Development of an interview-based warfarin nomogram predicting the time spent in the therapeutic INR range: A cost-effective, and non-invasive strategy building from a cross sectional study in a low resource setting

A cross-sectional study was conducted to predict time in therapeutic range (TTR) using clinical history, examination, and socioeconomic data. Study included warfarin-receiving patients from outpatient-clinic. In 203 patients studied, mean warfarin start-dose was 2.55 mg/day and maintenance-dose/week was 30.79 mg. Body mass index (BMI) (p ¼ 0.03), warfarin maintenance dose/day (p ¼ 0.02), and comorbidity presence (p ¼ 0.04) were significantly associated with TTR. Occupation (p ¼ 0.53), income (p ¼ 0.83), education (p ¼ 0.55), and socioeconomic score (p ¼ 0.73) showed non-significant association with TTR. A TTR predicting nomogram was built from clinical history and examination findings.

Análisis de la calidad de la anticoagulación con antagonistas de la vitamina K en tres escenarios clínicos en México / Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico

Resumen Introducción: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. Objetivo: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. Métodos: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. Resultados: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. Conclusiones: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Abstract Introduction: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. Objective: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. Methods: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. Results: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. Conclusions: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

Study on warfarin dose adjustment strategy at different stages after mechanical valve replacement of mitral valve / 中国胸心血管外科临床杂志

@#Objective    To explore the anticoagulant strategy of adjusting the dose of warfarin at different stages after mechanical valve replacement of mitral valve. Methods    Clinical data of a total of 302 patients, including 76 males and 226 females, with an average age of 50.1±10.1 years, who underwent mechanical mitral valve replacement in the Chinese adult cardiac surgery database from 2013 to 2017 were retrospectively analyzed. According to the dose adjustment strategy of taking warfarin, the patients were divided into a D group (adjusting warfarin dose in days) and a W group (adjusting warfarin dose in weeks) to evaluate the anti-coagulation effect of warfarin. Results    The total follow-up time was 423 277 d (1 159.7 years). There was no significant difference in the overall anticoagulant strength, and the warfarin dose adjusted in days was better in the early postoperative period (P<0.05), especially in patients over 60 years. It was better to adjust warfarin dose in weeks in the middle and long periods (P<0.05), especially in patients ≤40 years. In terms of the stability of anticoagulation, it was better to adjust the dosage of warfarin in weeks (P<0.05). It was better to adjust the dosage of warfarin in weeks for early, middle- and long-term anticoagulant therapy after operation (P<0.05), especially in the females aged >40 and ≤50 years. Conclusion    Within the target range of international normalized ratio (1.5-2.5), the anticoagulant strategy of adjusting warfarin dose in days after mechanical valve replacement of mitral valve can   achieve a better anticoagulant strength, and adjusting the dosage of warfarin in weeks is better in the middle- and long-term after operation. In general, the anticoagulant effect is more stable in the short term when warfarin dose is adjusted on a weekly basis.

SAMe-TT2R2 score for prediction of suboptimal time in therapeutic range in a Thai population with atrial fibrillation

INTRODUCTION@#International normalised ratio (INR) control is an important factor in patients with non-valvular atrial fibrillation (NVAF) being treated with warfarin. INR control was previously reported to be poorer among Asians compared to Westerners. We aimed to validate the SAMe-TT2R2 score for prediction of suboptimal INR control (defined as time in therapeutic range [TTR] < 65% in the Thai population) and to investigate TTR among Thai NVAF patients being treated with warfarin.@*METHODS@#INR data from patients enrolled in a multicentre NVAF registry was analysed. Clinical and laboratory data was prospectively collected. TTR was calculated using the Rosendaal method. Baseline data was compared between patients with and without suboptimal INR control. Univariate and multivariate analyses were performed to identify variables independently associated with suboptimal INR control.@*RESULTS@#A total of 1,669 patients from 22 centres located across Thailand were included. The average age was 69.1 ± 10.7 years, and 921 (55.2%) were male. The mean TTR was 50.5% ± 27.5%; 1,125 (67.4%) had TTR < 65%. Univariate analysis showed hypertension, diabetes mellitus, heart failure, renal disease and SAMe-TT2R2 score to be significantly different between patients with and without optimal TTR. The SAMe-TT2R2 score was the only factor that remained statistically significant in multivariate analysis. The C-statistic for the SAMe-TT2R2 score in the prediction of suboptimal TTR was 0.54.@*CONCLUSION@#SAMe-TT2R2 score was the only independent predictor of suboptimal TTR in NVAF patients being treated with warfarin. However, due to the low C-statistic, the score may have limited discriminative power.

The Impact of Clinical Pharmacy Services on the Quality of Warfarin Anticoagulation Therapy Management / 中国药学杂志

OBJECTIVE: To evaluate the effects of clinical pharmacy services in patients with warfarin and highlight the important role of clinical pharmacists. METHODS: Patients in need of warfarin were enrolled as intervention group during 2016.9-2017.9 to receive standard anticoagulation management and follow-up provided by clinical pharmacists, and clinical data of patients who meet the inclusion criteria during 2013.7-2015.7 as control group was analyzed retrospectively. International normalized ratio(INR) values, maintenance doses, time to achieve therapeutic range, and etc. were recorded and TTRs (time in therapeutic range) were calculated to compare the outcomes of each group. RESULTS: TTRs in intervention group were significantly higher than those in control group, and so was the percentage of patients with the best quality of warfarin therapy(47.89% vs. 20.09%,P<0.001).Time to achieve therapeutic range was shorter and the frequency of INR test was higher in intervention group compared with those in control group. Patients′ cognitive scores of warfarin therapy were substantially increased after pharmacist′s education. CONCLUSION: Anticoagulation therapy management provided by clinical pharmacists could significantly improve the quality of warfarin therapy.

Telemanagement of anticoagulant therapy for patients after mechanical heart valve replacement: A prospective cohort study / 中国胸心血管外科临床杂志

@#Objective To explore the safety and efficacy of mobile APP in telemanagement for patients who received oral warfarin anticoagulant therapy after mechanical heart valve replacement. Methods A prospective cohort study was performed. According to the inclusion and exclusion criteria, a total of 80 patients who underwent mechanical heart valve replacement for more than half a year and received oral warfarin anticoagulant therapy in outpatient department were included in our hospital from January 1, 2017 to December 31, 2017. These patients were divided into a telemanagement group (40 paitents, telemanagement using mobile APP) and a control group (40 patients, anticoagulant management in outpatient clinics) according to patients' wishes and local hospital international normalized ratio (INR) monitoring conditions. After 12-month follow-up, clinical effect of the two groups was compared. The INR, time in therapeutic range (TTR), fraction in therapeutic range (FTTR), anticoagulation-related complications and patient satisfaction were analyzed. Results During the follow-up period of anticoagulation, there was no significant difference in INR between the two groups (P=0.732). The average interval of INR monitoring in the telemanagement group was 3-65 (21.4 ± 12.5) days, while that in the control group was 7-93 (39.6 ± 14.7) days (P=0.012). TTR was 42.7% (6 027.6 d/14 116.0 d) in the control group and 67.9% (10 168.6 d/14 972.0 d) in the telemanagement group (P=0.018). And FTTR in the two groups was 45.6% (144/316) and 67.1% (432/644), respectively (P=0.015). No serious thromboembolism or hemorrhage events occurred in the 80 patients during the 12-month follow-up period. There was no significant difference in the incidence of anticoagulation-related complications, general bleeding and embolism between the two groups (P>0.05). Conclusion For patients with stable anticoagulation after cardiac mechanical valve replacement, it is safe and effective to telemanagement by mobile APP. Telemanagement can increase the frequency of anticoagulation monitoring without increasing anticoagulation risk, meanwhile, it also could obtain more convenient and rapid consultation, save time and economic costs,and improve the quality of life and patient satisfaction.

Quality of Anticoagulation with Warfarin in Korean Patients with Atrial Fibrillation and Prior Stroke: A Multicenter Retrospective Observational Study

BACKGROUND AND PURPOSE: The quality of anticoagulation is critical for ensuring the benefit of warfarin, but this has been less well studied in Korean ischemic stroke patients with atrial fibrillation (AF). METHODS: This study retrospectively analyzed the data of patients who had an AF-related ischemic stroke and were treated with long-term warfarin therapy in 16 Korean centers. The quality of warfarin therapy was primarily assessed by the time in therapeutic range [TTR; international normalized ratio (INR), 2.0–3.0] and additionally by the proportion of INR values within the therapeutic range. RESULTS: The long-term warfarin-treated cohort comprised 1,230 patients. They were aged 70.1±9.7 years (mean±SD), 42.5% were female, and their CHA₂DS₂-VASc score was 4.75±1.41. The TTR analysis included 33,941 INR measurements for 27,487 months: per patients, 27.6 (SD, 22.4) INR measurements for 22.4 (SD, 12.9) months. The mean TTR of individual patients was 49.1% (95% confidence interval, 47.9–50.3%), and the TTR quartiles were 64.5%. None of the 16 centers achieved a mean TTR of >60%. Of all INR measurements, 44.6% were within the therapeutic range, 41.7% were 3.0. CONCLUSIONS: In Korean ischemic stroke patients who had AF, the quality of warfarin therapy was low and might be inadequate to effectively prevent recurrent stroke or systemic embolism.

Tiempo en rango terapéutico (TRT) en clínica de anticoagulación Reportes de eventos adversos y factores asociados a bajo TRT / Time in therapeutic range (TTR) in anticoagulation clinic Reports of adverse events and factors associated with low TTR

En el tratamiento de anticoagulación con warfarina, la reducción de eventos tromboembólicos debe ser valorada con el riesgo de sangrado. El tiempo de rango terapéutico (TRT) por el método de Rosenda al es una herramienta que valora la calidad en la monitorización de la terapia anticoagulante y se correlaciona con presencia de eventos tromboembólicos o sangrados. En este estudio se describe el tiempo de rango terapéutico (TRT R), los factores relacionados con menor (TRT R) y los efectos adversos presentados en la clínica de anticoagulación. Métodos y resultados: Estudio descriptivo de corte transversal entre el 1º de enero de 2011 y el 29 de febrero de 2012. Fueron evaluados 2232 resultados de INR de 319 pacientes. 98.550 días de seguimiento. 44% (108) hombres, 66% (211) mujeres, la edad promedio 60.3 años, siete visitas promedio/año, dosis semanal de warfarina 29.8 mg. La dosis semanal presenta una relación inversa con la edad, en menores de 45 años 37.9 mg y en mayores de 75 años 22.1 mg. El TRT R incrementó de 48-54%, respectivamente. Las indicaciones para anticoagulación: fibrilación auricular (FA) 38% (121), enfermedad tromboembólica venosa (ETEV) 35% (112), prótesis valvulares (PV) 17.5%(56) y embolia o trombosis arterial (EA) 9.5%(30). 228 pacientes (71%) presentaron un TRT R promedio del 64%. (40-100) INR mayor de 5 en 2.24% e INR menor de 1.5 en 10.9%. Sangrados menores: 16 pacientes (5%), sangrado mayor se presentó en dos pacientes (0.65%) y un evento adverso por embolia (0.32%). Los factores asociados a un TRT R bajo fueron: sexo masculino, enfermedad tromboembólica venosa, uso de warfarina genérica, edad menor de 55 años, tiempo menor de un año y menos de cinco visitas. Conclusiones: El tiempo de rango terapéutico TRT es una medición útil para establecer la eficacia de la terapia anticoagulante con warfarina. La meta de 60% en tiempo de rango terapéutico garantiza menos efectos adversos por sangrado o trombosis. Un número bajo de visitas y anticoagulación menor de un año están asociados a bajo TRT. (Acta Med Colomb 2016; 41: 42-48).

In the treatment of warfarin anticoagulation, reduction of thromboembolic events must be evaluated with the risk of bleeding. Time in therapeutic range (TTR) by the method of Rosendaal is a tool that values quality monitoring anticoagulant therapy and correlates with the presence of thromboembolic events or bleeding. In this study time therapeutic range (TTR), factors associated with lower (TTR) and adverse effects presented in the anticoagulation clinic are presented. Methods and Results: A descriptive cross-sectional study from 1° January 2011 and 29th February 2012. 2232 results of INR of 319 patients were assessed. 98550 days follow up. 44% (108) were men, 66% (211) women, average age 60.3 years, seven average visits/year, warfarin weekly dose of 29.8mg. The weekly dose has an inverse relationship with age; in patients under 45 years 37.9 mg., and in patients over 75 years, 22.1 mg. The TTR increased from 48 to 54%, respectively. Indications for anticoagulation: atrial fibrillation (AF) 38% (121), venous thromboembolic disease (VTE) 35% (112), prosthetic valves (PV) 17.5% (56) and emboli or arterial thrombosis (EA) 9.5% (30). 228 patients (71%) had a TTR average of 64%. (40-100), INR greater than 5 in 2.24% and INR less than 1.5 in 10.9%. Minor bleeding: 16 patients (5%), major bleeding occurred in two patients (0.65%) and oneadverse event of embolism (0.32%). The factors associated with low TTR were male gender, venous thromboembolic disease, use of generic warfarin, age less than 55 years, time shorter than one year and less than five visits. Conclusions: TTR is a useful measurement to establish the efficacy of anticoagulant therapy with warfarin. The goal of a 60% TTR ensures fewer adverse effects from bleeding or thrombosis. A low number of visits and anticoagulation less than a year are associated with low TTR. (ActaMed Colomb 2016; 41: 42-48).

Quality Evaluation of Anticoagulant Therapy in Patients Who Taking Warfarin in Our Hospital / 中国药房

OBJECTIVE:To evaluate the quality of anticoagulant therapy in patients who took warfarin and provide data sup-porting for strengthening the management of these patients. METHODS:A retrospective analysis of related clinical data of 214 pa-tients who meet the inclusion criteria was performed. RESULTS:The average time for patients took warfarin was (321.64 ± 189.50)d,average times for tested INR was(12.01±7.03)times in clinic;when anticoagulant therapy,INR3.0 accounted for 8.91%;patients with target INR≤2.0 accounted for 45.33%,target INR=2.5 accounted for 38.32%,and target INR≥3.0 accounted for 0.93%;the average TTR was (50.80 ± 22.32)%;and there was no statistical significance in the TTR of different ages and diseases(P>0.05). CONCLUSIONS:The anti-coagulant therapy in some patients who took warfarin shows poor quality,it needs strengthening the quality management to make it safe and effective.

Point of care testing for proper use of warfarin in physician-pharmacist cooperative practice : assessment of patient adherence to therapeutic regimens and time in therapeutic range / 日本プライマリ・ケア連合学会誌

<b>Objectives</b> : A pharmacotherapeutic system for safe and proper use of warfarin was developed through physician-pharmacist cooperative practice ; its effects on patient adherence to therapeutic regimens and the therapeutic benefit of warfarin were assessed.<br><b>Methods</b> : Subjects were 12 outpatients or home-care patients receiving warfarin. Patients' level of understanding of warfarin therapy and time in therapeutic range (TTR) were used as indices of adherence and therapeutic benefit, respectively. Before the physician examination, patients were interviewed by pharmacists using point-of-care testing with the CoaguChek ^®XS to check their prothrombin time-international normalized ratio (PT-INR). Pharmacists reported status of warfarin administration, any adverse effects, and medication management status to each patient's physician using the medication record or inter-institute information exchange sheet. Patient adherence was assessed before and after the pre-examination interview and changes in TTR were evaluated.<br><b>Results</b> : Levels of understanding of warfarin therapy were significantly higher after pharmacists provided medication counseling (immediately before 4.8±1.9 vs 24 weeks after 6.8±2.4 ; P=0.0079, Wilcoxon signed-rank test). TTR significantly improved at 24 weeks after the interview (pre-interview 20.9±29.8% vs post-interview 60.5±30.5%, respectively ; P=0.0024, Wilcoxon signed-rank test).<br><b>Conclusion</b> : The results suggest that patients'adherence to warfarin regimens and the therapeutic benefit of warfarin is improved by pharmacists'obtaining information on PT-INR before patients'medical examinations, as well as by utilizing this information to establish a cooperative pharmacotherapeutic system for good TTR management, as supported by a common protocol across pharmacies and medical institutions.

Establishing the heparin therapeutic range using aPTT and anti-Xa measurements for monitoring unfractionated heparin therapy

BACKGROUND: Unfractionated heparin (UFH) has unstable pharmacokinetics and requires close monitoring. The activated partial thromboplastin time (aPTT) test has been used to monitor UFH therapy for decades in Korea, but its results can be affected by numerous variables. We established an aPTT heparin therapeutic range (HTR) corresponding to therapeutic anti-Xa levels for continuous intravenous UFH administration, and used appropriate monitoring to determine if an adequate dose of UFH was applied. METHODS: A total of 134 ex vivo samples were obtained from 71 patients with a variety of thromboembolisms. All patients received intravenous UFH therapy and were enrolled from June to September 2015 at Gyeongsang National University Hospital. All laboratory protocols were in accordance with the Clinical and Laboratory Standards Institute guidelines and the College of American Pathologist requirements for aPTT HTR. RESULTS: An aPTT range of 87.1 sec to 128.7 sec corresponded to anti-Xa levels of 0.3 IU/mL to 0.7 IU/mL for HTR under our laboratory conditions. Based on their anti-Xa levels, blood specimen distribution were as follows: less than 0.3 IU/mL, 65.7%; 0.3–0.7 IU/mL (therapeutic range), 33.6%; and more than 0.7 IU/mL, 0.7%. No evidence of recurring thromboembolism was observed. CONCLUSION: Using the conventional aPTT target range may lead to inappropriate dosing of UFH. Transitioning from the aPTT test to the anti-Xa assay is required to avoid the laborious validation of the aPTT HTR test, even though the anti-Xa assay is more expensive.

Evaluation of Peri-procedural Warfarin Therapy Undergoing Cardioversion in Patients with Atrial fibrillation

OBJECTIVE: Direct current cardioversion for atrial fibrillation could be associated with the risk of thromboembolic events. Anticoagulation therapy with warfarin (INR 2.0-3.0) is recommended 3 weeks before and 4 weeks after cardioversion to reduce the risk of thromboembolism. This study evaluated warfarin therapy in pharmacist-managed anticoagulant services (ACS). METHODS: This retrospective study was performed in 106 patients with atrial fibrillation from 2012 to 2013. The primary efficacy endpoint was the composite of stroke, transient ischemic attack, myocardial infarction, and cardiovascular death. The primary safety measure was major bleeding. To evaluate the peri-procedural effects of warfarin treatment, we studied whether target INR was maintained, as well as the maintenance period of the therapeutic range. Quality of treatment was measured by time in therapeutic range (TTR) by using the Rosendaal method. RESULTS: There were no thromboembolic events, but TEE examination at time of cardioversion showed a left atrial thrombus in three patients (2.8%). Bleeding complications after cardioversion occurred in 2 patients (1.9%). The average INR value at the time of cardioversion was 2.59±0.8, and was within the therapeutic range in 83 patients (78%). Analysis of the patients in whom the value was within the therapeutic range twice consecutively showed that the ratio of TTR was 80% and the therapeutic range was maintained in 67 patients (63%) for an average of 4.90 weeks prior to cardioversion. Similarly, 76 patients (72%) had a stable INR within the therapeutic range for an average of 5.70 weeks and a mean TTR of 83%. CONCLUSION: Pharmacists significantly contributed to appropriate warfarin treatment with close monitoring during cardioversion. Likewise, active pharmacist monitoring and systemic management should be considered to reduce thromboembolism and bleeding complications in the peri-cardioversion period.

Determinación del margen terapéutico y estudio de la equivalencia biofarmacéutica de las tabletas multifuentes de digoxina de 0.25 mg / Determination of therapeutic range and study of biopharmaceutical equivalence of two multisource Digoxin tablets of 0.25 mg

Determinar teóricamente el margen terapéutico y experimentalmente, los parámetros de la equivalencia biofarmacéutica de dos lotes de tabletas de multifuentes de digoxina de 0,25 mg. Material y Métodos: Se estudiaron dos lotes, cada una de 200 tabletas de multifuentes de digoxina de 0,25 mg, asignándoles el código de multifuente TDH025lote 105031 y TDF025 lote 10940431. El margen terapéutico teórico se determinó mediante la fórmula farmacocinética VT = Fracción α/ Fracción α predicha x concentración usual; luego, por diferencia de la CmE y CME se obtuvo el margen terapéutico. El Método analítico utilizado para la cuantificación del principio activo, fue el descrito en la Farmacopea Internacional de la Organización Mundial de la Salud (OMS); la prueba de desgaste por rozamiento y el grado de dureza, se determinó de acuerdo a la USP. Resultados: el margen terapéutico fue 1,2 ng/ml; los parámetros de la equivalencia biofarmacéutica: porcentajes de principio activo de los dos lotes de medicamentos multifuentes se encontraron dentro del rango de aceptación (90-110%) propuestos por la USP y la OMS: El desgaste por rozamiento del TDH025 presentó un 0,55% y el TDF025 tuvo un 0,56%, ambos valores estuvieron por debajo del 1% (valor aceptable) y la dureza indicó un soporte de choque mecánico aceptable. Las 06 tabletas se desintegraron completamente, al pasar por un tamiz Nº 10 (1700 μM), en un medio de disolución simulado de pH gástrico e intestinal en un tiempo menor de 5 minutos. Conclusión: Se demostró la equivalencia biofarmacéutica de los medicamentos multifuentes de digoxina de 0,25 mg TDH025 lote 105031 y del TDF025 lote 10940431, de acuerdo al criterio de aceptación de la USP y OMS, el principio activo (digoxina) cuantificado en cada lote estuvo dentro del rango de 90-110%; los parámetros de desgaste por rozamiento y la dureza, indicaron una adecuada estabilidad en su tiempo de vida útil...

To determine the therapeutic safety theoretically and experimentally, the biopharmaceutical equivalence parameters of two batches of multisource Digoxin tablets of 0.25mg. Material and Methods: Two batches, each of 200 tablets multisource digoxin 0.25 mg were studied, assigning code multisource TDH025 Lot 105031 and TDF025 Lot 10940431. The therapeutic range was determined by theoretical formula VT = αFraction pharmacokinetics / αpredicted fraction by usual concentration x, then by the difference CmE and CME, the therapeutic range was obtained. The analytical method used for quantification of the active ingredient, was described in The International Pharmacopoeia of the World Health Organization (WHO); while the fretting test and the hardness was determined according to the USP. Results: The therapeutic index is 1.2 ng/ml; and evaluation of the parameters of the biopharmaceutical equivalence percentages of active ingredient of the two lots of multisource drugs are within the acceptance range (90-110%) given in the USP and WHO. The fretting of TDH025 fretting batch 105031 was 0.55% and TDF025 was 0.56%, both values are below 1% which is acceptable value; and hardness indicates an acceptable mechanical shock endurance. The 06 tablets were completely disintegrated, passing through a No. 10 (1700 uM) sieve, in a dissolution medium simulating gastric and intestinal pH in less than 5 min. Conclusion: Biopharmaceutical equivalence of multisource drugs digoxin 0.25 mg TDH025 TDF025 batch batch 105031 and 10940431 was demonstrated according to the acceptance criteria of the WHO and USP, the active ingredient (digoxin) quantified in each batch were within the range of 90-110%; attrition and hardness parameters indicate adequate stability in their lifetime...

Factores asociados a irn fuera de rango terapéutico en usuarios de terapia anticoagulante oral con antagonistas de vitamina k / Factors determining inadequate inr values in patients receiving chronic anticoagulant treatment with vitamin k antagonists

Introducción: La terapia anticoagulante oral es una herramienta esencial para prevenir eventos tromboembólicos. Los fármacos más utilizados para este propósito son los antagonistas de vitamina K, cuyo efecto se monitoriza con el International Normalized Ratio (INR). Existen varios factores que afectan el nivel de anticoagulación. Objetivo: Identificar los factores asociados a un INR fuera de rango terapéutico. Metodología: Estudio observacional de corte transversal que analizó los datos de pacientes en TACO, controlados en un policlínico especializado del Hospital Naval Almirante Nef. Resultados: Se analizaron los datos de 374 pacientes, correspondiendo 196 a hombres (52,4 por ciento). La edad promedio fue de 74 +/- 12 años. Un total de 272 pacientes presentaron un INR en rango terapéutico (72,7 por ciento), 102 usuarios tenían un INR no adecuado para su patología (27.3 por ciento). Los principales motivos asociados a un INR fuera de rango fueron: Olvido en la toma de medicamentos (35,3 por ciento), alteraciones dietarias (16,7 por ciento) e interacciones farmacológicas (14,7 por ciento). Se encontró asociación estadísticamente significativa con una edad > 80 años y un INR fuera de rango terapéutico (p=0,03). Discusión: Los pacientes en TACO controlados en el policlínico especializado del Hospital Naval Almirante Nef, presentan una frecuencia mayor de INR dentro de rango terapéutico que lo reportado por la literatura. Los factores reportados como probables causas de presentar un nivel de anticoagulación fuera de rango terapéutico coinciden con los descritos en diversos estudios. Finalmente, queda de manifiesto la importancia del cuidado de los adultos mayores, dado que son los más susceptibles de presentar un control inadecuado, particularmente aquellos que tienen 80 o más años.

Introduction: Oral anticoagulant therapy is an essential tool for prevention of thromboembolic events. The drugs most commonly used for this purpose are the vitamin K antagonists, which are monitored through the International Normalized Ratio (INR). Several factors affect the level of anticoagulation. Aim: To identify factors associated with an INR outside the therapeutic range. Methods: Cross-sectional observational study that analyzed data from patients in oral anticoagulant therapy, controlled at the anticoagulant clinic of the Almirante Nef Naval Hospital. Results: We analyzed data from 374 patients, 196 of them men (52.4 percent). Mean age was 74 +/- 12 years. 272 patients (72.7 percent) had an INR within the therapeutic range; 102 (27.3 percent) had an inadequate INR. Major factors associated with an INR out of range were: forgetting to take the medication (35.3 percent), alterations in diet (16.7 percent) and drug interactions (14.7 percent). A statistically significant association was found between age over 80 years and an INR outside the therapeutic range (p = 0,03). Conclusions: Patients followed for oral anticoagulant therapy at a specialized clinic have an INR within therapeutic range most of the time. Factors reported as probable causes of inadequate INR were consistent with those described in several studies. Special attention should be paid to elderly patients, as they are the most susceptible to inadequate control.

Warfarina versus acenocumarol en alcanzar niveles terapéuticos en una población ambulatoria / Comparison of acenocumarol vs. warfarin in achieving oral anticoagulation therapeutic level in ambulatory patients

Introducción: La anticoagulación constituye una terapia farmacológica habitual en la práctica clínica diaria. En Chile, los ACO disponibles y utilizados son warfarina y acenocumarol, no existiendo mayores experiencias nacionales documentadas sobre el mayor beneficio de un fármaco en particular. Objetivo: Analizar y comparar la eficacia terapéutica de warfarina y acenocumarol en una población ambulatoria. Metodología: Estudio retrospectivo, longitudinal. Se analizó 188 pacientes que estuvieron en tratamiento con acenocumarol durante más de un año, y que luego fueron cambiados a warfarina. Se registró: sexo, edad, efectos adversos, diagnóstico y justificación de inicio de ACO. Se obtuvo el promedio del International Normalizad Ratio (INR) de los últimos 3 meses de tratamiento con acenocumarol. Luego, se sustituyó por warfarina, obteniendo luego de un año de tratamiento, el INR promedio de los últimos 3 meses. Los pacientes se agruparon en tres grupos: Bajo rango terapéutico (INR<2.0), en rango terapéutico (INR=2.0-3.0), sobre rango terapéutico (INR>3.0). Resultados: En los pacientes con acenocumarol, se observó 67 (35,64 por ciento) bajo rango terapéutico; 91 (48,4 por ciento) en rango terapéutico; y 30 (15,96 por ciento) sobre rango terapéutico. Luego del cambio a warfarina, 76 (40,43 por ciento) bajo rango terapéutico; 95 (50,53 por ciento) en rango terapéutico; y 17 (9,04 por ciento) sobre rango terapéutico, diferencias no significativas. Bajo el efecto de ambos fármacos no se registraron hemorragias mayores y no hubo diferencia significativa en hemorragias menores. Discusión: La eficacia terapéutica fue similar con ambos fármacos. A pesar de que con acenocumarol se obtuvo mayor porcentaje de pacientes sobre rango terapéutico, no se observaron complicaciones mayores en el periodo de seguimiento.

Background: oral anticoagulation is frequently needed in clinical practice. Warfarin and acenocumarol are available in Chile for this purpose. Locally there is no evidence favoring one over the other Aim: To compare the efficacy of warfarin and acenocumarol in an ambulatory population. Method: A retrospective study compared data on 188 patients with over 1 year of treatment with acenocumarol, before and after being switched over to treatment with warfarin. Demographic data, adverse effects, diagnosis and indication for oral anticoagulation were record. INRs obtained in the last 3 months of treatment with each agent were compared. Patients were classified in 3 groups: insufficient level (INR < 2.0), adequate level (INR 2.0- 3.0) and high level (INR > 3.0) of anticoagulation. Results: With acenocumarol, low level INR was present in 35.6 percent>, adequate INR in 48.4 percent> and high INR in 15.9 percent> of subjects. After switching to warfarin, corresponding levels in each group were 40.4 percent>, 50.3 percent> and 9 percent> (NS). There were no serious bleeding episodes in either group; minor hemorrhages occurred with similar frequency in both groups. Conclusion: There was similar clinical efficacy of oral anticoagulation with acenocumarol compared to warfarin. The slightly higher percentage of acenocumarol treated patients exhibiting a high IRN level did not result in increased risk of hemorrhage.

Evaluation of the activated partial thromboplastin time (aPTT) sensitivity to unfractionated heparin using three commercial reagents: Implication for therapeutic range.

At present, we are using the proposed therapeutic range for monitoring unfractionated heparin therapy which is the aPTT ratio of 1.5-2.5. However, the aPTT value is influenced by reagents and methods of detection. The College of American Pathologists and the American College of Chest Physicians recommended that site-specific validation of heparin therapeutic range should be established. The aim of this study was to determine the appropriate therapeutic range of unfractionated heparin therapy of our aPTT system by ex vivo study. For comparison, two other commercial reagents were also determined to observe the differences. Blood samples were drawn from 21 healthy blood donors who were not taking any medication and from other 24 patients suffering from either arterial or venous thrombosis, receiving continuous intravenous infusion of unfractionated heparin without concomitant oral anticoagulant therapy. Correlation coefficients between aPTT ratios and plasma heparin concentration varied between 0.722 (Actin FSL) to 0.817 (Actin FS). Calculated therapeutic ranges of aPTT ratios corresponding to the heparin level of 0.29 – 0.47 U/ml were 1.8 – 2.5, 1.9 - 2.5 and 2.7 - 4.6 for Actin FS, Actin FSL and Pathromtin SL, respectively. Therefore, the appropriate therapeutic range of our system obtained from this study might be aPTT ratio between 1.8 and 2.5 which is very closed to the ratio that we are using now.

Establishing Therapeutic Ranges of Activated Partial Thromboplastin Time for Heparin Therapy using Anti-Xa Activity / 대한임상병리학회지

BACKGROUND: The commonly recommended therapeutic range is an activated partial thromboplastin time(APTT) of 1.5 to 2.5 times the control value, which may be inappropriate for some reagents. The aim of this study is to evaluate the correlation of APTT and anti-Xa activity and to compare two methods of determining the therapeutic range of APTT during unfractionated heparin treatment. METHODS: We measured anti-Xa activity and APTT in 80 plasmas from patients treated with unfractionated heparin. We performed correlation analysis between anti-Xa activity and APTT or APTT ratio(heparinized APTT/baseline APTT). The therapeutic range determined by anti-Xa activity of 0.35-0.7 U/mL was compared with the therapeutic range based on minimizing potential thrombosis and bleeding error. RESULTS: The anti-Xa activity-vs-APTT correlation was slightly, but not significantly, improved by converting APTT(r=0.835) to APTT ratio(r=0.883). The APTT therapeutic range predicted by anti-Xa activity-vs-APTT regression analysis was 68.7 to 139.5 seconds(66.6-127.9 seconds for logarithmatically transformed APTT), whereas the range predicted by minimization-of-error technique was 68 to 97 seconds. CONCLUSIONS: The established therapeutic APTT range based on linear regression analysis was not considered to be optimal. The therapeutic range based on minimizing the potential clinical errors may further improve error rate, but prospective study with a larger number of patient samples would be required to apply in clinical field.