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      Reperfusion therapy in acute ischemic stroke: dawn of a new era?

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          Abstract

          Following the success of recent endovascular trials, endovascular therapy has emerged as an exciting addition to the arsenal of clinical management of patients with acute ischemic stroke (AIS). In this paper, we present an extensive overview of intravenous and endovascular reperfusion strategies, recent advances in AIS neurointervention, limitations of various treatment paradigms, and provide insights on imaging-guided reperfusion therapies. A roadmap for imaging guided reperfusion treatment workflow in AIS is also proposed. Both systemic thrombolysis and endovascular treatment have been incorporated into the standard of care in stroke therapy. Further research on advanced imaging-based approaches to select appropriate patients, may widen the time-window for patient selection and would contribute immensely to early thrombolytic strategies, better recanalization rates, and improved clinical outcomes.

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          Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis

          Summary Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26–1·86, p<0·0001), absolute benefit of 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30–1·90; p<0·0001), absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
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            Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism.

            Intravenous tissue-type plasminogen activator can be beneficial to some patients when given within 3 hours of stroke onset, but many patients present later after stroke onset and alternative treatments are needed. To determine the clinical efficacy and safety of intra-arterial (IA) recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours' duration caused by middle cerebral artery (MCA) occlusion. PROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled, multicenter, open-label clinical trial with blinded follow-up conducted between February 1996 and August 1998. Fifty-four centers in the United States and Canada. A total of 180 patients with acute ischemic stroke of less than 6 hours' duration caused by angiographically proven occlusion of the MCA and without hemorrhage or major early infarction signs on computed tomographic scan. Patients were randomized to receive 9 mg of IA r-proUK plus heparin (n = 121) or heparin only (n = 59). The primary outcome, analyzed by intention-to-treat, was based on the proportion of patients with slight or no neurological disability at 90 days as defined by a modified Rankin score of 2 or less. Secondary outcomes included MCA recanalization, the frequency of intracranial hemorrhage with neurological deterioration, and mortality. For the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25% for the r-proUK group and 27% for the control group. The recanalization rate was 66% for the r-proUK group and 18% for the control group (P<.001). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06). Despite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.
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              Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke.

              The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score < or =2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale < or =1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization. Three hundred thirty-five patients had a mean age 69+/-13 years and 48.5% were women (median baseline National Institutes of Health Stroke Scale score 16 [range, 3 to 32], mean time to transcranial Doppler 140+/-84 minutes, and mean time to intravenous tissue plasminogen activator 145+/-68 minutes). Distal middle cerebral artery occlusion had an OR of 2 for complete recanalization (50 of 113 [44.2%], 95% CI: 1.1 to 3.1, P=0.005), proximal middle cerebral artery 0.7 (49 of 163 [30%], 95% CI: 0.4 to 1.1, P=0.13), terminal internal carotid artery 0.1 (one of 17 [5.9%], 95% CI: 0.015 to 0.8, P=0.015), tandem cervical internal carotid artery/middle cerebral artery 0.7 (6 of 22 [27%], 95% CI: 0.3 to 1.9, P=0.5), and basilar artery 0.96 (3 of 10 [30%], 95% CI: 0.2 to 4, P=0.9). Prerecombinant tissue plasminogen activator National Institutes of Health Stroke Scale score, systolic blood pressure, glucose, and Thrombolysis in Brain Ischemia flow grade at the occlusion site were the negative independent predictors for complete recanalization in the final model. There were no associations among time to treatment, stroke mechanisms, or recanalization rate. Patients with no flow (Thrombolysis in Brain Ischemia 0) at the occlusion site had less probability of complete recanalization than patients with dampened flow (Thrombolysis in Brain Ischemia 3) (OR(adj): 0.256, 95% CI: 0.11 to 0.595, P=0.002). Continuous transcranial Doppler monitoring (exposure to ultrasound) was a positive predictor for complete recanalization (OR(adj): 3.02, 95% CI: 1.396 to 6.514, P=0.005). National Institutes of Health Stroke Scale score < or =2 at 24 hours was achieved in 66 of 305 patients (22%): distal middle cerebral artery 33% (35 of 107), tandem cervical internal carotid artery/middle cerebral artery 24% (5 of 21), proximal middle cerebral artery 16% (24 of 155), basilar artery 25% (2 of 8), and none of the patients with terminal internal carotid artery had dramatic recovery (0%, n=14; P=0.003). Modified Rankin Scale score < or =1 was achieved in 90 of 260 patients (35%): distal middle cerebral artery 52% (50 of 96), proximal middle cerebral artery 25% (33 of 131), tandem cervical internal carotid artery/middle cerebral artery 21% (3 of 14), terminal internal carotid artery 18% (2 of 11), and basilar artery 25% (2 of 8) (P<0.001). Patients with distal middle cerebral artery occlusion were twice as likely to have a good long-term outcome as patients with proximal middle cerebral artery (OR: 2.1, 95% CI: 1.1 to 4, P=0.025). Clinical response to thrombolysis is influenced by the site of occlusion. Patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term.
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                Author and article information

                Contributors
                (02) 8738 7168 , Sonu.Bhaskar@health.nsw.gov.au
                Peter.Stanwell@newcastle.edu.au
                Dennis.Cordato@health.nsw.gov.au
                John.Attia@newcastle.edu.au
                (02) 8738 8864 , Christopher.Levi@unsw.edu.au
                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1471-2377
                16 January 2018
                16 January 2018
                2018
                : 18
                : 8
                Affiliations
                [1 ]ISNI 0000 0000 9939 5719, GRID grid.1029.a, Western Sydney University (WSU), School of Medicine, South West Sydney Clinical School, ; Sydney, NSW 2170 Australia
                [2 ]ISNI 0000 0004 0527 9653, GRID grid.415994.4, Liverpool Hospital, Department of Neurology & Neurophysiology, ; Liverpool, 2170 NSW Australia
                [3 ]The Sydney Partnership for Health, Education, Research & Enterprise (SPHERE), Liverpool, NSW Australia
                [4 ]GRID grid.429098.e, Stroke & Neurology Research Group, , Ingham Institute for Applied Medical Research, ; 1 Campbell Street, Liverpool, NSW 2170 Australia
                [5 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, School of Medicine, , University of New South Wales (UNSW), ; Sydney, NSW Australia
                [6 ]ISNI 0000 0004 0577 6676, GRID grid.414724.0, Department of Neurology, , John Hunter Hospital, ; Newcastle, NSW Australia
                [7 ]ISNI 0000 0000 8831 109X, GRID grid.266842.c, Priority Research Centre for Stroke & Brain Injury, Faculty of Health & Medicine, , Hunter Medical Research institute (HMRI) and School of Medicine & Public Health, University of Newcastle, ; Newcastle, NSW Australia
                [8 ]ISNI 0000 0000 8831 109X, GRID grid.266842.c, Centre for Clinical Epidemiology & Biostatistics, , Hunter Medical Research Institute, University of Newcastle, ; Newcastle, NSW Australia
                Author information
                http://orcid.org/0000-0002-9783-3628
                Article
                1007
                10.1186/s12883-017-1007-y
                5771207
                29338750
                ccf6dde3-11da-4f5b-8cb3-1927e0c1e964
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 October 2017
                : 14 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001771, University of Newcastle Australia;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001081, Hunter Medical Research Institute;
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Neurology
                stroke,reperfusion therapy,prognosis,endovascular treatment,neurointervention
                Neurology
                stroke, reperfusion therapy, prognosis, endovascular treatment, neurointervention

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