The Chinese Stroke Association scientific statement: intravenous thrombolysis in acute ischaemic stroke

The most effective medical treatment for acute ischaemic stroke (AIS) is to offer intravenous thrombolysis during the ultra-early period of time after the onset. Even based on the Consensus of Chinese Experts on Intravenous Thrombolysis for AIS in 2012 and 2014 Chinese Guidelines on the Diagnosis and Treatment of AIS, the rate of thrombolysis for AIS in China remained around 2.4%, and the rate of intravenous tissue plasminogen activator usage was only about 1.6% in real world. The indication of thrombolysis for AIS has been expanded, and contraindications have been reduced with recently published studies. In order to facilitate the standardisation of treating AIS, improve the rate of thrombolysis and benefit patients who had a stroke, Chinese Stroke Association has organised and developed this scientific statement.
bAckground The most effective medical treatment for acute ischaemic stroke (AIS) is to offer intravenous thrombolysis during the ultraearly period of time after the onset (within 4.5 hours). Recombinant tissue plasminogen activator (tPA), as the primary thrombolytic agent, has been proven effective and beneficial in patients with AIS and recommended by many guidelines worldwide. The 2012 edition of Consensus of Chinese Experts on Intravenous Thrombolysis for AIS (Chinese Journal of Internal Medicine) and 2014 Chinese Guideline on the Diagnosis and Treatment of AIS (Chinese Journal of Neurology) have greatly standardised stroke therapy in China. However, the rate of thrombolysis for AIS in China remained around 2.4%, and the rate of intravenous tPA usage was only about 1.6%. [bib_ref] Stroke and stroke care in China: huge burden, significant workload, and a..., Liu [/bib_ref] In 2015, American Heart Association (AHA)/ American Stroke Association (ASA) published its Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke. [bib_ref] Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in..., Demaerschalk [/bib_ref] The indication of thrombolysis for AIS has been expanded, and contraindications have been reduced. In order to facilitate the standardisation of treating AIS, improve the rate of thrombolysis and benefit patients who had a stroke, Chinese Stroke Association (CSA) has organised and developed this scientific statement.
the evidence of intrAvenous thrombolysis for pAtients with Ais time window and tissue window AIS with the onset time within 4.5 hours In 1995, National Institute of Neurological and Stroke Study (National Institute of Neurological Disorders and Stroke (NINDS)) demonstrated that intravenous tPA was safe and effective in treating AIS within 3 hours of onset.It was the first time that intravenous tPA significantly improved the rate of survival and reduced disability. The sooner the treatment was provided, the better the outcome. [bib_ref] Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS,..., Hacke [/bib_ref] [bib_ref] Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of..., Wahlgren [/bib_ref] [bib_ref] Time to treatment with intravenous alteplase and outcome in stroke: an updated..., Lees [/bib_ref] This treatment paradigm was supported by the European Thrombolysis Registry and Chinese Thrombolysis Registry. [bib_ref] Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of..., Wahlgren [/bib_ref] In 2008, European Cooperative Acute Stroke Study III (ECASS 3) showed that intravenous tPA significantly improved the rate of 90-day favourable outcome (modified Rankin Scale (mRS) 0 or 1) in a selective group of patients with AIS within 3-4.5 hours of onset. This group was younger than 80 years old, without a history of diabetes or stroke and on any anticoagulant agents. ECASS 3 extended the treatment time window to 4.5 hours 11 . Subsequently, thrombolytic registries from China and other countries and a meta-analysis of intravenous thrombolysis provided further evidence to support the use of intravenous tPA within 3-4.5 hours. Currently, all international guidelines unanimously agreed that intravenous tPA to treat patients with AIS within 4.5 hours of onset was safe and effective according to those published studies [fig_ref] Table 1: Intravenous tPA trials for acute ischaemic stroke as listed by the year... [/fig_ref].

## Open access
Multimodal imaging-guided intravenous tPA therapy within 4.5-6 hours A 2010 pool analysis showed that the risk would outweigh benefit if intravenous tPA was given beyond 4.5 hours 12 . Using multimodal neuroimaging study to expand the treatment window remained controversial. [bib_ref] Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia, Chernyshev [/bib_ref] [bib_ref] Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging..., Davis [/bib_ref] [bib_ref] Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours:..., Garcia-Bermejo [/bib_ref] [bib_ref] Imaging of acute stroke prior to treatment: current practice and evolving techniques, Mair [/bib_ref] [bib_ref] MRI-based and CTbased thrombolytic therapy in acute stroke within and beyond established..., Schellinger [/bib_ref] By using MRI to look for mismatch of the ischaemic area between the perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI), the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) treated patients with AIS within 3-6 hours of onset. [bib_ref] Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging..., Davis [/bib_ref] In this trial, there was no significant difference in primary outcome between the intravenous tPA and placebo group. 14 However, cerebral reperfusion was improved, and infarct volume reduced in the patients who received intravenous tPA, with favourable outcomes on secondary outcome analysis. [bib_ref] Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in..., Thomalla [/bib_ref] Comparing with the control group, those who received intravenous tPA within 3-6 hours based on the findings of multimodal imaging mismatch had more favourable outcome. [bib_ref] Time to treatment with intravenous alteplase and outcome in stroke: an updated..., Lees [/bib_ref] Patients treated in the expanded time window had a similar rate of intracranial haemorrhage compared with those in the control group. [bib_ref] Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours:..., Garcia-Bermejo [/bib_ref] The comparison of the data of five prospective European stroke registries showed similar efficacy and safety among patients treated within 3 hours, who had only a routine CT scan. [bib_ref] MRI-based and CTbased thrombolytic therapy in acute stroke within and beyond established..., Schellinger [/bib_ref] In another prospective comparative study, the rate of symptomatic intracranial haemorrhage (sICH) was not related to the outcomes between patients selected by multimodal imaging but beyond time window and those treated within 4.5 hours had only a routine CT. [bib_ref] Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours:..., Garcia-Bermejo [/bib_ref] Multimodal-guided thrombolysis could potentially expand the intravenous treatment time window to 4.5-6 hours, though more research is necessary. The ongoing ExTEND (ECASS 4) trial and reanalysis of the International Stroke Trial (IST)-3 perhaps could provide new evidence. [bib_ref] European Cooperative Acute Stroke Study-4: extending the time for thrombolysis in emergency..., Amiri [/bib_ref] [bib_ref] Future directions of acute ischaemic stroke therapy, Fisher [/bib_ref] [bib_ref] A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of..., Thomalla [/bib_ref] [bib_ref] Protocol for the perfusion and angiography imaging sub-study of the Third International..., Wardlaw [/bib_ref] The time window of using intravenous tPA to treat patients with posterior circulation ischaemic infarctions About 20% of ischaemic stroke was in the posterior circulation. Whether the basilar artery was able to be recanalised by intravenous tPA or not could be related to the length of the thrombus. [bib_ref] Thrombolysis of basilar artery occlusion: impact of baseline ischemia and time, Strbian [/bib_ref] The reperfusion rate was about 20%-30% if the length of thrombus was >30 mm [bib_ref] Posterior vs. anterior circulation infarction: demography, outcomes, and frequency of hemorrhage after..., Dornak [/bib_ref]. The large multicentre observational Basilar Artery International Cooperation Study Registry (BASICS) included patients with acute basilar artery occlusion and treated with thrombolysis up to 9 hours 27 . Intravenous thrombolytic therapy and endovascular therapy have both demonstrated improved outcome, especially in patients with severe strokes. [bib_ref] Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery..., Schonewille [/bib_ref] [bib_ref] Acute basilar artery occlusion: outcome of mechanical thrombectomy with Solitaire stent within..., Baek [/bib_ref] [bib_ref] IV thrombolysis in very severe and severe ischemic stroke: results from the..., Mazya [/bib_ref] The patients with basilar artery occlusion might have an extended time window but still requires large clinical trials to confirm.
Stroke with unknown onset of time or stroke on awakening About 20%-25% of stroke happened during sleep so the onset time was often unclear. [bib_ref] A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of..., Song [/bib_ref] A retrospective study showed that in patients with AIS on awakening, selective thrombolysis (intravenous or intra-arterial thrombolysis) under the guidance of CT or MRI perfusion study had favourable clinical outcome but with increased mortality rate. [bib_ref] Population-based study of wake-up strokes, Mackey [/bib_ref] Since changes on the other standard MRI sequences (ie, increased T2 signal within affected tissues, best seen on FLAIR) occur later with the development of parenchymal oedema, this time difference between DWI and other MRI sequences has been used to estimate the time of stroke onset by assessing for a [bib_ref] Imaging of acute stroke prior to treatment: current practice and evolving techniques, Mair [/bib_ref]. In MR WITNESS Study, intravenous tPA is safe and feasible in selected subjects treated within 4.5 hours after symptoms discovery, with a median time to intravenous tPA of >11 hours since last time known well. However, asymptomatic ICH was often but not significant. Currently, the intravenous tPA for patients with wake-up stroke or stroke of unclear onset time is still being explored. dosages of intravenous tpA ECASS-I used intravenous tPA at the 1.1 mg/kg 32 . Most of other studies used the dosage of 0.9 mg/kg (maximum 90 mg, 10% intravenous bonus over 1 min, rest infused over an hour). The Japan thrombolysis registration studies suggested that 0.6 mg/kg tPA for patients with AIS was safe and effective, but the treatment did not compare with placebo. In 2011, one thrombolysis meta-analysis of data from Chinese, Korean Singaporean and Vietnamese showed that intravenous tPA 0.9 mg/ kg was more effective than that of 0.6 mg/kg, and with similar risk of haemorrhage. [bib_ref] Low vs standard dose of recombinant tissue plasminogen activator in treating east..., Dharmasaroja [/bib_ref] Recently, Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) found that patients in low-dose tPA (0.6 mg/kg) group failed to achieve the non-inferiority in primary outcome measurements (mortality or disability) when compared with those in standard dose group in 90 days. [bib_ref] Thrombolysis with low-dose tissue plasminogen activator 3-4.5 h After Acute Ischemic Stroke..., Morihara [/bib_ref] However, patients received 0.6 mg/ kg had significantly lower rate of sICH and mortality within 7 days of enrolment. [bib_ref] Thrombolysis with low-dose tissue plasminogen activator 3-4.5 h After Acute Ischemic Stroke..., Morihara [/bib_ref] The mortality rate was similar among both groups in 90 days. Therefore, low-dose IV tPA had better safety profile with less sICH but increased disability as measured by mRS comparing with those who received standard dose. [bib_ref] Thrombolysis with low-dose tissue plasminogen activator 3-4.5 h After Acute Ischemic Stroke..., Morihara [/bib_ref] Based on the findings from the ENCHANTED study, standard dose of tPA still should be the first option while low dose can be a choice in patients with higher risk of developing intracranial haemorrhage.
other intravenous thrombolytic drugs Urokinase (UK) is one of intravenous thrombolysis agents in clinical practice in rural area of China due to its low cost. Only one paper published in Chinese literature indicated its efficacy and safety.The trial enrolled 511 patients within 6 hours of onset and were assigned into three groups. early neurological deterioration (end) and combination with antiplatelet therapy END due to sICH END is defined as an increasing of >4 points of National Institution of Health Stroke Scale (NIHSS) score from the baseline after thrombolysis. About 4.5%-10% of patients with intravenous thrombolysis could have END and were associated with a poor prognosis. [bib_ref] Early clinical worsening in patients with TIA or minor stroke: the Austrian..., Ferrari [/bib_ref] The common causes Open Access of END included expansion of ischaemia volume, persistent occlusion of vessel or reocclusion, sICH, small vessel disease, malignant cerebral oedema, early recurrent stroke, epilepsy and so on. [bib_ref] Incidence and predictors of early recanalization after intravenous thrombolysis: a systematic review..., Seners [/bib_ref] Intracranial haemorrhage could be asymptomatic or symptomatic. [bib_ref] The HAT score: a simple grading scale for predicting hemorrhage after thrombolysis, Lou [/bib_ref] [bib_ref] A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator..., Cucchiara [/bib_ref] [bib_ref] Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated..., Menon [/bib_ref] sICH was one of the major causes of END. However, the definition of sICH could vary. Per NINDS criteria, sICH was defined by a CT or MR scan plus clinical neurological deterioration.Per ECASS 3 criteria, sICH was defined by worsening of NIHSS score by 4 points or death at 36 hours combined with presence of haematoma on imaging study. [bib_ref] Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke, Hacke [/bib_ref] The rate of sICH increases with the expansion of the treatment window. Although intravenous tPA increased the risk of serious haemorrhage, the overall mortality rate was not increased. On the contrary, it significantly reduced the rate of death and disability. Currently, there are five models to predict the risk of haemorrhage after intravenous tPA: the Haemorrhage after Thrombolysis (HAT) score [bib_ref] The HAT score: a simple grading scale for predicting hemorrhage after thrombolysis, Lou [/bib_ref] ; the Multicenter Stroke Survey (MSS) score [bib_ref] A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator..., Cucchiara [/bib_ref] ; the Glucose Level on Presentation, Race (Asian), Age, Sex (Male), Systolic Blood Pressure and Severity of Stroke on Presentation (GRASPS) prediction model [bib_ref] Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated..., Menon [/bib_ref] ; Safe Implementation of Treatments in Stroke (SITS) score [bib_ref] Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with..., Mazya [/bib_ref] and Blood Sugar, Early Infarct Signs, (Hyper) Dense Cerebral Artery Sign, Age, NIHSS score (SEDAN). [bib_ref] Stroke: Haemorrhage risk after thrombolysis-the SEDAN score, Lyden [/bib_ref] The predictive value of these models still requires further validation. The use of these tools should not exclude qualified candidates from receiving thrombolysis.

## Angio-oedema and its treatment
Angio-oedema is rare and happens in 1.3%-5.9% of patients after intravenous tPA. [bib_ref] Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome, Winkler [/bib_ref] [bib_ref] How to identify stroke mimics in patients eligible for intravenous thrombolysis?, Forster [/bib_ref] [bib_ref] A model to prevent fibrinolysis in patients with stroke mimics, Chang [/bib_ref] [bib_ref] A novel approach to the treatment of Orolingual Angioedema after tissue plasminogen..., Pahs [/bib_ref] About 0.3% to 0.8% require emergent intubation. [bib_ref] Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome, Winkler [/bib_ref] These patients first experienced hemi-tongue oedema that usually subside within 24 hours 54 . The predisposing risk factors included the combination use of ACE inhibitor or the stroke involved insular or frontal lobe. Treatments included steroid and antihistamines agents. [bib_ref] A novel approach to the treatment of Orolingual Angioedema after tissue plasminogen..., Pahs [/bib_ref] For those with severe symptoms, tracheostomy, intubation and artificial ventilation might be required. [bib_ref] A novel approach to the treatment of Orolingual Angioedema after tissue plasminogen..., Pahs [/bib_ref] Evidence of combination of antithrombotic therapy The evidence for early antithrombotic therapy after thrombolysis is insufficient. Antiplatelet Therapy in Combination With Recombinant t-PA Thrombolysis in Ischaemic Stroke (ARTIS) trial did not show improved outcome but increased rate of sICH. This randomised controlled study enrolled patients who had aspirin 300 mg at 90 min post intravenous tPA. [bib_ref] Early administration of aspirin in patients treated with alteplase for acute ischaemic..., Zinkstok [/bib_ref] Combined Approach to Lysis Utilising Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischaemic Stroke-Full Dose Regimen Stroke (CLEAR-FDR) trial found that the combination of standard dose of intravenous tPA and eptifibatide (glycoprotein IIb/IIIa inhibitors) was safe and effective but requires further approval. [bib_ref] Combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator in..., Adeoye [/bib_ref] Recommendation  For AIS patients with onset time <3 hours, intravenous thrombolysis should be offered if there are no contraindications (Class I, Level of Evidence A). Intravenous alteplase within the 3-4.5 hour window is also recommended for those patients who are <80 years old, without a history of both diabetes and prior stroke, NIHSS <25, not taking any oral anticoagulants and without imaging evidence of ischaemic injury involving more than one-third of the MCA territory (Class I, Level of Evidence B).  When considering intravenous tPA, the sooner the treatment, the greater the benefit and the less the risk (Class I, Level of Evidence A). The dosage of intravenous tPA is 0.9 mg/kg (maximum 90 mg), of which 10% is given as an intravenous bolus in 1 min, the remaining given as intravenous continuous infusion over 1 hour (Class I, Level of Evidence A).  Lower dose of tPA (0.6 mg/kg, maximum 60 mg, of which 15% is given as an intravenous bolus in 1 min, the remaining given as intravenous continuous infusion over 1 hour) could be considered in AIS patients with high risk of developing haemorrhage (Class IIB, Level of Evidence C).  If there is no tPA available or it is unaffordable, AIS patients within 6 hours of onset can be considered to receive IV UK. The dosage of UK is 100 million to 1.5 million IU, dissolved in 100-200 mL of saline and given as a continuous intravenous infusion over 30 min (Class IIb, Level of Evidence C).
use of intrAvenous tpA in pAtients with Ais within 3-4.5 hours And other speciAl conditions thrombolysis in the elderly After age of 55 years, the risk of having AIS doubles for every additional 10 years of life. AIS-related in-hospital mortality was 1-2 times higher in those ages older than 80 or 90 years according to the report from the Get with the Guidelines. The risk of sICH also increased after intravenous tPA in AIS patients older than 80 years old. [bib_ref] Incidence and predictors of early recanalization after intravenous thrombolysis: a systematic review..., Seners [/bib_ref] However, a meta-analysis still revealed that intravenous tPA reduced 3-month mortality in patients >80 years. [bib_ref] Intravenous thrombolysis in acute ischaemic stroke: a systematic review and meta-analysis to..., Bhatnagar [/bib_ref] The rate of sICH in older patients with AIS may vary by different criteria. When using the ECASS criteria, multiple observational studies found no increased risk of sICH in elderly patients post intravenous tPA. However, the rate of sICH doubled in patients older than 80 years post intravenous tPA in NINDS trial. [bib_ref] Intravenous thrombolysis in acute ischaemic stroke: a systematic review and meta-analysis to..., Bhatnagar [/bib_ref] A recent meta-analysis showed no significant difference post intravenous tPA comparing AIS patients 80 years with those <80 years. [bib_ref] Effect of treatment delay, age, and stroke severity on the effects of..., Emberson [/bib_ref] Moreover, patients older than 80 in the ENCHANTED trial were safe in their subgroup analysis. [bib_ref] Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, Anderson [/bib_ref] Recommendation  Older patients may have an overall poor prognosis post stroke with increased risk of mortality and haemorrhage comparing with younger patients. How-Open Access ever, older age does not change the potential benefit of thrombolytic treatment. In AIS patients who are >80 years and with onset time of <3 hours, intravenous tPA is recommended (Class I, Level of Evidence A). The benefit of full-dose intravenous tPA for AIS patients >80 years and within 3-4.5 hour of onset is unclear (Class IIb, Level of Evidence B).
the issue of stroke severity and stroke subtypes Mild or severe stroke was removed from the list of exclusion criteria [bib_ref] Guidelines for the early management of patients with acute ischemic stroke: a..., Jauch [/bib_ref] in the 2013 AHA/ASA guidelines on the management of AIS. For those strokes that take place within 3-4.5 hours of onset, patients with severe stroke were still excluded. [bib_ref] Guidelines for the early management of patients with acute ischemic stroke: a..., Jauch [/bib_ref] However, the ENCHANTED trial has shown that it was safe for both mild and severe stroke patients in its subgroup analysis. [bib_ref] Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, Anderson [/bib_ref] Severe strokes For severe stroke symptoms, intravenous alteplase is indicated within 3 hours from symptom onset. However, it was one of the contraindications for the 3-4.5 hour time window in ECASS 3. [bib_ref] Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke, Hacke [/bib_ref] The severity of stroke at baseline is the strongest predictor of future functional independence or mortality in patients after their first AIS. Subgroup analysis of NINDS studies found that patients with severe strokes could still benefit from IV with a favourable outcome comparing with those not treated.Patients with severe strokes had a higher rate of haemorrhagic transformation and in these patients, haemorrhage might not be related to the use of intravenous tPA. [bib_ref] IV thrombolysis in very severe and severe ischemic stroke: results from the..., Mazya [/bib_ref] The evidence is insufficient to not offer intravenous tPA to patients with severe strokes or early signs of infarction. Patients with severe stroke and early ischaemic changes on CT was not a contraindication for intravenous tPA. [bib_ref] Imaging of acute stroke prior to treatment: current practice and evolving techniques, Mair [/bib_ref] Mild stroke NINDS studies did not list the lower limit of the NIHSS score for using intravenous tPA.Several meta-analysis have found that patients with mild stroke were still significantly disabled at 3 months [bib_ref] Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant..., Smith [/bib_ref] [bib_ref] Outcome of stroke with mild or rapidly improving symptoms, Nedeltchev [/bib_ref] [bib_ref] Poor outcomes in patients who do not receive intravenous tissue plasminogen activator..., Smith [/bib_ref] [bib_ref] Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, singlecare..., Tsivgoulis [/bib_ref] [bib_ref] Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion..., Levine [/bib_ref] [bib_ref] What is a minor stroke, Fischer [/bib_ref]. Such disability could be from motor deficits, cognitive impairment, fatigue or depression, which could not be assessed by NIHSS. [bib_ref] Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant..., Smith [/bib_ref] Since then, the ENCHANTED trial has also included patients with mild strokes between 3 and 4.5 hours of onset. [bib_ref] Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, Anderson [/bib_ref] Although the trial did not reach its predetermined non-inferiority hypothesis, intravenous tPA 0.6 mg/kg showed some efficacy but less haemorrhage in this subgroup. [bib_ref] Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, Anderson [/bib_ref] Rapid improvement and mild stroke were two main reasons of why thrombolysis was not given. [bib_ref] Why are stroke patients excluded from TPA therapy? an analysis of patient..., Barber [/bib_ref] The treatment should not be delayed due to the improvement of symptoms, while the treatment time window missed. Thrombolytic therapy should be given as early as possible.
Recommendation  For AIS patients with severe stroke symptoms, intravenous tPA is recommended within 3 hours of symptom onset. Although risk of haemorrhagic transformation may increase, there is still proven clinical benefit (Class I, Level of Evidence A). For patients with mild but disabling stroke, intravenous tPA is indicated within 3 hours of onset (Class I, Level of Evidence A).  For patients with mild but non-disabling stroke within 3 hours of onset, intravenous tPA might be administrated (Class IIb, Level of Evidence C). For AIS patients with moderate or severe stroke however clinically improving but still have neurological deficit, intravenous tPA is recommended (Class IIa, Level of Evidence A).  Onset to treatment time is a main factor predicting the outcome; therefore, continuing to observe patient and delay the treatment with intravenous tPA is not recommended (Class III, Level of Evidence C).  Intravenous tPA treatment is indicated in patients with early ischaemic changes on CT stroke and within the tPA time treatment window (Class I, Level of Evidence A).  Intravenous tPA is reasonable for patients with moderate to severe ischaemic stroke and early improvement but remain moderately impaired and potentially disabled (Class IIb, Level of Evidence C).  Intravenous tPA is not recommended to patients with extensive hypodense lesion on CT scan. Extensive hypodense lesions may predict that the damage of brain is irreversible (Class III, Level of Evidence A).  For patients with mild but disabling stroke symptoms, intravenous tPA is indicated within 4.5 hours of symptom onset (Class IIb, Level of Evidence A). Treatment of patients with mild ischaemic stroke symptoms that are judged as non-disabling may be considered, but the benefit is unclear.

## Subtypes of stroke
The subgroup analysis of NINDS studies in 1995 has found that all subtypes of patients with AIS would benefit from intravenous tPA. [bib_ref] Efficacy of IV tissue plasminogen activator in acute stroke: does stroke subtype..., Hsia [/bib_ref] A multicentre registry study has found that a small number of patients with large vessel stenosis would have a better 7-day prognosis with thrombolysis. [bib_ref] Efficacy of intravenous thrombolysis according to stroke subtypes: the Madrid Stroke Network..., Fuentes [/bib_ref] However, all subtypes improved with no statistical significance by 90 days 81 . One study found that early intravenous tPA would benefit AIS patients with cardiogenic middle cerebral artery occlusion. [bib_ref] Differential pattern of tissue plasminogen activator-induced proximal middle cerebral artery recanalization among..., Molina [/bib_ref] Another large study did not find any significant difference in treating patients with cardiogenic or non-cardiogenic type of stroke. [bib_ref] Intravenous thrombolysis is more effective in ischemic cardioembolic strokes than in noncardioembolic?, Rocha [/bib_ref] One Chinese prospective single-centre study suggested that mild cardiogenic stroke was a predictor of mortality [bib_ref] Etiologic subtype predicts outcome in mild stroke: prospective data from a hospital..., Hao [/bib_ref] ; another study revealed that patients with cardioembolic stroke had an increase risk of haemorrhage after thrombolysis but without statistical significance among all subgroups of patients with sICH. [bib_ref] Comparisons of outcomes in stroke subtypes after intravenous thrombolysis, Pan [/bib_ref] About a quarter of stroke was of lacunar type and usually had favourable outcome, [bib_ref] Efficacy of IV tissue plasminogen activator in acute stroke: does stroke subtype..., Hsia [/bib_ref] which was supported by two large national registry studies. Lacunar stroke was also an independent prognostic factor for favourable outcome. However, some still had concerns of the risk with thrombolysis in patients with small vessel disease or previous history of small cerebral vasculopathy. Open Access Recommendation  Intravenous tPA is indicated for patients with AIS of all subtypes. There is no need to delay the treatment in order to rule out a possible cardiac source of emboli, such as in patients with atrial fibrillation (Class II, Level of Evidence A).  The benefit of intravenous tPA is unclear in AIS patients with small cerebral vasculopathy (Class III, Level of Evidence C).
intravenous tpA in patients with previous use of antithrombotic agents Patients who had a stroke are often on antithrombotic agents, oral anticoagulants, heparin or low molecular weight heparin (LMWH) and/or recent treated with of tPA. A small retrospective study explored the safety of thrombolysis in patients on antiplatelet agents and found that the risk of sICH was not increased, but parenchymal ICH rate rose substantially. [bib_ref] Outcome by stroke etiology in patients receiving thrombolytic treatment: descriptive subtype analysis, Mustanoja [/bib_ref] One retrospective study in China found potential risk of sICH in patients on antiplatelet therapy. [bib_ref] Does prior antiplatelet treatment increase the risk of hemorrhagic transformation and unfavorable..., Chen [/bib_ref] One large randomised controlled study reported that patients on antiplatelet agents had a trend of developing haemorrhage but without statistical significance, 7 which was supported by meta-analysis findings. [bib_ref] Outcomes after stroke thrombolysis according to prior antiplatelet use, Meseguer [/bib_ref] According to the previously published guidelines and drug information, INR >1.7 or PT >15 s in AIS patients with onset of <3 hours were two contraindications for intravenous tPA. In addition, regardless of the value of INR, it would be contraindicated if a patient was on anticoagulant. [bib_ref] Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke, Hacke [/bib_ref] One large registry study demonstrated that warfarin increased the risk of sICH. [bib_ref] Subtherapeutic warfarin therapy entails an increased bleeding risk after stroke thrombolysis, Ruecker [/bib_ref] However, after adjustment for stroke severity, age and comorbidities, the risk of sICH was not increased if INR was in the therapeutic range. [bib_ref] Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin..., Xian [/bib_ref] Compared with unfractionated heparin, LMWH does not prolong PTT but has more biological activity and longer duration of action. Therefore, patients on LMWH within 24 hours of onset of stroke are not suitable for intravenous thrombolytic therapy due to increased risk of haemorrhage.
Direct thrombin inhibitors (dabigatran and argatroban) have become the first-line treatment for stroke prevention in patients with non-valvular atrial fibrillation or peripheral vascular disease. A prospective study of 65 patients who received combination of intravenous argatroban and tPA found that the rate of recanalisation rate was 61% and rate of haemorrhage was 4.6%. [bib_ref] The argatroban and tissue-type plasminogen activator stroke study: final results of a..., Barreto [/bib_ref] Idarizumab, as the antidote of dabigatran, can block the action of dabigatran in several minutes. After careful consideration and reversal of dabigatran with idarizumab, intravenous tPA could be given. [bib_ref] Idarucizumab for Dabigatran reversal, Pollack [/bib_ref] PT and aPTT could be prolonged in patients on oral FXa inhibitors (apixaban and rivaroxaban). Even with normal aPTT, INR, platelet count, ecarin clotting time, thrombin time, or direct factor Xa activity assays, or no history of receiving these non-vitamin K oral anticoagulants in the past 48 hours (assuming renal function is normal), the efficacy and safety of intravenous tPA remains unclear.

## Platelet count
Although platelet count of <100 000 mm 3 was a contraindication for thrombolysis, clinically patients with thrombocytopaenia were rare and a large pooled analysis reported that it was present in only small number of cases. [bib_ref] Thrombolysis in stroke despite contraindications or warnings?, Frank [/bib_ref] Another two observational studies confirmed this finding and reported that the rate of sICH was low. In the past, test of clotting function was essential before thrombolysis. Clinical research found that INR was rarely elevated in patients not on any anticoagulants, or in hepatic failure, sepsis or other non-drug-related coagulopathy condition. One large registry study reported that 7 out of 152 patients with INR >1.7 or PT >15 s had sICH. [bib_ref] Off-label thrombolysis is not associated with poor outcome in patients with stroke, Meretoja [/bib_ref] After adjustment for age and baseline NIHSS, the prognosis of patients with INR >1.7 was not worse than others. Therefore, the safety or efficacy of intravenous tPA in patients with INR >1.7, aPTT >40 s, or PT >15 s cannot be confirmed currently. Since the chance of discovering thrombocytopaenia is rare in patients with AIS, unless there is a history of coagulopathy, it is unnecessary to check for coagulation studies prior to starting thrombolysis.

## Recommendation

## Open access
Issue of abnormal glucose level Hypoglycaemia and hyperglycaemia are known to produce acute focal neurological deficits. China National Stroke Registry has found that <1% had a stroke mimic condition. In AIS patients with blood glucose levels of <50 mg/dL or >400 mg/dL, neurological examination should be repeated once abnormal glucose levels are corrected. If stroke symptoms still exist, intravenous tPA should be considered.

## Recommendation
 Intravenous tPA is recommended in otherwise eligible patients with an initial glucose levels of >50 mg/ dL (Class I, Level of Evidence A).  If baseline blood glucose level is >400 mg/dL in patients with AIS, hyperglycaemia should be corrected first and then if neurological deficits are still present, intravenous tPA should be considered (Class IIb, Level of Evidence C).

## Seizure at stroke onset
In the literature, over 300 patients with seizures at onset of stroke were treated with intravenous tPA. [bib_ref] Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia, Chernyshev [/bib_ref] Among them, two had sICH. One of these patients had a remote history of surgical removal of a brain tumour. Therefore, seizure at onset of stroke is not an absolute contraindication for intravenous tPA.
Recommendation  Intravenous tPA is reasonable in patients with a seizure at the onset of acute stroke, and the limb impairment is 'thought' to be from stroke and not from Todd's paralysis (Class IIa, Level of Evidence C).

## Hypertension crisis
Patients with hypertension crisis may mimic stroke or top of the basilar artery occlusive syndrome. Uncontrolled or severe hypertension (systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg on two or more consecutive measurements) is a known risk factor for postintravenous tPA sICH. [bib_ref] Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with..., Larrue [/bib_ref] Therefore, intravenous tPA is contraindicated unless the very elevated blood pressure is emergently controlled. [bib_ref] Aggressive blood pressure-lowering treatment before intravenous tissue plasminogen activator therapy in acute..., Martin-Schild [/bib_ref] Two national stroke registries have found that the higher the blood pressure post intravenous tPA, the higher the risk of developing sICH. In the ENCHANTED trial, patients were randomised to the group with tight blood pressure control or standard blood pressure control. [bib_ref] Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, Anderson [/bib_ref] The trial found that patient had no better outcome if blood pressure was low. Presently, there is no strong evidence to support strict control of blood pressure prior to intravenous tPA aside from the recommended treatment range of <185/110 on administration and <180/105 thereafter. 100 Recommendation  In patients with history of potential haemorrhage diathesis or coagulopathy, the efficacy and safety of IV tPA are unknown. In these patients, intravenous tPA should be considered on an individual basis (Class IIb, Level of Evidence C).

## Recommendation

## Recent history of trauma, surgery or biopsy
A few studies considered that major surgeries should be the absolute contraindications for intravenous tPA. Clinicians must thoroughly balance the benefit of intravenous tPA and risk of haemorrhage with recent surgery. If the haemorrhage of a surgical site is compressible, thrombolysis can be given in selected patients. There is currently limited data on the use of intravenous tPA in patients with trauma. One report of 121 patients with dissections and treated with intravenous tPA showed no safety concerns when stroke their AIS was from the dissection of the cervical vessels related to trauma. [bib_ref] Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis..., Zinkstok [/bib_ref] Major intracranial/spinal surgeries might increase the risk of haemorrhage at the site of operation after intravenous tPA and therefore negate any benefit of thrombolysis. Previously, intravenous tPA was contraindicated in patients with AIS who had non-compressible arterial puncture site within 7 days of onset of stroke. [bib_ref] Guidelines for the early management of patients with acute ischemic stroke: a..., Jauch [/bib_ref] With the advent of bridging therapy, patients now are receiving both intravenous and IA therapy despite the puncture of the femoral artery after intravenous tPA. [bib_ref] Endovascular therapy after intravenous t-PA versus t-PA alone for stroke, Broderick [/bib_ref] [bib_ref] Randomized assessment of rapid endovascular treatment of ischemic stroke, Goyal [/bib_ref] [bib_ref] Thrombectomy within 8 hours after symptom onset in ischemic stroke, Jovin [/bib_ref] [bib_ref] American heart association/ american stroke association focused update of the 2013 guidelines..., Powers [/bib_ref] [bib_ref] Endovascular therapy for acute ischaemic stroke: a systematic review and meta-analysis of..., Sardar [/bib_ref] [bib_ref] Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke, Saver [/bib_ref] [bib_ref] Endovascular clot retrieval therapy: implications for the organization of stroke systems of..., Smith [/bib_ref] [bib_ref] Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and..., Rodrigues [/bib_ref] Therefore, groin puncture itself is not a contraindication for intravenous tPA anymore.
Recommendation  For patients with major head trauma or a history of intracranial/spinal surgery within the prior 3 months, intravenous tPA is potentially contraindicated (Class III, Level of Evidence C).
Open Access  The safety and efficacy of administering intravenous tPA to patients with AIS who have had an arterial puncture of a non-compressible site within 7 days is uncertain (Class IIb, Level of Evidence C).  Intravenous tPA therapy should be avoided in patients who have had lumbar puncture within last 7 days, although it can still be considered (Class IIb, Level of Evidence C).

## Previous intracranial abnormalities
Limited data are available in patients with history of stroke within 3 months and treated with intravenous tPA. Case series reports suggested that patients with a history of unruptured intracranial aneurysms were safe when treated with intravenous tPA and without significantly increased risk of haemorrhagic transformation. [bib_ref] Intravenous rt-PA is not associated with increased risk of hemorrhage in patients..., Sheth [/bib_ref] [bib_ref] Asymptomatic cerebral aneurysm in stroke patients eligible for intravenous thrombolytic therapy, Wang [/bib_ref] [bib_ref] Intracranial aneurysm rupture following intravenous thrombolysis for stroke, Haji [/bib_ref] [bib_ref] No hemorrhagic transformation after intravenous thrombolysis in a pontine infarction patient with..., Xu [/bib_ref] [bib_ref] Rupture of a concealed aneurysm after intravenous thrombolysis of a thrombus in..., Zaldivar-Jolissaint [/bib_ref] [bib_ref] Post-thrombolysis hemorrhage risk of unruptured intracranial aneurysms, Chen [/bib_ref] Even these reports could be biased, evidence indicated that intravenous tPA in these patients was relatively safe. Safety of intravenous tPA in patients with intracranial vascular malformations (cavernous haemangioma, telangiectasia, developmental venous abnormality, arteriovenous malformations and arteriovenous fistula) is unclear. [bib_ref] Thrombus in vertebrobasilar dolichoectatic artery treated with intravenous urokinase, De Georgia [/bib_ref] [bib_ref] Should thrombolysis be contraindicated in patients with cerebral arteriovenous malformations?, Sumner [/bib_ref] [bib_ref] Cerebrovascular malformation revealed during the prethrombolysis workup in acute ischemic stroke. Impact..., Guillon [/bib_ref] Recommendations  Use of intravenous tPA in patients presenting with AIS and a prior history of ischaemic stroke <3 months may be harmful (Class IIb, Level of Evidence B).  For AIS patients with a small or moderate sized (<10 mm) unruptured intracranial aneurysm, intravenous tPA is reasonable (Class IIb, Level of Evidence C).  In AIS patients with a giant unruptured intracranial aneurysm, the balance of benefit and risk is unclear (Class IIb, Level of Evidence C).

## Haemorrhagic retinopathy or other haemorrhagic ophthalmological conditions
The condition of having an ischaemic stroke and intraocular haemorrhage is rare. In patients without diabetes, the rate of developing retinal haemorrhage after intravenous tPA was around 0.003%. [bib_ref] Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute..., Mahaffey [/bib_ref] Such haemorrhage is also rare in patients with diabetes . Therefore, intravenous tPA is not contraindicated in patients with diabetic retinopathy. new pArAdigm on Ais And intrAvenous thrombolysis And the estAblishment of treAtment protocols conducting public education and prehospital emergency response system Only 24%-54% of AIS patients presented to the hospital within an hour of onset. Among them, 38%-65% came by emergency medical services (EMS). [bib_ref] Effect of the use of ambulance-based thrombolysis on time to thrombolysis in..., Ebinger [/bib_ref] Public stroke education may raise stroke awareness and improve stroke symptom recognition and shorten the onset to hospital arrival time and increase the rate of thrombolysis. [bib_ref] Streamlining of prehospital stroke management: the golden hour, Fassbender [/bib_ref] The recognition of stroke by EMS staff was around 30%-83%. Ongoing EMS education on stroke recognition may help prioritise transportation and make prenotification to the emergency room and stroke team at the designated stroke centres, hence improve the rate of thrombolysis. [bib_ref] Prehospital stroke care: new prospects for treatment and clinical research, Audebert [/bib_ref] The AHA/ASA guidelines recommend that EMS personnel use one of the simple stroke screening tools to recognise stroke: Cincinnati Prehospital Stroke Scale, Los Angeles Prehospital Stroke Scale or the Face Arm Speech Time Tool (FAST tool). Modelling, coding and quality improvement measures could help improve the sensitivity and specificity of their ability to recognise stroke. [bib_ref] Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in..., Meretoja [/bib_ref] [bib_ref] Recognition of Stroke by EMS is associated with improvement in Emergency Department..., Abboud [/bib_ref] [bib_ref] Improved performance of new prenotification criteria for acute stroke patients, Hsieh [/bib_ref] [bib_ref] Diagnosis and treatment of patients with stroke in a mobile stroke unit..., Walter [/bib_ref] Recently, the development of Stroke Recognition 120, a tool specifically designed to coincide with the Chinese emergency notification number, is being promoted by the C and its Red Ribbon Movement. [bib_ref] Stroke 1-2-0: a rapid response programme for stroke in China, Zhao [/bib_ref] Since FAST is a good acronym for English-speaking population to recognise stroke signs and symptoms, Stroke 120 is a Chinese way of recognising 'Face, Arm and Speech' abnormality in stroke. Stroke 120 designates '1 as looking at One face for any asymmetry, 2 as looking for Two arms for any weakness and 0 as Listening for any speech abnormality'. Its usefulness is currently being studied.

## Recommendation
optimising stroke treatment in the emergency room Optimising the process for intravenous thrombolysis will benefit more stroke patients, open more vessels, minimise disability and improve outcome. The benefit of intravenous tPA is significant when given within 3 hours, moderate within 3-4.5 hours and unclear beyond 4.5 hours. The guidelines require that the time of Open Access initiating intravenous tPA on arrival be within 60 min (door to needle time, DTN). [bib_ref] Guidelines for the early management of patients with acute ischemic stroke: a..., Jauch [/bib_ref] In China, one of the main delays was the period between completing a brain scan and treatment, mainly from the consenting process. [bib_ref] Hospital variation in thrombolysis times among patients with acute ischemic stroke: the..., Sauser [/bib_ref] Through process improvement, the rate of DTN of <60 min was improved from 29.6% to 53.3%, and rate of mortality and haemorrhage was lowered in the USA. [bib_ref] Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute..., Fonarow [/bib_ref] Helsinki stroke model gave an example of requiring the emergency medical services to provide prenotification to emergency before patient's arrival. [bib_ref] Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in..., Meretoja [/bib_ref] EMS staff sent patient directly from the ambulance to the CT scan, and physician in emergency room were ready to administer intravenous tPA in CT scanner right after the CT was completed and showed no contraindications. [bib_ref] Diagnosis and treatment of patients with stroke in a mobile stroke unit..., Walter [/bib_ref] Their DTN has been shortened to less than 20 min. [bib_ref] Telemedicine in prehospital stroke evaluation and thrombolysis: taking Stroke treatment to the..., Itrat [/bib_ref] consent A written consent is needed before treatment according to the Chinese medical regulation, even the indication of intravenous tPA within 3 hours in AIS is an approved therapy. On average, it takes about 10 to 15 min to explain to the patients and relatives about the stroke and ask them to sign the consent.
process for bridging therapy and standardisation of system of transfer for endovascular therapy Despite the effectiveness of intravenous thrombolysis, intravenous tPA could only open about 17%-38% of large vessel occlusive strokes. The benefit was modest. Patient's prognosis was directly related to the ability to re-establish the cerebral blood flow. The earlier the vessel opens up, the better the prognosis. [bib_ref] Time to reperfusion and treatment effect for acute ischemic stroke: a randomized..., Fransen [/bib_ref] The key therefore is to improve the rate of recanalisation of the occluded vessels.
Between 2015 and 2016, seven published randomised controlled trials have confirmed that the combination of intravenous tPA with endovascular thrombectomy was safe and effective. [bib_ref] Randomized assessment of rapid endovascular treatment of ischemic stroke, Goyal [/bib_ref] For those patients with large vessel occlusive type of AIS (only 15%-20% of AIS), bridging intravenous with IA therapy was better than intravenous thrombolysis alone. [bib_ref] Incidence and predictors of early recanalization after intravenous thrombolysis: a systematic review..., Seners [/bib_ref] Hence, the interventional treatment guidelines from both USA and China have recommended the bridging therapy for those AIS with anterior circulation large vessel occlusive AIS. For those with posterior circulation large vessel occlusive stroke, the large multicentre BASICS showed no improved outcome with either the combination or standard intravenous therapy only. [bib_ref] Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery..., Schonewille [/bib_ref] However, the Dutch National Registry Study showed that bridging therapy had equivalent of outcome for those with posterior circulation large vessel stroke compared with those in the Multicenter Randomised Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) trial. [bib_ref] Safety and outcome of intra-arterial treatment for basilar artery occlusion, Van Houwelingen [/bib_ref] It is proven that combined intravenous and IA endovascular therapy may improve the outcome in AIS patients with large vessel occlusive strokes only. 109 Therefore, stroke system of care and stroke care policy should be adjusted accordingly. Telestroke is one of the efficient method for comprehensive stroke centre to screen for a potential thrombolysis candidate and further transfer these patients from a primary centre or comprehensive stroke centre. Patients post intravenous tPA should immediately have the imaging study to check for any large vessel occlusion. If such occlusion is found, the patient should be taken to the stroke centre that can offer IA thrombectomy. A database should be established to track and evaluate the quality measures and clinical outcome at these stroke centres. China is actively establishing stroke centres and exploring different stroke system of care models. Recommend clinical quality improvement process by using these key performance indicators: door to CT time, DTN, door to puncture time and door to reperfusion time. (Class I, Level of Evidence B). 6. At stroke centres with ample resources, thrombolysis should be given in a room with monitors. Recommend performing laboratory tests, imaging studies and signing of consent simultaneously so to avoid the delay of treatment (Class IIb, Level of Evidence B). 7. Emergent stroke care can be completed at a primary stroke centre that offers intravenous tPA. Initial non-invasive vascular imaging should be completed quickly. Select those AIS patients eligible for endovascular therapy and transfer them to the nearest comprehensive stroke centre as soon as possible (Class IIb, Level of Evidence B). 8. Endovascular treatment should be performed in experienced stroke centres that can complete neurovascular imaging studies quickly and by experienced and certified interventional physicians. Conduct quality measures on the diagnostic and treatment process and patients treated should be followed up (Class I, Level of Evidence C).

## Recommendation
contributors QD, AX and YW designed this scientific statement and revised it for four times. YD, YZ and HZ contributed to organise the published studies and drafted the manuscript. LL has organised the whole processing, reframed the manuscript and revised the draft. All authors have read the manuscript and agreed to be published.
competing interests The Chinese Stroke Association affirms the value of this scientific statement as an educational tool for neurologists. The members of the CSA Scientific Statement on Intravenous Thrombolysis in Acute Ischemic Stroke Writing Group make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional or business interest of a member of the writing panel. QD is employed at Huashan Hospital; has received NSF grants; is part of the speakers' bureau and received honoraria from Boehringer Ingelheim, Pfizer and Sanofi-Aventis; has received consultancy fees/served in the advisory board of Boehringer open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by-nc/ 4. 0/
[table] Table 1: Intravenous tPA trials for acute ischaemic stroke as listed by the year of publication Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischemic Stroke; ECASS, European Cooperative Acute Stroke Study; ENCHANTED, Enhanced Control of Hypertension and Thrombolysis Stroke Study; IV, intravenous; mRS, modified Rankin Scale; NINDS, National Institute of Neurological Disorders and Stroke; tPA, tissue plasminogen activator.DWI-FLAIR mismatch. Although DWI changes can be identified within minutes of stroke onset, FLAIR changes may not be apparent until several hours later. Patients with large areas of mismatch are therefore deemed to have had likely a more recent onset time of stroke and could potentially be eligible for intra- [/table]
[table] Table 2: List of other intravenous thrombolytic drugs [/table]