Prevalence, contemporary trends and associated factors of potentially inappropriate prescription of edoxaban in real-world clinical practice: A subanalysis of the SUNSHINE registry.

AIM: As the direct oral anticoagulant most recently approved in China, data pertaining to clinical edoxaban use are still scarce. This study investigated the prevalence of and contemporary trends in edoxaban prescription among Chinese patients as well as factors associated with its inappropriate use in a multicentre registry of patients treated in real-world clinical practice. METHODS: This real-world, prospective, multicentre and non-interventional study included 1005 inpatients treated with edoxaban. According to National Medical Products Administration and European Heart Rhythm Association guidelines, edoxaban therapy was determined to be appropriate or inappropriate in each case. RESULTS: The median patient age was 70.0 years (interquartile range 61.0-78.0 years) and 46.3% were women. Overall, 456 (45.4%) patients received inappropriate edoxaban therapy, and common issues included an inappropriately low dosage (183, 18.2%) or wrong drug selection (109, 10.8%), high dosage (73, 7.3%), unreasonable off-label use (49, 4.9%), contraindicated medication combinations (27, 2.7%) and incorrect administration timing (16, 1.6%). Several factors, such as age ≥75 years (odds ratio [OR] = 1.921, 95% confidence interval [CI] 1.355-2.723, P < 0.001), weight >60 kg (OR = 2.657, 95%CI 1.970-3.583, P < 0.001), severe renal insufficiency (OR = 1.988, 95% CI 1.043-3.790, P = 0.037), current anaemia (OR = 1.556, 95% CI 1.151-2.102, P = 0.004) and history of bleeding (OR = 2.931, 95% CI 1.605-5.351, P < 0.001) were associated with an increased risk of inappropriate edoxaban therapy, whereas factors associated with cardiovascular specialties, such as admission to a cardiovascular department (OR = 0.637, 95% CI 0.464-0.873, P = 0.005), dronedarone use (OR = 0.065, 95% CI 0.026-0.165, P < 0.001) and amiodarone use (OR = 0.365, 95% CI 0.209-0.637, P < 0.001) decreased this risk. CONCLUSION: In this real-world study, 45.4% of patients received an inappropriate treatment with edoxaban. Multiple clinical characteristics can help identify patients who should receive edoxaban. Further development and implantation of educational activities and management strategies are needed to ensure the correct use of edoxaban.

Efficacy and safety of dabigatran and rivaroxaban in atrial fibrillation patients with impaired liver function: a multicenter retrospective cohort study.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients with impaired liver function (ILF) have not been sufficiently studied. The aim of this study was to evaluate the efficacy and safety of DOACs for stroke prevention in patients with AF and ILF. METHOD: This study was based on data from 15 centers in China, including 4,982 AF patients. The patients were divided into 2 subgroups based on their liver function status: patients with normal liver function (NLF)(n = 4213) and patients with ILF (n = 769). Logistic regression analysis was used to investigate the risk of total bleeding, major bleeding, thromboembolism, and all-cause deaths in AF patients with NLF and ILF after taking dabigatran or rivaroxaban, respectively. RESULTS: Among AF patients treated with dabigatran or rivaroxaban, patients with ILF were associated with significantly higher major bleeding, compared with NLF patients (aOR: 4.797; 95% CI: 2.224-10.256; P < 0.001). In patients with NLF, dabigatran (n = 2011) had considerably lower risk of total bleeding than rivaroxaban (n = 2202) (aOR: 1.23; 95% CI: 1.002-1.513; P = 0.049). In patients with ILF, dabigatran (n = 321) significantly favored lower risks of major bleeding compared with rivaroxaban(n = 448) (aOR: 5.484; 95% CI: 1.508-35.269; P = 0.026). CONCLUSION: After using dabigatran or rivaroxaban, patients with ILF had remarkably increased risk of major bleeding compared with patients with NLF. In AF patients with NLF, dabigatran had the distinct strength of significantly reduced risk of total bleeding compared with rivaroxaban. In patients with AF and ILF, dabigatran use was associated with lower risk for major bleeding compared with rivaroxaban.

Safety and efficacy of direct oral anticoagulation in patients with and without radiofrequency ablation of non-valvular atrial fibrillation: a multicenter retrospective cohort study.

BACKGROUND: Based on the few available studies on the prognostic benefit of using direct oral anticoagulants (DOACs) after atrial fibrillation (AF) ablation. Therefore, this study aimed to evaluate the prognostic differences between patients who underwent radiofrequency ablation (RFA) and those without RFA taking DOACs. METHODS: This is a multicenter retrospective cohort study enrolling 6137 patients with non-valvular AF (NVAF) at 15 hospitals in China. Patient information was collected through a mean follow-up of 10 months and medical record queries. Clinical outcomes included major bleeding, total bleeding, thrombosis, all-cause death, and a composite endpoint of bleeding, thrombosis, and all-cause death. RESULTS: After adjusting for confounders and propensity score matching (PSM), patients with RFA of NVAF had a significantly lower risk of major bleeding [OR 0.278 (95% CI, 0.150-0.515), P<0.001], thrombosis [OR 0.535 (95% CI, 0.316-0.908), P=0.020] and the composite endpoint [ OR 0.835 (95% CI, 0.710-0.982), P=0.029]. In the RFA PSM cohort, dabigatran was associated with reduced all-cause death in patients with RFA of NVAF [OR 0.420 (95% CI, 0.212-0.831), P=0.010]. In the no RFA PSM cohort, rivaroxaban was associated with a reduction in major bleeding [OR 0.521 (95% CI, 0.403-0.673), P<0.001], total bleeding [OR 0.114 (95% CI, 0.049-0.266), P<0.001], and the composite endpoint [OR 0.659 ( 95% CI, 0.535-0.811), P<0.001]. CONCLUSION: Among patients with NVAF treated with DOACs, RFA was a negative correlate of major bleeding, thrombosis, and composite endpoints but was not associated with total bleeding or all-cause mortality.

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.

Association between Body Mass Index and Clinical Outcomes in Patients with Non-valvular Atrial Fibrillation Receiving Direct Oral Anticoagulants: A New Piece of Evidence on the Obesity Paradox from China.

PURPOSE: We conducted a multicenter real-world study in China to assess the association between body mass index (BMI) and clinical outcomes in patients with atrial fibrillation (AF) taking direct oral anticoagulants (DOACs). METHOD: This is a retrospective multicenter cohort study conducted in 15 centers in China. We collected demographic information through the hospital information system and obtained clinical events through follow-up visits to patients or relatives. Clinical outcomes include major, minor, total bleeding, thromboembolism, and all-cause death. RESULT: A total of 6164 patients with non-valvular AF (NVAF) were included in this study. The incidence of major bleeding in patients with NVAF differed significantly by BMI category (P < 0.001), with 5.2% in the underweight group, 2.6% in the normal group, 1.4% in the overweight group, 1.1% in the obese I group, and 1.3% in the obese II group. There was no significant difference in minor, total bleeding, and thrombosis in the five groups (P = 0.493; P = 0.172; P = 0.663). All-cause death was significantly different among the five groups (P < 0.001), with 8.9% in the underweight group, 6.3% in the normal group, 4.8% in the overweight group, 2.2% in the obese I group, and 0.4% in the obese II group. High BMI was negatively associated with major bleeding (OR = 0.353, 95% CI 0.205-0.608), total bleeding (OR = 0.664, 95% CI 0.445-0.991), and all-cause death (OR = 0.370, 95% CI 0.260-0.527). CONCLUSION: In patients with NVAF treated with DOACs, higher BMI was associated with lower major bleeding and better survival. BMI was a negative correlate of total bleeding, but not minor bleeding and thrombosis.

Effects of sodium-glucose cotransporter type 2 inhibitors on cardiovascular, renal, and safety outcomes in patients with cardiovascular disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Controlled studies and observational studies have shown that sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for the survival of patients with heart failure (HF). However, it is unclear whether SGLT-2i can provide benefit in patients with other cardiovascular diseases. Here, we conducted a systematic review and meta-analysis to determine the outcomes of cardiovascular, renal, and safety outcomes of SGLT-2i administration in patients with cardiovascular diseases. METHODS: We searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and ClinicalTrials.gov databases for randomised controlled trials written in English from inception until November 1, 2020. Two reviewers independently identified randomised controlled trials comparing the effects of SGLT-2i in patients with cardiovascular disease with or without diabetes. Primary outcomes were cardiovascular outcomes and renal outcomes. Secondary outcomes were safety outcomes, including adverse endocrine outcomes and adverse infection outcomes. The effects of SGLT-2i were evaluated using RevMan5.3 software. The Cochrane risk of bias tool was used to assess study quality. RESULTS: We identified 10 randomised controlled trials (25,108 patients in the SGLT-2i group and 18,574 patients in the placebo group). Meta-analysis revealed that SGLT-2i treatment significantly reduced all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (HHF) in patients with cardiovascular disease (all-cause mortality relative risk [RR]: 0.86; 95% confidence interval [CI] 0.81-0.91; P < 0.00001; I2 = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79-0.92; P < 0.0001; I2 = 26%; HHF RR: 0.69; 95% CI 0.64-0.81; P < 0.00001; I2 = 0%). In patients with HF, mortality and HHF after SGLT-2i treatment for HF with reduced ejection fraction were significantly reduced, whereas HF with preserved ejection fraction did not differ compared with placebo treatment. Moreover, SGLT-2i induced a lower incidence of renal damage and myocardial infarction than the placebo group; however, the risk of infection, amputation, volume depletion, and diabetic ketoacidosis was higher. CONCLUSIONS: SGLT-2i had significant clinical effects on cardiovascular outcomes and significantly influenced acute kidney injury. The effects of SGLT-2i on cardiovascular disease were independent of diabetic status. Sotagliflozin could have advantages over other SGLT-2i in lowering HHF.

Correction: Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.2196/18386.].

Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: An increasing number of patients have received prophylactic or therapeutic oral anticoagulants (OACs) for thromboembolic complications of diseases. The use of OACs is associated with both clinical benefits and risks. Considering the challenges imposed by this class of drugs, as well as the enormous progress made in portable device technology, it is possible that technology-based interventions may improve clinical benefits for patients and optimize anticoagulation management. OBJECTIVE: This study was designed to comprehensively evaluate the role of technology-based interventions in the management of OACs. METHODS: We searched 6 databases-PubMed, EMBASE, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Scopus, and PsycINFO-to retrieve relevant studies published as of November 1, 2019, to evaluate the effect of technology-based interventions on oral anticoagulation management. RevMan (version 5.3; Cochrane) software was used to evaluate and analyze clinical outcomes. The methodological quality of studies was assessed by the Cochrane risk of bias tool. RESULTS: A total of 15 randomized controlled trials (RCTs) were selected for analysis. They reported data for 2218 patients (1110 patients in the intervention groups and 1108 patients in the control groups). A meta-analysis was performed on the effectiveness and safety data reported in the RCTs. Technology-based interventions significantly improved the effectiveness of oral anticoagulation management (mean difference [MD]=6.07; 95% CI 0.84-11.30; I2=72%; P=.02). The safety of oral anticoagulation management was also improved, but the results were not statistically significant. Bleeding events were reduced (major bleeding events MD=1.02; 95% CI 0.78-1.32; I2=0%; P=.90; minor bleeding events MD=1.06, 95% CI 0.77-1.44; I2=41%; P=.73) and thromboembolism events were reduced (MD=0.71; 95% CI 0.49-1.01; I2=0%; P=.06). In general, patients were more satisfied with technology-based interventions, which could also improve their knowledge of anticoagulation management, improve their quality of life, and reduce mortality and hospitalization events. CONCLUSIONS: Using technology to manage OACs can improve the effectiveness and safety of oral anticoagulation management, result in higher patient satisfaction, and allow greater understanding of anticoagulation.

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.

Development and Validation of a Clinical Risk Score to Predict Immune-mediated Liver Injury Caused by Sintilimab: Assessed for Causality Using Updated RUCAM.

Background and Aims: Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event. Methods: The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors. Results: Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids. Conclusions: This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.

Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known.

BACKGROUND: This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment. METHODS: PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms. RESULTS: The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors. CONCLUSIONS: The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.

Tryptanthrin inhibits tumor angiogenesis via Notch/Dll4 signaling pathway in zebrafish.

Background: Anti-angiogenic pathways are important for inhibiting tumor growth and migration. Tryptanthrin has anticancer properties in vivo but its anti-angiogenesis activities and associated mechanisms remain unclear. Methods: The effects of tryptanthrin were investigated in vivo using fluorescent labeling of blood vessels in zebrafish. Fluorescence quantitation was conducted to analyze the level of delta-like ligand 4 (Dll4) gene expression. Transcriptome sequencing and quantitative polymerase chain reaction (qPCR) analyses were performed to explore the molecular mechanisms of anti-tumor angiogenesis. Results: Significant anti-tumor effects were observed in all 48-hpf (hours post-fertilization) zebrafish treated with tryptanthrin (P<0.05). The 6-hpf zebrafish were cultured to 48 and 72 hpf following tryptanthrin treatment. It was found that compared with the control groups, the fluorescence area and the number of complete internode vessels reduced significantly following treatment with medium and high concentrations of tryptanthrin (P<0.05). The relative expression of Dll4 in the 48-hpf zebrafish was significantly inhibited only in the high concentration group (P<0.05). qPCR analysis revealed that the levels of Krt18b, desma, Tnnt2c, and Krt4 gene expression were significantly up-regulated in zebrafish following Dll4 overexpression. After Dll4 knockdown, the level of desma and Tnnt2c gene expression was significantly up-regulated. Conclusions: Tryptanthrin can inhibit tumor growth in vivo in a concentration-dependent manner by down-regulating Dll4 protein expression, and at the same time up-regulating the level of desma and Tnnt2c gene expression.

Off-label dose direct oral anticoagulants and clinical outcomes in Asian patients with atrial fibrillation: A new evidence of Asian dose.

AIM: This study aimed to evaluate the label compliance of DOACs in the Chinese AF population and explore the relationship between inappropriate DOACs dosage and clinical results. METHODS AND RESULTS: This is a retrospective multicenter cohort study conducted in 14 centers in China. According to the China Food and Drug Administration(CFDA) label and the recommendations of international guidelines, we divided patients into on-label dosage and off-label dosage. We then compared the clinical results after propensity score matching. We collect demographic information through the hospital information system and obtain clinical events through follow-up of patients or their families. Clinical results include major, minor, total bleeding, thrombosis, and all-cause death. 4191 patients with non-valvular AF (NVAF) were included, and approximately 55.6% and 1.7% of AF patients received off-label underdose and off-label overdose of DOACs, respectively. Compared with the on-label dose, DOACs with off-label underdose were associated with a significantly reduced risk of major bleeding (P = 0.004, OR = 0.23,95% CI: 0.08-0.69) and all-cause death (P<0.001, OR = 0.49,95% CI: 0.33-0.73). However, there was no significant difference in thrombotic events (P = 0.865 OR = 1.06,95% CI: 0.54-2.07) and minor bleeding (P = 0.465, OR = 1.10,95% CI: 0.85-1.43) risk. CONCLUSIONS: About 57.3% of Asian AF patients received an off-label dose of DOACs in daily practice. Off-label underdose DOACs were associated with significantly lower risks of major bleeding, all-cause death, and similar risks of minor bleeding, thrombotic events compared with on-label dose DOACs. Further prospective randomized trials are needed to determine the optimal dose of DOACs in Asian patients with AF at high bleeding risk.

Efficacy and Safety of Direct Oral Anticoagulants in Patients With Atrial Fibrillation Combined With Hypertension: A Multicenter, Retrospective Cohort Study.

Whether there are differences in direct oral anticoagulants efficacy and safety in patients with atrial fibrillation (AF) combined with hypertension is unclear. We therefore conducted a multicenter retrospective cohort study to assess the differences in the efficacy and safety of direct oral anticoagulants in patients with AF combined with hypertension. This multicenter retrospective cohort study was based on data from 15 centers in China and included 2086 patients with AF. We divided the patients into dabigatran and rivaroxaban groups according to their direct oral anticoagulants. Propensity score matching was used to balance the covariates between the groups. Due to our limited sample size, the number of cases of some clinical events with low incidence was small. During a mean follow-up period of 10 months, a total of 268 (12.9%) bleeding events occurred, including 27 (1.3%) major bleeding events and 241 (11.6%) minor bleeding events, and 45 (2.2%) thromboembolic events. In patients with AF combined with hypertension, rivaroxaban was associated with a higher major bleeding incidence than dabigatran (odds ratio [OR], 2.89 [95% confidence interval [CI, 1.22-6.87]; P = .012). In contrast, the risk of thromboembolism and minor bleeding was similar for rivaroxaban (OR, 0.55 [95%CI, 0.29-1.01]; P = .069) and dabigatran (OR, 0.82 [95%CI, 0.63-1.08]; P = .150). Based on the results of this study, in patients with AF and hypertension treated with direct oral anticoagulants, the incidence of thromboembolism and minor bleeding was not statistically different between dabigatran and rivaroxaban, but compared with rivaroxaban, dabigatran was associated with a lower risk of major bleeding.

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.

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.

MiRNA-1202 promotes the TGF-ß1-induced proliferation, differentiation and collagen production of cardiac fibroblasts by targeting nNOS.

BACKGROUND: Atrial fibrillation (AF) is a clinically common arrhythmia that affects human health. Myocardial fibrosis serves as an important contributor to AF. Recently, miRNA-1202 have been reported to be up-regulated in AF. However, the role of miRNA-1202 and its mechanism in myocardial fibrosis remain unclear. METHODS: Human cardiac fibroblasts (HCFs) were used to construct a fibrosis model by TGF-ß1 induction. The expression of miR-1202 was measured by qRT-PCR. Cell proliferation was assessed by CCK-8 assays. Protein expression levels were measured by western blot. Collagen accumulation was measured by ELISA. The relationship between miR-1202 and nNOS was investigated by luciferase reporter assays. RESULTS: MiR-1202 expression was obviously increased in HCFs and was both time- and dose-independent. MiR-1202 could increase the proliferation and collagen I, collagen III, and α-SMA levels with or without TGF-ß1. MiR-1202 could also increase TGF-ß1 and p-Smad2/3 protein levels in comparison to the control group. However, they were obviously decreased after inhibitor transfection. MiR-1202 targets nNOS for negative regulation of HCFs fibrosis by decreasing cell differentiation, collagen deposition and the activity of the TGF-ß1/Smad2/3 pathway. Co-transfection of miR-1202 inhibitor and siRNA of nNOS inhibited nNOS protein expression, thereby enhancing the HCFs proliferation. Furthermore, co-transfection of the miR-1202 inhibitor and siRNA of nNOS significantly promoted collagen I, collagen III, TGF-ß1, Smad2/3 and α-SMA protein expression and Smad2/3 protein phosphorylation. These findings suggested that miR-1202 promotes HCFs transformation to a pro-fibrotic phenotype by targeting nNOS through activating the TGF-ß1/Smad2/3 pathway.

hsa-miR-4443 inhibits myocardial fibroblast proliferation by targeting THBS1 to regulate TGF-ß1/α-SMA/collagen signaling in atrial fibrillation.

Fibrosis caused by the increase in extracellular matrix in cardiac fibroblasts plays an important role in the occurrence and development of atrial fibrillation (AF). The aim of this study was to investigate the role of hsa-miR-4443 in AF, human cardiac fibroblast (HCFB) proliferation, and extracellular matrix remodeling. TaqMan Stem-loop miRNA assay was used to measure hsa-miR-4443 expression in patients with persistent AF (n=123) and healthy controls (n=100). Patients with AF were confirmed to have atrial fibrosis by late gadolinium enhancement. At the cellular level, after hsa-miR-4443 mimic and inhibitor were transfected with HCFBs, proliferation, apoptosis, migration, and invasion were analyzed. Lastly, hsa-miR-4443-targeted gene and transforming growth factor (TGF)-ß1/α-SMA/collagen pathway were evaluated by dual-luciferase reporter assay and western blot, respectively. In patients with AF, hsa-miR-4443 decreased significantly and collagen metabolism level increased significantly. Logistic regression analysis showed that low hsa-miR-4443 level was a risk factor of AF (P<0.001). The receiver operating characteristic curve revealed that hsa-miR-4443 was useful for predicting AF (area under the curve: 0.828, sensitivity: 0.71, specificity: 0.78, P<0.001). In HCFBs, hsa-miR-4443 targeted thrombospondin-1 (THBS1) and downregulated TGF-ß1/α-SMA/collagen pathway. The inhibition of hsa-miR-4443 expression promoted HCFB proliferation, migration, invasion, myofibroblast differentiation, and collagen production. The significant reduction of hsa-miR-4443 can be used as a biomarker for AF. hsa-miR-4443 protected AF by targeting THBS1 and regulated TGF-ß1/α-SMA/collagen pathway to inhibit HCFB proliferation and collagen synthesis.

The efficacy and safety of Sacubitril/Valsartan in the treatment of chronic heart failure: a meta-analysis.

OBJECTIVE: A meta-analysis of the studies involving Sacubitril/Valsartan in chronic heart failure was performed to compare the efficacy and safety of Sacubitril/Valsartan with traditional drug therapy in chronic heart failure. METHODS: We searched databases from PubMed, EMBASE, the Cochrane Library, Web of Science, and clinicaltrials.gov for studies published between 2010 and 2020 that reported efficacy and safety following Sacubitril/Valsartan administration. RESULTS: Ten studies enrolling 1689 patients were included. Sacubitril/Valsartan outperformed traditional medicine (especially the Non-ARNI group) in terms of blood pressure, biomarkers and cardiac reverse remodeling indices, with striking changes in left ventricular ejection fraction, systolic blood pressure. Sacubitril/Valsartan showed significant benefit in renal function in patients with chronic heart failure. CONCLUSIONS: Compared with traditional drugs, Sacubitril/Valsartan significantly improved echocardiography, vital signs and biomarkers of patients with chronic heart failure, and reduced the incidence of hyperkalemia, renal dysfunction and other adverse reactions. Further large sample trials are needed in the future to determine the long-term effects of Sacubitril/Valsartan on efficacy and safety in patients with chronic heart failure.

Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and changes in bowel movements. Effective therapy for visceral hypersensitivity in IBS patients remains challenging. This study investigated the roles of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) and the effect of ANA-12 (a selective antagonist of TrkB) on chronic visceral hypersensitivity in an IBS-like rat model. METHODS: An IBS-like rat model was established through neonatal maternal separation (NMS), and visceral hypersensitivity was assessed by electromyographic (EMG) responses of the abdominal external oblique muscles to colorectal distention (CRD). Different doses of ANA-12 were injected intrathecally to investigate the effect of that drug on visceral hypersensitivity, and the open field test was performed to determine whether ANA-12 had side effects on movement. Thoracolumbar spinal BDNF, TrkB receptor and Protein kinase Mζ (PKMζ) expression were measured to investigate their roles in chronic visceral hypersensitivity. Whole-cell recordings were made from thoracolumbar superficial dorsal horn (SDH) neurons of lamina II. RESULTS: The expression of BDNF and TrkB was enhanced in the thoracolumbar spinal cord of the NMS animals. ANA-12 attenuated visceral hypersensitivity without side effects on motricity in NMS rats. PKMζ expression significantly decreased after the administration of ANA-12. The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased in the thoracolumbar SDH neurons of lamina II in NMS rats. The amplitude and frequency of sEPSCs were reduced after perfusion with ANA-12 in NMS rats. CONCLUSIONS: Neonatal maternal separation caused visceral hypersensitivity and increased synaptic activity by activating BDNF-TrkB-PKMζ signalling in the thoracolumbar spinal cord of adult rats. PKMζ was able to potentiate AMPA receptor (AMPAR)-mediated sEPSCs in NMS rats. ANA-12 attenuated visceral hypersensitivity and synaptic activity by blocking BDNF/TrkB signalling in NMS rats. SIGNIFICANCE: ANA-12 attenuates visceral hypersensitivity via BDNF-TrkB-PKMζ signalling and reduces synaptic activity through AMPARs in NMS rats. This knowledge suggests that ANA-12 could represent an interesting novel therapeutic medicine for chronic visceral hypersensitivity.