Pacientes con fibrilación auricular no valvular tratados con antivitamina K o anticoagulantes directos: perfil de paciente y efectos a largo plazo / Patients with non-valvular atrial fibrillation on vitamin k antagonists or direct-acting oral anticoagulants: patients profile and long-term follow up outcomes

Resumen Introducción: La llegada de los anticoagulantes directos (ACD) ha supuesto un cambio en el tratamiento de la fibrilación auricular no valvular (FANV) en los últimos años. Los objetivos de este estudio son determinar el grado de control de la anticoagulación con antivitamina K (AVK) y su posible implicación en efectos cardiovasculares adversos mayores (ECAM) y evaluar las diferencias entre el grupo en tratamiento con AVK respecto del grupo con ACD. Pacientes y métodos: Estudio de cohorte prospectivo que incluyó a pacientes consecutivos diagnosticados con FANV valorados en el Servicio de Cardiología con un seguimiento de 18 meses. Se analizaron diferencias demográficas, clínicas y analíticas entre grupos, incluido el grado de control de la anticoagulación del grupo AVK y su posible relación con ECAM. Resultados: Se incluyó a 273 pacientes: 46.5% tratados con AVK, 42.5% con ACD y 11% sin tratamiento anticoagulante. El control de la anticoagulación con AVK fue del 62.1%, sin diferencias en ECAM en función de control. El grupo ACD presentó menos ECAM que el grupo de AVK (13.4 vs. 4.3%; HR, 0.90; 0.83-0.98; p = 0.01), con una menor mortalidad cardiovascular (0.0 vs. 5.5%; HR, 0.94; 0.90-0.98; p = 0.01) y total (0.9 vs. 12.6%; HR, 0.88; 0.82-0.94; p menor que 0,01), aunque sin diferencias significativas en eventos hemorrágicos (0.9 vs. 4.7%; p = 0.07) ni isquémicos (2.6 vs. 0.8%; p = 0.27). Discusión: Los pacientes con AVK poseen un perfil clínico diferente en comparación con los que reciben ACD. El control de anticoagulación del grupo de AVK fue inadecuado en casi la mitad de los casos. El grupo de AVK presentó más ECAM que el grupo de ACD.

Abstract Introduction: The arrival of direct-acting oral anticoagulants (DOACs) has led to a change in the management of non-valvular atrial fibrillation (NVAF) in recent years. The objectives of this study are to determine the level of therapeutic control of anticoagulation with vitamin K antagonists (VKA) and its possible involvement in major adverse cardiovascular events (MACE) and to evaluate differences between the group on VKA with respect to the group on DOACs. Patients and methods: Prospective cohort study that included consecutive patients diagnosed with NVAF in Cardiology Consultations with a clinical follow-up of 18 months. Demographic, clinical and analytical differences between groups were analyzed, including the level of therapeutic control of anticoagulation on the VKA group and its association with MACE. Results: Overall, 273 patients were included: 46.5% on VKA, 42.5% on DOACs, 11% without antithrombotic treatment. Patients on VKA spent 62.1% of their time within therapeutic range (TTR by the Rosendaal formule). There were no differences in MACE depending on anticoagulation control. The DOACs group presented lesser MACE rate than the VKA group (13.4 vs. 4.3%; 0.90; HR 0.90; 0.83-0.98 p = 0.01) with lower cardiovascular mortality (0.0 vs. 5.5%; HR, 0.94; 0.90-0.98; p = 0.01) and total mortality (0.9 vs. 12.6%; HR, 0.88; 0.82-0.94; p less 0.01) although without significant differences in hemorrhagic (0.9 vs. 4.7 %; p = 0.07), or ischemic events (2.6 vs. 0.8%, p = 0.27). Conclusions: Patients on VKA have a different clinical profile than those who receive DOACs. Patients on VKA have an inadequate control of the anticoagulation in quite the half of the cases. The VKA group presented more MACE than the DOACs group.

Diagnostic accuracy of thromboelastometry and its correlation with the HPLC-MS/MS quantification test

The aim of the study was to evaluate the diagnostic accuracy of thromboelastometry for assessing rivaroxaban concentrations. The accuracy of thromboelastometry was compared with the high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method, which is the gold standard for drug plasma monitoring (the reference standard). Forty-six clinically stable patients were treated with 10, 15, or 20 mg of rivaroxaban once daily (OD group) or 15 mg twice a day (BID group) (no particular indication for treatment). Patient samples were collected 2 h after the use of the medication (peak) and 2 h before the next dose (trough). The rivaroxaban plasma concentrations were determined via HPLC-MS/MS, and thromboelastometry was performed using a ROTEM® delta analyzer. There were significant prolongations in clotting time (CT) for the 10, 15, and 20 mg of rivaroxaban treatments in the OD groups. In the 15 mg BID group, the responses at the peak and trough times were similar. At the peak times, there was a positive correlation between the plasma concentration of rivaroxaban and CT (Spearman correlation rho=0.788, P<0.001) and clot formation time (rho=0.784, P<0.001), and a negative correlation for alpha angle (rho=−0.771, P<0.001), amplitude after 5 min (rho=−0.763, P<0.001), and amplitude after 10 min (rho=−0.680, P<0.001). The CT presented higher specificity and sensitivity using the cut-off determined by the receiver characteristics curve. ROTEM has potential as screening tool to measure possible bleeding risk associated with rivaroxaban plasma levels.

Manejo perioperatorio de pacientes con tratamiento anticoagulante crónico / Perioperative management of patients with chronic anticoagulant therapy

Resumen La terapia anticoagulante es ampliamente utilizada en la práctica clínica, como profilaxis en pacientes con riesgo de presentar fenómenos tromboembólicos o como tratamiento en aquellos que han presentado algún evento trombótico. Cada vez es más frecuente enfrentarse a pacientes en tratamiento anticoagulante crónico que serán intervenidos mediante procedimientos quirúrgicos, por lo que es importante y necesario conocer el manejo perioperatorio de los diferentes fármacos anticoagulantes, para disminuir los riesgos y complicaciones asociados a la suspensión o mantención de estos en el período perioperatorio. Para lograr este objetivo se debe evaluar y balancear el riesgo de sangrado versus el riesgo de eventos tromboembólicos, considerando la condición médica de cada paciente y el tipo de procedimiento quirúrgico que recibirá. La recomendación para fármacos anticoagulantes orales antagonistas de vitamina K es mantenerlos en cirugías con bajo riesgo de sangrado y suspenderlos 5 días antes de procedimientos quirúrgicos con riesgo hemorrágico moderado y alto, controlando el international normalized ratio el día previo a la cirugía. Los nuevos anticoagulantes orales no requieren monitorización de rutina, recomendándose suspenderlos a las 24-96 h previas al procedimiento quirúrgico, dependiendo del riesgo hemorrágico de cada cirugía y de la función renal. En relación con los anticoagulantes parenterales, la heparina no fraccionada en infusión intravenosa se recomienda suspenderla 4-5 h antes de la cirugía, mientras que la utilizada vía subcutánea, 12 h previas a la intervención quirúrgica. Las heparinas de bajo peso molecular en dosis de tratamiento se sugiere descontinuarlas 24 h previas a la cirugía, mientras que las usadas en dosis profilácticas, solo 12 h antes.

Anticoagulant therapy is widely used in clinical practice, as prophylaxis in patients at risk of presenting thromboembolic phenomena or as treatment in those who have presented a thrombotic event. It is increasingly the number of patients on chronic anticoagulant therapy to undergo surgical procedures, so it is important and necessary to know the perioperative management of the different anticoagulant drugs to reduce the risks and complications associated with suspension or maintenance of these in the perioperative period. To achieve this goal, the risk of bleeding should be evaluated and balanced against the risk of thromboembolic events, considering the medical condition of each patient and the type of surgical procedure to which they have undergone. The recommendation for vitamin K antagonist oral anticoagulant drugs is to maintain them for surgeries at low risk of bleeding and to suspend them 5 days before surgical procedures with moderate and high bleeding risk, controlling 'International Normalized Ratio' the day before surgery. The new oral anticoagulants do not require routine monitoring, recommending suspending them 24-96 h prior to the surgical procedure, depending on the hemorrhagic risk of each surgery and renal function of patient. In relation to parenteral anticoagulants, unfractionated heparin in intravenous infusion is recommended to be discontinued 4-5 h prior to surgery, while the subcutaneous route, 12 h prior to surgery. Low-molecular-weight heparins in treatment doses should be suspended 24 h prior to surgery, while in prophylactic doses, only 12 h earlier.

Nuevos anticoagulantes orales: actualización / New oral anticoagulants: a review

Resumen: Los anticoagulantes orales clásicos del tipo cumarinas han estado disponibles para uso clínico por más de medio siglo. Tienen gran eficacia para tratar o prevenir trombosis y tromboembolias, y son drogas cuyo uso ha aumentado con el mejor conocimiento clínico, el aumento de los factores de riesgo y el envejecimiento de la población. Entre sus desventajas se incluyen la alta variabilidad de su efecto en cada sujeto y entre individuos, la influencia del nivel de ingesta de vitamina K, la necesidad de control periódico del nivel de anticoagulación, su interacción con múltiples drogas. Si bien, el rango terapéutico está estandarizado, es estrecho, haciendo que el tiempo en rango terapéutico sea de ≈ 60%. Por estas limitaciones, se han creado nuevos anticoagulantes orales (NACOs), siendo progresivamente aprobados para uso clínico por agencias internacionales. Genéricamente, son de 2 tipos: inhibidores selectivos de trombina (dabigatrán) o de FXa (rivaroxabán, apixabán, edoxabán y betrixabán). Los NACOs se caracterizan por su dosificación una o dos veces al día, rapidez de acción, corta vida media en la circulación, predictibilidad de su efecto, dosis preestablecidas, sin necesidad de control periódico y con escasa o nula interacción con otras drogas. Estas ventajas no se han traducido en la mayoría de los ensayos en un superior efecto antitrombótico o menor riesgo de sangrado, y en su mayoría (salvo dabigatrán) carecen de antídoto específico demostrado.

Abstracts: Vitamin K inhibitors, coumarins, have been used for more than 50 years with no dispute by other drugs. Coumarins have demonstrated great efficacy in the treatment and prophylaxis of thrombotic and thromboembolic disorders, and their use has increased progressively with the advance of clinical knowledge as well as the increase of risk factors and aging of the population. Limitations of coumarins include great variability intra and inter-individuals, the influence of foods rich in vitamin K, the need for periodical assessment of the anticoagulant level and drug interactions. The therapeutic range is standardized using the INR (International Normalized Ratio). However, the therapeutic window is narrow, with frequent periods of either over or under-dosing, with the concomitant increase of bleeding and thrombotic risks, respectively. Long-term accredited anticoagulant clinics and clinical trials report that, at best, only ≈60% of time in treatment the patients are within the therapeutic range. These limitations have created the need for new oral anticoagulants (NOACs), and several of them have been approved for clinical use by international agencies after exhaustive and specific clinical trials. Generically, NACOs are belong in two types: selective inhibitors of thrombin (dabigatran) or FXa (rivaroxaban, apixaban, edoxaban and betrixaban). NOACs are prescribed once or twice daily, the onset of action is very fast, have a low T1/2 in the circulation, their effects are highly predictable, doses are pre-established, do not need laboratory control and have a low rate of interaction with other drugs. Despite these advantages most clinical trials have shown NOACs to be not inferior with respect to coumarin. However, NOACs have no clear advantages over warfarin in antithrombotic effect or bleeding reduction. Furthermore, most of them (except dabigatran) have no specific antidotes yet.

Apixabana, rivoraxabana e dabigratana em pacientes com fibrilação atrial não valvar / Apixabana, rivoraxabana and dabigratana in patients with non-valvular atrial fibrillation

CONTEXTO: A fibrilação atrial (FA) é um preditor de acidente vascular e está presente em 0,4% da população geral e em 3% a 5% daqueles com mais de 65 anos. O tratamento anticoagulante disponível no SUS é a varfarina, capaz de reduzir em torno de 65% a 80% a incidência de acidentes vasculares cerebrais, sendo necessário ajustes posológicos baseados nos resultados de tempo de protrombina (TAP)/ razão normalizada internacional (RNI ou INR). EVIDÊNCIAS CIENTÍFICAS: Em revisão realizada até a data de 29 de maio de 2015, foram identificados os ensaios RE-LY (2009), ROCKET-AF (2011) e ARISTOTLE (2011), referentes à Dabigatrana, Rivaroxibana e Apixabana respectivamente. Apenas um estudo (RE-LY) demonstrou redução de AVC isquêmico: HR 0,76 (IC 95% 0,60 a 0,98). Porém, por ser um estudo com imitações metodológica e de não inferioridade, não é possível afirmar superioridade do medicamento. DISCUSSÃO: A varfarina é um medicamento de baixo custo, com perfil de segurança conhecido e boa efetividade. Potencialmente, os novos anticoagulantes apresentam um significativo impacto orçamentário, sem ganho significativo de eficácia. Ainda, a necessidade de controle laboratorial é controversa e a ausência de antídoto eficaz em casos de sangramento grave. CONSULTA PÚBLICA: Foi recebido um total 20 contribuições de pessoas físicas na consulta pública que não alteraram a posição inicial desfavorável à incorporação dos anticoagulantes. RECOMENDAÇÃO DA CONITEC: Os membros presentes deliberaram por unanimidade recomendar a não incorporação da apixabana, rivaroxabana e dabigatrana para prevenção de Acidente Vascular Cerebral em pacientes com Fibrilação Atrial crônica não valvar. Foi assinado o Registro de Deliberação n˚157/2015. A recomendação será encaminhada para decisão do Secretário da SCTIE. DECISÃO: Não incorporação dos medicamentos apixabana, rivaroxabana e dabigatrana para prevenção de acidente vascular cerebral em pacientes com fibrilação atrial crônica não valvar, no âmbito do Sistema Único de Saúde- SUS, dada pela Portaria SCTIE-MS nº 11, de 4 de fevereiro de 2016, publicada no Diário Oficial da União nº 26 de 10 de fevereiro de 2016.

Nuevos anticoagulantes orales en fibrilación auricular / New oral anticoagulants in atrial fibrillation

La fibrilación auricular es la arritmia más frecuente y se relaciona con una alta tasa de accidente cerebrovascular y embolia sistéc)mica. La terapia establecida tanto para prevención primaria como secundaria es la anticoagulación con warfarina, antagonista de la vitamina K. Existen escalas que predicen el riesgo tromboembólico y la probabilidad de beneficiarse de terapia antitrombótica. El CHADS2ha sido la más simple y ampliamente utilizada, pero actualmente el CHA2DS2-VASc ha incorporado otros factores de riesgo, otorgando una mejor estratificación. El estrecho margen terapéc)utico de la warfarina y la interacción con fármacos y alimentos requiere controles seriados de la intensidad de la anticoagulación, limitando su uso clínico. Han aparecido nuevos anticoagulantes que ofrecen ventajas sobre los antagonistas de vitamina K. Estos actúan en dos sitios distintos de la cascada de la coagulación: inhibiendo directamente la trombina como el dabigatran, o el factor X activado como el rivaroxaban, apixaban, edoxaban y betrixaban. Estos nuevos fármacos han ido reemplazando a la warfarina y ya están incluidos en las guías de manejo de fibrilación auricular no valvular.

Atrial fibrillation is the most common arrhythmia and is a major risk factor for ischemic stroke and systemic embolism. The therapy for primary and secondary prevention is the anticoagulation with warfarin; antagonist of vitamin K. There are scores to predict the risk of thromboembolism and the benefit of the antitrombotic therapy. The CHADS2 score has been the easiest one and it has been used widely, but today the CHA2DS2-VASc score includes new risk factors and gives a better risk stratification. The narrow therapeutic. margin and the interaction with food and drugs requires frequents tests of intensity of anticoagulation limiting usefulness in clinical practice. There are new anticoagulants that offer advantages compared with warfarin. These drugs act in two different points of the cascade of anticoagulation; directly inhibiting thrombin like dabigatran or factor X activated like rivaroxaban, apixaban, edoxaban and betrixaban. These new agents are replacing warfarin and they are already included in the guidelines of atrial fibrillation.