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Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

ABSTRACT: Importance:Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives:To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants:The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ?150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions:Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n?=?581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n?=?570) for up to 72 hours. Main Outcomes and Measures:The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results:Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P?=?.55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance:Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration:ClinicalTrials.gov Identifier: NCT01369069.

SUBMITTER: Johnston KC

PROVIDER: S-EPMC6652154 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

Johnston Karen C KC Bruno Askiel A Pauls Qi Q Hall Christiana E CE Barrett Kevin M KM Barsan William W Fansler Amy A Van de Bruinhorst Katrina K Janis Scott S Durkalski-Mauldin Valerie L VL

JAMA 20190701 4

<h4>Importance</h4>Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown.<h4>Objectives</h4>To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke.<h4>Design, setting, and participants</h4>The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration ...[more]

PMID: 31334795

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Project description:ObjectiveAlterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS.ApproachThe Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin-antithrombin (TAT) complex; D-dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor-1 (PAI-1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two-way analysis of variance.ResultsA total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA (P = 0.02) and PAI-1 (P = .04) and FVIIa (P = .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes (P = .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes (P = .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome (P = .006).ConclusionsIntensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS.

Project description:BackgroundMixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.MethodsIn this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05.ResultsAmong the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0).ConclusionsIn a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke.Trial registrationClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

Project description:Currently, few studies are reported on the composition of microbiota in stroke patients and the association with stroke prognosis. This study investigated the differing microbiota composition in stroke patients and confirmed the association of microbiota composition with poor functional outcome. Between January of 2018 and December of 2019, 198 patients with acute cerebral infarction were included in this study. For the case-control study, age and sex-matched normal healthy subjects (n = 200) were included when receiving their health screening examinations. We isolated bacterial extracellular membrane vesicles and extracted DNA from blood samples. Taxonomic assignments were performed by using the sequence reads of 16S rRNA genes following blood microbiota analysis. Statistical analysis was conducted appropriately by using Statistical Analysis System software. The mean age of the stroke patients were 63.7 ± 12.5 years, and the male sex was 58.5%. Of the total enrolled patients, poor functional outcome (modified Rankin Score ≥ 3) was noted in 19.7%. The principal component analysis of microbiota composition revealed significant differences between healthy control subjects and stroke patients. At the genus level, Aerococcaceae(f), ZB2(c), TM7-1(c), and Flavobacterium were significantly increased in stroke patients compared to the healthy controls, whereas Mucispirillum, rc4-4, Akkermansia, Clostridiales(o), Lactobacillus, and Stenotrophomonas were decreased considerably. For the functional outcome after ischemic stroke, Anaerococcus, Blautia, Dialister, Aerococcaceae(f), Propionibacterium, Microbacteriaceae(f), and Rothia were enriched in the group with good outcomes, whereas Ruminococcaceae(f) and Prevotella were enriched in the group with poor outcome. There was apparent dysbiosis of blood microbiota in patients with acute ischemic stroke compared to healthy people. Ruminococcaceae(f) and Prevotella were elevated in stroke patients with poor functional outcome.

Project description:ObjectiveTo determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm.MethodsIn a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.ResultsOf 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥0.07).ConclusionsWe found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS.Classification of evidenceThis study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.Clinical trial registrationClinicaltrials.gov identifier NCT01422616.

Project description:ObjectiveHyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke.MethodsMice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to 1-hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin-induced hyperglycemic conditions after which stroke outcomes, platelet activation, and platelet-neutrophil aggregate (PNA) formation were examined.ResultsUnder normoglycemic conditions, DKO mice were protected from ischemic stroke with smaller brain infarct volumes and improved cerebral blood flow. In addition, DKO mice had reduced platelet activation, PNA, and cerebral neutrophil recruitment after stroke. Hyperglycemia significantly increased infarct size and cerebral Evans blue extravasation and worsened neurological outcomes and cerebral blood flow in both WT and DKO mice, abolishing the protective effect witnessed under normoglycemic conditions. Flow cytometric analysis after stroke demonstrated increased platelet activation and neutrophil trafficking to the brain, independent of platelet glucose metabolism. Finally, platelets from healthy DKO mice were unable to become procoagulant upon dual agonist stimulation. Conversely, hyperglycemia increased platelet mitochondrial reactive oxygen species production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice.ConclusionHyperglycemia aggravates ischemic stroke outcome independent of platelet glucose uptake. Furthermore, we demonstrated that hyperglycemia primes procoagulant platelet formation. This underlines the therapeutic potential for strategies targeting procoagulant platelet formation for the treatment of acute ischemic stroke.

Dataset Information

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

Publications

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

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