgery and invasive procedures. In the same, they handled comparative schemes of follow-up and treatment which simplifies the decision making by the specialists participants.
Assuntos
Humanos , Fibrilação Atrial/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Anticoagulantes/administração & dosagem , Administração Oral , Anticoagulantes/farmacologiaRESUMO
OBJECTIVE: Nonvalvular atrial fibrillation (NVAF) is a risk factor for ischemic stroke and systemic embolism. New oral anticoagulants are currently available. The objective of this study was to assess the incremental cost-utility ratio (ICUR) for apixaban vs. acenocoumarol in patients treated in Chile's public health system. STUDY DESIGN AND SETTING: We assessed cost-utility from the payer perspective with a lifetime Markov model. Epidemiologic characteristics, costs, and utilities were obtained from a Chilean cohort; data were completed with information from international literature. RESULTS: Incremental costs when using apixaban vs. acenocoumarol over a lifetime are CH$2,108,600 with an incremental effectiveness of 0.173 years of life gained (YLG) and 0.182 quality-adjusted life-year (QALY). The ICUR of apixaban vs. acenocoumarol was CH$12,188,439 per YLG and CH$11,585,714 per QALY. One to 3 times gross domestic product (GDP) per capita threshold is acceptable based on World Health Organization (WHO) norms. Chilean GDP per capita was CH$7,797,021 in 2013. The sensitivity analysis shows that these results are sensitive to the ischemic stroke risk with apixaban, and the intracranial hemorrhage risk due to the use of acenocoumarol. CONCLUSION: The use of apixaban in patients with NVAF in moderate-to-high risk of stroke is cost-effective, considering the payment threshold suggested by WHO.