7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Approach to reperfusion therapy for acute ischemic stroke : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates pre-hospital emergency services, emergency medicine, stroke neurology, intensive care services, interventional neuroradiology, and neurosurgery to provide optimal treatment. This topic will review the use of reperfusion therapy for patients with acute ischemic stroke, focusing on early thrombolytic therapy with intravenous thrombolysis (IVT). The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Mechanical thrombectomy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke".) REPERFUSION THERAPIES 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. The long-term goal is to improve https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 1/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis (IVT) and mechanical thrombectomy (MT). Intravenous thrombolysis Alteplase IVT with alteplase is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of the time last known well. Eligibility criteria are outlined in the table ( table 1). Because the benefit of alteplase is time dependent, it is critical to treat patients as quickly as possible. Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. Benefit by time to treatment IVT with alteplase improves functional outcome at three to six months when given within 4.5 hours of ischemic stroke onset [1-8]. The benefit of IVT for acute ischemic stroke decreases continuously over time from symptom onset, as shown in meta-analyses of randomized trials [1,3,4,9] and a registry that analyzed data from over 58,000 patients treated with IVT within 4.5 hours of ischemic stroke symptom onset [2]. In the registry, each 15-minute reduction in the time to initiation of IVT treatment was associated with an increase in the odds of walking independently at discharge (4 percent) and being discharged to home rather than an institution (3 percent) and a decrease in the odds of death before discharge (4 percent) and symptomatic hemorrhagic transformation of infarction (4 percent) [2]. Similarly, another study of over 61,000 patients treated with IVT found that shorter door-to-needle times were associated with lower all-cause mortality at one year and a reduced risk of hospital readmission at one year [10]. A 2014 meta-analysis evaluated individual patient data from 6756 patients (including more than 1700 who were older than age 80 years) with acute ischemic stroke who were allocated to IVT or control in the NINDS, ATLANTIS, ECASS (1, 2, and 3), EPITHET, and IST-3 trials [4]. The primary outcome measure was the proportion of patients achieving a good stroke outcome at three or six months as defined by a modified Rankin scale score ( table 2) of 0 or 1 (ie, no significant disability). The following observations were reported: For treatment within 3 hours of stroke onset, alteplase led to a good outcome for 33 percent, versus 23 percent for control (odds ratio [OR] 1.75, 95% CI 1.35-2.27). The number needed to treat (NNT) for one additional patient to achieve a good outcome was 10. For treatment from 3 to 4.5 hours, the proportion with a good outcome in the alteplase and control groups was 35 and 30 percent (OR 1.26, 95% CI 1.05-1.51, NNT 20). https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 2/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate For treatment beyond 4.5 hours, the proportion with a good outcome in the alteplase and control groups was no longer significant at 33 and 31 percent (OR 1.15, 95% CI 0.95-1.40, NNT 50). The benefit of alteplase was similar regardless of patient age or stroke severity. Alteplase increased the risk of symptomatic intracranial hemorrhage (6.8 percent, versus 1.3 percent for control, OR 5.55, 95% CI 4.01-7.70); the number needed to harm (NNH) for one additional patient to have a symptomatic intracranial hemorrhage was 18. Alteplase also increased the risk of fatal intracranial hemorrhage within seven days (2.7 versus 0.4 percent, OR 7.14, 95% CI 3.98-12.79, NNH 44); this risk was similar regardless of age, stroke severity, or treatment delay. Alteplase treatment had no significant effect on other early or late causes of death. Death at 90 days was slightly higher in the alteplase group (17.9 percent, versus 16.5 percent in the control group, hazard ratio 1.11, 95% CI 0.99-1.25), a result that just missed statistical significance. In agreement with other meta-analyses [1,3,7], these observations confirm that the sooner IVT is initiated, the more likely it is to be beneficial, and that the benefit extends to treatment started within 4.5 hours of stroke onset [4]. The results also show that alteplase is beneficial regardless of patient age, stroke severity, or the associated increased risk of symptomatic or fatal intracranial hemorrhage in the first days after alteplase treatment. The odds of a favorable three-month outcome decrease as the interval from stroke onset to start of alteplase treatment increases ( figure 1) [1]. Beyond 4.5 hours, harm may exceed benefit. Benefit with imaging selection of patients IVT may be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion magnetic resonance imaging (MRI) but no corresponding hyperintensity on fluid- attenuated inversion recovery (FLAIR) MRI. This imaging mismatch (diffusion positive/FLAIR negative) correlates with a stroke onset time of 4.5 hours or less [11]. Limited clinical trial evidence suggests that IVT is beneficial for select patients who meet imaging criteria indicative of recent cerebral infarction and/or significant salvageable brain tissue, even if they do not qualify based upon traditional time windows, although results have been inconsistent: The placebo-controlled Wake-Up Stroke trial selected 500 adults with unwitnessed stroke onset who had an ischemic parenchymal brain lesion on MRI diffusion-weighted imaging https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 3/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate but no corresponding hyperintensity on FLAIR [12]. Nearly 90 percent of enrolled patients awoke from sleep with stroke symptoms. The trial excluded patients last known to be well within 4.5 hours, since they would fulfill standard eligibility criteria for alteplase; the trial also excluded patients who were to receive MT. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the modified Rankin Scale [mRS]) was more likely for patients assigned to intravenous alteplase compared with those assigned to placebo (53 versus 42 percent, adjusted OR 1.61, 95% CI 1.09-2.36). However, the mortality rate was nonsignificantly higher in the alteplase group (4 versus 1 percent, OR 3.38, 95% CI 0.92-12.52), as was the rate of symptomatic intracranial hemorrhage (2.0 versus 0.4 percent, OR 4.95, 95% CI 0.57- 42.87). Limitations to the trial include stopping early (for lack of funding) and exclusion of patients planned for MT. The EXTEND trial was stopped early after publication of the Wake-Up Stroke trial. EXTEND enrolled 225 adults (of a planned 310) who had hypoperfused but salvageable brain tissue on automated perfusion imaging (with computed tomography [CT] or MRI) and could be treated between 4.5 and 9 hours after the onset of ischemic stroke or awoke with stroke symptoms, if within 9 hours from the midpoint of sleep [13]. Patients were randomly assigned to intravenous alteplase or to placebo. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the mRS) was more likely for the intravenous alteplase group compared with the placebo group, after adjustment for age and clinical severity at baseline (35 versus 30 percent, risk ratio [RR] 1.44, 95% CI 1.01-2.06). However, there was no difference between treatment groups in unadjusted analysis (RR 1.2, 95% CI 0.82-1.76). Symptomatic intracranial hemorrhage within 36 hours of treatment was increased with alteplase (6 versus 1 percent) and mortality was nonsignificantly higher with alteplase (12 versus 9 percent). Limitations to the trial include stopping early and lack of efficacy in unadjusted analyses. In the ECASS 4 trial, stopped early for slow recruitment, 119 patients (of a planned 264) with acute ischemic stroke and salvageable brain tissue identified by MRI were randomly assigned to treatment with alteplase or placebo between 4.5 and 9 hours after the onset of symptoms [14]. At 90 days, there was no difference between the alteplase and placebo groups in the mRS distribution (OR 1.20, 95% CI 0.63-2.27); mortality was nonsignificantly higher with alteplase (12 versus 7 percent). A meta-analysis pooled individual patient data (n = 414) from three trials (EXTEND, ECASS 4, and EPITHET) of intravenous alteplase that used imaging to identify and treat patients with salvageable brain tissue who had ischemic stroke 4.5 to 9 hours after onset or had wake-up stroke [15]. There was a higher rate of excellent functional outcome (defined by a mRS score 0 of 1) at three months for patients assigned to alteplase compared with those assigned to placebo https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 4/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate (36 versus 29 percent, adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99). Symptomatic intracerebral hemorrhage was more frequent in the alteplase group (5 versus 0.5 percent), but this result did not nullify the overall benefit of alteplase. Limitations to this meta-analysis include small sample size and early stopping of two of the included trials (EXTEND and ECASS 4). Another meta-analysis of four trials (including Wake-Up Stroke, EXTEND, and ECASS 4) with individual patient data from over 843 patients reported similar findings [16]. Although this approach seems promising, additional trials are needed to confirm the efficacy and safety of IVT using imaging selection of patients with a stroke onset time >4.5 hours or an unknown stroke onset time [17]. Imaging with MRI or CT perfusion appears to be essential to determine if the cerebral infarction is recent and if there is significant salvageable brain tissue. Results of the TWIST trial suggest that selecting patients with noncontrast head CT alone (to exclude hemorrhage or large infarction) is unlikely to identify patients with wake-up stroke who will benefit from IVT [18]. Risk of intracerebral hemorrhage Treatment with IVT within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, but this risk is offset by later benefit in the form of reduced disability (see 'Benefit by time to treatment' above) [4]. In clinical trials of intravenous alteplase, the rates of symptomatic intracerebral hemorrhage were 5 to 7 percent [4,19], using the National Institute of Neurological Disorders and Stroke (NINDS) definition. In addition, most community-based studies of intravenous alteplase have shown similar rates [20-24]. These studies suggest that IVT can be used safely to treat acute ischemic stroke in routine clinical practice. The number needed to harm (NNH) with IVT is very high, because most cases of symptomatic intracerebral hemorrhage occur in patients with severe deficits and poor anticipated prognosis before lysis [25]. Also, some hemorrhages occur in areas of the brain that are already infarcted and so do not result in additional measurable deficits. As an example from the NINDS trials, for an outcome of severely disabled or dead (defined by an mRS score 4) with IVT-related symptomatic hemorrhage, the NNH was 126, and for a worsened outcome (defined by an mRS score 1), the NNH ranged from approximately 30 to 40. Differences in the criteria used to define symptomatic intracerebral hemorrhage likely account for much of the variability in the rates of hemorrhage reported in different trials [26]. The NINDS trial definition of symptomatic intracerebral hemorrhage includes any hemorrhagic transformation temporally related to any neurologic worsening [19], which may be overly inclusive because it captures small petechial hemorrhages associated with minimal neurologic deterioration that are unlikely to have altered long-term functional outcome [27,28]. By contrast, the ECASS 2, ECASS-3 and SITS-MOST definitions of symptomatic intracerebral hemorrhage include only hemorrhage associated with substantial clinical worsening of 4 points on the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 5/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) stroke scale [24,29,30], which may be more predictive of intracerebral hemorrhages that adversely affect long-term outcome. As an example, the SITS-MOST study enrolled over 30,000 patients, mainly from Europe, who were treated with intravenous alteplase at 669 centers [24]. Symptomatic intracerebral hemorrhage by the NINDS definition occurred in 7.4 percent, and by the SITS-MOST definition in 1.8 percent. Lower rates have also been reported in other trials using stricter definitions of symptomatic intracerebral hemorrhage, including ECASS 3 [29]. Several risk assessment methods, including the HAT score, DRAGON score, SEDAN score, Stroke- Thrombolytic Predictive Instrument, SPAN-100 index, and the SITS SICH risk score, have been devised to predict the risk of intracerebral hemorrhage and/or prognosis for patients with acute stroke who are treated with IVT [24,31-39]. However, additional validation studies are needed to confirm the utility of these methods before they should be used in clinical practice. Recanalization Full or partial recanalization up to 24 hours after onset of acute stroke is associated with a more favorable outcome than persistent occlusion after thrombolysis [40-44]. In a prospective, multicenter study of 575 patients with acute ischemic stroke and intracranial arterial occlusion on baseline CT angiography (CTA), the rate of successful recanalization detected on repeat CTA was greater for patients who received IVT compared with those who did not (30 versus 13 percent, absolute difference 17 percent, 95% CI 10-26 percent) [45]. As observed in this and other studies, factors associated with the response to thrombolytic therapy include location of the symptomatic occlusive thrombus in the arterial tree, and clot-specific features such as size, composition, and source: Clot size and site Larger clots and more proximal clots (versus more distal location) are more resistant to thrombolysis [45-50]. As an example, internal carotid artery occlusions are more resistant than middle cerebral artery occlusions to IVT treatment. This may be due at least in part to the larger size of clots that lodge in larger vessels [51]. Clot occluding the cervical internal carotid artery may promote adjacent thrombosis extending to the intracranial internal carotid artery, resulting in a very long thrombus that is unlikely to be lysed by IVT alone. In large vessels, in situ thromboses associated with atherosclerotic lesions may be more resistant to recanalization than fibrin rich embolic occlusions arising from the heart [52]. In addition, higher residual flow (a measure of thrombus permeability) of intracranial arteries on baseline angiography is associated with successful recanalization [45]. Clot age and composition The age and composition of thromboembolic material likely affect its response to thrombolytic therapy [53,54]. The ability to recanalize in experimental embolic stroke is related to the amount of red cells in the emboli and inversely related to https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 6/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate the volume of emboli and to the fibrin content and density of the clots [55]. Thrombolytic drugs are unlikely to disrupt other types of embolic material, such as calcific plaque and fat. Other variables affecting outcome Early recanalization is probably the most important determinant of good outcome after thrombolysis, but a number of additional variables may impact neurologic outcome and the risk of intracerebral hemorrhage [56,57]. These include age, sex, stroke severity, availability of collateral blood supply, and early ischemic change on CT or MRI. However, these factors do not necessarily predict which patients will or will not benefit from IVT. The only factor known to independently alter response to IVT is time to treatment. (See 'Benefit by time to treatment' above.) Whenever possible, the potential risks and benefits of thrombolysis should be discussed objectively with the patient and/or family or health care proxy prior to initiating treatment. (See 'Issues regarding consent' below.) Age Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. (See 'Age 80 years and older' below.) Stroke severity The severity of neurologic deficit as measured on the NIHSS score ( table 3) is associated with an increased risk of intracerebral hemorrhage [6,58]. However, stroke severity alone cannot be used to select or exclude patients for IVT. A 2014 meta-analysis of individual patient data from 6756 subjects found that the benefit of alteplase was similar regardless of stroke severity [4]. Early ischemic changes on CT The presence of extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT suggests a longer time since stroke onset and is an exclusion for use of IVT ( table 1). This finding should be distinguished from milder early ischemic edema as discussed below. (See 'Early ischemic changes on neuroimaging' below.) Hyperglycemia Hyperglycemia before reperfusion in patients with acute ischemic stroke has been associated with diminished neurologic improvement, greater infarct size, and worse clinical outcome at three months after treatment with IVT [59-61]. Cerebral microbleeds Cerebral microbleeds are small chronic hemorrhages that are best visualized on susceptibility-weighted MRI sequences. Meta-analyses published in 2015 [62], 2016 [63], and 2017 [64] found that the presence of cerebral microbleeds on pretreatment brain MRI was associated with an increased risk of intracerebral hemorrhage (ICH) in patients treated with IVT for acute ischemic stroke. In https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 7/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate one of these reports, the risk of symptomatic ICH was significantly greater for patients with a high burden of cerebral microbleeds (>10) compared with patients who had a lower burden of microbleeds (1 to 10 or 0 to 10) [63]. However, the small number of patients in the subgroup with >10 microbleeds (n = 15) limits the strength of this conclusion. In another meta-analysis, the presence of cerebral microbleeds was not associated with symptomatic ICH but was associated with an increased risk of parenchymal hemorrhage, and the presence of >5 cerebral microbleeds was associated with poor functional outcome at three to six months [64]. Since decisions to proceed IVT treatment are usually made based upon CT imaging without MRI, these results should not affect patient selection or mandate additional imaging that will prolong the time to treatment. Sex There are conflicting data regarding whether benefit from early IVT of acute ischemic stroke differs by sex [65-67]. Tenecteplase Tenecteplase, a type of recombinant tissue plasminogen activator (tPA), is a modified version of alteplase, the only approved tPA for treating acute ischemic stroke. Tenecteplase differs from human tPA by having three amino acid substitutions. Because of the modifications, tenecteplase is more fibrin-specific and has a longer duration of action compared with alteplase. The single bolus dosing of tenecteplase is far easier to give in an emergency department and translates into faster door-to-needle times compared with alteplase [68]. Although not licensed in the US for IVT in acute ischemic stroke treatment, there is moderate- to high-quality evidence that intravenous tenecteplase, given in a single bolus at 0.25 mg/kg (maximum 25 mg), has similar efficacy and safety outcomes compared with alteplase, including rates of excellent functional outcome, symptomatic intracerebral hemorrhage, and mortality at 90 days [68-81]. As an example, the EXTEND-IA TNK trial found that tenecteplase led to better functional outcomes compared with alteplase and higher rates of reperfusion of the involved ischemic territory [70]. Furthermore, in an analysis of pooled individual patient data from several trials and a registry of patients with large vessel occlusion who were treated with intravenous thrombolysis, tenecteplase treatment (n = 492) compared with alteplase treatment (n = 401) was associated with higher rates of prethrombectomy reperfusion, which in turn was associated with improved outcomes [82]. However, higher doses of tenecteplase ( 0.4 mg/kg) should not be used for IVT because such doses may be associated with harm, although the evidence is inconsistent. In the original NOR- TEST trial, most of the 1100 patients had minor strokes (the median NIHSS score was 4), and the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 8/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate tenecteplase group, treated with 0.4 mg/kg, had similar safety and efficacy outcomes compared with the alteplase group [69]. However, the NOR-TEST 2, part A trial was stopped early, after enrolling only 204 patients, due to higher numbers of symptomatic intracranial hemorrhage in the tenecteplase group [83]. NOR-TEST 2 included patients with moderate to severe ischemic stroke (the median NIHSS was 11) who were within 4.5 hours of the time last known well; the patients were randomly assigned to tenecteplase 0.4 mg/kg or alteplase 0.9 mg/kg. At three months, compared with the alteplase group, the tenecteplase group showed a trend toward an increased rate of symptomatic intracranial hemorrhage (6 versus 1 percent, OR 6.57, 95% CI 0.78-55.62). Furthermore, the tenecteplase group had a lower rate of a favorable outcome, defined as an mRS score of 0 to 1 (32 versus 51 percent, OR 0.45, 95% CI 0.25-0.80), and a higher rate of mortality (16 versus 5 percent, OR 3.56, 95% CI 1.24-10.21). Mechanical thrombectomy (MT) Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive IVT for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) Patient selection for MT is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT followed by MT Treatment with IVT prior to MT, known as bridging therapy, is recommended for most patients who are candidates for both reperfusion therapies. Patients with ischemic stroke from large vessel occlusion should receive IVT without delay, if eligible, even if MT is being considered [84]. Mechanical thrombectomy treatment should then be started as quickly as possible [85,86], and should not be delayed to assess the response to IVT. Potential advantages of IVT before MT include complete or partial lysis of the thrombus causing the large vessel occlusion (the target of MT), lysis of thrombotic emboli in distal vessels beyond the reach of MT, and faster resolution of brain ischemia [87]. Potential disadvantages of giving IVT first include a delay in the time to the start of the MT procedure, an increased risk of symptomatic brain hemorrhage, and partial lysis of the large vessel thrombus that allows it to travel to more distal vessels beyond the reach of MT. MT alone (without preceding IVT) is an alternative strategy, but the available data, while inconsistent, have not proven the efficacy of this approach compared with the combination of IVT and MT for improved clinical outcomes or safety [88-98]. Rather, the preponderance of the evidence favors bridging therapy over MT alone. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 9/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate RAPID EVALUATION All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly screened for treatment with intravenous thrombolysis (IVT). Simultaneously, patients with suspected acute ischemic stroke involving the anterior circulation should be evaluated for mechanical thrombectomy (MT). (See "Mechanical thrombectomy for acute ischemic stroke".) Prehospital recognition and management Emergency medical responders should identify patients with a suspected stroke, preferably using a validated stroke screening tool (see "Use and utility of stroke scales and grading systems", section on 'Stroke diagnosis'), and transport them rapidly to the nearest medical facility that can provide urgent stroke care with the capability to treat with IVT, or IVT and MT. The use of mobile stroke units (MSUs) offers the potential for more rapid identification and treatment of acute ischemic stroke [99,100]. MSUs are ambulances equipped with point-of-care laboratory testing and a CT scanner; they are staffed by medical personnel trained to diagnose and treat patients in the ambulance using thrombolytic therapy and to make triage decisions for mechanical thrombectomy, in conjunction with telemedicine communication to hospital stroke experts. However, MSUs are expensive, and availability is limited to only a few metropolitan areas throughout the world. The potential benefit of MSUs for improving outcome from acute ischemic stroke is illustrated by two prospective, nonrandomized controlled studies. One was a multicenter study from the United States of 1047 patients who were within 4.5 hours after stroke symptom onset; patients were assigned by week of enrollment to receive MSU or standard emergency medical services (EMS) care [101]. Among patients eligible for intravenous thrombolysis, the rate of thrombolysis was higher in the MSU group compared with the EMS group (97.1 versus 79.5 percent), and the median time to thrombolysis was shorter (72 versus 108 minutes). At 90 days, the proportion of patients with no or minimal disability (ie, a score of 0 to 1 on the modified Rankin Scale [mRS]) was greater in the MSU group (55.0 versus 44.4 percent), while mortality was lower (8.9 versus 11.9 percent). The rate of symptomatic intracerebral hemorrhage in each group was 2 percent. In a similar prospective study of over 1500 patients from Berlin, Germany, dispatch of an MSU compared with EMS was associated with a shorter median time to treatment with thrombolysis (50 versus 70 minutes) and a lower level of global disability at 90 days [102]. In a 2022 meta- analysis that included these two nonrandomized studies, MSU use was associated with higher rates of excellent outcome, defined by an mRS score of 0 to 1 at 90 days, compared with usual care (adjusted odds ratio [OR] 1.64, 95% CI 1.27-2.13) [103]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 10/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Further confirmation of clinical benefit along with evidence of cost-effectiveness will be needed before widespread use of MSUs can be considered. Other unproven strategies to reduce time to treatment with MT are being explored, including direct transport to a thrombectomy-capable center [104], and even flying the thrombectomy intervention clinical team to the local stroke center [105]. In-hospital timeline A door-to-needle time of 60 minutes is the benchmark for achieving rapid treatment with IVT [84]. The following in-hospital timeline is suggested as a goal for all patients with acute ischemic stroke who are eligible for treatment with IVT: Evaluation by physician 10 minutes elapsed from arrival Stroke or neurologic expertise contacted (ie, stroke team) 15 minutes elapsed Head CT or MRI scan 25 minutes elapsed Interpretation of neuroimaging scan 45 minutes elapsed Start of IVT 60 minutes elapsed Although IVT is the first priority, evaluation and preparation for possible MT should proceed during and after IVT. Patients with suspected infarction involving the anterior circulation should have cerebral angiography (eg, CT angiography [CTA] or magnetic resonance angiography [MRA]) as soon as possible to determine whether they have a proximal intracranial large artery occlusion that might also benefit from MT. However, IVT should not be delayed by angiography or MT. The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Investigations Diagnostic neuroimaging is essential before considering reperfusion therapy for acute ischemic stroke. The only other test that is mandatory for all patients before initiation of IVT is blood glucose. In most cases, the results of routine laboratory tests including 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.