coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless one of the following conditions is present [84]: Clinical suspicion of a bleeding abnormality or thrombocytopenia Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs]) Use of anticoagulants is not known https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 11/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Potential exclusions to treatment Exclusion criteria for IVT are listed in the table ( table 1); these criteria have evolved with time as experience with IVT has increased. Several clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke. Among these are rapidly improving stroke symptoms and early ischemic changes on neuroimaging. Patients on anticoagulants Current anticoagulant use with evidence of anticoagulant effect by laboratory tests is a contraindication to IVT. Coagulation tests For patients without recent use of oral anticoagulants or heparin, treatment with IVT can be started before availability of coagulation test results if there is no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have no known liver disease, hematologic disease, or advanced kidney disease). In such cases, alteplase treatment should be discontinued if the international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively elevated ( table 1). For patients with inadequate historical information, IVT should not be started until the aPTT and either the PT or the INR are available. Preliminary data suggest that normal coagulation parameters can be predicted on arrival to the emergency department by assessing three questions [106]: Is the patient taking an oral anticoagulant? Is the patient taking heparin or low molecular weight heparin? Is the patient on hemodialysis? In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that included 299 patients, "no" answers to all three questions predicted normal range PT and aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit earlier treatment with alteplase in selected patients with acute stroke [106]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [107]. Patients on DOACs Accumulating evidence suggests that recent use of a DOAC is not associated with an increased risk of symptomatic intracerebral hemorrhage following IVT [108,109]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function [84]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 12/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate DOAC reversal DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [110]. An observational cohort study identified 51 patients treated with idarucizumab for dabigatran reversal prior to thrombolysis and found that idarucizumab-treated patients had similar rates of symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality compared with patients not treated with idarucizumab [111]. Rapidly improving stroke symptoms Rapidly improving stroke symptoms (RISS) should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are nondisabling [112]. The decision regarding use of IVT or MT should be made based upon monitoring neurologic deficits for no longer than the time needed to prepare and begin treatment; treatment should not be delayed by continued monitoring for improvement. Disabling versus nondisabling stroke deficits Qualifying patients who have an acute ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite improvement of any degree while being evaluated, should be treated urgently with IVT and/or MT as appropriate. Any of the following should be considered disabling deficits [112]: Complete hemianopia: 2 on the National Institutes of Health Stroke Scale (NIHSS) question 3 ( table 3) Severe aphasia: 2 on NIHSS question 9 ( table 3) Visual extinction: 1 on NIHSS question 11 ( table 3) Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 ( table 3) Any deficits that lead to a total NIHSS >5 (calculator 1) Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work [113]. Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly disabling; there was no difference in the rate of a favorable functional outcome (defined as a modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or to aspirin (78.2 versus 81.5 percent) [113]. However, the trial was stopped very early solely because of slow https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 13/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate recruitment, having enrolled only 313 of a planned 948 subjects, and therefore its findings are not definitive. Early ischemic changes on neuroimaging Minor ischemic changes on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray- white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign ( image 1). We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1), although there are few data to determine a threshold of ischemic severity or extent that modifies treatment response to alteplase [114]. Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Role of ASPECTS method'.) Issues regarding consent Alteplase is an approved therapy for acute ischemic stroke because of substantial evidence of safety and efficacy. Consent is not required to administer alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute ischemic stroke if patient or surrogate consent is not possible [84]. In such cases, the need for informed consent is outweighed by the need for urgent intervention, and the patient can be treated under the principle of presumption of consent. Furthermore, given the lack of clinical equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not appropriate [115]. Whether to proceed to thrombolysis in an individual patient should be based upon a brief discussion of the risks and benefits with the patient and family or health care proxy, if possible. However, neurologic deficits caused by acute stroke often preclude the ability of the patient to participate in the decision. Explaining benefits and risks Procedures for informed decision-making and informed consent vary among different centers; we explain the risks and benefits of alteplase as follows [115]: "There is a treatment for your stroke called alteplase that must be given within 4.5 hours after the stroke started. It is a 'clot-buster' drug. Getting alteplase reduces your risk of being disabled. People who get alteplase for stroke have a better chance of recovering without disability and getting back to the activities they enjoy compared to people who do not receive the treatment. All medicines have some risk. With alteplase, there is a risk of serious bleeding. However, time is https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 14/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate important as well. We know that the sooner we start treatment with alteplase, the greater the chance that patients will have a good outcome." Some patients will accept any risk, including an increased risk of intracranial bleeding, for an increased chance of avoiding severe permanent disability. Others are more risk averse and prefer to accept disability, especially if there is a chance of recovery over time. Need for transfer to stroke center Most hospitals in more economically developed countries are able to treat acute ischemic stroke with IVT. In situations where local stroke expertise is not routinely or immediately available, accumulating data suggest that the decision to administer IVT can be guided safely and effectively via telemedicine (telestroke) [116]. By contrast, MT is not as widely available. Transfer to an expert stroke center may be necessary for patients with acute ischemic stroke in the anterior circulation who present to medical facilities that lack resources and expertise to deliver MT. However, eligible patients can receive standard treatment with IVT if they present to hospitals where thrombectomy is not an option, and those with qualifying anterior circulation strokes can then be transferred to stroke centers where intra-arterial thrombectomy is available, a strategy called "drip and ship" [117,118]. Screening of patients for transfer is aided by the ability of networked hospitals to share brain and neurovascular imaging studies via cloud computing, which allows the stroke center hub to read a CTA (or MRA) done locally and thereby determine whether the patient has a large vessel occlusion, a key requirement for MT. Reducing delay Inordinate treatment delay can occur during any of the steps involved in reperfusion therapy, including emergency department triaging, initial telephone triage by the stroke physician, physician evaluation, neuroimaging, obtaining and waiting for results of blood and laboratory tests, obtaining consent, treating hypertension that would otherwise exclude the use of IVT (ie, systolic blood pressure 185 mmHg or diastolic 110 mmHg), and delivery of alteplase from the pharmacy to the bedside. Expedited stroke protocols may reduce treatment delays and improving patient outcomes. Such protocols may include the following features [119,120]: Prehospital notification by emergency medical personnel/ambulance of a patient with a possible stroke Blast paging of all relevant hospital stroke personnel, including CT technicians In-person triage of all code strokes without telephone triage; the stroke physician on-call proceeds immediately to the bedside Direct transfer of the patient, without fully undressing, from triage onto the CT scanner table via the ambulance stretcher https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 15/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate No delays pending formal neuroimaging interpretation; the on-call stroke physician reads the brain CT or MRI scan Unmixed alteplase is available at the bedside during the evaluation No delays pending electrocardiogram (ECG), coagulation tests, chest radiograph, or stool guaiac unless specifically indicated No delays pending written consent; verbal consent is obtained if the patient is able to consent or if family members or health care proxy are nearby While an expedited evaluation might increase the risk of giving IVT in cases of stroke mimics, data suggest that the intracranial hemorrhage rate in patients who later are diagnosed with a stroke mimic is approximately 1 percent [121,122]. TREATMENT BY TIME FROM SYMPTOM ONSET "Time is brain." The sooner intravenous thrombolysis (IVT) treatment with alteplase is initiated after ischemic stroke, the more likely it is to be beneficial [123-125]. Eligible patients should start treatment as quickly as possible within the appropriate 3- or 4.5-hour time window from stroke onset; treatment should not be delayed until the end of the time window. Mechanical thrombectomy (MT) is also time-dependent, with clear benefit for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who are treated within 6 hours of symptom onset. Beyond 6 hours, MT may be an option at specialized stroke centers using imaging-based selection of patients with anterior circulation stroke who have symptom onset 6 to 24 hours before treatment. (See "Mechanical thrombectomy for acute ischemic stroke".) Less than 3 hours For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with intravenous alteplase (or intravenous tenecteplase) when treatment is initiated within 3 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 3 to 4.5 hours The benefit of alteplase extends to 4.5 hours, as discussed above. For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest (ie, a weak recommendation) IVT with alteplase provided that treatment is initiated within 3 to 4.5 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 16/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate There are additional exclusion criteria ( table 1) for IVT in the 3- to 4.5-hour time window (age >80 years old, an National Institutes of Health Stroke Scale (NIHSS) score >25, a combination of previous stroke and diabetes, and oral anticoagulant use regardless of INR). However, we do not consider these as absolute contraindications to IVT in the 3- to 4.5-hour time window, given evidence that alteplase is still beneficial in patients who would otherwise be excluded by these criteria [4,114,126,127]. The additional exclusions from 3 to 4.5 hours were made to satisfy safety concerns from the European regulatory agency and were employed to select patients for treatment in the ECASS 3 trial [29], which established the benefit of IVT in the 3- to 4.5-hour time window. 4.5 to 6 hours Patients within 4.5 to 6 hours from stroke symptom onset should not routinely receive IVT because harm may exceed benefit, but they should be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 6 to 24 hours Patients beyond 6 hours from ischemic stroke symptom onset are not eligible for treatment with IVT. However, MT is an option at specialized stroke centers using imaging- based selection of patients with anterior circulation stroke who have were last known to be well at 6 to 24 hours before treatment. This is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) Beyond 24 hours Patients beyond 24 hours from ischemic stroke symptom onset generally are not eligible for treatment with IVT or MT. Limited retrospective data suggest possible benefit for selected patients treated with MT beyond 24 hours of last known well, but confirmation from prospective trials is needed [128]. Unwitnessed stroke onset and "wake-up" stroke When the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal. For patients whose stroke symptoms are first noted upon awakening from sleep, the last time known to be normal may be the time they went to bed (if the patient can report this reliably) or the last time seen normal by a friend or family member. Such patients are not ordinarily eligible for IVT unless the time last known to be normal is less than 4.5 hours. However, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to select patients with wake-up stroke or unknown stroke onset time for IVT. (See 'Benefit with imaging selection of patients' above.) Imaging-based selection of patients for treatment with MT who were last known to be normal 6 to 24 hours before treatment is an option at specialized stroke centers. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 17/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate SPECIAL POPULATIONS Different clinical presentations and patient populations may affect the decision to use intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) for acute ischemic stroke, as discussed below. Posterior circulation stroke All eligible patients with acute ischemic stroke should be treated with IVT, including those with stroke in the posterior circulation. Mechanical thrombectomy is beneficial for select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, but trials that established the benefit of MT largely excluded patients with posterior circulation infarcts. However, endovascular interventions for vertebrobasilar occlusions, including MT, may be treatment options stroke centers with appropriate expertise. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Posterior circulation stroke'.) Age 80 years and older Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. Therefore, we do not consider age to be a contraindication to IVT treatment for otherwise eligible patients. However, age >80 years is a relative contraindication in the 3- to 4.5-hour time window. (See '3 to 4.5 hours' above.) A 2014 meta-analysis of individual patient data from 6756 subjects (including more than 1700 subjects older than age 80 years) found that benefit of alteplase was similar regardless of patient age [4]. In a prespecified secondary analysis of individual participant data (n = 6756) from a 2016 meta-analysis of nine trials of alteplase versus control for acute ischemic stroke, the increased risk of intracerebral hemorrhage with alteplase in the first seven days after treatment did not differ by age [6]. Older age is not an exclusion for MT [129]. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) Prestroke disability or dementia Treatment decisions regarding IVT or MT for patients with significant prestroke disability or dementia should be individualized using shared decision- making that incorporates patient values and preferences [130]. Such patients were largely excluded from randomized trials of reperfusion therapies for acute ischemic stroke. However, observational data suggest that patients with disability or dementia at baseline may still benefit from reperfusion for acute stroke, despite an overall worse prognosis and possibly higher mortality [130]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 18/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Pregnancy Although pregnancy has been considered a relative contraindication to the use of thrombolysis for acute stroke, IVT can be given in pregnancy after careful discussion of the potential risks and benefits. The use of thrombolytic therapy in pregnancy is discussed separately. (See "Cerebrovascular disorders complicating pregnancy", section on 'Acute ischemic stroke'.) Children Safety and efficacy data for reperfusion therapy of acute ischemic stroke are lacking in patients younger than 18 years of age. However, IVT and MT may be options for some children, particularly adolescents (age 13 years), with acute ischemic stroke on neuroimaging who are evaluated and treated at pediatric stroke centers. (See "Ischemic stroke in children: Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Goals and options for reperfusion The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. Intravenous thrombolysis (IVT) is the mainstay of reperfusion therapy for acute ischemic stroke. Mechanical thrombectomy (MT) is indicated for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation. (See 'Reperfusion therapies' above.) Benefit of reperfusion therapy IVT improves functional outcome at three to six months for appropriately selected patients when given within 4.5 hours of ischemic stroke onset. (See 'Alteplase' above and 'Tenecteplase' above.) MT improves functional outcome at three months for appropriately selected patients if treatment is started within 24 hours from the time the patient was last known well. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Efficacy of mechanical thrombectomy'.) Evaluation All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly evaluated for treatment with IVT. Simultaneously, patients with suspected acute https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 19/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate ischemic stroke involving the anterior circulation should be evaluated for MT. (See 'Rapid evaluation' above.) Patient selection For IVT Eligibility criteria for treatment with IVT are outlined in the table ( table 1). For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with alteplase, provided that treatment is initiated within 3 hours of the time last known well (Grade 1A). For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest IVT, provided that treatment is initiated within 3 to 4.5 hours of the time last known well (Grade 2A). For patients with wake-up stroke or unknown stroke onset time, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for IVT. (See 'Less than 3 hours' above and '3 to 4.5 hours' above and 'Unwitnessed stroke onset and "wake-up" stroke' above.) For MT Intra-arterial mechanical thrombectomy is recommended for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation who can start treatment within 24 hours of the time last known well. Indications and eligibility criteria for MT are discussed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT administration The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. 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