A Comparative Study of the Clinical Benefits of Rivaroxaban and Warfarin in Patients With Non-valvular Atrial Fibrillation With High Bleeding Risk.

OBJECTIVE: To compare the clinical benefits of rivaroxaban and warfarin in patients with non-valvular atrial fibrillation (NVAF) with high bleeding risk. METHODS: A retrospective study was conducted on patients with high bleeding risk NVAF who were hospitalized at the First Affiliated Hospital of Zhengzhou University between May 31, 2016 and May 31, 2019 and took at least rivaroxaban and warfarin. The clinical benefits of both drugs were assessed by efficacy benefit and safety risk. The primary efficacy benefit was a composite end point for stroke (both ischemic and hemorrhagic) and systemic embolism. The secondary efficacy end points were death and myocardial infarction (MI). The principal safety end point was the composite end point of fatal bleeding and critical organ bleeding. RESULTS: A total of 1,246 patients with high bleeding risk were enrolled, including 787 patients in the rivaroxaban group and 459 patients in the warfarin group. Results of the primary efficacy benefit endpoint were obtained from 104 patients (13.2%) in the rivaroxaban group and 88 (19.2%) patients in the warfarin group (hazard ratio [HR]: 0.681; 95% confidence interval [CI]: 0.512-0.906; P < 0.001 for non-inferiority). The principal safety end points were observed in 49 (6.23%) patients in the rivaroxaban group and in 55 (11.98%) patients in the warfarin group (HR: 0.469 in the rivaroxaban group; 95% CI: 0.314-0.702; P < 0.001). With respect to secondary efficacy and benefit endpoints, 28 (3.56%) patients in the rivaroxaban group and 22 (4.79%) patients in the warfarin group died, with an HR of 0.760 (95% CI: 0.435-1.329; P = 0.336); 32 (4.07%) patients in the rivaroxaban group; and 26 (5.66%) patients in the warfarin group had MI, with an HR of 1.940 (95% CI: 0.495-1.069, P = 0.254) in the rivaroxaban group. CONCLUSIONS: Rivaroxaban is non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with high blood NVAF. Rivaroxaban is superior to warfarin in reducing fatal bleeding and bleeding in critical organs. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trials Registry, identifier ChiCTR2100052454.

Cytochrome P450 2E1 predicts liver functional recovery from donation after circulatory death using air-ventilated normothermic machine perfusion.

The optimal oxygen concentration is unclear for normothermic machine perfusion (NMP) of livers from donation after circulatory death (DCD). Our purposes were to investigate the effect of air-ventilated NMP on the DCD liver, analyze the underlying mechanism and select the targets to predict liver functional recovery with NMP. NMP was performed using the NMP system with either air ventilation or oxygen ventilation for 2 h in the rat liver following warm ischemia and cold-storage preservation. Proteomics and metabolomics were used to reveal the significant molecular networks. The bioinformation analysis was validated by administering peroxisome proliferator activator receptor-γ (PPARγ) antagonist and agonist via perfusion circuit in the air-ventilated NMP. Results showed that air-ventilated NMP conferred a better functional recovery and a less inflammatory response in the rat DCD liver; integrated proteomics and metabolomics analysis indicated that intrahepatic docosapentaenoic acid downregulation and upregulation of cytochrome P450 2E1 (CYP2E1) expression and activity were associated with DCD liver functional recovery with air-ventilated NMP; PPARγ antagonist worsened liver function under air-oxygenated NMP whereas PPARγ agonist played the opposite role. In conclusion, air-ventilated NMP confers a better liver function from DCD rats through the DAP-PPARγ-CYP2E1 axis; CYP2E1 activity provides a biomarker of liver functional recovery from DCD.

Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.