Adherencia y calidad de vida en pacientes con fibrilación auricular e insuficiencia cardíaca anticoagulados con Apixaban

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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.

Recomendaciones de manejo de los anticoagulantes orales directos (DOACs) anti Xa y anti IIa / Recommendations for the practical management of the direct oral anticoagulants anti Xa and anti IIa

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.

Efecto de las diferentes drogas anticoagulantes sobre el ensayo de fibrinógeno derivado del tiempo de protrombina / Effect of different anticoagulant drugs on the prothrombin time-derived fibrinogen assay

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.

Safety of oral anticoagulants in advanced chronic kidney disease / Seguridad de los anticoagulantes orales en enfermedad renal crónica avanzada

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).

Optimization of the Extraction Procedure of Apixaban from Dried Rat Plasma Spots

Aims: Apixaban is an anticoagulant used to treat and prevent blood clots, as well as to prevent stroke in people with atrial fibrillation. The dried spot analyses, including dried blood spots and dried plasma spots, are used to simplify techniques for determining drug concentrations in blood and plasma. In this case, equipment with highly sensitive detector is required, for example, mass spectrometer, as well as a high level of drug extraction from the dried spot. In this work, apixaban extraction from dried plasma spots (DPS) was studied in order to determine the optimal parameters of the extraction method.Study Design:Short Research Articles.Place and Duration of Study: Core Facility of Mass Spectrometric Analysis, Institute of Chemical Biology and Fundamental Medicine SB RAS, between September 2019 and February 2020.Methodology: The organic extraction method was chosen for evaluation as the most suitable for LC-MS assay. Several parameters: percentage of organic solvent, presence or absence of 0.1% formic acid (FA), time, volume and temperature of extraction were investigated to find the best combination for recovery of apixaban from DPS for further LC-MS analysis.Results: The results showed that the main influence on the extraction is the composition of the solvent, volume of solvent, as well as temperature and time of extraction. Pure acetonitrile is the worst solvent for extracting apixaban from DPS. Solvents: MeOH:H2O (100:0, v: v), MeOH: 0.1% FA in H2O(80:20, v:v), ACN: 0.1% FA in H2O (90:10, v:v) or ACN:MeOH (90:10, v:v) provide better recovery of apixaban. The optimum extraction parameters were as follows: 90% acetonitrile concentration, extraction temperature of 40°C, extraction time of 15 min, and solvent volume of 100L.Conclusion: For the extraction of apixaban from DPS, subject to further analysis by LC-MS, the most suitable solvent is 90% acetonitrile under the conditions described above

Bioequivalence of apixaban tablets in healthy Chinese subjects / 中国临床药理学与治疗学

AIM: To evaluate the bioequivalence of the two preparations of apixaban tablets administered once orally under fasting and fed conditions. METHODS: The study was designed as randomized, open, self-crossover, and twenty four healthy volunteers were recruited respectively in fasting and fed conditions. Subjects were assigned to receive a single oral of the test or reference formulation per period at a dose of 2.5 mg. The plasma apixaban concentration was analyzed by LC-MS/MS. The major pharmacokinetic parameters were calculated by WinNonlin 6.4 and the bioequivalence was evaluated.RESULTS:The main pharmacokinetic parameters of a single oral apixaban under fasting condition for T and R were as follows: Cmax (80±14) and (87±21) ng/mL, AUC0-t (713±136) and (733±142) h•ng•mL-1, AUC0-∞ (722±143) and (741±142) h•ng•mL-1, tmax 2.5 h and 2.5 h, t1/2 (9±8) and (8±6) h. The relative bioavailability was 97.16% for AUC0-t, 97.20% for AUC0-∞. The main pharmacokinetic parameters of a single oral apixaban under fed condition for T and R were as follows: Cmax (70±13), (72±13) ng/mL; AUC0-t (642±130), (690±135) h•ng•mL-1; AUC0-∞ (652±129), (704±138) h•ng•mL-1. tmax 2.5 h and 2.5 h, t1/2 (8±4) and (12±9) h. The relative bioavailability was 93.03% for AUC0-t, 92.62% for AUC0-∞. CONCLUSION: The test preparation of apixaban tablets is bioequivalent to the reference preparation under both fasting and fed conditions.

The synthesis process optimization of 1(- 4-aminophenyl)-5, 6-dihydro-3- (4-morpholinyl)-2(1H)-pyridinone, an important intermediate for the apixaban synthesis / 国际药学研究杂志

Objective: To optimize the synthesis process of 1-(4-aminophenyl)-5, 6-dihydro-3-(4-orpholinyl)-2(1H)-pyridinone.Methods: Using p-nitroaniline as the raw material, the target compound was obtained by amidation, cyclization, chlorination, nitration and reduction reactions. The sodium hydride catalyst for cyclization was taken out in the reaction, the reaction acid binding agent was improved, the reaction temperature of intermediate was reduced, the optimal ratio and reaction ratio condition were investigated, and the post-processing conditions were optimized for each reaction. Results: The target compound was confirmed by 1H NMR and 13C NMR data, and the total yield was 65.4%. Conclusion: The optimized process is simple to operate, mild and controllable, and the solvent is easy to recycle, low-polluting and more conducive to industrial production.

Development And Validation Of Stability Indicating Hptlc Method For Determination Of Apixaban As Bulk Drug

Objective: To develop and validate simple, sensitive stability indicating HPTLC (High performance thin layer chromatography) method for apixaban. Methods: The chromatographic separation was performed on aluminium plates precoated with silica gel 60 F254 using toluene: ethyl acetate: methanol (3:6:1 v/v/v) as mobile phase followed by densitometric scanning at 279 nm. Results: The chromatographic condition shows sharp peak of apixaban at Rf value of 0.38±0.03. Stress testing was carried out according to international conference on harmonization (ICH)Q1A (R2) guidelines and the method was validated as per ICH Q2(R1) guidelines. The calibration curve was found to be linear in the concentration range of 100-500 ng/band for apixaban. The limit of detection and quantification was found to be 11.66ng/bandand35.33ng/band, respectively. Conclusion: A new simple, sensitive, stability indicating high performance thin layer chromatographic (HPTLC) method has been developed and validated for the determination of apixaban.

Quantification of apixaban in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry

Apixaban, an inhibitor of direct factor Xa, is used for the treatment of venous thromboembolic events or prevention of stroke. Unlike many other anticoagulant agents, it does not need periodic monitoring. However, monitoring is still required to determine the risk of bleeding due to overdose or surgery. Usually, apixaban concentrations are indirectly quantified using an anti-factor Xa assay. However, this method has a relatively narrow analytical concentration range, poor selectivity, and requires an external calibrator. Therefore, the goal of current study was to establish an analytical method for determining plasma levels of apixaban using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). To this end, apixaban was separated using 2.5 mM ammonium formate (pH 3.0) (A) and 100% methanol containing 0.1% formic acid (B) using the gradient method with a Thermo hypersil GOLD column. The mass detector condition was optimized using the electrospray ionization (ESI) positive mode for apixaban quantification. The developed method showed sufficient linearity (coefficient of determination [r² ≥ 0.997]) at calibration curve ranges. The percentage (%) changes in accuracy, precision, and all stability tests were within 15% of the nominal concentration. Apixaban concentration in plasma from healthy volunteers was quantified using the developed method. The mean maximum plasma concentration (C(max)) was 371.57 ng/mL, and the median time to achieve the C(max) (T(max)) was 4 h after administration of 10 mg apixaban alone. Although the results showed low extraction efficiency (~16%), the reproducibility (% change was within 15% of nominal concentration) was reliable. Therefore, the developed method could be used for clinical pharmacokinetic studies.

Practical guide to choosing dabigatran 150 mg twice daily or apixaban 5 mg twice daily for patients with atrial fibrillation / Journal of Rural Medicine

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.

Comparison of Apixaban and Low Molecular Weight Heparin in Preventing Deep Venous Thrombosis after Total Knee Arthroplasty in Older Adults

PURPOSE: To compare the effect of apixaban and low molecular weight heparin (LMWH) in the prevention and treatment of deep venous thrombosis (DVT) after total knee arthroplasty in older adult patients. MATERIALS AND METHODS: A total of 220 patients (average age of 67.8±6.4 years) undergoing total knee arthroplasty were randomly selected as research subjects and were divided into apixaban and LMWH groups (110 in each group). RESULTS: The incidence of DVT was lower in the apixaban group than in the LMWH group (5.5% vs. 20.0%, p=0.001). Activated partial thromboplastin times (35.2±3.6 sec vs. 33.7±2.2 sec, p=0.010; 37.8±4.6 sec vs. 34.1±3.2 sec, p<0.001; 39.6±5.1 sec vs. 35.7±3.0 sec, p=0.032) and prothrombin times (14.0±1.0 sec vs. 12.8±0.9 sec, p<0.001; 14.5±1.2 sec vs. 13.0±1.1 sec, p<0.001; 15.3±1.4 sec vs. 13.2±1.3 sec, p=0.009) in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were higher than those in the LMWH group. Platelet and fibrinogen levels in the apixaban group were lower than those of the LMWH group. Also, capillary plasma viscosity and erythrocyte aggregation in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were lower than those in the LMWH group. CONCLUSION: Apixaban, which elicits fewer adverse reactions and is safer than LMWH, exhibited better effects in the prevention and treatment of DVT after total knee arthroplasty in older adults.

Trends and Current Status of Oral Anticoagulant Use in Hospitalized Patients in China / 中国药学杂志

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.

Successful resolution with apixaban of a massive left atrial appendage thrombus due to nonrheumatic atrial fibrillation: A case report and review

A 32-year-old woman with a past medical history of paroxysmal atrial fibrillation, long QT syndrome, and implantation of an automatic iimplantable cardioverter-defibrillator (AICD) following cardiac arrest presented with disabling symptoms of paroxysmal atrial fibrillation due to recurrent AICD shocks. Before curative ablation, transesophageal echocardiography was performed to assess for existing thrombi. This is a rare case of successful resolution with apixaban of a massive left atrial appendage thrombus due to non-rheumatic atrial fibrillation that was successfully treated with apixaban.

Non-Vitamin K Oral Anticoagulants Associated Bleeding and Its Antidotes / 대한뇌졸중학회지

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.

Risk Factors of Gastrointestinal Bleeding in Patients Receiving New Oral Anticoagulants / 대한Helicobacter연구학회지

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.

Reunión multidisciplinaria sobre el uso de los anticoagulantes orales directos en la fibrilación auricular no valvular / Multidisciplinary meeting about the use of direct oral anticoagulants in nonvalvular atrial fibrillation

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.

Direct Oral Anticoagulant for the Treatment of Venous Thromboembolism in Japanese Patients with Cancer

<p>Background/Aim: There is almost no study on direct oral anticoagulant (DOAC) for the treatment of venous thromboembolism (VTE) in Japanese patients with advanced cancer. The aim of this study was to evaluate the efficacy of DOAC for the treatment of VTE in Japanese patients with advanced cancer. Methods: We retrospectively reviewed patients with active cancer who had new-onset proximal deep vein thrombosis and/or pulmonary embolism at our hospital. We compared two DOACs, edoxaban and apixaban, with warfarin and evaluated the incidence of VTE recurrence and bleeding in a period of 3 months. The recurrence was diagnosed based on computed tomography or echography findings. Results: The number of patients treated with edoxaban, apixaban, and warfarin was 47, 31, and 30, respectively. In the warfarin group, the mean international normalized ratio of prothrombin time (2SD) after 3 months was 2.11 (0.42). There was no incidence of major bleeding. Non-major bleeding occurred in 17%, 10%, and 27% of the patients treated with edoxaban, apixaban, and warfarin, respectively (edoxaban vs. warfarin, risk ratio [RR]: 0.64, 95% confidence interval [CI]: 0.27–1.52; apixaban vs. warfarin, RR: 0.38, 95% CI: 0.11–1.28). All bleeding episodes occurred in 30%, 26%, 57% of patients treated with edoxaban, apixaban, and warfarin, respectively (edoxaban vs. warfarin, RR: 0.53, 95% CI: 0.31–0.90; apixaban vs. warfarin, RR: 0.46, 95% CI: 0.23–0.89). Recurrent VTE in edoxaban, apixaban, and warfarin groups occurred in 8%, 3%, and 16% of the patients, respectively (edoxaban vs. warfarin, RR: 0.52, 95% CI: 0.18–2.18; apixaban vs. warfarin, RR: 0.22, 95% CI: 0.03–1.80). Fisher’s exact test was used for statistical analysis. Conclusion: Our study suggests that the DOAC groups are relatively at a lower risk of VTE recurrence, non-major bleeding, as well as all bleeding episodes, as compared with the warfarin group. Therefore, DOAC might be useful in the treatment of VTE in Japanese patients with advanced cancer.</p>

Pharmacokinetic-pharmacodynamic study of apixaban in rats / 药物评价研究

Objective To study pharmacodynemics and pharmacokenitics of apixaban in rats and investigate the correlation between them.Mehtods The UPLC-MS/MS method was applied to determining the plasma concentration of apixaban and draw the concentration-time curve.Meanwhile,the extension rate of prothrombin time (PT) was determined to draw the effect-time curve.Then the relationship between concentration and effect could be evaluated.Results After iv administration of apixaban (2 mg/kg) in rats,the main pharmacokinetic parameters AUC0-∞ and T1/2z were (4 016.07 ± 1 160.46) μg·h/L and (2.95 ± 1.59) h,respectively.After ig administration of apixaban (10 mg/kg),the main pharmacokinetic parameters AUC0-∞,T1/2z,Cmax,Tmax and bioavailability were (17 973.48 ± 3145.30) μg·h/L,(1.52 ± 0.36) h,(4 949.12 ± 615.38) μg/L,(1.00 ± 0.71) h and 89.5％,respectively.Apixaban (10 mg/kg) significantly increased PT and the effect lasted about 2 h.The changes of apixaban plasma concentration and PT extension rate were synchronous.Conclusion Apixaban has the characteristics of high oral bioavailability and rapid absorption.There is a significant correlation between PT extension rate and its plasma concentration after ig administration of 10 mg/kg in rats.

Determination of residual organic solvents in Apixaban bulks drug by headspace gas chromatography / 药物评价研究

Objective To establish a method for determination of the twelve residual organic solvents,including methanol,ethanol,acetone,isopropanol,tert-Butyl methyl ether,dichloromethane,aceticether,tetrahydrofuran,triethylamine,trimethylorthofor-Mate,morpholine,N,N-Dimethylformamide in Apixaban bulks drug.Methods Gas head-space chromatography was applied to this study.The column was DB-624 silica capillary column (30.0 m × 0.53 mm × 3.00 μm) and the carrier gas was high purity nitrogen;The vial temperature was 100 ℃,and the vial time was 20 min.The Column temperature was kept at 40 ℃ for 6 min,then the temperature was raised to 220 ℃ at the rate of 20 ℃/min and subsequently sustained for 10 min.FID detector temperature and injection temperature were both 250 ℃.The N2 flow rate was 2.8 mL/min.Split ratio was 5∶1.Results Twelve kinds of solvents were completely separated and determined with a good linearity (r =0.9994-0.9999).The RSD values of precision experiments and the average recovery was in line with the requirements.Conclusion Theanalytical method is simple,accurate and sensitive,which could be used for determination of residual organic solvents in Apixaban bulks drug.

Anticoagulantes orales directos: monitorización y reversión, dos grandes dificultades / Direct oral anticoagulants: measurement and reversal, Two big trouble

La tromboembolia representa una importante causa de morbimortalidad, siendo la anticoagulación el pilar del tratamiento. Los anticoagulantes orales directos, constituyen una opción que supera algunos de los inconvenientes con warfarina, como la monitorización rutinaria. No obstante con su inclusión en la práctica clínica, surgieron otras limitaciones: la dificultad para su medición cuando se requiere, debido a la poca disponibilidad y estandarización de pruebas hemostáticas; y la falta de antídotos para reversión, frente a hemorrágicas severas. Sin embargo recientemente fue aprobado idarucizumab, un anticuerpo monoclonal que neutraliza al dabigatrán, no disponible en Colombia. Se concluye que estos fármacos, son una opción atractiva, que requieren el desarrollo de pruebas diagnósticas y agentes de reversión específicos accesibles. Se realizó una búsqueda en bases de datos como Pubmed, Clinical Key, Embase, Evidence- Based MEDICINE, con las palabras clave dabigatrán, rivaroxabán, apixabán, monitorización, sangrado. Se incluyó literatura en idioma inglés y español entre 1998-2016.

Thromboembolism is a major cause of morbidity and mortality, with anticoagulation being the mainstay of treatment. The direct oral anticoagulants are an option to overcome some of the drawbacks of warfarin, such as routine monitoring. Nevertheless, new constraints have emerged by their inclusion in clinical practice: the difficulty in measuring, due to the limited availability and standardization of hemostatic tests; and the lack of antidotes for reversal, to deal with severe bleeding. However, idarucizumab was recently approved, it's a monoclonal antibody that neutralizes dabigatran, but is not available in Colombia. We concluded that these drugs are an attractive option, which require the development of diagnostic tests and available specific reversal agents. We made the research on databases such as Pubmed, Clinical Key, Embase, Evidence-Based Medicine, with keywords dabigatran, rivaroxaban, apixaban, monitoring, bleeding. We include the literature in English and Spanish language between 1998 and 2016.