Prescriber compliance to direct oral anticoagulant labels and impact on outcomes in Thailand.

AIMS: This study aimed to evaluate the prescriber compliance to the approved labels of direct oral anticoagulants (DOACs) and impact of appropriateness of dosing on clinical outcomes. METHODS: A retrospective study was conducted using simple-stratified random sampling of adult patients receiving ≥6 months of DOACs for various indications during 2013-2017 in 10 tertiary care hospitals. Patients were classified into 3 dosing groups including approved dose, underdosing and overdosing based on the Thai Food and Drug Administration-approved labels. Cox proportional hazard models were used to evaluate the impact of different dosings on thromboembolic and bleeding events. RESULTS: From 1200 patients included in the data analysis, prescribing of DOACs was consistent with the approved indications in 1130 cases (94.2%) while 70 patients (5.8%) received DOACs despite having contraindications or with off-label usage. Among 1026 cases of dosing evaluation cohort, 688 patients (67.1%) received approved doses. There were 227 (21.9%) and 110 (10.7%) cases of underdosing and overdosing, respectively. Multivariate analysis showed that underdosing was associated with an increased risk of thromboembolism 3.023 (95% confidence interval [CI]: 1.291-7.080; P = .011) while overdosing was associated with an increased risk of bleeding requiring hospitalization (adjusted hazard ratio, 3.045; 95% CI, 1.501-6.178; P = .002) and Bleeding Academic Research Consortium type 2 or more (adjusted hazard ratio, 2.196; 95% CI, 1.083-4.452; P = .029). CONCLUSION: Prescribers' compliance to approved indications were high. However, 1/3 of DOAC prescriptions were inconsistent with approved dosing. Dosing deviation was associated with an increase in adverse clinical outcomes.

Genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions in Thai population.

OBJECTIVE: This study aimed to describe the genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions (PHT-induced cADRs) in Thai patients. METHOD: A retrospective case-control study was conducted among 88 PHT- cADRs (25 SJS/TEN, 37 DRESS/DIHS and 26 MPE) compared to 70 PHT-tolerant controls during 2008-2017. Genotyping was performed by Taqman RT-PCR (EPHX1 337 T > C, EPHX1 416A > G and CYP2C9*3), pyrosequencing (UGT1A1*28, UGT1A1*6) and polymerase chain reaction-sequence-specific oligonucleotide probe (HLA-B). Chi-squared test and binary logistic regression were used to identify factors associated with PHT-cADRs. RESULTS: Multivariate analysis showed that HLA-B*46:01 was significantly associated with all PHT-induced cADRs (OR 2.341; 95% CI, 1.078-5.084; P = .032). Age of ≥60 years showed a significant association with PHT-induced SJS/TEN (OR 3.600; 95% CI, 1.214-10.672; P = .021). CYP2C9*3 was almost reaching statistically associated with an increased risk of PHT-induced SJS/TEN (OR 4.800; 95% CI, 0.960-23.990; P = .056). While HLA-B*56:02/04 was found to have a significant association with PHT-induced DRESS/DIHS (OR 29.312; 95% CI, 1.213-707.994; P = .038). Moreover, female gender and HLA-B*40:01 were associated with an increased risk of PHT-induced MPE at OR 5.734; 95% CI, 0.910-58.351; P = .042 and OR 3.647; 95% CI, 1.193-11.147; P = .023, respectively. CONCLUSION: Both clinical (advanced age, female gender) and genetic factors (HLA-B*46:01, CYP2C9*3, HLA-B*56:02/04 and HLA-B*40:01) contributed to the risk of PHT-induced cADRs. Further studies with larger sample size may be warranted to confirm these findings and also the influence of EPHX1 gene.

Incidence, risk factors, and outcomes of warfarin-associated major bleeding in Thai population.

PURPOSE: This study aimed to describe incidence, risk factors, and outcomes of warfarin-associated major bleeding (WAMB) in Thai patients. METHOD: A nested case-control study was conducted in a cohort of adult patients receiving ≥6 months of warfarin therapy who were prospectively followed up at a tertiary care hospital in Thailand during January 2011 to December 2014. Logistic regression was used to identify risk factors associated with WAMB. The area under the receiver operating characteristic (AUROC) curve was used to assess the performance of the HAS-BLED score to predict WAMB in patients with non-valvular atrial fibrillation (NVAF). RESULTS: Among 1604 patients (2972 patient-year of follow-up), there were 93 major bleeding that occurred in 76 patients. The incidence of WAMB was 3.13 events per 100 patient-year. Time in therapeutic range (TTR) of <60% (RR: 3.62, 95% CI: 1.94-6.73, P < 0.001), mechanical valve replacement at mitral position (RR 3.43, 95% CI: 1.92-6.16, P < 0.001) cancer (RR: 2.84, 95% CI: 1.11-7.29, P = 0.029), and age ≥ 65 years (RR: 2.37, 95% CI: 1.20-4.67, P = 0.012) were independent risk factors for WAMB. There were 17 fatalities and 12 cases of disabilities from WAMB. Mean cost of WAMB was 45 341.54 THB/event. An exploratory analysis suggested that HASBLED score demonstrated an excellent discriminatory capacity to predict WAMB among NVAF patients (AUROC of 0.91, 95% CI: 0.85-0.97, P < 0.001). CONCLUSION: WAMB in Thai population is common and associated with high rate of morbidity and mortality. Improvement in anticoagulation control is clearly needed.

Population pharmacokinetics of vancomycin in Thai patients.

Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft-Gault equation, CL(Cr) (mL/min): CL = 0.044 × L(Cr). Meanwhile, volume of central compartment, V(1) (L), was linearly related with the age (years old): V(1) = 0.542 × Age. Intercompartment clearance (Q) and volume of peripheral compartment (V(2)) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V(1), Q, and V(2) was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of -1.43 mg/L (95% CI: -5.82-2.99) and a precision of 12.2 mg/L (95% CI: -1.60-26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study.

Knowledge of stroke and medication adherence among patients with recurrent stroke or transient ischemic attack in Indonesia: a multi-center, cross-sectional study.

BackgroundThere is a limited data in Indonesia regarding the stroke knowledge and medication adherence among stroke survivors.ObjectiveTo assess the level of stroke knowledge and medication adherence along with their relationship among stroke survivors.SettingTwo tertiary-care hospitals in Surabaya, East Java, Indonesia.MethodsA prospective, cross-sectional study was conducted among 215 stroke survivors. Stroke Knowledge Test and the Morisky Green Levine Adherence Scale questionnaires were used to evaluate stroke knowledge and medication adherence, respectively. Binary logistic regression was performed to assess the rela tionship between stroke knowledge and medication adherence. Main outcome measuresRelationship between stroke knowledge and medication adherence.ResultsA total of 215 patients with mean age of 56.34 ± 8.69 years were recruited into this study. Mean Stroke Knowledge Test score was 7.89 ± 3.38 with 76.7% had low level of stroke knowledge. Mean Morisky Green Levine Adherence Scale was 3.05 ± 1.11 with 52.1% had low to medium medication adherence. Education and duration of stroke correlated with stroke knowledge level (Spearman's correlation coefficient: 0.307, p = 0.001 and 0.128, p = 0.041, respectively). Age and disability correlated with medication adherence (Spearman's correlation coefficient: 0.169; p = 0.013 and 0.171; p = 0.012), respectively. After adjustment for covariates, stroke knowledge level was independently associated with medication adherence (adjusted OR: 4.37, 95% CI 2.00-9.53; p < 0.001).ConclusionStroke knowledge was low among Indonesian stroke survivors and independently related to medication adherence. Attempts should be made to increase stroke knowledge which may improve medication adherence among stroke survivors.

Real-World Comparative Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants vs. Warfarin in a Developing Country.

We aimed to compare effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin for stroke prevention in nonvalvular atrial fibrillation (NVAF) in a developing country where anticoagulation control with warfarin is suboptimal. A real-world study was conducted among patients with NVAF in Thailand receiving NOACs and warfarin from 9 hospitals during January 2012 to April 2018. Propensity-score weighting was used to balance covariates across study groups. Cox regression models were used to compare the risk of thromboembolism, major bleeding, and net adverse clinical events across matched cohorts. A total of 2,055 patients; 605, 604, 441, and 405 patients receiving warfarin, rivaroxaban, dabigatran, and apixaban, respectively, were included. Median (interquartile range) time in therapeutic range (TTR) for warfarin users was 49.5% (26.6%-70.3%). Compared with warfarin, NOACs were associated with a significant reduction in major bleeding either when analyzed as a group (adjusted hazard ratio (HR) (95% confidence interval (CI)) of 0.46 (0.34-0.62) or by each agent. Compared with warfarin users with poor TTR, apixaban (adjusted HR 0.48, 95% CI 0.26-0.86, P = 0.013) and dabigatran (adjusted HR 0.44, 95% CI 0.21-0.90, P = 0.025) were associated with a lower risk of thromboembolism, in addition to markedly lower risk of major bleeding. In a healthcare system where anticoagulation control with warfarin is suboptimal, use of NOACs was associated with a profound reduction in major bleeding. The effectiveness and safety advantages of NOACs were more pronounced compared with warfarin users with low TTR.

Formulation development of morphine sulfate sustained-release tablets and its bioequivalence study in healthy Thai volunteers.

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.

Relationship of anemia and clinical outcome in heart failure patients with preserved versus reduced ejection fraction in a rural area of Thailand.

BACKGROUND: Heart failure (HF) has become a significant health burden in developing countries where anemia is highly prevalent. Limited data exists on the effects of anemia on HF in these population. METHODS: A retrospective observational study was conducted in all adult patients hospitalized due to HF at Buriram Hospital in Thailand, during July 2010 to June 2015. Survival analysis was performed to evaluate the impact of anemia on 1- year all-cause mortality for the overall cohort, patients with HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). RESULTS: A total of 414 HF patients including 287 HFpEF patients (69.3%) and 127 HFrEF patients (30.7%) were included in our analysis. Mean age was 62.51 ±â€¯14.89 years, with 55% female. Overall prevalence of anemia in HF was 62.6% (259 patients). One-year all-cause mortality was significantly higher in patients with anemia than in non-anemia groups (20.08% vs 12.26%, p = 0.041). When analyzed based on types of HF, anemia significantly increased mortality risk in HFpEF group [adjusted hazard ratio (HR) 2.667, 95%CI, 1.216-5.853, p = 0.014] but not with HFrEF group (adjusted HR 0.901, 95%CI, 0.376-2.155, p = 0.804). The mortality of anemic patients who were left untreated was significantly higher than those who were treated (adjusted HR 2.13, 95%CI, 1.13-3.99, p = 0.027). CONCLUSION: Anemia significantly increased mortality in HF patients, especially among HFpEF. Attempts to identify, diagnose and manage anemia should be integrated in HF care plan in developing countries with high prevalence of anemia.

Prognostic Value of Serum Procalcitonin level for the Diagnosis of Bacterial Infections in Critically-ill Patients.

BACKGROUND: Procalcitonin (PCT) is a diagnostic biomarker for bacterial infections in critically-ill patients. However, the cut-off value of PCT for the diagnosis of bacterial infections is unclear and unreliable. This study aimed to determine the optimal cut-off value of PCT for the diagnosis of bacterial infections in critically-ill patients. MATERIALS AND METHODS: We conducted a retrospective study involving 311 adult patients who had been admitted to the medical or surgical intensive care unit for more than 24 hours from 2013 to 2015. At least one blood test for PCT level was performed for all patients within the first 24 hours of suspecting an infection. RESULTS: One hundred and fifty-seven patients had bacterial infections, while 154 did not. Patients with bacterial infections had a significantly higher median PCT level than those without bacterial infections (1.90 ng/mL vs. 0.16 ng/mL, P <0.001). The area under the receiver operating characteristic curve of PCT for discriminating between bacterial and non-bacterial infections was 0.874 (95% confidence interval: 0.834, 0.914; P <0.001). The optimal cut-off value of PCT for differentiating between fevers due to bacterial infections from those due to non-bacterial infections was 0.5 ng/mL, with a sensitivity of 84.7%, specificity of 79.9%, positive predictive value of 81.1%, and negative predictive value of 83.7%. CONCLUSION: PCT was found to be an accurate biomarker for the diagnosis of bacterial infections among patients admitted to medical and surgical intensive care units. The optimal cut-off value of PCT for the diagnosis of bacterial infections was 0.5 ng/mL.

Comparative performance of pharmacogenetics-based warfarin dosing algorithms derived from Caucasian, Asian, and mixed races in Thai population.

AIM: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin dosing algorithms derived from Caucasian, Asian, and mixed population to identify a suitable algorithm for Thai population. METHODS: Ten warfarin dosing algorithms derived from different population including Caucasian, East Asian, South-East Asian, and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP). Sensitivity analysis for predictive accuracy was also conducted by stratifying patients into low (AWMD ≤21 mg/wk), intermediate (AWMD >21 to <49 mg/wk), and high maintenance dose (AWMD ≥49 mg/wk) groups. RESULTS: Data of 165 patients were included for the analyses. Mean actual warfarin dose of the study population was 25.03 ± 10.53 mg/wk. Large variability of MDE, ranging from -12.11 to 11.24 mg/wk, among algorithms was observed. International Warfarin Pharmacogenetics Consortium, Gage et al, and Ohno et al algorithms had comparable performances to Sangviroon et al algorithm, as observed by MDE of <1 mg/wk with percentage of IDP ≥40%. Further sensitivity analyses among patients requiring low and intermediate maintenance doses confirmed such findings with IDP percentage ranging from 37.8% to 59.2%. Among high-dose group, only Ohno et al and Sarapakdi et al algorithms had acceptable performance. CONCLUSIONS: Warfarin PGx-guided dosing algorithms derived from large, mixed population performed comparably to Sangviroon et al algorithm. Certain algorithms should be avoided due to significant dose prediction error.

Pharmacokinetics of ofloxacin in drug-resistant tuberculosis.

The pharmacokinetics of ofloxacin were investigated in 11 drug-resistant pulmonary tuberculosis (TB) patients with a mean age (SD) of 38.09 (11.97) years. All patients received ofloxacin 10 mg/kg once daily combined with other active anti-TB drugs. Following an 8-h overnight fast, serum samples were drawn prior to and from 0.25 up to 24 hours after dosing. Serum ofloxacin concentrations were determined by high performance liquid chromatography (HPLC) assay. Pharmacokinetics of ofloxacin were well described by a linear, 2-compartment open model with first-order absorption and first-order elimination. Mean +/- SD of Cmax was 9.61 +/- 2.17 microg/ml occurred at 1.68 +/- 1.21 hours. Means +/- SD of AUC(0-24) and AUC(0-infinity) were 70.57 +/- 26.40 and 82.45 +/- 43.64 microg x h/ml, respectively. Ofloxacin distributed widely with a mean +/- SD of Vss/F of 1.37 +/- 0.24 L/kg. Mean +/- SD of CL/F was 8.19 +/- 2.53 L/h, whereas mean +/- SD of T(1/2beta) and mean residence time were 8.03 +/- 3.37 and 10.77 +/- 4.55 hours, respectively. The free Cmax/MIC of Mycobacterium tuberculosis of 7.7-15.4:1 was estimated. These suggested that ofloxacin 10 mg/kg once daily combined with other active anti-TB drugs provides sufficient Cmax/MIC ratio and long T(1/2beta) which supported its use in drug-resistant TB.

Adverse drug events in rheumatoid arthritis and osteoarthritis ambulatory patients.

AIM: We aimed to determine the prevalence and characteristics of adverse drug events (ADE) in rheumatoid arthritis (RA) and (osteoarthritis) OA patients. METHOD: A cross-sectional study at rheumatology clinics, was performed by random selection of RA and OA out-patients by a research pharmacist. All suspected ADEs occurring during the last hospital visit and the subjects were identified by retrospective chart review and direct patient interview. ADE characteristics, including causative drug groups, affected organ severity and patient outcomes, were recorded. RESULTS: One hundred and forty-three patients consisting of 129 RA and 14 OA were recruited. The patients' mean ages were 54.3 ± 14.3 years and 121 (84.6%) patients were female. A total of 68 ADEs were detected in 51 patients. The prevalence and rate of ADE were 35.7% and 47.6 events per 100 patients, respectively. Thirty out of 68 ADEs (44.1%) were preventable. Disease-modifying anti-rheumatic drugs and non-steroidal anti-inflammatory drugs resulted in ADEs by 41 (59.4%) and 10 (14.5%) events, respectively. Common affected organs were skin, gastrointestinal tract and eyes which accounted for 20 (29.4%), 18 (26.5%) and eight events (11.6%), respectively. Continuation of the suspected drug was noted in 42 ADEs (61.8%), classified as severity level 1 and 2a-b, and 43 ADEs (63.2%) were completely or partially resolved during the study period. CONCLUSION: ADEs are common in RA and OA patients with prevalence of 35.7%. High exposure to potentially harmful drugs might explain the higher rate of ADE in these patients.

Pharmacokinetics and clinical application of intravenous valproate in Thai epileptic children.

Roles of intravenous administration of valproate in status epilepticus and serial seizures are documented in adults and children. Pharmacokinetic parameters are necessary to predict the optimum therapeutic level after administration. A cross-sectional study to determine the pharmacokinetic parameters and safety of intravenous valproate for future application was conducted in Thai children from January to December 2008. There were eleven children, age-range 1-15 years (mean age 9.5 years) enrolled. Valproate of 15-20 mg/kg was administrated intravenously at the rate of 3 mg/kg/min, followed by 6 mg/kg every 6 h. Valproate level was determined prior to the initial dose and at ½, 1, 2, 4, 5, and 6 h postdose. Complete blood count, serum ammonia, and liver function tests were collected prior to the initial dose and at 6 h. Median loading dose was 19 mg/kg (range 15-20.5 mg/kg). Median maximum concentration at 30 min after infusion was 98.8 mcg/mL (range 67-161 mcg/mL). Median volume of distribution was 0.20 L/kg (range 0.15-0.53 L/kg). Median half-life was 9.5 h (range 4.4-24.2 h). Median clearance was 0.02 L/h/kg (range 0.01-0.05 L/h/kg). Six hours after initial dose, eight children did not have recurrent seizure. One child had brief seizure at 20 min after initial dose. Seizure recurred in two children at 4th and 5th hour. Asymptomatic transient elevation of serum ammonia was observed in two children. Volume of distribution of 0.20 L/kg could be applied for initial intravenous administration with a favorable efficacy.