Effects of intensive, targeted education by pharmacists on anticoagulant patients with atrial fibrillation: a multicenter randomized controlled trial from China.

AIMS: Many people diagnosed with atrial fibrillation (AF) may lack awareness of AF and anticoagulants. The purpose of this study is to investigate the effects of intensive, targeted education by pharmacists on anticoagulant patients with AF. METHODS AND RESULTS: Three hundred seventy-six AF patients were randomly assigned to receive standard care or pharmacist education. Follow-up is scheduled after 1, 3, 6, and 12 months. Pharmacists provided intensive education on knowledge deficits revealed by the Jessa Atrial Fibrillation Knowledge Questionnaire (JAKQ) during each visit. Patients also completed two questionnaires to assess their medication adherence and satisfaction. Clinical outcomes were recorded during follow-up. 361 patients completed follow-up. Baseline scores on the JAKQ were similar in the education group (median: 31.3%) and the standard care group (median: 31.3%) (p = 0.911). Over time, the knowledge score of the education group increased significantly (1 month: 68.8%, 3 months: 81.3%; P <0.001), while there was no significant improvement in the standard care group (1 month: 37.5%, 3 months: 37.5%; P = 0.314). Adherence scores improved significantly over time in the education group (P < 0.001) but not in the standard care group (P =0.101). Compared with standard care, pharmacist education was associated with a significantly lower risk of bleeding (P=0.034). CONCLUSIONS: Given the knowledge deficiency of AF patients in China, standardized patient education should be a part of their daily care. Pharmacist-led education intervention can significantly improve the disease-related knowledge, medication adherence, and drug treatment satisfaction of AF patients while significantly reducing the risk of bleeding.

Construction of warfarin population pharmacokinetics and pharmacodynamics model in Han population based on Bayesian method.

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.

A new score for predicting intracranial hemorrhage in patients using antiplatelet drugs.

Antiplatelet drugs in patients increase the risk of intracranial hemorrhage (ICH), which can seriously affect patients' quality of life and even endanger their lives. Currently, there is no specific score for predicting the risk of ICH caused by antiplatelet drugs. We aimed to identify factors associated with ICH in patients on antiplatelet drugs and to construct and validate a predictive model that would provide a validated tool for the clinic. Data were obtained from the patient medical records inpatient system. Prediction models were built by logistic regression, the area under the curve (AUC), and column line plots. Internal validation, analytical identification and calibration of the model using AUC, calibration curves and Hosmer-Lemeshow test. The registration number of this study is ChiCTR2000031909, and the ethical review number is 2020KY087. This single-center retrospective study enrolled 753 patients treated with antiplatelet drugs, including 527 in the development cohort. Multifactorial analysis showed that male, headache or vomiting, hypertension, cerebrovascular disease, CT-defined white matter hypodensity, abnormal GCS, fibrinogen and D-dimer were independent risk factors for ICH, and lipid-lowering drugs was a protective factor. The model was constructed using these nine factors with an AUC value of 0.949. In the validation cohort, the model showed good discriminatory power with an AUC value of 0.943 and good calibration (Hosmer-Lemeshow test P value of 0.818). Based on 9 factors, we derived and validated a predictive model for ICH with antiplatelet drugs in patients. The model has good predictive value and may be an effective tool to reduce the occurrence of ICH.

Vegetation canopy structure mediates the response of gross primary production to environmental drivers across multiple temporal scales.

Gross primary production (GPP) is a critical component of the global carbon cycle and plays a significant role in the terrestrial carbon budget. The impact of environmental factors on GPP can occur through both direct (by influencing photosynthetic efficiency) and indirect (through the modulation of vegetation structure) pathways, but the extent to which these mechanisms contribute has been seldom quantified. In this study, we used structural equation modeling and observations from the FLUXNET network to investigate the direct and indirect effects of environmental factors on terrestrial ecosystem GPP at multiple temporal scales. We found that canopy structure, represented by leaf area index (LAI), is a crucial intermediate factor in the GPP response to environmental drivers. Environmental factors affect GPP indirectly by altering canopy structure, and the relative proportion of indirect effects decreased with increasing LAI. The study also identified different effects of environmental factors on GPP across time scales. At the half-hourly time scale, radiation was the primary driver of GPP. In contrast, the influences of temperature and vapor pressure deficit took on greater prominence at longer time scales. About half of the total effect of temperature on GPP was indirect through the regulation of canopy structure, and the indirect effect increased with increasing time scale (GPPNT-based models: 0.135 (half-hourly) vs. 0.171 (daily) vs. 0.189 (weekly) vs. 0.217 (monthly); GPPDT-based models: 0.139 vs. 0.170 vs. 0.187 vs. 0.215; all values were reported in gC m-2 d-1 °C-1, P < 0.001); while the indirect effect of radiation on GPP was comparatively lower, accounting for less than a quarter of the total effect. Furthermore, we observed a direct, negative-to-positive impact of precipitation on GPP across timescales. These findings provide crucial information on the interplay between environmental factors and LAI on GPP and enable a deeper understanding of the driving mechanisms of GPP.

New score for predicting thromboembolic events in patients with atrial fibrillation using direct oral anticoagulants.

Determinants of thrombotic events remain uncertain in patients with atrial fibrillation treated with direct oral anticoagulants (DOACs). Our aim was to identify risk factors associated with thromboembolism in patients with at atrial fibrillation on DOACs and to construct and externally validate a predictive model that would provide a validated tool for clinical assessment of thromboembolism. In the development cohort, prediction model was built by logistic regression, the area under the curve (AUC), and Nomogram. External validation and calibration of the model using AUC and Hosmer-Lemeshow test. This national multicenter retrospective study included 3263 patients with atrial fibrillation treated with DOACs. The development cohort consisted of 2390 patients from three centers and the external validation cohort consisted of 873 patients from 13 centers. Multifactorial analysis showed that heavy drinking, hypertension, prior stroke/transient ischemic attack (TIA), cerebral infarction during hospitalization were independent risk factors for thromboembolism. The Alfalfa-TE risk score was constructed using these four factors (AUC = 0.84), and in the external validation cohort, the model showed good discriminatory power (AUC = 0.74) and good calibration (Hosmer-Lemeshow test P value of 0.649). Based on four factors, we derived and externally validated a predictive model for thromboembolism with DOACs in patients with atrial fibrillation (Alfalfa-TE risk score). The model has good predictive value and may be an effective tool to help reduce the occurrence of thromboembolism in patients with DOACs.

Safety and efficacy of direct oral anticoagulants in stroke prevention in patients with atrial fibrillation complicated with anemia and/or thrombocytopenia: a retrospective cohort study.

BACKGROUND: There are limited data about the clinical benefits and harm of direct oral anticoagulants (DOACs) in stroke prevention in patients with atrial fibrillation (AF) complicated with anemia or thrombocytopenia. METHODS: This is a multi-center retrospective cohort study involving 5469 AF patients from 15 hospitals in China. Patients were divided into three groups according to hemoglobin and platelet levels: Group 1 (hemoglobin male ≥ 130 g/L; female ≥ 120 g/L and platelet ≥ 100 × 109/L), Group 2 (hemoglobin male < 130 g/L; female < 120 g/L or platelet < 100 × 109/L), and Group 3 (hemoglobin male < 130 g/L; female < 120 g/L and platelet < 100 × 109/L). Patients in each category are further divided into two groups according to their stroke prevention strategies: rivaroxaban or dabigatran. Clinical results include major, minor, total bleeding, thrombosis, and the composite outcome of major bleeding and thrombosis. RESULTS: Higher hemoglobin levels were associated with a reduced risk of total bleeding and major bleeding, while platelet counts were not associated with any event. Compared with Group 1, Group 2 had a higher risk of major bleeding (aOR 1.70, 95%CI 1.12-2.57, P = 0.012), and the composite endpoint of major bleeding and thrombosis (aOR 1.70, 95%CI 1.19-2.44, P = 0.004). Compared with Group 1, Group 3 had a higher total bleeding risk (aOR 2.15, 95%CI 1.14-4.05, P = 0.018). Compared with dabigatran, rivaroxaban was associated with higher composite risk in Group 1 (aOR 2.91, 95% CI 1.66-5.16, P < 0.001) and Group 2 (aOR 3.05, 95%CI 1.46-6.39, P = 0.003), but there was no significant difference in Group 3 (aOR 1.78, 95%CI 0.23-13.54, P = 0.577). CONCLUSIONS: Higher hemoglobin levels are associated with a reduced risk of total bleeding and major bleeding in patients with AF. Dabigatran was associated with better clinical outcomes than rivaroxaban in patients with anemia or thrombocytopenia but not in those with anemia and thrombocytopenia.

The anti-photoaging effect of C-phycocyanin on ultraviolet B-irradiated BALB/c-nu mouse skin.

Introduction: C-phycocyanin (C-PC), a photosynthetic protein obtained from Spirulina, is regarded a highly promising commercially available biochemical. Numerous in vitro and in vivo studies have provided evidence of C-PC's ability to mitigate the inflammatory response, alleviate oxidative stress, and facilitate wound healing. However, despite the existing knowledge regarding C-PC's protective mechanism against cellular apoptosis induced by ultraviolet B (UVB) radiation, further in vivo experiments are needed to explore its anti-photoaging mechanism. Methods: In this study, a UVB-induced skin photoaging model was established using BALB/c-nu mice, and the potential protective effects of topically administered c-PC were investigated by various molecular biology tools. In addition, a novel delivery system, C-PC nanodispersion, was developed to facilitate the transdermal delivery of C-PC. Results: C- PC demonstrated significant anti-photoaging activities in the UVB-induced skin. The application of C-PC to the dorsal skin of the mice resulted in improved macroscopic characteristics, such as reduced sagging and coarse wrinkling, under UVB irradiation Histological analyses showed that C-PC treatment significantly decreased the symptoms of epidermal thickening, prevented dermal collagen fiber loosening, increased the hydroxyproline (Hyp) content and activities of antioxidant enzymes (such as superoxide dismutase, catalase, and glutathione peroxidase) in mouse skin, decreased malondialdehyde levels and expressions of inflammatory factors (interleukin-1α [IL-1α], IL-1ß, IL-6, and tumor necrosis factor-α), reduced matrix metalloproteinase [MMP-3 and MMP-9] expressions, and inhibited the phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 proteins in the mitogen-activated protein kinase family. Discussion: By analyzing the results of the study, a new drug delivery system, C-PC nano-dispersion, was proposed, and the anti-photoaging effect of C-PC and its mechanism were investigated.

Application of a warfarin dosing calculator to guide individualized dosing versus empirical adjustment after fixed dosing: a pilot study.

Background: Warfarin has a narrow therapeutic window and individual variation, and patients require regular follow-up and monitoring of the International Normalized Ratio (INR) for dose adjustment. The calculation method of Warfarin Dosing Calculator (WDC) software is based on the European and American populations, and its accuracy in the Chinese population is yet to be verified. Objective: This study was to evaluate the feasibility of applying Warfarin Dosing Calculator software intervention in a real-world clinical research setting in China. Methods: The pilot study divided the included patients after valve replacement into an experimental group and a control group, with 38 cases in each group. In the control group, the initial dose was fixed at 2.5 mg/d and the dose was adjusted empirically during the study period; in the experimental group, the Warfarin Dosing Calculator software was applied to guide the dosing, and patients in both groups were followed up for 3 months. Analysis of the incidence anticoagulation outcomes and excessive anticoagulation events in both groups. Kaplan-Meier survival curves were used to analyze the correlation between different dosing regimens and first International Normalized Ratio attainment, and Logrank tests were performed. Results: The mean time required for first International Normalized Ratio compliance in the experimental group was 4.38 days less than in the control group, and the mean number of tests was 1.43 less (p < 05). Time in therapeutic range (TTR) was significantly higher in the experimental group than in the control group (p < 05). Kaplan-Meier survival curve analysis showed that the first International Normalized Ratio attainment rate was significantly higher in the experimental group than in the control group (p = 01). No major bleeding events occurred in either group, but other excessive anticoagulation events (INR>3.5 and minor bleeding) were significantly reduced in the experimental group compared with the control group (p < 05). Conclusion: Application of Warfarin Dosing Calculator software to guide individualized warfarin dosing may be better than a fixed dose of 2.5 mg/d. It may be shorten the time to first International Normalized Ratio attainment, and the attainment rate in the same time, and can better improve the mean Time in therapeutic range level value and reduce excessive anticoagulation events, which improves the safety of warfarin anticoagulation therapy in clinical practice. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=52793, ChiCTR2000032393.

The application of composite scaffold materials based on decellularized vascular matrix in tissue engineering: a review.

Decellularized vascular matrix is a natural polymeric biomaterial that comes from arteries or veins which are removed the cellular contents by physical, chemical and enzymatic means, leaving only the cytoskeletal structure and extracellular matrix to achieve cell adhesion, proliferation and differentiation and creating a suitable microenvironment for their growth. In recent years, the decellularized vascular matrix has attracted much attention in the field of tissue repair and regenerative medicine due to its remarkable cytocompatibility, biodegradability and ability to induce tissue regeneration. Firstly, this review introduces its basic properties and preparation methods; then, it focuses on the application and research of composite scaffold materials based on decellularized vascular matrix in vascular tissue engineering in terms of current in vitro and in vivo studies, and briefly outlines its applications in other tissue engineering fields; finally, it looks into the advantages and drawbacks to be overcome in the application of decellularized vascular matrix materials. In conclusion, as a new bioactive material for building engineered tissue and repairing tissue defects, decellularized vascular matrix will be widely applied in prospect.

Non-major bleeding risk of direct oral anticoagulants versus vitamin K antagonists for stroke prevention with atrial fibrillation: a systematic review and network meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) are associated with bleeding. Patients often stop taking DOACs due to non-major bleeding, which may lead to stroke recurrence. We aimed to determine the risk of non-major bleeding using different DOACs to prevent strokes in atrial fibrillation (AF). METHODS: A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting non-major bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. RESULTS: Nineteen randomized controlled trials (RCTs) (involving 85,826 patients) were included. For clinically relevant non-major bleeding, the risk for bleeding was lowest for apixaban (SUCRA, 93.9), followed by that for VKAs (SUCRA, 47.7), dabigatran (SUCRA, 40.3), rivaroxaban (SUCRA, 35.9), and edoxaban (SUCRA, 32.2). The minor bleeding safety of DOACs was ranked from highest to lowest as follows: apixaban (SUCRA, 78.1), edoxaban (SUCRA, 69.4), dabigatran (SUCRA, 48.8), and VKAs (SUCRA, 3.7). CONCLUSIONS: Based on current evidence, for stroke prevention in patients with AF, the safest DOAC is apixaban in terms of non-major bleeding. This suggests that apixaban may have a lower risk of non-major bleeding than other anticoagulants and may help provide some clinical reference for choosing a more appropriate drug for the patient.

Risk factors for thrombolysis-related intracranial hemorrhage: a systematic review and meta-analysis.

BACKGROUND: Thrombolysis-related intracranial hemorrhage has a high mortality rate, and many factors can cause intracranial hemorrhage. Until now, systematic reviews and assessments of the certainty of the evidence have not been updated. AIM: We conducted a systematic review to identify risk factors for thrombolysis-related intracranial hemorrhage. METHOD: The protocol for this systematic review was prospectively registered with PROSPERO (CRD42022316160). All English studies that met the inclusion criteria published before January 2022 were obtained from PubMed, EMBASE, Web of Science, and Cochrane Library. Two researchers independently screened articles, extracted data, and evaluated the quality and evidence of the included studies. Risk factors for intracranial hemorrhage were used as the outcome index of this review. Random or fixed-effect models were used in statistical methods. RESULTS: Of 6083 citations, we included 105 studies in our analysis. For intracranial hemorrhage, moderate-certainty evidence showed a probable association with age, National Institutes of Health stroke scale, leukoaraiosis, hypertension, atrial fibrillation, diabetes, total cholesterol, proteinuria, fibrinogen levels, creatinine, homocysteine, early infarct signs, antiplatelet therapy and anticoagulant therapy; In addition, we found low-certainty evidence that there may be little to no association between risk of intracranial hemorrhage and weight, sex, platelet count, uric acid, albumin and white matter hyperintensity. Leukoaraiosis, cardiovascular disease, total cholesterol, white blood cell count, proteinuria, fibrinogen levels, creatinine, homocysteine and early CT hypodensities are not included in most intracranial hemorrhage risk assessment models. CONCLUSION: This study informs risk prediction for thrombolysis-related intracranial hemorrhage, it also informs guidelines for intracranial hemorrhage prevention and future research.

Lysine content and its relationship with protein content in indica rice landraces of China.

Lysine is a limiting essential amino acid in rice. This study determined the variation in lysine content and evaluated the relationship between lysine and protein content in indica rice landraces of four provinces (Guangdong, Guangxi, Hunan, and Sichuan) in China by using the data (n = 654) collected from the Chinese Crop Germplasm Information System. Results showed that grain lysine content ranged from 0.25 % to 0.54 %, with 139 landraces having a grain lysine content of more than 0.40 %. Lysine content of protein ranged from 28.4 to 48.1 mg g-1, with 20 landraces having a lysine content of protein of more than 45.0 mg g-1. Guangdong had 5-21 % higher median of grain lysine content and 3-6 % higher median of lysine content of protein than the other three provinces. Lysine content of protein was significantly negatively related to protein content across four provinces.

Risk mapping of lung cancer: a comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies.

INTRODUCTION: A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. METHODS: Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. RESULTS: In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95% CI 1.18-1.75; P = 0.001) and blood copper (OR 1.14, 95% CI 1.01-1.29; P = 0.039) significantly associated with increased risk of lung cancer, whereas aspirin use (OR 0.67, 95% CI 0.50-0.89; P = 0.006) showed protective effects. CONCLUSION: This study mapped putative associations of risk factors for lung cancer, revealing the causal hazard effect of smoking, blood copper, and the protective effect of aspirin use in the development of lung cancer. CLINICAL TRIAL REGISTRY: This study is registered with PROSPERO (CRD42020159082).

New score for predicting major bleeding in patients with atrial fibrillation using direct oral anticoagulants.

PURPOSE: Our aim was to identify factors associated with major bleeding in patients with atrial fibrillation (AF) on direct oral anticoagulants (DOACs) and to construct and externally validate a predictive model that would provide a validated tool for clinical assessment of major bleeding. METHODS: In the development cohort, prediction model was built by logistic regression, the area under the curve (AUC), and Nomogram. External validation, analytical identification and calibration of the model using AUC, calibration curves and Hosmer-Lemeshow test. RESULTS: The development cohort consisted of 4209 patients from 7 centers and the external validation cohort consisted of 1800 patients from 12 centers. Multifactorial analysis showed that age > 65 years, history of bleeding, anemia, vascular disease, antiplatelet therapy/non-steroidal anti-inflammatory drugs and rivaroxaban were independent risk factors for major bleeding, and gastrointestinal protective agents was a protective factor. The Alfalfa-MB model was constructed using these seven factors (AUC = 0.807), and in the external validation cohort, the model showed good discriminatory power (AUC = 0.743) and good calibration (Hosmer-Lemeshow test P value of 0.205). The predictive power of the six bleeding scores was ORBIT (AUC = 0.706), HAS-BLED (AUC = 0.648), ATRIA (AUC = 0.645), HEMORR2 HAGES (AUC = 0.632), ABC (AUC = 0.619) and Shireman (AUC = 0.599) in descending order. CONCLUSION: Based on 7 factors, we derived and externally validated a predictive model for major bleeding with DOACs in patients with AF (Alfalfa-MB). The model has good predictive value and may be an effective tool to help reduce the occurrence of major bleeding in patients with DOACs.

Risk Factors for Anticoagulant-Associated Intracranial Hemorrhage: A Systematic Review and Meta-analysis.

BACKGROUND: Anticoagulant-associated intracranial hemorrhage has a high mortality rate, and many factors can cause intracranial hemorrhage. Until now, systematic reviews and assessments of the certainty of the evidence have not been published. METHODS: We conducted a systematic review to identify risk factors for anticoagulant-associated intracranial hemorrhage. The protocol for this systematic review was prospectively registered with PROSPERO (CRD42022316750). All English studies that met the inclusion criteria published before January 2022 were obtained from PubMed, EMBASE, Web of Science, and Cochrane Library. Two researchers independently screened articles, extracted data, and evaluated the quality and evidence of the included studies. Risk factors for intracranial hemorrhage were used as the outcome index of this review. Random or fixed-effect models were used in statistical methods. I2 statistics were used to evaluate heterogeneity. RESULTS: Of 7322 citations, we included 20 studies in our analysis. For intracranial hemorrhage, moderate-certainty evidence showed a probable association with race, Glasgow Coma Scale, stroke, leukoaraiosis, cerebrovascular disease, tumor, atrial fibrillation, previous bleeding, international normalized ratio, serum albumin, prothrombin time, diastolic blood pressure, and anticoagulant. Low-certainty evidence may be associated with age, cerebral microbleeds, smoking, alcohol intake, platelet count, and antiplatelet drug. In addition, we found very low-certainty evidence that there may be little to no association between the risk of intracranial hemorrhage and hypertension and creatinine clearance. Leukoaraiosis, cerebral microbleeds, cerebrovascular disease, and international normalized ratio are not included in most risk assessment models. CONCLUSIONS: This study informs risk prediction for anticoagulant-associated intracranial hemorrhage and informs guidelines for intracranial hemorrhage prevention and future research.

Severe Bleeding Risk of Direct Oral Anticoagulants Versus Vitamin K Antagonists for Stroke Prevention and Treatment in Patients with Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.

PURPOSE: We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF). METHODS: A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. RESULTS: Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1). CONCLUSION: Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.

Population Pharmacokinetic Analysis for Model-Based Therapeutic Drug Monitoring of Tacrolimus in Chinese Han Heart Transplant Patients.

BACKGROUND AND OBJECTIVE: Tacrolimus has become the first-line immunosuppressant for preventing rejection after heart transplantation. The present study aimed to investigate genetic variants and clinical factors affecting the variability of tacrolimus in Chinese Han heart transplant patients using a population pharmacokinetic approach. METHODS: The retrospective study included 53 hospitalized patients with 547 tacrolimus concentrations for analysis. Nonlinear mixed-effects modeling was used to develop the population pharmacokinetics model for tacrolimus in patients with heart transplants, followed by Monte Carlo simulations to design initial dosing regimens. RESULTS: In our study, the mutation rate of CYP3A4*18B (C>T) was 27.36%. An oral one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetics of tacrolimus in heart transplant patients. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 532.5 L/h [12.20% interindividual variability, IIV] and 16.87 L (23.16% IIV), respectively. Albumin, postoperative time, and rs2242480 (CYP3A4*18B) gene polymorphisms were the significant covariates affecting CL/F, and creatinine clearance had significant effects on the V/F. CONCLUSION: The population pharmacokinetic model of tacrolimus in heart transplant patients can better estimate the population and individual pharmacokinetic parameters of patients and can provide a reference for the design of individualized dosing regimens.

Direct oral anticoagulants for venous thromboembolism in cancer patients: a systematic review and network meta-analysis.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs), including dabigatran, apixaban, rivaroxaban, and edoxaban, for preventing and treating venous thromboembolism (VTE) in patients with cancer is unclear. METHODS: We searched the PubMed, Embase, Web of Science, and Cochrane Library databases from the establishment to November 30, 2021. In the frequency-based network meta-analysis, the odds ratio with a 95% confidence interval was reported. The relative ranking probability of each group was generated based on the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 15 randomized controlled trials involving a total of 6162 patients. Apixaban reduced the risk of VTE compared with low-molecular heparin [OR = 0.53, 95% CI (0.32, 0.89)]. The efficacy of drugs was ranked from highest to lowest as follows: apixaban (SUCRA, 81.0), rivaroxaban (73.0), edoxaban (65.9), dabigatran (51.4), warfarin (30.8), and low-molecular-weight heparin (LMWH) (27.4). Edoxaban increased the risk of major bleeding compared with LMWH [OR = 1.83, 95% CI (1.04, 3.22)]. The safety of drugs was ranked from highest to lowest as follows: major bleeding-apixaban (SUCRA, 68.5), LMWH (55.1), rivaroxaban (53.0), warfarin (35.9), dabigatran (29.2), edoxaban (16.5) and clinically relevant non-major bleeding-LMWH (73.0), apixaban (57.8), edoxaban (45.8), rivaroxaban (35.3), and warfarin (10.8). CONCLUSIONS: For preventing and treating VTE, in terms of VTE occurrence and major bleeding, apixaban had the lowest risk; in terms of clinically relevant non-major bleeding, LMWH had the lowest risk, followed by apixaban. Generally, apixaban is the most efficient and safest DOAC and presents better efficacy and relatively low bleeding risk among the VTE prevention and treatment drugs for patients with cancer.

Risk of nonmajor bleeding upon use of direct oral anticoagulants for preventing and treating venous thromboembolism: A network meta-analysis.

INTRODUCTION: Direct oral anticoagulants (DOACs) are associated with bleeding. Patients often stop taking DOACs due to nonmajor bleeding, which may lead to venous thromboembolism (VTE) recurrence. We aimed to determine the risk of nonmajor bleeding using different DOACs to prevent and treat VTE. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched from inception until January 6, 2021. The incidence of clinically relevant nonmajor bleeding and minor bleeding was investigated. In frequentist-based network meta-analysis, we analyzed the odds ratio (OR) with 95% CI and the surface under the cumulative ranking curves (SUCRA). RESULTS: Twenty-seven randomized controlled trials (RCTs) (involving 64,493 patients) were included. For preventing VTE, the risk for clinically relevant nonmajor bleeding was lowest for apixaban, followed by that for low-molecular weight heparin (LMWH), dabigatran, edoxaban, and rivaroxaban. The risk for minor bleeding was lowest for apixaban, followed by that for rivaroxaban, LMWH, dabigatran, and edoxaban. For treating VTE, the risk for clinically relevant nonmajor bleeding was also lowest for apixaban, followed by that for edoxaban, vitamin K antagonists (VKAs), and rivaroxaban. The risk for minor bleeding was lowest for apixaban, followed by that for rivaroxaban and VKAs. CONCLUSIONS: Regardless of whether it was used for preventing or treating VTE, apixaban had the lowest risk of nonmajor bleeding. This suggests that apixaban may have a lower risk of nonmajor bleeding than other anticoagulants and may help provide some clinical reference for choosing a more appropriate drug for the patient.