Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Validation of a Computerized Cognitive Training Tool to Assess Cognitive Impairment and Enable Differentiation Between Mild Cognitive Impairment and Dementia.

BACKGROUND: Age-related cognitive decline is a chronic, progressive process that requires active clinical management as cognitive status changes. Computerized cognitive training (CCT) provides cognitive exercises targeting specific cognitive domains delivered by computer or tablet. Meanwhile, CCT can be used to regularly monitor the cognitive status of patients, but it is not clear whether CCT can reliably assess cognitive ability or be used to diagnose different stages of cognitive impairment. OBJECTIVE: To investigate whether CCT can accurately monitor the cognitive status of patients with cognitive impairment as well as distinguish patients with dementia from patients with mild cognitive impairment (MCI). METHOD: We included 116 patients (42 dementia and 74 MCI) in final analysis. Cognitive ability was assessed by averaging the patient performance on the CCT to determine the Cognitive Index. The validity of the Cognitive Index was evaluated by its correlation with neuropsychological tests, and internal consistency was measured to assess the reliability. Additionally, we determined the diagnostic ability of the Cognitive Index to detect dementia using receiver operating characteristic (ROC) analysis. RESULTS: The Cognitive Index was highly correlated with the Montreal Cognitive Assessment (r = 0.812) and the Mini-Mental State Examination (r = 0.694), indicating good convergent validity, and the Cronbach's alpha coefficient was 0.936, indicating excellent internal consistency. The area under the ROC curve, sensitivity, and specificity of the Cognitive Index to diagnose dementia were 0.943, 83.3%, and 91.9%, respectively. CONCLUSIONS: CCT can be used to assess cognitive status and detect dementia in patients with cognitive impairment.

Development and validation of a nomogram for predicting varices needing treatment in compensated advanced chronic liver disease: A multicenter study.

BACKGROUND: Only a small proportion of patients with compensated advanced chronic liver disease (cACLD) had varices needing treatment (VNT) after recommended esophagogastroduodenoscopy (EGD) screening. We aimed to create a non-invasive nomogram based on routine tests to detect VNT in cACLD patients. METHODS: The training cohort included 162 cACLD patients undergoing EGD in a university hospital, between January 2014 and September 2019. A nomogram was developed based on the independent predictors of VNT, selected using a multivariate logistic regression analysis. Thirty-three patients from eight university hospitals were prospectively enrolled as validation cohort between December 2018 and December 2019. RESULTS: The prevalence of VNT was 32.7% (53/162) and 39.4% (13/33) in training and validation cohorts, respectively. The univariate analysis identified six risk factors for VNT. On the multivariate analysis, four of them, i.e., gallbladder wall thickness (odds ratio [OR]: 1.23; 95% confidence interval [CI]: 0.98-1.56), spleen diameter (OR: 1.02; 95% CI: 1.00-1.04), platelet count (OR: 0.98; 95% CI: 0.97-0.99), and international normalized ratio (OR: 0.58; 95% CI: 0.06-5.84) were independently associated with VNT. Thus, a nomogram based on the four above - mentioned variables was developed, and showed a favorable performance for detecting VNT, with an area under receiver operating characteristic curve of 0.848 (95% CI: 0.769-0.927) in training cohort. By applying a cut-off value of 105 in validation cohort, 31.0% of EGD were safely spared with 3.4% of missed VNT. CONCLUSION: A nomogram based on routine clinical parameters was developed for detecting VNT and avoiding unnecessary EGD in cACLD patients.

Accuracy of liver stiffness-based model by different imaging modalities in compensated advanced chronic liver disease.

OBJECTIVES: A liver stiffness × spleen size/platelet count score (LSPS) model which can rule out high-risk varices and identify high likelihood of clinically significant portal hypertension in patients with compensated cirrhosis has been endorsed by American Association for the Study of Liver Diseases in the 2016 practice guidance on portal hypertension bleeding. This study aims to evaluate the accuracy of LSPS model assessed by ultrasound in well characterized patients with compensated advanced chronic liver disease. METHODS: Eligible patients with compensated advanced chronic liver disease were retrospectively enrolled between January 2017 and March 2018, who had undergone routine clinical and laboratory tests, liver stiffness measurement, ultrasound examination, and computed tomography scanning. Spleen sizes were evaluated by ultrasound and computed tomography reconstructed model, respectively. The correlation and agreement of spleen size and LSPS derived from ultrasound and computed tomography imaging modality were compared. RESULTS: A total of 158 patients were included and analyzed. Spleen size showed a moderate correlation (R = 0.649, P < 0.001) according to ultrasound and computed tomography imaging. Also, the correlation between the two LSPS models based on ultrasound and computed tomography was excellent (R = 0.985, P < 0.001). The Bland-Altman plots demonstrated a superior agreement of LSPS model values evaluated by ultrasound and computed tomography, respectively. CONCLUSION: This study demonstrated the accuracy of LSPS model based on ultrasound in a well characterized cohort of fully compensated patients with advanced chronic liver disease.

Development and validation of a radiomics signature for clinically significant portal hypertension in cirrhosis (CHESS1701): a prospective multicenter study.

Clinically significant portal hypertension (CSPH) is associated with an incremental risk of esophageal varices and overt clinical decompensations. However, hepatic venous pressure gradient (HVPG) measurement, the gold standard for defining CSPH (HVPG≥10 mm Hg) is invasive and therefore not suitable for routine clinical practice. This study aims to develop and validate a radiomics-based model as a noninvasive method for accurate detection of CSPH in cirrhosis. The prospective multicenter diagnostic trial (CHESS1701, ClinicalTrials.gov identifier: NCT03138915) involved 385 patients with cirrhosis from five liver centers in China between August 2016 and September 2017. Patients who had both HVPG measurement and contrast-enhanced CT within 14 days prior to the catheterization were collected. The noninvasive radiomics model, termed rHVPG for CSPH was developed based on CT images in a training cohort consisted of 222 consecutive patients and the diagnostic performance was prospectively assessed in 163 consecutive patients in four external validation cohorts. rHVPG showed a good performance in detection of CSPH with a C-index of 0·849 (95%CI: 0·786-0·911). Application of rHVPG in four external prospective validation cohorts still gave excellent performance with the C-index of 0·889 (95%CI: 0·752-1·000, 0·800 (95%CI: 0·614-0·986), 0·917 (95%CI: 0·772-1·000), and 0·827 (95%CI: 0·618-1·000), respectively. Intraclass correlation coefficients for inter- and intra-observer agreement were 0·92-0·99 and 0·97-0·99, respectively. A radiomics signature was developed and prospectively validated as an accurate method for noninvasive detection of CSPH in cirrhosis. The tool of rHVPG assessment can facilitate the identification of CSPH rapidly when invasive transjugular procedure is not available.