Efficacy and safety of glycyrrhizic acid combined to essential phospholipids (Phosphogliv) at non-alcoholic fatty liver disease: results of multicenter double blind randomized placebo-controlled post-registration clinical study (IV phase) «Gepard» (PHG-M2/P02-12)

Aim of investigation. To estimate efficacy and safety of two pharmacological forms of «Phosphogliv» (lyophilizate for intravenous administration and capsules) for the treatment of fatty liver degeneration of non-alcoholic etiology. Material and methods. Original study included overall 180 patients with nonalcoholic fatty liver disease that were randomized to the basic and control groups in the ratio of 2:1. The basic group patients received Phosphogliv 5 mg/day as intravenous bolus injection for 2 weeks, followed by oral intake of 2 capsules t.i.d. for 10 weeks (the total treatment duration was 12 weeks), control group patients received placebo in the same mode. Serum levels of inflammatory marker adiponectin, NAFLD fibrosis score, treatment effect on quality of life and safety of patients were monitored. Results. In 12 wks in patients with more significant cytolysis (threefold and higher serum alanine transaminase activity) and the rate of adiponectin level improvement on the background of Phosphogliv was 57.9% versus only 10.0% (p=0.019) in the placebo group. The mean NAFLD fibrosis score in the basic group remained almost unchanged, while in the control group negative dynamics was revealed, that resulted in statistically significant differences between groups (2.5±1.2 units versus 2.0±1.3 units respectively; р=0.009). At Phosphogliv injection already during the first 2 wks more pronounced improvement of subjective perception of dyspeptic symptoms was observed (mean score was 5.6±1.3 versus 5.1±1.4; р=0.021). When the treatment course was completed the basic group patients had higher mean score by «level of energy» scale (5.9±1.0 versus 5.6±1.0; р=0.034). Only sporadic adverse effects were found to the background of treatment, no statistically significant differences in their rate in were recorded. Dynamics of the basic physical parameters and laboratory tests was comparable as well. Conclusions. Treatment of non-alcoholic fatty liver disease that includes Phosphogliv provides reduction of steatohepatitis activity, retardation of fibrosis progression, improvement of overall disease prognosis and high satisfaction of patients at a favorable safety profile

Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury

Background: In several small studies, anticoagulant therapy reduced the incidence of venous thromboembolism (VTE) in patients with isolated lower-limb injuries. Objectives: To compare the efficacy and safety of fondaparinux 2.5 mg (1.5 mg in patients with a creatinine clearance between 30 and 50 mL min-1) over nadroparin 2850 anti-factor Xa IU. Patients and Methods: In this international, multicenter, randomized, open-label study, patients with an isolated non-surgical unilateral below-knee injury having at least one additional major risk factor for VTE and requiring, in the Investigator's opinion, rigid or semi-rigid immobilization for 21-45 days with thromboprophylaxis up to complete mobilization received subcutaneously once-daily either fondaparinux or nadroparin. The primary efficacy outcome was the composite of VTE (symptomatic or ultrasonographically detected asymptomatic deep vein thrombosis of the lower limb or symptomatic pulmonary embolism) and death up to complete mobilization. The main safety outcome was major bleeding. Results: We randomized 1349 patients (mean age 46 years): 88.7% had a bone fracture, and 83.8% had a plaster cast fitted (mean duration of immobilization, 34 days). The primary efficacy outcome occurred in 15 of 584 patients (2.6%) in the fondaparinux group and 48 of 586 patients (8.2%) in the nadroparin group (odds ratio, 0.30; 95% confidence interval [CI], 0.15-0.54; P < 0.001). A single major bleed was experienced by fondaparinux-treated patients and none by nadroparin-treated patients. These results were maintained up to the end of follow-up. Conclusions: Fondaparinux 2.5 mg day-1 may be a valuable therapeutic option over nadroparin 2850 anti-FXa IU day-1 for preventing VTE after below-knee injury requiring prolonged immobilization in patients with additional risk factors

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen