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.

Effects and Mechanism of Action of Panax notoginseng Saponins on the Pharmacokinetics of Warfarin.

BACKGROUD: The interactions between Chinese herbs and drugs pose a great challenge to the combined clinical application of Chinese herbs and drugs. Chinese medicinal products contain complex pharmacologically active components that may influence the in vivo processes of drugs in a variety of ways. In China, drugs based on Panax ginseng total saponins (PNS) are often combined with warfarin for the treatment of cardiovascular diseases. OBJECTIVES: To assess the effects of Panax notoginseng saponins (PNS) on the pharmacokinetics of warfarin and its mechanism. METHOD: Blood was collected for the determination of the prothrombin time (PT) and international normalized ratio (INR) from rats treated with warfarin alone or with warfarin + PNS. The plasma concentration of warfarin was determined by high-performance liquid chromatography. Western blot was used to detect the expression of cytochrome P450 (CYP) enzymes. RESULTS: When warfarin and PNS were co-administered, the PT and INR increased compared to when warfarin was given alone. 72 hours after administration, compared to the warfarin alone group, the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups showed 110%, 122%, and 126% increases in PT, respectively (all P < 0.05), as well as 111%, 124%, and 128% increases in INR (all P < 0.05). Compared with the warfarin alone group, the clearance rate (CL/F) of warfarin in the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups was 10% (P > 0.05), 23% (P < 0.05), and 33% (P < 0.05) lower, respectively, while the systemic exposure (area under the concentration-time curve, AUC0-t) increased by 106% (P > 0.05), 119% (P < 0.05), and 134% (P < 0.05), respectively, and the blood concentration of warfarin incresed by 112%, 113%, and 114%, respectively (all P > 0.05). After combined treatment of HepG2 cells with warfarin + PNS, CYP1A2 expression was upregulated (P < 0.05) and CYP3A4 was downregulated (P < 0.05) but there was no effect on CYP2C9. In animal experiments, PNS had different effect on the expression of CYP1A2 in different doses. While a low dose of PNS resulted in downregulated CYP1A2 expression (P < 0.05), a medium dose resulted in upregulation (P < 0.05), and CYP1A2 expression was not significantly affected by a high dose of PNS (P > 0.05). Meanwhile, PNS at all doses downregulated the expression of CYP3A4 (P < 0.05) but had no effect on the expression of CYP2C9 (P > 0.05). CONCLUSION: PNS can increase the blood concentration of warfarin, as well as the exposure time, and it can enhance the anticoagulant effect of warfarin by inhibiting the expression of the liver enzyme CYP3A4.

Editor's Choice - Severe Bleeding Risks of Direct Oral Anticoagulants in the Prevention and Treatment of Venous Thromboembolism: A Network Meta-Analysis of Randomised Controlled Trials.

OBJECTIVE: The aim of this study was to determine the severe bleeding safety of direct oral anticoagulants (DOACs) for the prevention and treatment of venous thromboembolism (VTE). METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched up to 6 January 2021. The incidence of severe bleeding (major, gastrointestinal [GI], intracranial, and fatal) was investigated. Using frequentist network meta-analysis, interventions that were not compared directly could be compared indirectly by the 95% confidence interval (CI), making the search results more intuitive. Based on surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. RESULTS: Thirty-one randomised controlled trials (76 641 patients) were included. For the treatment of VTE, the risk of major bleeding with apixaban was significantly lower than dabigatran (odds ratio [OR] 2.10, 95% CI 1.07 - 4.12) and edoxaban (OR 2.64, 95% CI 1.36 - 5.15). The safety of the drugs was ranked from highest to lowest as follows: major bleeding: apixaban (SUCRA 98.0), rivaroxaban (SUCRA 69.6), dabigatran (SUCRA 50.7), edoxaban (SUCRA 26.5), and vitamin K antagonists (VKAs; SUCRA 5.1); GI bleeding: apixaban (SUCRA 80.7), rivaroxaban (SUCRA 66.8), edoxaban (SUCRA 62.3), VKAs (SUCRA 34.4), and dabigatran (SUCRA 5.8); intracranial bleeding: rivaroxaban (SUCRA 74.4), edoxaban (SUCRA 70.4), dabigatran (SUCRA 58.2), apixaban (SUCRA 44.4), and VKAs (SUCRA 5.6); fatal bleeding: edoxaban (SUCRA 82.7), rivaroxaban (SUCRA 59.2), dabigatran (SUCRA 48.6), apixaban (SUCRA 43.0), and VKAs (SUCRA 16.3). For the prevention of VTE, the risk of major bleeding with apixaban was significantly lower than rivaroxaban (OR 2.14, 95% CI 1.02 - 4.52). Among the four types of bleeding, apixaban had the lowest bleeding risk among DOACs (major bleeding: SUCRA 81.6; GI bleeding: SUCRA 75.4; intracranial bleeding: SUCRA 64.1; fatal bleeding: SUCRA 73.6). CONCLUSIONS: For the treatment of VTE, in terms of major bleeding and GI bleeding, apixaban had the lowest bleeding risk; in terms of intracranial bleeding, rivaroxaban had the lowest bleeding risk; in terms of fatal bleeding, edoxaban had the lowest bleeding risk. For the prevention of VTE, apixaban had the lowest bleeding risk.

Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats.

Astragaloside IV (AGS-IV), a new glycoside of cycloartane-type triterpene isolated from the root of Astragalus membranaceus (Fisch.) Bunge, has been used experimentally for its potent immune-stimulating, anti-inflammatory, and antioxidative actions. A recent study has shown AGS-IV to be an aldose-reductase inhibitor and a free-radical scavenger. This study examined the effects of AGS-IV on motor nerve conduction velocity (MNCV), tailflick threshold temperature, biochemical indexes, and the histology of the sural nerve after diabetes was induced in rats with 75 mg/kg streptozotocin (STZ). AGS-IV (3, 6, 12 mg/kg, twice a day) was administered by oral gavage for 12 weeks after diabetes was induced. Compared with control (nondiabetic) rats, obvious changes in physiological behaviors and a significant reduction in sciatic MNCV in diabetic rats were observed after 12 weeks of STZ administration. Morphological analysis showed that AGS-IV suppressed a decrease in myelinated fiber area, an increase in myelinated fiber density, and an increase in segmental demyelination in diabetic rats. The protective mechanism of AGS-IV involved a decrease in declining blood glucose concentration and HbA1C levels, and an increase in plasma insulin levels. AGS-IV increased the activity of glutathione peroxidase in nerves, depressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes. Moreover, AGS-IV elevated Na+,K+-ATPase activity in both the nerves and erythrocytes of diabetic rats. These results indicate that AGS-IV exerts protective effects against the progression of peripheral neuropathy in STZ-induced diabetes in rats through several interrelated mechanisms.

Protective effects of Astragalus saponin I on early stage of diabetic nephropathy in rats.

Diabetic nephropathy (DN) has become the leading cause of end stage failure, but no renoprotective treatment has been very available for use in DN. Astragalus saponin I (AS I), a component extracted from Astragalus membranaceus BUNGE, was studied in experimental DN induced by administration of streptozotocin in male rats. The early DN rats were treated with 3 doses of AS I for 8 weeks to analyze its efficacy with different parameters. By comparison with vehicle-treated DN rats, the renal hypertrophy, the oxidative stress intensity, and the blood glucose level of DN rats were ameliorated by AS I. Also, the microalbuminuria level, advanced glycated end-products either in serum or in kidney cortex, and the aldose reductase activity were significantly reduced. Furthermore, the expression of transforming growth factor beta1 mRNA in kidney cortex by RT-PCR analysis was markedly declined. Both the relative grade of mesangium hyperplasia by microscopical observation and the thickness of glomerular base membrane by electron microscope measurement were decreased significantly. Therefore, the results suggest that AS I has therapeutic effects on several pharmacological targets in the progress of DN and is a potential drug for prevention of early stage DN.