Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials

Lees, Kennedy R.; Bluhmki, Erich; Kummer, Rüdiger von; Brott, Thomas G.; Toni, Danilo; Grotta, James C.; Albers, Gregory W.; Kaste, Markku; Marler, John R.; Hamilton, Scott; Bar, Michal; Davis, Stephen M.; Donnan, Geoffrey A.; Hacke, Werner

doi:10.1016/s0140-6736(10)60491-6

Cited by 1,921 publications

(1,477 citation statements)

References 27 publications

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“…Human rtPA is the only thrombolytic treatment of ischemic stroke and leads to improvement of the clinical outcome in stroke patients despite an increase in the incidence of intracerebral hemorrhage. 9 In addition to its thrombolytic activity, rtPA could interact with different receptors in the brain, such as the low density lipoprotein receptor-related protein, 19 the N-methyl-D-aspartate receptor 20 or annexin II, 21 resulting in parenchymal cell injury. Cerebral ischemia studies performed with tPA-deficient animals have clearly underlined that endogenous tPA has a role in brain infarction and BBB dysfunction as well.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Lenglet

Montecucco

Coutts

et al. 2014

J Cereb Blood Flow Metab

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The effect of recombinant human tissue plasminogen activator (rtPA) on neuroinflammation after stroke remains largely unknown. Here, we tested the effect of rtPA on expression of cellular adhesion molecules, chemokines, and cytokines, and compared those with levels of inflammatory cell recruitment, brain injury, and mortality over 3 days after transient middle cerebral artery occlusion (MCAO) in mice. Mortality was dramatically increased after rtPA treatment compared with saline treatment during the first day of reperfusion. Among the animals that survived, rtPA significantly increased CCL3 expression, microglia recruitment, and cerebral infarction 6 hours after MCAO. In contrast, the extent of neutrophils and macrophages infiltration in the brain was similar in both saline-and rtPA-treated animals. Recombinant human tissue plasminogen activator induced Il1b and Tnf expression, 6 and 72 hours after MCAO, respectively, and dramatically reduced interleukin 6 (IL-6) level 24 hours after reperfusion. A dose response study confirmed the effect of rtPA on CCL3 and Il1b expressions. The effect was similar at the doses of 1 and 10 mg/kg. In conclusion, we report for the first time that rtPA amplified microglia recruitment early after stroke in association with a rapid CCL3 production. This early response may take part in the higher susceptibility of rtPA-treated animals to reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Lenglet

Montecucco

Coutts

et al. 2014

J Cereb Blood Flow Metab

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“…That was possibly explained by a more careful selection of patients over 80 years old who were adequate candidates to IV-rtPA, given that shorter time to treatment increases benefit and decreases risk, 28 and taking into account the more dubious safety/benefit profile of these patients. Another possible contributing explanation may be the geographical context of the hospital with an elderly population living near the hospital, consequently having a quicker access.…”

Section: Article In Pressmentioning

confidence: 99%

Thrombolysis in Patients Aged over 80 Years Is Equally Effective and Safe

Pego

Nunes

Ferreira

et al. 2016

Journal of Stroke and Cerebrovascular Diseases

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Background: Despite stroke's high prevalence in the elderly, intravenous thrombolysis is licensed in Europe only for patients younger than 80 years old. We aimed to compare the functional outcomes and complication rates in patients older versus younger than 80 years old treated with intravenous thrombolysis. Methods: A retrospective observational study of patients who received intravenous thrombolysis in a stroke unit between January 1, 2009, and June 30, 2012, was conducted. Variables were compared between 2 subgroups (≤80 and >80 years). Results: Overall, 512 patients underwent intravenous thrombolysis, of which 13.1% were over 80 years. The mean age was 65.4 years in the younger subgroup and 82.9 years in the older subgroup. Prior independence rates did not differ between the subgroups. Prevalence of atrial fibrillation and cardioembolic stroke was higher in the older subgroup (P = .004 and .026). Only 3% of the elderly with atrial fibrillation were taking oral anticoagulants. Symptoms-to-needle time was lower in the older subgroup (P = .048). Stroke severity was higher in patients over 80 years (P = .026). There was significant improvement in the National Institutes of Health Stroke Scale score 7 days after intravenous thrombolysis (P < .001) in both subgroups. The proportion of patients with 3 months' favorable outcome and independence, hemorrhagic transformation, and mortality rates were similar in both subgroups. Conclusions: Elderly patients' benefits and outcomes from intravenous thrombolysis treatment were identical to the younger subgroup without excess hemorrhagic transformation or mortality. These results favor the use of intravenous thrombolysis in patients over 80 years. Key Words: Stroke-elderlythrombolysis-over 80 years.

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“…rt‐PA has been shown to improve outcomes of survival and independence 7, 8, 12, 13, 14, 15. However, its use is limited by the very short window of opportunity for treatment and risk of bleeding, making less than 6% of stroke patients eligible for such treatment 16, 17.…”

Section: Discussionmentioning

confidence: 99%

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

Venketasubramanian

Lee

Wong

et al. 2015

Journal of Evidence-Based Medicine

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ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

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Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials

Cited by 1,921 publications

References 27 publications

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Thrombolysis in Patients Aged over 80 Years Is Equally Effective and Safe

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

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