In the presence of a patient with suspected ischaemic stroke who is potentially eligible for reperfusion therapy, clinical assessment should be targeted at identifying and excluding possible conditions similar to stroke (so-called stroke mimics) and at establishing the time of onset of symptoms [1], which is the main criterion for a patient being eligible for reperfusion treatment, as well as the main factor that may limit the effectiveness of the treatment itself [2–4]. When the time of onset of symptoms is unknown, it is conventionally traced back to the last time the patient was seen to be healthy. When the symptoms of stroke are already present on awakening, the time of onset is traced back to the time the patient went to bed [1]. The clinical neurological evaluation must be carried out using the NIHSS [5]. According to AHA/ASA guidelines, the blood tests to be performed in the acute phase are glycaemia, renal function, blood count with platelets, cardiac enzymes, PT (prothrombin time), INR and PTT (partial thromboplastin time) [1]. For patients who are not on anticoagulation therapy or do not show any signs of thrombocytopenia, coagulopathy or liver disease, it is not necessary to wait for the results of the blood counts and coagulation tests before starting reperfusion treatment, as the incidence of non-suspected coagulopathy is very low, less than 1 % [6, 7]. This recommendation is not confirmed in the European guidelines by the European Stroke Organization (ESO) nor in the latest edition of the SPREAD guidelines of 2012 [8, 9]. On the contrary, it is absolutely necessary to acquire the value of capillary blood glucose (CBG) because symptomatic hypoglycaemia is one of the potential stroke mimics. Furthermore, measurement of O₂ saturation is recommended, as is its correction with O₂ supplementation, if the patient is hypoxemic as well as the acquisition of electrocardiogram and blood pressure measurement.

An urgent CT brain scan without contrast medium can provide the informations necessary to develop therapeutic decisions [1]. This concept was confirmed in the updating of AHA/ASA guidelines on endovascular therapy, which was published in June 2015 [10]. In fact, although brain MRI has more sensitivity and more specificity in detecting acute ischaemic lesions than CT brain scan because of its higher resolution (especially on the structures of the posterior fossa) and the possibility of using DWI which can detect acute ischaemic lesions at a very early stage [11], it is an exam that takes time and cannot be performed on patients carrying pacemakers or other metallic devices. Furthermore, MRI is more sensitive to motion artefacts; it is less likely to be tolerated, especially by agitated or confused patients [1]; and it is not always available in urgency. The presence of early signs of ischaemia detected by means of a CT brain scan without contrast must not be a contraindication to intravenous reperfusion therapy because, even if signs are visible, the patient can still benefit from the treatment. Consideration must however be taken of the extent of the early signs of ischaemia: >1/3 of the territory of the middle cerebral artery (MCA) increases the risk of haemorrhage [12, 13]. The recommendations of the AHA/ASA guidelines state that early signs of ischaemia (if time of onset of symptoms is certain) must never be a reason for not delivering intravenous reperfusion therapy, unless a “clear hypodensity” is present, extending >1/3 of the territory of MCA [1]. An easy method of reading a CT scan without contrast, in order to determine the extension of an early ischaemic lesion, is the ASPECTS score [14]. The involvement of 1/3 of MCA territory corresponds to an ASPECTS score = ≤7. A non-invasive intracranial vascular neuroimaging CT angiogram needs to be performed when endovascular therapy is recommended, but it must not delay the administration of intravenous thrombolysis. CT or MRI perfusion techniques are indicated to detect ischaemic penumbra in special situations, primarily to assess the existence of a potential benefit from reperfusion therapy in patients with symptom onset outside the therapeutic window or when the time of symptom onset is uncertain (recommendation Level C according to AHA/ASA guidelines). The AHA/ASA, ESO and ISO guidelines agree on the fact that if the patient has an onset of symptoms that can be set with certainty within the therapeutic window, it is not necessary to search for ischaemic penumbra because it makes no contribution to the decision-making strategy. The AHA/ASA guidelines outline an ideal timing to be observed in the different stages of clinical and instrumental evaluations of acute stroke patients:

Intravenous reperfusion treatment with alteplase is indicated for acute ischaemic stroke (dosage 0.9 mg/kg, maximum 90 mg, of which 10 % administered initially as a bolus and the remaining quantity over a period of 60 min). According to the results of the NINDS study [15], the therapeutic window (time from onset of symptoms) within which intravenous thrombolytic treatment can be delivered was originally 3 h. The data analysis of subsequent trials, such as ECASS III and IST-3 [16], showed that treating patients within 3–4.5 h of onset of symptoms gives a more modest clinical benefit than early treatment against a small increased risk of bleeding. When more than 4.5 h have elapsed from onset of symptoms, the clinical benefit is not significant [2–4, 16, 17]; for this reason the therapeutic window was extended to 4.5 h from symptom onset. The FDA (Food and Drug Administration), in contrast to EMA (European Medicines Agency) and AIFA (Agenzia Italiana del Farmaco), has not accepted the extension of the therapeutic window to 4.5 h. Thus AHA/ASA guidelines, unlike ESO and ISO guidelines, assign an indication of Level B and not of Level A to the administration of alteplase for treatment of acute stroke within 4.5 h, with the recommendation that a more restrictive approach be adopted regarding the other criteria if the thrombolytic is administered between 3 and 4.5 h [1]. All the guidelines agree on recommending administration of the drug as early as possible, given the inverse linear relation existing between the efficacy of reperfusion therapy and the time the therapy is administered [18]. The AHA/ASA guidelines indicate a precise timing: the therapy should be delivered within 60 min from the patient’s arrival at the emergency department. According to AHA/ASA, the absolute exclusion criteria for intravenous thrombolytic therapy are as follows:

According to 2012 SPREAD guidelines, if more than one intravenous administration of antihypertensive is needed to reach the therapeutic blood pressure target, this is a contraindication to administrating alteplase. In the update of ISO recommendations dated March 2015 [19], it is stated that the therapy is in any case indicated once the therapeutic target has been achieved. No limitations are mentioned regarding the therapy needed in order to reach the therapeutic target.

Regarding therapy with Warfarin, new ISO recommendations from March 2015 agree on the indication of thrombolytic therapy, provided that PT INR is ≤1.7, while EMA recommendations contraindicate the use of thrombolytic even with subtherapeutic INR, provided it is over the normal range. It has been demonstrated that patients on OAT (oral anticoagulant therapy) with subtherapeutic INR who receive intravenous thrombolysis are more likely to suffer a symptomatic haemorrhagic transformation of the ischaemic lesion, but there is no evidence of worse outcome or increased mortality when compared to patients who are not treated with warfarin [20]. However, with patients on anticoaugulants and who have INR ≤1.7, AHA/ASA guidelines restrict the indication of therapy to administration within 3 h from onset of symptoms. With patients on anticoagulant therapy, thrombolytic therapy is always contraindicated between 3 and 4.5 h. This restriction is not mentioned in the Italian guidelines. As for heparin therapy, EMA and AIFA indications are in line with AHA/ASA guidelines (contraindication in patients who have received heparin therapy in the previous 48 h, with altered aPTT); the SPREAD guidelines from 2012 restrict contraindication to 24 h before the event, without mentioning the aPTT value. As regards indication of thrombolytic therapy during treatment with new oral anticoagulants, the 2012 SPREAD guidelines are in line with AHA/ASA guidelines which emphasize the need for negative results in specific tests which can assess the activities of the NOACs, in order to enable administration of a thrombolytic drug.

According to EMA and AIFA recommendations, there are further contraindications to intravenous administration of thrombolytic drug which are not directly connected to its use in treating ischaemic acute stroke, but to its general use:

AHA/ASA guidelines include some “relative” contraindications, which were originally absolute and have subsequently been revised on the basis of data derived from clinical experience and trials carried out after NINDS: