ABSTRACT
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.
ABSTRACT
RESUMEN: El uso de Anticoagulantes Orales de Acción Directa (ACOD) ha aumentado considerablemente en el último tiempo. En procedimientos odontológicos, como la exodoncia, es crucial un manejo óptimo de la hemostasia de pacientes bajo tratamiento con ACOD, para equilibrar el riesgo de hemorragia y tromboembolismo. Aun no existe consenso sobre el protocolo a aplicar en pacientes con ACOD sometidos a exodoncias. El objetivo fue evaluar la necesidad de suspender o continuar el tratamiento con ACOD en pacientes sometidos a exodoncia en relación con la incidencia de episodios hemorrágicos y protocolos utilizados. Se realizó una revisión sistemática en base a los estamentos PRISMA, en las bases de datos Pubmed, Wiley, Scopus. La búsqueda incluyó estudios publicados entre 2010 - 2020 en inglés, realizados en humanos, en pacientes bajo terapia con ACOD sometidos a exodoncia y que evalúan la incidencia de hemorragia en este procedimiento. Se excluyeron estudios que involucran pacientes que reciben otros tratamientos antitrombótico concomitante, o procedimientos distintos a la exodoncia. La calidad de los estudios seleccionados fue evaluada de acuerdo con la clasificación del Centro Oxford de Medicina Basada en la Evidencia. Luego de la búsqueda, en base a criterios de inclusión/exclusión, 34 artículos fueron analizados a texto completo. Trece artículos relevantes fueron seleccionados. Once participaron en la revisión final, contando con ocho estudios de cohorte, dos casos-controles y uno serie de casos. Los estudios evidencian que no es necesario suspender la terapia con ACOD en pacientes sometidos a exodoncia, se sugiere que el momento de baja concentración farmacológica puede ser utilizado a favor del tratante. Sin embargo, existe una gran diversidad de protocolos y medidas aplicadas entre estudios, por lo que es necesario realizar estudios clínicos aleatorizados controlados, para determinar un protocolo estándar en el manejo odontológico de estos pacientes.
ABSTRACT: The use of Direct Acting Oral Anticoagulants (ACOD) has increased considerably in recent times. In dental procedures, such as tooth extraction, optimal management of hemostasis in patients treated with ACOD is crucial to balance the risk of bleeding and thromboembolism. There is still no consensus on the protocol to be applied in patients with ACOD in dental extraction. The aim was to evaluate the need to suspend or continue treatment with ACOD in patients submitted to dental extraction in relation to the incidence of bleeding episodes and the protocols used. A systematic review was carried out based on the PRISMA estates, in the Pubmed, Wiley, Scopus databases. The search included studies published between 2010-2020 in English conducted in humans, in patients under therapy with ACOD submitted to dental extraction and that evaluate the incidence of bleeding in this procedure. Studies involving patients receiving other concomitant antithrombotic treatments or procedures other than dental extraction were excluded. The quality of the selected studies was evaluated according to the Oxford Center for Evidence-based Medicine classification. After the search, based on inclusion/ exclusion criteria, 34 articles were analyzed in full text. 13 relevant articles were selected. 11 participated in the final review, including 8 cohort studies, 2 case-controls and 1 case series. Studies show that it is not necessary to suspend therapy with ACOD in patients who have undergone dental extraction, it is suggested that the moment of low pharmacological concentration can be used in favor of the treatment. However, there is a great diversity of protocols and measures applied between studies, so it is necessary to carry out randomized controlled clinical studies to determine a standard protocol in the dental management of these patients.
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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.
ABSTRACT
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.
Subject(s)
Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Argentina , Dabigatran , AnticoagulantsABSTRACT
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.
Subject(s)
Aged , Anticoagulants , Atrial Fibrillation , China , Dabigatran , Humans , Male , Middle Aged , Prospective Studies , Risk Assessment , Risk Factors , StrokeABSTRACT
Dabigatran is a new/direct oral anticoagulant drug unlike warfarin. It is being increasingly used to prevent thromboembolism in patients with nonvalvular atrial fibrillation. We present the case of a 77-year-old woman with a giant left atrial thrombus in spite of anticoagulation therapy with dabigatran 300 mg/day. She had developed a cerebral infarction 18 months previously and was switched from warfarin to dabigatran. However, magnetic resonance imaging showed multiple new cerebral infarcts, and computed tomography scan and echocardiogram revealed a giant thrombus measuring 37×29 mm in the left atrium. Thrombectomy and left atrial appendage closure were urgently performed. Dabigatran was changed to warfarin again after the operation. She has had no recurrent thromboembolic event since then.
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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.
Subject(s)
Health Evaluation , Anticoagulants , Warfarin , Cost-Benefit Analysis , Drug-Related Side Effects and Adverse Reactions , Rivaroxaban , DabigatranABSTRACT
The primary aortic thrombosis (PAT) is an uncommon noncardiac cause of distal peripheral embolization to lower extremities. Also, this condition develops in the absence of extensive atherosclerosis of aorta or abnormal dilatation like aneurysm of the aorta. In most of the cases, there was either no or minimal atherosclerosis of the aorta. The disease can involve any part of the aorta, but in most of the cases, the thoracic aorta below the origin of the left subclavian artery followed by the infrarenal portion of the abdominal aorta was the most common site of involvement. In our case, there was extensive thrombosis starting from the lower part of the thoracic aorta extending across both the renal arteries up to the aortic bifurcation without any underlying aortic pathology or hypercoagulable disease. There are no guidelines for the management of the PAT, but our experience is based on few case series, case reports, and meta-analysis where there are variable success rate using conservative medical management, endovascular procedure, or surgical thrombectomy. Vitamin K antagonist was the drug of choice in all the cases as a part of conservative medical management or used to prevent recurrence after the endovascular or surgical procedure. We present a case of PAT where the use of dabigatran leads to complete resolution and prevented the recurrence of the disease during two-year follow-up, which is the first and unique case report of the literature.
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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.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Atrial Fibrillation/prevention & control , Atrial Flutter/prevention & control , Thromboembolism/prevention & control , Warfarin/therapeutic use , Dabigatran/therapeutic use , Anticoagulants/therapeutic use , Atrial Fibrillation/complications , Atrial Flutter/complications , Thromboembolism/etiology , Brazil , Retrospective Studies , Risk Factors , Follow-Up Studies , Treatment Outcome , Statistics, Nonparametric , Stroke/etiology , Stroke/prevention & control , Ambulatory Care Facilities , Hemorrhage/prevention & control , Anti-Arrhythmia Agents/therapeutic useABSTRACT
@#Dabigatran etexilate mesylate(DE)and tadalafil(TD)are BCS class II drugs with poor water solubility. 〓 In this study coamorphization technique was used to improve their solubilities/dissolutions and hence to enhance their oral absorptions. The coamorphous DE-TD were prepared by solvent-evaporation method and characterized by PXRD, DSC, FTIR and TGA. In addition, dissolution behavior and physical stability were also investigated. Only halo pattern and a single Tg of 119 °C was observed on the PXRD and DSC of the co-evaporated product, respectively, indicating the formation of coamorphous DE-TD. FTIR result suggested that a hydrogen bond was probably formed between N-H group of DE and C==O group of TD. In comparison to crystalline counterparts, coamorphous DE-TD showed a significantly improved intrinsic dissolution rate and prolonged supersaturation time in intrinsic dissolution and supersaturation dissolution studies, respectively. No crystallization was observed under affecting factors testing(30 days)as well as long-term and accelerated stability testing(90 days)for the prepared coamorphous DE-TD under 25°C/60%RH or 40°C/75%RH, while amorphous DE crystalized at 10 days under 25 ℃/75% RH.
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OBJECTIVE: To investigate the trends and current status of oral anticoagulant (OAC) use in hospitalized patients. METHODS: OAC prescriptions of inpatients during 2012 to 2016 were extracted from the database of hospital prescription analysis cooperation program. The extracted prescriptions were restricted to hospitals which located in 5 major cities of China. The number of patients and cost of drugs were calculated and analyzed. RESULTS: A total of 258 276 prescriptions were extracted. The number of patients using OAC increased every year. Warfarin was the most frequently prescribed OAC, but the portion of warfarin decreased. Non vitamin-K antagonist anticoagulants (NOAC) including rivaroxaban increased rapidly. Imbalance existed between warfarin and NOAC on patient population and cost. The use of OAC differed by indications and specialists. CONCLUSION: The number of patients and cost of drugs increased every year while NOAC had taken a large portion of cost. Attention should be payed to the rationality of OAC use.
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@#Background: Direct oral anticoagulants (DOACs) especially dabigatran, have gain popularity for their efficacy, fixed dosing and favourable safety profile. A dabigatran prescribing checklist has been prepared by the Ministry of Health, Malaysia (MOH) to ensure rational and safe prescribing of dabigatran. This study therefore aimed to audit the utilization and documentation of this checklist and use of dabigatran in the government healthcare facilities. Methods: This is a nationwide retrospective audit on the documentation of Dabigatran Prescribing and Dispensing Checklist for a period of two years from January 2013 till December 2014. Data from these Dabigatran Checklists (indication, dose, duration, renal function and adverse drug reactions encountered) were extracted by the pharmacist at MOH healthcare facilities. Results: A total of 52 out of 56 (92.9%) of MOH facilities complied to usage of checklist at their centres involving a total of 582 patients of which 569 (97.7%) patients were initiated on dabigatran for the approved indications. The recommended dose of dabigatran was used correctly in 501 (99.6%) of patients. Reason for switching to DOACs use was only documented in 76.7% (131/171) of patients. The most common reason for switching from warfarin was poor INR control (n=39), history of bleeding/overwarfarinisation (n=22) and unable to attend regular INR clinic (n=21). There were 75 cases of adverse events reported. The most common adverse event reported were abdominal discomfort (n=10) followed by gum bleeding (n=9) and dizziness (n=5). Conclusions: Compliance to the dabigatran check list was high with 70% of patients prescribed the appropriate dosing.
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Objective To observe the effect of low-dose dabigatran etexilate on the clinical efficacy of elderly patients with venous thromboembolism (VTE). Methods Seventy-five elderly (≥ 80 years old) VTE patients admitted to Cangzhou Central Hospital from October 2016 to June 2018 were enrolled, they were treated according to the VTE guidelines, and low dose dabigatran etexilate was the anticoagulant therapy selected, 110 mg once daily for 6 months. After treatment for 6 months, the thrombus regression situation with color Doppler ultrasonography;clinical efficacy was evaluated by clinical symptoms and ultrasonographic results, the changes in platelet count (PLT), coagulation parameters [international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (Fib)] before and after treatment were detected and the occurrence of adverse reactions were recorded and safety of drug was evaluated. Results There were no significant differences in PLT, INR and Fib before and after treatment [PLT (×109/L): 197.88±58.00 vs. 199.88±65.15, INR: 1.02±0.10 vs. 1.05±0.13, Fib (g/L): 2.89±0.67 vs. 2.84±0.70, all P > 0.05], the APTT after treatment was significantly prolonged compared with that before treatment (seconds:40.9±7.34 vs. 26.2±3.16), the difference being statistically significant (P < 0.05), the amount of APTT prolongation after treatment did not exceed 2 times [average (1.75±0.24) times] of the baseline value before treatment. The total effective rate of low-dose dabigatran etexilate for treatment of elderly patients with VTE for 6 months was 90.7% (68/75);no obvious adverse reactions occurred during the treatment. Conclusion Low-dose dabigatran etexilate for treatment of elderly patients with VTE is safe and effective without any obvious adverse reactions, and is worthy to be promoted for clinical use.
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Based on previous reports, we propose a practical guide to choose dabigatran 150 mg twice daily or apixaban 5 mg twice daily for patients with atrial fibrillation. We recommend the use of dabigatran 150 mg twice daily for patients with atrial fibrillation who have a high risk of embolism (e.g., ischemic stroke on other oral anticoagulants, presence of left atrial appendage thrombus) and a low risk of bleeding. However, the prevalence of such patients with atrial fibrillation is considered low because patients with atrial fibrillation with a high risk of embolism usually have a high risk of bleeding. In most other patients with atrial fibrillation, the use of apixaban 5 mg twice daily should be considered.
ABSTRACT
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)
Subject(s)
Humans , Osteoblasts , Surgery, Oral , Tooth Extraction , Warfarin , Postoperative Hemorrhage , Dabigatran , Anticoagulants/therapeutic use , Cohort StudiesABSTRACT
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].
Subject(s)
Anticoagulants , Atrial Fibrillation , Stroke , Rivaroxaban , DabigatranABSTRACT
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.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Tooth Extraction/adverse effects , Warfarin/adverse effects , Blood Loss, Surgical , Dabigatran/adverse effects , Anticoagulants/adverse effects , Reference Values , Time Factors , Bleeding Time , Prospective Studies , Risk Factors , Treatment Outcome , Statistics, NonparametricABSTRACT
Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.
Subject(s)
Anticoagulants , Antidotes , Avena , Cerebral Hemorrhage , Dabigatran , Hemorrhage , Humans , Mortality , Partial Thromboplastin Time , Prothrombin , Prothrombin Time , Rivaroxaban , Vitamin KABSTRACT
New oral anticoagulants (NOACs) are now widely used for the prevention and treatment of venous thrombosis, and for the prevention of stroke and systemic embolism in patients with atrial fibrillation. As compared with warfarin, NOACs have the advantage of rapid onset of action and less drug interaction. However, they carry a higher risk of gastrointestinal (GI) bleeding than warfarin. The risk of GI bleeding in patients using NOACs varies according to the type and dose of the drug. By contrast, apixaban and edoxaban are reported to carry similar risks as warfarin, and the risks with dabigatran and rivaroxaban are higher than that with warfarin. In patients using NOACs, old age, impaired renal function, impaired liver function, concurrent use of antiplatelet agents, and nonsteroidal anti-inflammatory drugs are considered major risk factors of GI bleeding, and gastroprotective agents such as histamine-2 receptor antagonist and proton pump inhibitor have preventive effects. To prevent GI bleeding associated with NOACs, the characteristics of each NOAC and the risk factors of bleeding should be recognized.