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Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial.
Ni, J, Chen, H, Chen, G, Ji, Y, Yi, F, Zhang, Z, Yang, Y, Wu, J, Cai, X, Shao, B, et al
BMC neurology. 2020;(1):282
Abstract
BACKGROUND Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. METHODS Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. RESULTS In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. CONCLUSIONS The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. TRIAL REGISTRATION Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.
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Ginkgol Biloba extract as an adjunctive treatment for ischemic stroke: A systematic review and meta-analysis of randomized clinical trials.
Ji, H, Zhou, X, Wei, W, Wu, W, Yao, S
Medicine. 2020;(2):e18568
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OBJECTIVE Ginkgo biloba extract (GBE) is widely used as an adjunctive treatment for ischemic stroke. This meta-analysis aimed to evaluate the effectiveness and safety of GBE specifically for long-term users at the convalescence stage of ischemic stroke. METHODS MEDLINE, Cochrane Central Register of Controlled Trials, Embase Database, WHO Clinical Trials Registration Platform, Chinese National Knowledge Infrastructure, Wanfang Database, and Chinese Scientific Journal Database were searched from inception to 20 September 2018. Risk ratio (RR) and mean difference (MD) with a 95% confidence interval (CI) were used as effect estimates using RevMan software (5.3; Review Manager [RevMan], Nordic Cochrane Centre, Copenhagen, Denmark). A meta-analysis was performed where data were available. A trial sequential analysis was used to control random errors for recurrence rate and the GRADE (grading of recommendations, assessment, development, and evaluations) approach was used to assess the quality of the body of evidence. The meta-analysis design was registered on PROSPERO (CRD42018110211, http://www.crd.york.ac.uk/PROSPERO). RESULTS We identified 15 randomized clinical trials involving 1829 participants. The majority of the included trials were of high risk of bias in methodological quality. For acute ischemic stroke, adding GBE to conventional therapy led to higher Barthel index scores (MD: 5.72; 95% CI: 3.11-8.33) and lower neurological function deficit scores (MD: -1.39; 95% CI: -2.15 to -0.62). For patients in their convalescence (or sequelae) stage of ischemic stroke, GBE was superior in improving dependence (MD: 7.17; 95% CI: 5.96-8.38) and neurological function deficit scores (MD: -1.15; 95% CI: -1.76 to -0.53) compared with placebo or conventional therapy, but there was no difference in vascular events (RR: 0.70; 95% CI: 0.44-1.14), recurrence rate (RR: 0.57; 95% CI: 0.26-1.25; trial sequential analysis: conclusive) and mortality (RR: 1.07; 95% CI: 0.41-2.81). CONCLUSIONS GBE appears to improve neurological function and dependence compared with conventional therapy for ischemic stroke at different stages and appears generally safe for clinical application. The lack of improvement in recurrence rate was confirmed by trial sequential analysis. Due to the generally weak evidence, further large, rigorous trials are warranted.
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Association between carotid intima media thickness and small dense low-density lipoprotein cholesterol in acute ischaemic stroke.
Zhou, P, Shen, Y, Wang, L, Cao, Z, Feng, W, Liu, J, Wang, L, Meng, P, Yang, J, Xu, WY, et al
Lipids in health and disease. 2020;(1):177
Abstract
BACKGROUND Intima-media thickness (IMT) and small dense low-density lipoprotein cholesterol (sdLDL-C) have been reported to be related to atherosclerosis and stroke. This study is trying to explore the association between IMT and sdLDL-C in Chinese acute ischaemic stroke (AIS) subjects. METHODS This study enrolled total 368 consecutive AIS patients and 165 non-AIS controls from November 2016 to February 2019. Mean IMT and carotid plaques were measured by using carotid ultrasonography method. Blood glucose and lipid parameters were measured by using an automatic biochemical instrument. SdLDL-C was detected by using the Lipoprint LDL system. IMT > 1.0 mm was defined as increased IMT. Plaque stability based on the nature of the echo was determined by ultrasound examination. Risk factors for IMT were identified by using multivariate logistic regression analysis. A logistic regression model was established to predict AIS risk. Python software (Version 3.6) was used for the statistical analysis of all data. RESULTS The carotid IMT, proportion of plaques, and the sdLDL-C, triglycerides (TG) and glucose levels were obviously higher in AIS patients than those in controls. SdLDL-C level in the IMT thickening group was higher than that in the normal IMT group. SdLDL-C and total cholesterol (TC) were risk factors for IMT, while sdLDL-C was an independent risk factor. The IMT value of the unstable plaque group was markedly higher than that of the stable plaque group. The predictive value of IMT for AIS was better than that of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) but not as good as that of sdLDL-C. A logistic regression model was established to predict AIS risk. Additionally, carotid IMT and sdLDL-C were closely related to AIS severity and outcomes. CONCLUSIONS SdLDL-C and TC were risk factors for increased IMT, while sdLDL-C was an independent risk factor. A prediction model based on IMT and other variables was established to screen the population with high AIS risk.
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Matrix Gla protein polymorphism rs1800801 associates with recurrence of ischemic stroke.
Hendrix, P, Sofoluke, N, Adams, M, Kunaprayoon, S, Zand, R, Kolinovsky, AN, Person, TN, Gupta, M, Goren, O, Kirchner, HL, et al
PloS one. 2020;(6):e0235122
Abstract
The MGP single nucleotide polymorphism (SNP) rs1800801 has previously been associated with recurrent ischemic stroke in a Spanish cohort. Here, we tested for association of this SNP with ischemic stroke recurrence in a North American Caucasian cohort. Acute ischemic stroke patients admitted between 10/2009 and 12/2016 at three hospitals within a large healthcare system in the northeastern United States that were enrolled in a healthcare system-wide exome sequencing program were retrospectively reviewed. Patients with recurrent stroke within 1 year after index event were compared to those without recurrence. Of 9,348 suspected acute ischemic strokes admitted between 10/2009 and 12/2016, 1,727 (18.5%) enrolled in the exome-sequencing program. Among those, 1,068 patients had exome sequencing completed and were eligible for inclusion. Recurrent stroke within the first year of stroke was observed in 79 patients (7.4%). In multivariable analysis, stroke prior to the index stroke (OR 9.694, 95% CI 5.793-16.224, p ≤ 0.001), pro-coagulant status (OR = 3.563, 95% CI 1.504-8.443, p = 0.004) and the AA genotype of SNP rs1800801 (OR = 2.408, 95% CI 1.079-4.389, p = 0.004) were independently associated with recurrent stroke within the first year. The AA genotype of the MGP SNP rs1800801 is associated with recurrence within the first year after ischemic stroke in North American Caucasians. Study of stroke subtypes and additional populations will be required to determine if incorporation of allelic status at this SNP into current risk scores improves prediction of recurrent ischemic stroke.
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Cortical atrophy and transcallosal diaschisis following isolated subcortical stroke.
Cheng, B, Dietzmann, P, Schulz, R, Boenstrup, M, Krawinkel, L, Fiehler, J, Gerloff, C, Thomalla, G
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2020;(3):611-621
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Following acute ischemic stroke, isolated subcortical lesions induce gray matter atrophy in anatomically connected, yet distant cortical brain regions. We expand on previous studies by analyzing cortical thinning in contralesional, homologous regions indirectly linked to primary stroke lesions via ipsilesional cortical areas. For this purpose, stroke patients were serially studied by magnetic resonance imaging (diffusion tensor imaging and high-resolution anatomical imaging) in the acute (days 3-5) and late chronic stage one year after stroke. We analyzed changes of gray and white matter integrity in 18 stroke patients (median age 68 years) with subcortical stroke. We applied probabilistic fiber tractography to identify brain regions connected to stroke lesions and contralesional homologous areas. Cortical thickness was quantified by semi-automatic measurements, and fractional anisotropy was analyzed. One year after stroke, significant decrease of cortical thickness was detected in areas connected to ischemic lesions (mean -0.15 mm; 95% CI -0.23 to -0.07 mm) as well as homologous contralateral brain regions (mean -0.13 mm; 95% CI -0.07 to -0.19 mm). We detected reduced white matter integrity of inter- and intrahemispheric fiber tracts. There were no significant associations with clinical recovery. Our results indicate that impact of subcortical lesions extends to homologous brain areas via transcallosal diaschisis.
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Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.
Woo, PYM, Ho, JWK, Ko, NMW, Li, RPT, Jian, L, Chu, ACH, Kwan, MCL, Chan, Y, Wong, AKS, Wong, HT, et al
BMC neurology. 2020;(1):401
Abstract
ASBTRACT BACKGROUND There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.
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Body weight changes and incidence of cachexia after stroke.
Scherbakov, N, Pietrock, C, Sandek, A, Ebner, N, Valentova, M, Springer, J, Schefold, JC, von Haehling, S, Anker, SD, Norman, K, et al
Journal of cachexia, sarcopenia and muscle. 2019;(3):611-620
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BACKGROUND Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single-centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome. METHODS Sixty-seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2 , 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0-12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow-up. Body composition was examined by dual energy X-ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2 ) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient. RESULTS According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non-cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non-cachectic patients after 12 months. The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow-up (OR 137.9, P < 0.05). CONCLUSIONS In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity.
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Carotid Plaque Positron Emission Tomography Imaging and Cerebral Ischemic Disease.
Chaker, S, Al-Dasuqi, K, Baradaran, H, Demetres, M, Delgado, D, Nehmeh, S, Osborne, JR, Christos, PJ, Kamel, H, Gupta, A
Stroke. 2019;(8):2072-2079
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Background and Purpose- The clinical utility of positron emission tomography (PET) imaging in evaluating carotid artery plaque vulnerability remains unclear. Two tracers of recent interest for carotid plaque imaging are 18F-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF). We performed a systematic review and meta-analysis evaluating the association between carotid artery 18F-FDG or 18F-NaF uptake and recent or future cerebral ischemic events. Methods- A systematic review of Ovid MEDLINE, Ovid EMBASE, and the Cochrane library was conducted from inception to December 2017 for articles evaluating PET tracer uptake in recently symptomatic versus asymptomatic carotid arteries, and articles evaluating carotid uptake in relation to future ischemic events. Cerebral ischemic events were defined as ipsilateral strokes, transient ischemic attacks, or amaurosis fugax. We quantitatively pooled studies by a random-effects model when 3 or more studies were amenable for analysis. We assessed the standardized mean difference between tracer uptake in the symptomatic versus asymptomatic carotid artery using Cohen's d metric. Results- After screening 4144 unique articles, 13 prospective cohort studies assessing carotid artery 18F-FDG uptake in patients with recent cerebral ischemia were eligible for review. Eleven cohorts of 290 subjects scanned with 18F-FDG were eligible for meta-analysis. We found that carotid arteries ipsilateral to recent ischemic events had significantly higher 18F-FDG uptake than asymptomatic arteries (Cohen's d =0.492; CI=0.130-0.855; P=0.008) as well as significant heterogeneity (Cochran's Q =31.5; P=0.0005; I2=68.3%). Meta-regression was not performed due to the limited number of studies in the analysis. Only 2 studies investigating 18F-NaF PET imaging, and another 2 articles investigating ischemic event recurrence were found. Conclusions- Recent ipsilateral cerebral ischemia may be associated with increased carotid 18F-FDG uptake on PET imaging regardless of degree of carotid stenosis, although significant heterogeneity was found, and these results should be interpreted with caution. Emerging evidence suggests a similar association may be present with 18F-NaF plaque uptake. More studies are warranted to provide definitive conclusions on the utility of 18F-FDG or 18F-NaF in carotid plaque evaluation before investigating carotid PET as a diagnostic tool for cerebral ischemic events.
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White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study.
Schirmer, MD, Dalca, AV, Sridharan, R, Giese, AK, Donahue, KL, Nardin, MJ, Mocking, SJT, McIntosh, EC, Frid, P, Wasselius, J, et al
NeuroImage. Clinical. 2019;:101884
Abstract
White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.
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PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab.
Bruckert, E, Kereiakes, DJ, Koren, MJ, Louie, MJ, Letierce, A, Miller, K, Cannon, CP
Journal of clinical lipidology. 2019;(3):443-454
Abstract
BACKGROUND Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins. OBJECTIVE To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke. METHODS Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, alirocumab dose, and control (placebo or ezetimibe). RESULTS Baseline LDL-C, non-high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%-62.9%) and without (43.6%-58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C-lowering efficacy of alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%-84.8% and 63.7%-74.7%, respectively. The safety profile of alirocumab was generally similar regardless of prior MI/ischemic stroke status. CONCLUSIONS Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke.