Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

Hacke, Werner; Kaste, Markku; Bluhmki, Erich; Brozman, M; Dávalos, Antoni; Guidetti, Donata; Larrue, Vincent; Lees, Kennedy R.; Medeghri, Zakaria; Machnig, Thomas; Schneider, Dietmar; Kummer, Rüdiger von; Wahlgren, Nils; Toni, Danilo

doi:10.1056/nejmoa0804656

Cited by 5,969 publications

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“…Hemorrhagic transformation was previously assessed14 using the European Cooperative Acute Stroke Study (ECASS) III criteria 15. All head CTs obtained through day 7 of the initial hospitalization were analyzed (median time to CT 1.2 days; IQR: [1.0–2.1]), discrepancies were adjudicated by consensus, and those performing the imaging analysis were blinded to all clinical data.…”

Section: Methodsmentioning

confidence: 99%

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Wolcott

Batra

Bevers

et al. 2017

Ann Clin Transl Neurol

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Objective ST2 is a member of the toll‐like receptor superfamily that can alter inflammatory signaling of helper T‐cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke.MethodsWe measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0‐2 and 3‐6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan–Meier survival analysis and receiver operating characteristic curves.Results646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2–12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7–49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9–55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54–5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58–8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40–37.44, P = 0.039).InterpretationSoluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke.

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Section: Methodsmentioning

confidence: 99%

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Wolcott

Batra

Bevers

et al. 2017

Ann Clin Transl Neurol

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“…However, recombinant tissue plasminogen activator (rtPA) remains the only FDA‐approved drug for the treatment of ischemic stroke. Few ischemic stroke patients receive rtPA due to a limited therapeutic time window with increased risk of hemorrhagic transformation if given outside of the window (Fonarow et al., 2014; Hacke et al., 2008; Saver et al., 2009). Additionally, the severity of an ischemic stroke largely depends on the extent of spreading neuroinflammation into the penumbra (Iadecola & Anrather, 2011).…”

Section: Introductionmentioning

confidence: 99%

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

et al. 2017

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BackgroundResolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA 4) is an anti‐inflammatory, pro‐resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML‐111. We hypothesized that post‐ischemic, intravenous treatment with BML‐111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML‐111 on the post‐stroke molecular and cellular profile.MethodsA total of 133 male Sprague‐Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML‐111 administration was started at the time of reperfusion. Two methods of week‐long BML‐111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl−1 hr−1), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML‐111 and characterized an optimal dose and a dosing schedule for the administration of BML‐111.ResultsOne week of BML‐111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post‐ischemic treatment with BML‐111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro‐inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti‐inflammatory M2 microglia/macrophage cell populations in the post‐ischemic brain.ConclusionThese data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long‐term protection.

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“…Even though studies did not find overall reduced benefit of tPA in diabetic patients,12 decreased rates of tPA administrations are observed in diabetic patients 13. Guidelines recommend against tPA use in the 3‐ to 4.5‐hour window in patients with prior stroke plus diabetes based on insufficient evidence for its effectiveness, as patients with both prior stroke and diabetes were excluded from the European Cooperative Acute Stroke Study 3 trial 14. In this study, we sought to evaluate the relationship between admission hyperglycemia and the chronic hyperglycemic state on clinical outcomes in acute ischemic stroke patients with and without a recognized history of diabetes who were treated with tPA.…”

Section: Introductionmentioning

confidence: 99%

Association of Acute and Chronic Hyperglycemia With Acute Ischemic Stroke Outcomes Post‐Thrombolysis: Findings From Get With The Guidelines‐Stroke

Masrur

Cox

Bhatt

et al. 2015

JAHA

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BackgroundHyperglycemia has been associated with adverse outcomes in patients with acute ischemic stroke (AIS) and may influence outcomes after tissue plasminogen activator (tPA). We sought to analyze the association of acute and chronic hyperglycemia on clinical outcomes in tPA‐treated patients.Methods and ResultsWe identified 58 265 AIS patients from 1408 sites who received tPA from 2009 to 2013 in Get With The Guidelines‐Stroke. Acute hyperglycemia at admission was defined as a plasma glucose level >140 mg/dL. Chronic hyperglycemia was defined by plasma glycosylated hemoglobin (HbA1c) >6.5%. Post‐tPA outcomes were analyzed using logistic regression. Blood glucose >140 mg/dL and HbA1c >6.5 were associated with worse clinical outcomes (symptomatic intracranial hemorrhage [sICH], life‐threatening hemorrhage, and in‐hospital mortality and length of stay) in diabetic and nondiabetic patients. Among patients with documented history of diabetes, increasing admission glucose up to 200 mg/dL was associated with increased adjusted odds ratio (aOR) of in‐hospital mortality (aOR, 1.07) and sICH (aOR, 1.05) per 10 mg/dL increase in blood glucose. Increasing HbA1C to 8% was associated with increased odds of in‐hospital mortality (aOR, 1.19) and sICH (aOR, 1.16) per 1% increase in HbA1c. Similar findings were observed in patients without a documented history of diabetes. There was no further increase in poor outcomes above the blood glucose level of 200 mg/dL or HbA1c >8.ConclusionAcute and chronic hyperglycemia are both associated with increased mortality and worse clinical outcomes in AIS patients treated with tPA. Controlled trials are needed to determine whether acute correction of hyperglycemia can improve outcomes after thrombolysis.

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Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

Cited by 5,969 publications

References 22 publications

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

Association of Acute and Chronic Hyperglycemia With Acute Ischemic Stroke Outcomes Post‐Thrombolysis: Findings From Get With The Guidelines‐Stroke

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Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

Cited by 5,969 publications

References 22 publications

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

Association of Acute and Chronic Hyperglycemia With Acute Ischemic Stroke Outcomes Post‐Thrombolysis: Findings From Get With The Guidelines‐Stroke

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Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery