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Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke.

ABSTRACT: Ischaemic stroke can occur when an artery to the brain is blocked by a blood clot. The use of thrombolytic agents, such as tissue plasminogen activator (tPA), to dissolve the occluding clot is limited by the risk of intracerebral haemorrhage (ICH), a known side effect associated with tPA. We developed a computational thrombolysis model for a 3D patient-specific artery coupled with a compartmental model for temporal concentrations of tPA and lysis proteins during intravenous infusion of tPA, in order to evaluate the effects of tPA dose on the efficacy of thrombolytic therapy and the risk of ICH. The model was applied to a 3-mm-long fibrin clot with two different fibrin fibre radii in the middle cerebral artery (MCA) - a setting relevant to ischaemic stroke, and results for different tPA dose levels and fibrin fibre radii were compared. Our simulation results showed that clot lysis was accelerated at higher tPA doses at the expense of a substantial increase in the risk of ICH. It was also found that a fine clot with a smaller fibre radius dissolved much slowly than a coarse clot due to a slower tPA penetration into the clots.

SUBMITTER: Piebalgs A

PROVIDER: S-EPMC6202379 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke.

Piebalgs Andris A Gu Boram B Roi Dylan D Lobotesis Kyriakos K Thom Simon S Xu Xiao Yun XY

Scientific reports 20181025 1

Ischaemic stroke can occur when an artery to the brain is blocked by a blood clot. The use of thrombolytic agents, such as tissue plasminogen activator (tPA), to dissolve the occluding clot is limited by the risk of intracerebral haemorrhage (ICH), a known side effect associated with tPA. We developed a computational thrombolysis model for a 3D patient-specific artery coupled with a compartmental model for temporal concentrations of tPA and lysis proteins during intravenous infusion of tPA, in o ...[more]

PMID: 30361673

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Project description:BackgroundMost ischaemic strokes are caused by blockage of a cerebral artery by a thrombus. Intravenous administration of recombinant tissue plasminogen activator given within 4.5 hours is now standard treatment for this condition. Percutaneous vascular interventions use an intra-arterial, mechanical approach for thrombus disruption or removal (thrombectomy). Recent randomised trials indicate that percutaneous vascular interventions are superior to usual care (usual care usually included intravenous thrombolysis). However, intravenous thrombolysis was usually given in both arms of the trial and there was a lack of direct comparison of percutaneous vascular interventions with intravenous thrombolysis.ObjectivesTo assess the effectiveness and safety of percutaneous vascular interventions compared with intravenous thrombolytic treatment for acute ischaemic stroke.Search methodsWe searched the Cochrane Stroke Group Trials Register (last search: August 2018). In addition, in September 2017, we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and Science Citation Index; and Stroke Trials Registry, and US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov.Selection criteriaRandomised controlled trials (RCTs) that directly compared a percutaneous vascular intervention with intravenous thrombolytic treatment in people with acute ischaemic stroke.Data collection and analysisTwo review authors applied the inclusion criteria, extracted data, and assessed risk of bias. We obtained both published and unpublished data. We assessed the quality of the evidence using the GRADE approach.Main resultsWe included four trials with 450 participants. Data on functional outcome and death at end of follow-up were available for 443 participants from three trials. Compared with intravenous thrombolytic therapy, percutaneous vascular intervention did not improve the proportion of participants with good functional outcome (modified Rankin Scale score 0 to 2, risk ratio (RR) 1.01, 95% confidence interval (CI) 0.82 to 1.25, P = 0.92). The quality of evidence was low (outcome assessment was blinded, but not the treating physician or participants). At the end of follow-up, there was a non-significant increase in the proportion of participants who died in the percutaneous vascular intervention group (RR 1.34, 95% CI 0.84 to 2.14, P = 0.21). The quality of evidence was low (wide confidence interval). There was no difference in the proportion of participants with symptomatic intracranial haemorrhages between the intervention and control groups (RR 0.99, 95% CI 0.50 to 1.95, P = 0.97). The quality of evidence was low (wide confidence interval). Data on vascular status (recanalisation rate) were only available for seven participants from one trial; we considered this inadequate for statistical analyses.Authors' conclusionsThe present review directly compared intravenous thrombolytic treatment with percutaneous vascular interventions for ischaemic stroke. We found no evidence from RCTs that percutaneous vascular interventions are superior to intravenous thrombolytic treatment with respect to functional outcome. Quality of evidence was low (outcome assessment was blinded, but not the treating physician or participants). New trials with adequate sample sizes are warranted because of the rapid development of new techniques and devices for such interventions.

Project description:BackgroundSpecific clinical risk factors may contribute to improving or worsening neurological functions in acute ischemic stroke (AIS) patients pre-treated with a combined cholesterol reducer and recombinant tissue plasminogen activator (rtPA) therapy. In this study, clinical risk factors associated with good or poor presenting neurological symptoms in ischemic stroke patients with prior cholesterol reducer use, specifically a statin and rtPA therapy was investigated.MethodsRetrospective data for baseline clinical and demographic data for patients with AIS taking cholesterol reducers prior to rtPA treatment from January 2010 to June 2016 in a regional stroke center was analyzed. Improving (NIHSS score ≤ 7) or worsening (NIHSS score > 7) of neurologic functions were the determined measures of treatment outcome. Multivariate logistic regression models identified demographic and clinical factors associated with worsening or improving neurologic functions.ResultsAdjusted multivariate analysis showed that in an AIS population with a combined rtPA and cholesterol reducer medication history, increasing age (OR = 1.032, 95% CI, 1.015-1.048, P < 0.001) and atrial fibrillation (OR = 1.859, 95% CI, 1.098-3.149, P = 0.021) demonstrated a likely association with worsening neurologic functions, while direct admission (OR = 0.411, 95% CI, 0.246-0.686, P = 0.001) and being Caucasian (OR = 0.496, 95% CI, 0.297-0.827, P = 0.007) showed an association with improving or progressing neurologic functions.ConclusionA prior cholesterol reducer, namely a statin, plus rtPA combination may be associated with worsening neurological function for elderly AIS patients with atrial fibrillation, while Caucasians directly admitted to a neurology unit are more likely to show an association with progress or improvements in neurologic functions. While combining statin with rtPA treatment may facilitate worsening neurologic functions in elderly AIS patients with atrial fibrillation, they should not be denied of this therapy. The decision to combine statin and rtPA for AIS patients with atrial fibrillation can be done after clinical stabilization following appropriate clinical management.

Project description:OBJECTIVE:The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA). DESIGN:Eligible patients had IVT started within 4.5?hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90?min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0-2 at day 90. RESULTS:Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13-21). Median stroke onset to IVT start was 120?min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0-1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0-2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021). CONCLUSIONS:The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival. TRIAL REGISTRATION NUMBER:NCT01745692; Results.

Project description:BackgroundCerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries.ObjectivesTo assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke.Search methodsIn May 2016 we searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian Databases. We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma).Selection criteriaRandomised controlled trials (RCTs) comparing cerebrolysin, started within 48 hours of stroke onset and continued for any time, with placebo or no treatment in people with acute ischaemic stroke.Data collection and analysisTwo review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data.Main resultsWe identified six RCTs (1501 participants) that met the inclusion criteria.We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians.None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset).All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence).Serious adverse events: two trials reported on this outcome, with 90% confidence cerebrolysin increased the risks of serious adverse events by at least one third compared to placebo: 62/589 in cerebrolysin group versus 46/600 in placebo group; RR 1.37 90% CI 1.01 to 1.86 (2 trials, 1189 participants, moderate-quality evidence).Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence).Authors' conclusionsThe findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence suggesting that serious adverse events may be more common with cerebrolysin use in acute ischaemic stroke.

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Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke.

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Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke.

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