Efficacy and safety of the combined metabolic medication, containing inosine, nicotinamide, riboflavin and succinic acid, for the treatment of diabetic neuropathy: a multicenter randomized, double-blind, placebo-controlled parallel group clinical trial (CYLINDER).

INTRODUCTION: Antioxidants may have positive impact on diabetic polyneuropathy (DPN), presumably due to alleviation of oxidative stress. We aimed to evaluate the efficacy and safety of combination of antioxidants: succinic acid, inosine, nicotinamide, and riboflavin (SINR) in the treatment of DPN. RESEARCH DESIGN AND METHODS: In a double-blind, placebo-controlled clinical trial, men and women aged 45-74 years with type 2 diabetes and symptomatic DPN, with initial Total Symptom Score (TSS) ˃5, were randomized into experimental (n=109) or placebo (n=107) group. Patients received study medication/placebo intravenously for 10 days, followed by oral administration for 75 days. Statistical significance was defined as a two-tailed p<0.05. RESULTS: In SINR group, mean TSS change after 12 weeks was -2.65 (±1.46) vs -1.73 (±1.51) in the placebo group (p<0.0001; t-test). Reduction of symptoms in the SINR group was achieved regardless of hemoglobin A1c levels, but better results were observed in patients with initial TSS <7.5. The analysis of TSS subscores revealed statistically significant between-group differences by dynamics of the intensity of paresthesia and of numbness starting from day 11 (p=0.035 and p=0.001, respectively; mixed model); by day 57, statistically significant between-group differences were detected also by dynamics of burning intensity (p=0.005; mixed model). Study limitations are small effect size, moderate proportion of patients with severe DPN symptoms, subjective assessment of outcomes, exclusion of participants who received injectable glucose-lowering medications other than insulins, and patients with uncontrolled and type 1 diabetes. CONCLUSIONS: The combination of SINR effectively alleviates DPN symptoms in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04649203; Unique Protocol ID: CTF-III-DM-2019).

Enhancing and accelerating stroke treatment in Eastern European region: Methods and achievement of the ESO EAST program.

INTRODUCTION: Despite the availability of prevention and therapies of stroke, their implementation in clinical practice, even of low-cost ones, remains poor. In 2015, the European Stroke Organisation (ESO) initiated the ESO Enhancing and Accelerating Stroke Treatment (EAST) program, which aims to improve stroke care quality, primarily in Eastern Europe. Here, we describe its methods and milestones. PATIENTS AND METHODS: The ESO EAST program is using an implementation strategy based on a 'detecting-understanding-reducing disparities' conceptual framework: stroke care quality is first measured (after developing a platform for data collection), gaps are identified in the current service delivery, and ultimately feedback is provided to participating hospitals, followed by the application of interventions to reduce disparities. The ESO EAST program is carried out by establishing a stroke quality registry, stroke management infrastructure, and creating education and training opportunities for healthcare professionals. RESULTS: Program management and leadership infrastructure has been established in 19 countries (Country Representatives in 22 countries, National Steering Committee in 19 countries). A software platform for data collection and analysis: Registry of Stroke Care Quality was developed, and launched in 2016, and has been used to collect data from over 90,000 patients from >750 hospitals and 56 countries between September 2016 and May 2019. Training in thrombolysis, nursing and research skills has been initiated. DISCUSSION: ESO EAST is the first pan-Eastern European (and beyond) multifaceted quality improvement intervention putting evidence-informed policies into practice. Continuous monitoring of stroke care quality allows hospital-to-hospital and country-to-country benchmarking and identification of the gaps and needs in health care.

Importance of cerebral artery recanalization in patients with stroke with and without neurological improvement after intravenous thrombolysis.

BACKGROUND AND PURPOSE: Recanalization status after intravenous thrombolysis (IVT) in patients with ischemic stroke is a reference point to proceed with a rescue reperfusion intervention, although early neurological improvement (NI) may preclude endovascular procedures. We aimed to evaluate the importance of restoration of blood flow at the arterial occlusion site in subgroups of patients with stroke stratified by early NI after IVT. METHODS: The following patients were recruited from the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register: (1) with baseline vessel occlusion documented by computed tomographic (CT) or magnetic resonance (MR) angiography and follow-up angioimaging between 22 and 36 hours after IVT available; and (2) with dense cerebral artery sign on admission CT scan and results of follow-up CT reported. Recanalization at 24 hours was defined as absence of vessel occlusion or as resolution of dense cerebral artery sign on follow-up 22- to 36-hour imaging. NI was assessed at 2 hours and 24 hours after IVT and was defined as improvement by 20% from baseline National Institute of Health Stroke scale score. Primary outcome measure was independence, defined as modified Rankin scale score 0 to 2 after 3 months. RESULTS: Of 28136 cases registered between December 2003 and November 2009, 5324 cases (19%) met the inclusion criteria. Patients with both NI at 2 hours post-treatment and vessel recanalization had the best chances to achieve independence at 3 months (adjusted odds ratio, 15.8; 95% confidence interval, 12.5-20.0), followed by those who had NI despite persistent occlusion (adjusted odds ratio, 4.7; 95% confidence interval, 3.6-6.1); and those without NI despite recanalization (adjusted odds ratio, 2.7; 95% confidence interval, 2.2-3.3). CONCLUSIONS: Recanalization of an occluded artery in acute stroke is associated with favorable functional outcome both in patients with and without NI after IVT. In future evaluations of mechanical thrombectomy and other additional strategies, recanalization should be considered in patients with persisting occlusion after IVT even after significant NI.

Association of early National Institutes of Health Stroke Scale improvement with vessel recanalization and functional outcome after intravenous thrombolysis in ischemic stroke.

BACKGROUND AND PURPOSE: Early neurological improvement (ENI) after thrombolytic therapy of acute stroke has been linked with recanalization and favorable outcome, although its definition shows considerable variation. We tested the ability of ENI, as defined in previous publications, to predict vessel recanalization and 3-month functional outcome after intravenous thrombolysis recorded in an extensive patient cohort in the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). METHODS: Of 21,534 patients registered between December 2002 and December 2008, 798 patients (3.7%) had CT- or MR angiography-documented baseline vessel occlusion and also angiography data at 22 to 36 hours post-treatment. ENI definitions assessed at 2 hours and 24 hours post-treatment were (1) National Institutes of Health Stroke Scale (NIHSS) score improvement ≥4 points from baseline; (2) NIHSS 0, 1, or improvement ≥8; (3) NIHSS ≤3 or improvement ≥10; (4) improvement by 20%; (5) 40% from baseline; or (6) NIHSS score 0 to 1. Receiver operating curve analysis and multiple logistic regression were performed to evaluate the association of ENI with vessel recanalization and favorable functional outcome (modified Rankin Scale score 0 to 2 at 3 months). RESULTS: ENI at 2 hours had fair accuracy to diagnose recanalization as derived from receiver operating curve analysis. Definitions of improvement based on percent of NIHSS score change from baseline demonstrate better accuracy to diagnose recanalization at 2 hours and 24 hours than the definitions based on NIHSS cutoffs (the best performance at 2 hours was area under the curve 0.633, sensitivity 58%, specificity 69%, positive predictive value 68%, and negative predictive value 59% for 20% improvement; and area under the curve 0.692, sensitivity 69%, specificity 70%, positive predictive value 70%, and negative predictive value 62% for 40% improvement at 24 hours). ENI-predicted functional outcome with OR 2.8 to 6.0 independently from recanalization in the angiography cohort (n=695) and with OR of 6.9 to 9.7 in the whole cohort (n=18 181). CONCLUSIONS: Early 20% neurological improvement at 2 hours was the best predictor of 3-month functional outcome and recanalization after thrombolysis, although fairly accurate, and may serve as a surrogate marker of recanalization if only imaging evaluation of vessel status is not available. If recanalization status is required after intravenous thrombolysis, vascular imaging is recommended despite ENI.

Hyperdense middle cerebral artery sign on admission CT scan--prognostic significance for ischaemic stroke patients treated with intravenous thrombolysis in the safe implementation of thrombolysis in Stroke International Stroke Thrombolysis Register.

BACKGROUND: Hyperdense middle cerebral artery sign (HMCAS) on CT scan before stroke thrombolysis is associated with increased risk for haemorrhage and unfavourable outcome in several small studies. METHODS: We examined baseline characteristics, intracranial haemorrhage and outcomes of intravenous thrombolysis in patients with and without HMCAS using the internet-based Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. Symptomatic intracerebral haemorrhage (SICH) was defined as a National Institute of Health Stroke Scale (NIHSS) score decrease of >or=4 points plus type 2 parenchymal haemorrhage on imaging [Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) definition], or any haemorrhage on follow-up imaging combined with a decrease of at least 1 point on the NIHSS [randomized controlled trial (RCT) definition]. Three-month outcomes were mortality and independence (modified Rankin scale score = 0-2). RESULTS: 1,905 of 10,023 (19.0%) patients had HMCAS. Patients with HMCAS (vs. no HMCAS) were younger (median age 68 vs. 70 years, p < 0.001), had severer stroke (baseline NIHSS score 17 vs. 11, p < 0.05), higher mortality [23% (95% CI 20.0-25.1) vs. 13% (95% CI 12.1-13.7)] and lower independence [31% (95% CI 28.5-33.0) vs. 56% (95% CI 54.8-57.2)]. SICH rates per the SITS-MOST were 1.3% (95% CI 0.8-1.9) versus 1.8% (95% CI 1.5-2.1) and per the RCT definition 10.3% (95% CI 9.0-11.8) versus 6.8% (95% CI 6.2-7.3). In multivariable analysis, HMCAS was not an independent predictor of SICH but of mortality and independence per the SITS-MOST. CONCLUSIONS: HMCAS patients had severer stroke and a worse 3-month outcome. The risk for SICH per the SITS-MOST definition was similar compared to non-HMCAS patients, although increased per the RCT definition. There is not sufficient evidence to exclude these patients from intravenous thrombolysis. Combined treatment approaches might be considered in the perspective of the severe outcome and evaluated in RCTs.