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Approach to reperfusion therapy for acute ischemic stroke

Approach to reperfusion therapy for acute ischemic stroke
Authors:
Jamary Oliveira-Filho, MD, MS, PhD
Owen B Samuels, MD
Section Editors:
José Biller, MD, FACP, FAAN, FAHA
Jonathan A Edlow, MD, FACEP
Alejandro A Rabinstein, MD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Nov 2022. | This topic last updated: Dec 08, 2022.

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 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).

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 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 (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 establish 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].

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 [4,18], using the National Institute of Neurological Disorders and Stroke (NINDS) definition. In addition, most community-based studies of intravenous alteplase have shown similar rates [19-23]. These studies suggest that IVT can be used safely to treat acute ischemic stroke in routine clinical practice.

The NINDS trial definition of symptomatic intracerebral hemorrhage includes any hemorrhagic transformation temporally related to any neurologic worsening [18], 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 [24,25]. By contrast, the ECASS 2 and SITS-MOST definitions of symptomatic intracerebral hemorrhage includes only hemorrhage associated with substantial clinical worsening of ≥4 points on the National Institutes of Health Stroke Scale (NIHSS) stroke scale [23], 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 [23]. Symptomatic intracerebral hemorrhage by the NINDS definition occurred in 7.4 percent, and by the SITS-MOST definition in 1.8 percent.

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 [23,26-34]. 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 [35-39]. 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) [40]. 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 [40-45]. 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 [46]. 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 [47]. In addition, higher residual flow (a measure of thrombus permeability) of intracranial arteries on baseline angiography is associated with successful recanalization [40].

Clot age and composition – The age and composition of thromboembolic material likely affect its response to thrombolytic therapy [48,49]. The ability to recanalize in experimental embolic stroke is related to the amount of red cells in the emboli and inversely related to the volume of emboli and to the fibrin content and density of the clots [50]. 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 [51,52]. 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 [6,53]. 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 [54-56].

Cerebral microbleeds – Cerebral microbleeds are small chronic hemorrhages that are best visualized on susceptibility-weighted MRI sequences.

Meta-analyses published in 2015 [57], 2016 [58], and 2017 [59] 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 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) [58]. 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 [59].

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 [60-62].

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.

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 [63-74]. 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 [64].

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 tenecteplase group, treated with 0.4 mg/kg, had similar safety and efficacy outcomes compared with the alteplase group [63]. 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 [75]. 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).

Further evidence is awaited from ongoing trials to confirm the efficacy and safety of tenecteplase 0.25 mg/kg for the treatment of acute ischemic stroke.

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 reviewed in the algorithm (algorithm 1) and 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 [76]. Mechanical thrombectomy treatment should then be started as quickly as possible [77,78], 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 [79]. 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 [80-89]. However, the preponderance of the evidence seems to favor bridging therapy over MT alone.

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) (algorithm 1).

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 [90,91]. 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 [92]. 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 [93]. 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) [94].

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 [95], and even flying the thrombectomy intervention clinical team to the local stroke center [96].

In-hospital timeline — A door-to-needle time of ≤60 minutes is the benchmark for achieving rapid treatment with IVT [76]. 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 (algorithm 1). 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 [76]:

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

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 [97]:

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 [97]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [98].

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 [99,100]. 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 [76].

DOAC reversal – DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [101]. 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 [102].

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 [103]. 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 [103]:

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 [104].

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) [104]. However, the trial was stopped very early solely because of slow 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 [105].

Patient selection for MT requires that the infarct core is small, with only limited signs of early ischemic change on neuroimaging, as determined by the Alberta Stroke Program Early CT Score (ASPECTS). This method described in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on '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 [76]. 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 [106].

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 [106]:

"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 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) [107].

By contrast, MT is not 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" [108,109]. 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 [110,111]:

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

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 [112,113].

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 [114-116]. 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.)

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 [4,105,117,118]. 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 [119], 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 normal or at neurologic baseline 6 to 24 hours before treatment. This is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later treatment'.)

Beyond 24 hours — Patients beyond 24 hours from ischemic stroke symptom onset are not eligible for treatment with IVT or MT.

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 treatment'.)

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 [120]. (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 [121]. 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 [121].

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 ischemic stroke involving the anterior circulation should be evaluated for MT (algorithm 1). (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 listed in the algorithm (algorithm 1) and 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. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".)

MT procedure – Procedural details for MT are discussed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Procedure'.)

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