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Thrombolytics for acute stroke

  • Updated 2018 Jul 26 01:01:00 PM: IV alteplase within 3 hours after stroke onset may not improve functional outcome and increases risk of symptomatic intracerebral hemorrhage compared to aspirin in patients with NIHSS score ≤ 5 and no clearly disabling deficits at presentation (JAMA 2018 Jul 10) view update
  • MRI-guided IV alteplase may reduce risk of neurologic disability at 90 days, but increases risk of parenchymal hemorrhage in patients with unknown time of stroke onset but with MRI suggestive of onset within 4.5 hours (N Engl J Med 2018 May 16 early online) view update
  • IV alteplase within 3 hours may not improve outcomes in mild stroke without disability (International Stroke Conference 2018) view update

 

Topic Editor

Alexander Rae-Grant, MD
Recommendations Editor

Amir Qaseem, MD, PhD, MHA, FACP
Deputy Editor

Alan Ehrlich, MD

Note to Readers

  • This DynaMed topic (Thrombolytics for acute stroke) provides a synthesis of critically evaluated evidence and guidance written for use during clinical practice and is continuously updated with systematic literature surveillance and user feedback. This topic can be viewed in open access form or in DynaMed which supports easier navigation and search features.

 

Overview

  • IV alteplase (tissue plasminogen activator [t-PA], recombinant tissue plasminogen activator [rt-PA], Activase, Actilyse) may improve outcomes when given within 4.5 hours of acute ischemic stroke
    • standard dose: 0.9 mg/kg (maximum dose 90 mg) over 60 minutes with initial 10% of dose given as bolus over 1 minute
    • most guideline organizations do not have recommendations for use > 4.5 hours after stroke onset
    • assess blood glucose levels before starting IV alteplase (AHA/ASA Class I, Level B-R ); administer IV alteplase if initial blood glucose > 50 mg/dL and patient meets other criteria (AHA/ASA Class I, Level A)
    • other non-imaging laboratory tests should not delay IV alteplase in otherwise eligible patients
    • contraindications include intracranial hemorrhage; infective endocarditis; aortic arch dissection; intra-axial intracranial neoplasm; laboratory indications of coagulopathy; low molecular weight heparin within past 24 hours; structural gastrointestinal malignancy; gastrointestinal bleed within previous 21 days; and recent (within past 3 months) ischemic stroke, severe head trauma, or intracranial/intraspinal surgery;
    • if elevated blood pressure, lower to < 185/110 mm Hg before administering alteplase (AHA/ASA Class I, Level B-NR), and maintain at < 180/105 mm Hg for at least the first 24 hours (AHA/ASA Class IIa, Level B-NR)
    • discontinue infusion and obtain emergency computed tomography (CT) if patient develops severe headache, acute hypertension, nausea, vomiting, or has worsening neurological examination
    • post-stroke antiplatelet therapy within 24 hours of starting IV alteplase is generally avoided, but can be considered in some cases
  • tenecteplase 0.4 mg/kg IV single bolus might be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion (AHA/ASA Class IIb, Level B-R)
  • intra-arterial thrombolysis within 6 hours of stroke onset
    • is beneficial in carefully selected patients with major ischemic stroke with middle cerebral artery (MCA) occlusion; however, mechanical thrombectomy with stent retrievers is recommended over intra-arterial thrombolysis
    • might be considered in carefully selected patients with contraindications to IV rt-PA, but consequences not known

Assessment

Time of symptom onset

  • establishing time of symptom onset is important for administration of thrombolytics(1)
    • time of stroke onset is typically when patients were last at their previous baseline or symptom-free state
    • if patient cannot give this information, time of onset is when patient was last awake and symptom-free or known to be "normal"
    • if patient had neurological symptoms that resolved, time of symptom onset begins anew
  • for details related to specific time windows, see sections on

NIH Stroke Scale

Modified Rankin Scale

  • modified Rankin Scale (mRS) commonly used to report functional outcomes in stroke studies
    Modified Rankin Scale:
    Score Description Classification
    0No symptomsNot disabled
    1No significant disability, able to carry out all dutiesNot disabled
    2Unable to carry out some previous activities but able to look after own affairs without assistance Slight disability
    3Requiring some help but able to walk without assistanceModerate disability
    4Unable to walk without assistance and unable to meet bodily needs without assistanceModerately severe disability
    5Bedridden, incontinent, and requiring constant nursing careSevere disability
    Reference - J Neurol Neurosurg Psychiatry 1991 Dec;54(12):1044.

Neuroimaging for determining eligibility for thrombolytics

  • professional organizations recommend performing urgent brain imaging to evaluate for intracranial hemorrhage, which is a contraindication for IV alteplase
    • American Heart Association/American Stroke Association (AHA/ASA) recommendations (1)
    • Canadian Stroke Best Practice Recommendations (CSBPR)(6)
      • if patient arrives within 4.5 hours of stroke onset and are potentially eligible for IV alteplase, immediately perform non-contrast CT (NCCT) to determine eligibility for alteplase (CSBPR Level A)
      • do not give IV alteplase if any hemorrhage on brain imaging
      • advanced CT imaging, such as CT perfusion and CT angiography, can be considered (CSBPR Level B) but should not substantially delay decisions regarding thrombolytics or endovascular therapy
      • if there is uncertainty regarding image interpretation, consult a radiologist (CSBPR Level C)
      • if appropriateness of alteplase is unclear, urgently consult with a stroke specialist within the institution or via telestroke services (CSBPR Evidence Level C)
    • Stroke Foundation (Australia) recommendations(5 )
      • all patients with suspected stroke who are potentially eligible for reperfusion should have immediate brain imaging (SF Strong recommendation)
      • either CT or MRI are acceptable, but these need to be immediately accessible to avoid delay
      • do not give IV alteplase if
        • acute intracranial hemorrhage
        • extensive frank hypodensity on CT scan ( > 1/3 of middle cerebral artery territory or equivalent)
          • if frank hypodensity present reassess stroke onset time
          • subtle ischemic changes (loss of gray-white differentiation) are not a contraindication to IV alteplase but do indicate irreversible injury
    • The Royal College of Physicians Intercollegiate Stroke Working Party recommendations(3)
      • give brain imaging urgently and within 1 hour of hospital arrival
      • only appropriately trained healthcare professionals should interpret images
    • Japan Stroke Society recommendations(4)
      • use noncontrast CT or MRI to rule out intracranial hemorrhage and evaluate degrees of early ischemic change (JSS Grade A, Level Ia)
      • do not give IV alteplase if evidence of extensive early ischemic change; greater extent of change may result in greater risk of symptomatic intracranial hemorrhage (JSS Grade C2, Level Ia)
      • cerebrovascular assessment is not required, but it may help determine if increased caution is needed as benefit of alteplase depends on site of vascular occlusion (JSS Grade C1, Level IIa)
      • limit additional diagnostic imaging to avoid unnecessary loss of time (JSS Grade A, Level IV)
  • hypoattenuation of < one-third of middle cerebral artery territory on baseline CT may be associated with better outcome with t-PA treatment (level 2 [mid-level] evidence), while lack of any hypoattenuation or hypoattenuation > one-third of middle cerebral artery territory may be associated with increased fatal hemorrhage with rt-PA (level 2 [mid-level] evidence)
    • based on secondary analysis of European Cooperative Acute Stroke Study (ECASS) I data without blinding
    • in ECASS I, 620 patients with acute ischemic hemisphere stroke were randomized to recombinant tissue plasminogen activator (rt-PA) vs. placebo
      • inclusion criteria included
        • patients with moderate-to-severe neurological deficit
        • no or only minor early infarct signs on initial computed tomography (CT)
      • exclusion criteria included
        • hemiplegia and impairment of consciousness or forced head and eye deviation
        • major infarct signs on initial CT (diffuse swelling of affected hemisphere or parenchymal hypodensity in > 33% of middle cerebral artery territory)
    • 3 readers evaluated 603 baseline CTs for hypoattenuation of 0% (none), ≤ 33% (small), or > 33% (large)
    • 90-day mortality comparing rt-PA vs. placebo
      • 16% vs. 10% in 336 patients with no hypoattenuated area (not significant)
      • 24% vs. 22% in 215 patients with small hypoattenuated area (not significant)
      • 48% vs. 29% in 52 patients with large hypoattenuated area (not significant)
    • 90-day lack of disability comparing rt-PA vs. placebo
      • 47% vs. 41% in 336 patients with no hypoattenuated area (not significant)
      • 28% vs. 10% in 215 patients with small hypoattenuated area (p < 0.05, NNT 6)
      • 6% vs. 14% in 52 patients with large hypoattenuated area (not significant)
    • 90-day fatal hemorrhage rate comparing rt-PA vs. placebo
      • 5% vs. 1% in 336 patients with no hypoattenuated area (p < 0.05, NNH 25)
      • 4% vs. 5% in 215 patients with small hypoattenuated area (not significant)
      • 16% vs. 0% in 52 patients with large hypoattenuated area (p = 0.07)
    • Reference - Radiology 1997 Nov;205(2):327
  • early ischemic changes in > one-third middle cerebral artery territory on CT suggest increased mortality if given thrombolytics (level 2 [mid-level] evidence)
    • based on limited evidence
    • early ischemic changes in > one-third middle cerebral artery territory on CT suggest increased mortality if given thrombolytics (level 3 [lacking direct] evidence)
      • based on reanalysis of randomized trial with inadequate power to rule out clinically significant differences
      • 616 patients randomized in NINDS trial to rt-PA vs. placebo within 3 hours of stroke onset and stratified by baseline CT
      • 194 (31%) had early ischemic changes on baseline head CT, including any of
        • loss of gray/white matter distinction
        • hypodensity or hypoattenuation
        • compression of cerebrospinal fluid spaces
      • early ischemic changes on baseline CT associated with worse outcomes, but not significant after adjustment for stroke severity
      • early ischemic CT results did not affect functional outcome results when comparing rt-PA vs. placebo groups
      • 90-day mortality comparing rt-PA vs. placebo
        • 14% vs. 20% in patients without early ischemic changes (not statistically significant)
        • 18% vs. 18% in patients with early ischemic changes < one-third of middle cerebral artery territory (not statistically significant)
        • 34% vs. 26% in patients with early ischemic changes > one-third of middle cerebral artery territory (not statistically significant)
      • Reference - JAMA 2001 Dec 12;286(22):2830 full-text, commentary can be found in JAMA 2002 May 8;287(18):2361
    • exclusion of patients with > one-third early ischemic changes of middle cerebral artery territory from thrombolytic use reported to decrease death and dependency (level 3 [lacking direct] evidence)
      • based on case series in London, Ontario (indirect comparisons)
      • 30 patients were treated with t-PA based on NINDS criteria except for exclusion of patients with > one-third involvement of middle cerebral artery territory on neuroimaging
      • NINDS criteria included
        • ischemic stroke with clear time of onset
        • measurable deficit
        • base-line CT without evidence of intracranial hemorrhage
        • exclusions included
          • stroke or serious head trauma within preceding 3 months
          • major surgery within 14 days
          • history of intracranial hemorrhage
          • systolic blood pressure above 185 mm Hg or diastolic blood pressure above 110 mm Hg
          • rapidly improving or minor symptoms
          • symptoms suggestive of subarachnoid hemorrhage
          • gastrointestinal hemorrhage or urinary tract hemorrhage within previous 21 days
          • arterial puncture at a noncompressible site within previous 7 days
          • seizure at the onset of stroke
      • patient outcomes were compared to NINDS trial
      • comparing London patients vs. treated arm of NINDS trial
        • more London patients were treated after 90 minutes (p < 0.0001)
        • fewer patients dead or severely disabled at 3 months (p = 0.04)
      • comparing London patients vs. placebo arm of NINDS trial
        • more patients made partial recovery at 24 hours (p = 0.02)
        • more had normal outcomes (p = 0.03)
        • fewer dead or severely disabled at 3 months (p = 0.004)
      • Reference - Can J Neurol Sci 2001 May;28(2):113
  • Alberta Stroke Program Early CT Score (ASPECTS) to guide use of alteplase (t-PA) has mixed results in analysis of 2 randomized trials
    • based on reanalysis of CT scans from ECASS II and NINDS trials
    • ASPECTS value ≤ 7 suggests major stroke based on involvement of ≥ 3 of 10 regions of middle cerebral artery territory
    • in ECASS II, 800 patients randomized to alteplase vs. placebo within 6 hours of symptom onset
      • 788 baseline CT scans retrospectively read and assigned to either ASPECTS of ≤ 7 or > 7
      • outcomes were secondary parenchymal hematoma and modified Rankin Scale at 90 days
      • higher risk of thrombolysis-related hemorrhage after t-PA for ASPECTS of ≤ 7 vs. > 7 (p = 0.033)
      • patients with high ASPECTS values had better outcomes than those with low values, regardless of thrombolytic treatment (p = 0.011)
      • Reference - Stroke 2006 Apr;37(4):973 full-text
    • in NINDS t-PA, 624 patients randomized to alteplase vs. placebo within 3 hours of symptom onset
      • 608 baseline CT scans were retrospectively read by expert ASPECTS readers and consensus score derived
      • early ischemic changes seen on 57.2% of CTs with ASPECTS value < 10
      • ASPECTS dichotomized into ≤ 7 vs. > 7 not associated with treatment effect for better outcome
      • Reference - Stroke 2005 Oct;36(10):2110 full-text
  • perfusion CT reported to select patients who could receive thrombolytics > 3 hours after stroke onset and have low rates of mortality (3%) and symptomatic intracranial hemorrhage (4%) with high rate of functional independence (70%) (level 3 [lacking direct] evidence)
    • based on systematic review of mostly uncontrolled studies
    • systematic review of 13 studies reporting outcomes in patients treated with IV thrombolytics after perfusion CT
    • among patients treated > 3 hours after symptom onset
      • 90-day mortality 2.9% (95% CI 0%-12.7%) among 3 studies with 23 patients eligible for analysis
      • modified Rankin Scale score ≤ 2 at 90 days in 69.9% (95% CI 0%-83.5%) among 3 studies with 53 patients eligible for analysis
      • symptomatic intracranial hemorrhage in hospital in 3.9% (95% CI 0.8%-9.2%) among 5 studies with 77 patients eligible for analysis
    • Reference - Radiology 2015 Jan;274(1):103
  • see Neuroimaging for acute stroke for additional information

Additional testing before thrombolytics

  • some but not all guidelines recommend assessing blood glucose levels before starting IV alteplase; other non-imaging laboratory tests should not delay decisions regarding IV alteplase
    • American Heart Association / American Stroke Association (AHA/ASA) recommendations(1)
      • assess blood glucose levels before starting IV alteplase (AHA/ASA Class I, Level B-R)
      • administer IV alteplase if initial blood glucose > 50 mg/dL and patient meets other eligibility criteria (AHA/ASA Class I, Level A)
      • other non-imaging laboratory tests should not delay IV alteplase in eligible patients
        • baseline electroencephalography is recommended for assessment in patient presenting with acute ischemic stroke but it should not delay treatment with IV alteplase (AHA/ASA Class I, Level B-NR )
        • baseline troponin assessment is recommended for assessment in patient presenting with acute ischemic stroke but it should not delay treatment with IV alteplase (AHA/ASA Class I, Level B-NR)
        • chest x-ray in setting of hyperacute stroke but in absence of acute pulmonary, cardiac or pulmonary vascular disease has unclear benefit and obtaining it should not delay treatment with IV alteplase (AHA/ASA Class IIb, Level B-NR)
        • urgent IV alteplase treatment should not be delayed while awaiting results of hematology or coagulation testing in patients with no suspicion of abnormal findings (AHA/ASA Class IIa, Level B-NR )
    • Canadian Stroke Best Practice Recommendations (CSBPR)(6)
      • do not delay imaging or other assessments for decisions regarding IV alteplase or endovascular therapy for
        • acute blood work - electrolytes, random glucose, complete blood count, coagulation status, and creatinine
        • electrocardiogram in the hemodynamically stable patient
        • chest x-ray in the hemodynamically stable patient
    • Japan Stroke Society (JSS)(4)
      • use laboratory testing to assess for bleeding tendencies or risk factors for symptomatic intracranial hemorrhage (JSS Grade A, Level IV)
      • DynaMed commentary -- An explicit recommendation to delay or not delay IV alteplase for laboratory testing was not provided
  • see Stroke (acute management) for additional information on diagnostic testing

Informed Decision-Making

Prediction of outcomes with thrombolytics

Prediction of functional outcome following IV rt-PA

  • DRAGON score predicts 3-month functional outcome following IV alteplase in patients with ischemic stroke (level 1 [likely reliable] evidence)
    • based on derivation and validation cohort study
    • derivation cohort included 1,319 patients (median age 69 years) treated with IV alteplase within 4.5 hours of onset of ischemic stroke, excluding patients with basilar artery occlusion
      • 60.5% had good functional outcome (modified Rankin Scale score 0-2) at 3 months
      • 13.8% had poor functional outcome (modified Rankin Scale score 5-6) at 3 months
    • validation cohort included 333 patients (median age 75 years) treated with IV alteplase within 4.5 hours of onset of ischemic stroke
      • 56.8% had good functional outcome at 3 months
      • 19.8% had poor functional outcome at 3 months
    • DRAGON score (total score 0-10 points)
      • hyperdense cerebral artery sign on admission computed tomography (CT) scan - 1 point
      • early infarct signs on admission CT scan - 1 point
      • prestroke modified Rankin Scale score > 1 - 1 point
      • age - 0 points if < 65 years, 1 point if 65-79 years, 2 points if ≥ 80 years
      • glucose level at admission > 8 mmol/L (144 mg/dL) - 1 point
      • onset to treatment time > 90 minutes - 1 point
      • admission National Institutes of Health Stroke Scale (NIHSS) score - 0 points if 0-4, 1 point if 5-9, 2 points if 10-15, 3 points if > 15
    • 3-month outcomes by DRAGON score in derivation cohort
      Results:
      DRAGON Score Number of Patients Good Outcome (mRS Score 0-2) inPoor Outcome (mRS Score 5-6) in
      0-1 point13796%0%
      2 points20888%2%
      3 points28774%5%
      4 points24955%10%
      5 points19645%16%
      6 points14725%31%
      7 points7213%56%
      8 points160%70%
      9-10 points70%100%
      Abbreviation: mRS, modified Rankin Scale.
    • DRAGON score had similar predictive performance in validation cohort
      Results:
      DRAGON Score Number of Patients Good Outcome (mRS Score 0-2) inPoor Outcome (mRS Score 5-6) in
      0-1 point799%0%
      2 points3190%0%
      3 points4176%7%
      4 points5872%10%
      5 points8662%15%
      6 points6133%25%
      7 points3222%56%
      8 points141%72%
      9-10 points80%99%
      Abbreviation: mRS, modified Rankin Scale.
    • Reference - Neurology 2012 Feb 7;78(6):427
  • stroke-thrombolytic predictive instrument (Stroke-TPI) may predict likelihood of good or poor outcome following IV t-PA for acute ischemic stroke (level 2 [mid-level] evidence)
    • based on validation cohort study with modest predictive accuracy
    • Stroke-TPI derived from 2,184 patients in 5 randomized trials of tissue plasminogen activator (t-PA) within 0-6 hours of stroke onset (Stroke 2006 Dec;37(12):2957 full-text)
    • validation study included 301 patients receiving t-PA within 4.5 hours of acute ischemic stroke from ongoing prospective registry
      • 35% had good outcome defined as modified Rankin Scale score 0-1 at 3 months
      • 26% had poor outcome defined as modified Rankin Scale score 5-6 at 3 months
      • Stroke-TPI "reasonably valid" for predicting outcome but
        • overestimated good outcome at 45%
        • underestimated poor outcome at 17%
      • Reference - J Neurol Neurosurg Psychiatry 2008 Sep;79(9):1079
    • addition of serum glucose and signs of current infarction on pretreatment brain scan to Stroke-TPI score might improve predictive performance
      • based on cohort study without validation
      • Stroke-TPI score was recalibrated using data from 4,072 patients
      • addition of serum glucose and signs of current infarction on pretreatment brain scan to Stroke-TPI score associated with reduced discrepancy between predicted and observed outcomes
      • Reference - Stroke 2012 Dec;43(12):3378 full-text
    • simplified Stroke-TPI score including age, stroke severity, and serum glucose levels can be found in Neurology 2015 Sep 15;85(11):942

Prediction of intracerebral hemorrhage following IV rt-PA

  • 6 different scoring systems have moderate ability to predict symptomatic intracerebral hemorrhage in patients with ischemic stroke following IV thrombolysis treatment, SEDAN score may have highest predictive power (level 1 [likely reliable] evidence)
    • based on prognostic cohort study
    • 3,012 patients (median age 71 years) with ischemic stroke treated with IV thrombolysis were assessed for risk of symptomatic intracranial hemorrhage by 6 prediction scores
      • SEDAN
      • Glucose Race Age Sex Pressure Stroke Severity (GRASPS)
      • Safe Implementation of Thrombolysis in Stroke (SITS)
      • Hemorrhage After Thrombolysis (HAT)
      • Multicenter Stroke Survey (MSS)
      • Stroke Prognostication using Age and NIH Stroke Scale (SPAN-100)
    • symptomatic intracerebral hemorrhage in
      • 7.3% using National Institute of Neurological Disorders and Stroke (NINDS) definition (any deterioration in NIHSS score or death within 7 days combined with intracerebral hemorrhage of any type [including petechial] on any posttreatment imaging after start of thrombolysis)
      • 4.7% using European Cooperative Acute Stroke Study (ECASS) II definition (any type of intracerebral hemorrhage on any posttreatment imaging after start of thrombolysis and increase ≥ 4 points on NIHSS from baseline, or from lowest value within 7 days, or death)
      • 2.9% using SITS Monitoring Study (SITS-MOST) definition (type 2 parenchymal hemorrhage plus ≥ 4-point deterioration on NIHSS or death)
    • all scores had modest-to-moderate predictive performance across all intracerebral hemorrhage definitions (c-statistics 0.55-0.7)
    • SEDAN score associated with significantly greater performance against all other scores (except GRASPS with NINDS and ECASS intracerebral hemorrhage definitions)
    • SPAN-100 score associated with significantly lower performance against all other scores with NINDS and ECASS intracerebral hemorrhage definitions
    • Reference - Stroke 2014 Mar;45(3):752
  • SEDAN score has moderate ability to predict symptomatic intracerebral hemorrhage following IV t-PA treatment (level 1 [likely reliable] evidence)
    • based on validation cohort study
    • 45,074 patients with stroke treated with IV t-PA were evaluated
    • symptomatic intracerebral hemorrhage in
      • 1.7% of 36,127 patients with complete data using SITS-MOST definition (type 2 parenchymal hemorrhage plus ≥ 4-point deterioration on NIHSS or death)
      • 5.1% of 36,027 patients with complete data using ECASS II definition (any type of intracerebral hemorrhage on any posttreatment imaging after start of thrombolysis and increase ≥ 4 points on NIHSS from baseline, or from lowest value within 7 days, or death)
    • SEDAN score (total score 0-6 points)
      • baseline blood glucose = 1 point if 145-216 mg/dL, 2 points if > 216 mg/dL
      • early infarct signs on baseline computed tomography scan = 1 point
      • hyperdense cerebral artery sign on baseline computed tomography scan = 1 point
      • age > 75 years = 1 point
      • baseline National Institutes of Health Stroke Scale score ≥ 10 = 1 point
    • rate of symptomatic intracerebral hemorrhage by SEDAN score
      Total ScoreBy SITS-MOST DefinitionBy ECASS II Definition
      0 points0.8%1.6%
      1 point1.5%3.3%
      2 points2%5.4%
      3 points2.3%8.8%
      4 points3%12.3%
      ≥ 5 points5.4%16.9%
      Abbreviations: ECASS, European Cooperative Acute Stroke Study; SITS-MOST, Safe Implementation of Treatments in Stroke Monitoring Study.
    • statistical assessment of predictive ability of SEDAN score was
      • moderate for symptomatic intracerebral hemorrhage using ECASS II definition (c-statistic 0.66)
      • low for symptomatic intracerebral hemorrhage using SITS-MOST definition (c-statistic 0.6)
      • DynaMed commentary -- c-statistic values range from 0.5 to 1 with 0.8-1 considered strong, but unclear if c-statistic is optimal analysis method to rate predictive ability of continuous score
    • Reference - Stroke 2013 Jun;44(6):1595
  • Safe Implementation of Treatments in Stroke (SITS) score predicts risk of symptomatic intracerebral hemorrhage following IV t-PA treatment (level 1 [likely reliable] evidence)
    • based on derivation and validation cohort study
    • 31,627 patients with acute ischemic stroke who were treated with IV t-PA were randomly divided into derivation cohort with 15,814 patients and validation cohort with 15,813 patients
    • symptomatic intracerebral hemorrhage in
      • 1.8% using SITS-MOST definition (type 2 parenchymal hemorrhage plus ≥ 4-point deterioration on NIHSS or death)
      • 5.1% using ECASS II definition (any type of intracerebral hemorrhage on any posttreatment imaging after start of thrombolysis and increase ≥ 4 points on NIHSS from baseline, or from lowest value within 7 days, or death)
      • 7.4% using NINDS definition (any deterioration in NIHSS score or death within 7 days combined with intracerebral hemorrhage of any type [including petechial] on any posttreatment imaging after start of thrombolysis)
    • SITS score derived based on risk factors significantly associated with symptomatic intracerebral hemorrhage (using SITS-MOST definition) (total score 0-12 points)
      • drug therapy = 3 points if aspirin plus clopidogrel, 2 points if aspirin monotherapy
      • NIHSS = 2 points if ≥ 13 points, 1 point if 7-12 points
      • blood glucose ≥ 180 mg/dL = 2 points
      • age ≥ 72 years = 1 point
      • systolic blood pressure ≥ 146 mm Hg = 1 point
      • history of hypertension = 1 point
      • weight ≥ 95 kg (209.4 lbs) = 1 point
      • onset-to-treatment time ≥ 180 minutes = 1 point
    • rate of symptomatic intracerebral hemorrhage in combined cohorts by SITS score
      Results:
      Total ScoreBy SITS-MOST DefinitionBy ECASS II Definition By NINDS Definition
      0 points0.2%1.4%1.4%
      3 points1.09%3.6%5.4%
      6 points3.14%7.5%11%
      ≥ 9 points9.25%23.2%25.8%
      Abbreviations: ECASS, European Cooperative Acute Stroke Study; NINDS, National Institute of Neurological Disorders and Stroke; SITS-MOST, Safe Implementation of Treatments in Stroke Monitoring Study.
    • Reference - Stroke 2012 Jun;43(6):1524 full-text, correction can be found in Stroke 2012 Sep;43(9):e102
  • GRASPS score may predict risk of symptomatic intracranial hemorrhage within 36 hours after treatment with IV t-PA (level 2 [mid-level] evidence)
    • based on cohort study with incomplete external validation
    • 10,242 patients who received IV t-PA within 3 hours of acute ischemic stroke were randomly divided into derivation cohort (70%) and internal validation cohort (30%)
    • 496 (4.8%) patients overall had symptomatic intracranial hemorrhage within 36 hours of treatment
    • 6 risk factors significantly associated with symptomatic intracranial hemorrhage after t-PA treatment were identified in derivation cohort and confirmed in internal validation cohort
    • GRASPS score for risk of symptomatic intracranial hemorrhage derived with points for risk factors based on combined derivation and validation cohorts (total score 45-101 points)
      • blood glucose = 2 points if < 100 mg/dL, 6 points if 100-149 mg/dL, 8 points if ≥ 150 mg/dL
      • Asian ethnicity = 9 points
      • age = 8 points if ≤ 60 years old, 11 points if aged 61-70 years, 15 points if aged 71-80 years, 17 points if > 80 years old
      • male = 4 points
      • systolic blood pressure = 10 points if < 120 mm Hg, 14 points if 120-149 mm Hg, 18 points if 150-179 mm Hg, 21 points if ≥ 180 mm Hg
      • stroke severity by National Institutes of Health Stroke Scale score = 25 points if 0-5, 27 points if 6-10, 34 points if 11-15, 40 points if 16-20, 42 points if > 20
    • predicted risk of symptomatic intracranial hemorrhage within 36 hours of IV t-PA treatment by GRASPS score
      Results:
      Total ScorePredicted Risk of Symptomatic Intracranial Hemorrhage
      45-73 points1%-5%
      74-82 points6%-10%
      83-87 points10%-15%
      88-92 points15%-20%
      93-95 points20%-25%
      96-98 points25%-30%
      ≥ 99 points> 30%
    • limited data reported showing validation of GRASPS score in external cohort of 309 patients from NINDS trial
    • Reference - Stroke 2012 Sep;43(9):2293 full-text
  • hemorrhage after thrombolysis (HAT) score may predict risk of intracerebral hemorrhage after IV t-PA (level 2 [mid-level] evidence)
    • based on small combined cohorts study
    • HAT score 0-5 based on
      • pretreatment NIHSS score
        • 1 point if 15-20
        • 2 points if ≥ 20
      • extent of hypodensity on computed tomography (CT) scan
        • 1 point if any hypodensity but < one-third middle cerebral artery territory
        • 2 points if ≥ one-third middle cerebral artery territory
      • history of diabetes of baseline blood glucose > 200 mg/dL (11.1 mmol/L) - 1 point
    • HAT score derived from 9 studies reporting factors predicting hemorrhagic transformation after t-PA for acute ischemic stroke
    • HAT score validated in 302 patients in NINDS trials 1-2 and 98 consecutively treated patients at authors' institution
    • rates of intracerebral hemorrhage with HAT Score in combined cohorts (400) patients
      Results:
      HAT Score 0 1 2 3 4-5
      Number of patients15312184339
      Any intracerebral hemorrhage6%16%23%36%78%
      Symptomatic intracerebral hemorrhage2%5%10%15%44%
      Fatal intracerebral hemorrhage0%3%7%6%33%
      Abbreviation: HAT, hemorrhage after thrombolysis.
    • Reference - Neurology 2008 Oct 28;71(18):1417 full-text

Risk factors for poor outcomes with thrombolytics

  • DynaMed commentary -- because these studies only included thrombolytic-treated patients, they cannot determine whether thrombolytics have more harm or benefit compared with placebo in patients with risk factors
  • factors associated with increased risk of intracranial hemorrhage following recombinant tissue plasminogen activator (rt-PA) treatment
    • based on systematic review
    • systematic review of 55 studies reporting intracranial hemorrhage following rt-PA treatment for acute ischemic stroke in 65,264 patients
    • analyses evaluated associations between baseline variables and incidence of intracranial hemorrhage after treatment with rt-PA
    • baseline factors associated with increased risk of intracranial hemorrhage following rt-PA treatment included
      • more severe ischemic changes in middle cerebral artery territory on computed tomography (CT) (odds ratio [OR] 3.46, 95% CI 1.92-6.21)
      • renal impairment (OR 2.79, 95% CI 1.19-6.54)
      • leukoaraiosis on imaging (OR 2.45, 95% CI 1.64-3.66)
      • brain lesion on imaging (OR 2.39, 95% CI 1.59-3.58)
      • prestroke antiplatelet treatment (OR 2.08, 95% CI 1.46-2.97)
      • heart failure (OR 1.96, 95% CI 1.3-2.94)
      • atrial fibrillation (OR 1.86, 95% CI 1.5-2.31)
      • older age (OR 1.78, 95% CI 1.17-2.71)
      • prestroke statin treatment (OR 1.72, 95% CI 1.14-2.61)
      • more severe stroke symptoms (OR 1.55, 95% CI 1.11-2.16)
      • diabetes (OR 1.54, 95% CI 1.18-2.02)
      • ischemic heart disease (OR 1.54, 95% CI 1.08-2.2)
      • prior hypertension (OR 1.5, 95% CI 1.18-1.89)
    • smoking associated with decreased risk of intracranial hemorrhage (OR 0.7, 95% CI 0.55-0.89)
    • Reference - Stroke 2012 Nov;43(11):2904 full-text
  • diabetes associated with poorer outcome in patients treated with thrombolysis
    • based on retrospective cohort study
    • 12,686 patients with acute stroke were analyzed
      • 3,228 had diabetes
      • 1,689 were treated with thrombolysis
    • comparing patients with diabetes vs. no diabetes treated with thrombolysis
      • 30-day mortality or disability at discharge in 75.7% vs. 68.9% (p = 0.01)
      • symptomatic intracranial hemorrhage in 7.5% vs. 6.8% (not significant)
    • no significant difference in predicted response to thrombolysis (as predicted by iScore) comparing stroke patients with diabetes vs. without diabetes
    • Reference - Diabetes Care 2013 Jul;36(7):2041
  • longer occlusion in M1 segment of middle cerebral artery associated with reduced likelihood of favorable outcome at 3 months after IV thrombolysis for middle cerebral artery stroke
    • based on prognostic cohort study
    • 80 patients (mean age 71 years, 59% female) having IV rt-PA within 4.5 hours for acute middle cerebral artery stroke (71% with isolated M1 segment occlusion and 29% with extension to M2 segment) were assessed
      • all patients had 4-dimensional computed tomography angiography of middle cerebral artery occlusion at admission and 22-26 hours after IV rt-PA
      • length of occlusion determined using temporal maximum intensity projection
    • 46% had successful recanalization after rt-PA and 31% had favorable outcome defined as modified Rankin Score 0-2 at 3 months
    • median M1 segment occlusion 8.1 mm in patients with favorable outcome vs. 14.3 mm in patients without favorable outcome (p < 0.001)
    • longer length of M1 segment occlusion associated with reduced likelihood of
      • favorable outcome (odds ratio 0.79, 95% CI 0.69-0.91)
      • successful recanalization (odds ratio 0.82, 95% CI 0.73-0.92)
    • Reference - Stroke 2014 Jul;45(7):2010
  • risk factors for in-hospital mortality include older age and altered level of consciousness
  • risk factors for lack of improvement at 24 hours include glucose level > 144 mg/dL (8 mmol/L), cortical involvement, and longer time to treatment
  • stroke severity (increasing NIHSS score) may predict discharge to rehabilitation or nursing facility
    • based on cohort study of 546 patients with treated with rt-PA for acute ischemic stroke
    • patients with symptomatic intracerebral hemorrhage were never discharged to home
    • Reference - Arch Neurol 2004 Jul;61(7):1061 full-text
  • posterior circulation stroke associated with lower risk of symptomatic intracranial hemorrhage than anterior circulation stroke in patients treated with thrombolysis
    • based on prospective cohort study of 883 patients receiving thrombolysis for acute ischemic stroke
    • 11% (mean age 63 years, National Institutes of Health Stroke Scale [NIHSS] score 9) had posterior circulation stroke
    • 89% (mean age 67 years, NIHSS score 12) had anterior circulation stroke
    • comparing posterior vs. anterior circulation stroke at 3 months
      • symptomatic intracranial hemorrhage in 0% vs. 5% (p = 0.025)
      • mortality 9% vs. 13% (not significant)
      • favorable outcome in 66% vs. 47% (not significant in adjusted analysis)
    • Reference - Stroke 2011 Sep;42(9):2498
  • medications prior to thrombolysis
    • antithrombotic therapy
      • for patients who were using antithrombotic therapy before the stroke
        • if the therapy consisted of antiplatelets, IV alteplase is generally still recommended
        • if the therapy consisted of other antithrombotic agents, IV alteplase may be contraindicated or recommended only with careful consideration
        • see Eligibility for specific recommendations
      • chronic antiplatelet therapy prior to IV thrombolytics in high-risk patients may increase risk of symptomatic intracerebral hemorrhage
        • based on prospective cohort study with significant baseline differences
        • 301 consecutive patients who had IV thrombolytics for ischemic stroke were followed for 3 months
        • 89 (29.5%) patients had antiplatelet drugs prior to thrombolysis
        • comparing patients taking antiplatelet therapy vs. patients not taking antiplatelet therapy
          • mean age 73 years vs. 66 years
          • previous stroke in 46.1% vs. 5.2%
          • hypertension in 58.4% vs. 38.6%
          • symptomatic intracerebral hemorrhage in 13.5% vs. 2.8% (p = 0.001, NNH 9)
          • favorable outcome at 3 months defined as modified Rankin Scale score ≤ 2 in 50.6% vs. 44.8% (not significant)
        • Reference - Arch Neurol 2008 May;65(5):607
      • antiplatelet therapy may increase risk of symptomatic intracerebral hemorrhage, but without adverse effect on mortality or functional outcome in patients on antiplatelet therapy at onset of ischemic stroke
        • based on cohort of 11,865 patients receiving thrombolysis for acute ischemic stroke
        • pretreatment with 1 or 2 antiplatelet drugs in 31.9% patients
        • overall incidence of symptomatic intracerebral hemorrhage 1.5% by Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) definition (deterioration in NIHSS 4 plus intracerebral hemorrhage type 2 within 24 hours)
        • antiplatelet pretreatment associated with increased risk of intracerebral hemorrhage by SITS-MOST definition (odds ratio 1.28, 95% CI 1.08-1.52)
        • antiplatelet pretreatment not associated with increased risk of
          • mortality
          • poor functional outcomes
        • Reference - Stroke 2010 Feb;41(2):288 full-text
      • subtherapeutic warfarin use may not be associated with increased risk of intracranial hemorrhage, serious hemorrhage, or mortality with thrombolytics for acute stroke
        • based on 2 cohort studies
        • retrospective cohort study
          • 23,437 patients with ischemic stroke and baseline INR ≤ 1.7 received IV t-PA
          • 7.7% receiving warfarin prior to admission
          • no significant differences in symptomatic intracranial hemorrhage, life-threatening or serious systemic hemorrhage, or in-hospital mortality comparing preadmission warfarin use to no warfarin use
          • Reference - JAMA 2012 Jun 27;307(24):2600 full-text, editorial can be found in JAMA 2012 Jun 27;307(24):2637
        • prospective cohort study
          • 1,739 patients received thrombolysis for acute ischemic stroke
          • 7.2% were receiving warfarin prior to admission with INR < 1.7
          • preadmission warfarin associated with reduced risk of poor functional outcomes (odds ratio 0.6, 95% CI 0.3-0.9)
          • preadmission warfarin not significantly associated with in-hospital mortality (adjusted), symptomatic intracerebral hemorrhage, secondary intracerebral hemorrhage, or gastrointestinal hemorrhage
          • Reference - Stroke 2011 Apr;42(4):1041 full-text
    • statin pretreatment may not increase risk of symptomatic intracranial hemorrhage or all-cause death in patients treated with IV thrombolysis for acute ischemic stroke
      • based on cohort study
      • 1,600 patients (mean age 67 years, 59% men) with acute ischemic stroke treated with IV thrombolysis were followed for 3 months
      • 23% had statin pretreatment and 67% had no pretreatment
      • comparing statin pretreatment to no pretreatment in adjusted analyses
        • no significant differences in risk of symptomatic intracranial hemorrhage (by any of 3 definitions), all-cause death, or favorable functional outcome at 3 months
        • statin pretreatment associated with increased clinical recovery within 24 hours of stroke onset (adjusted odds ratio 1.91, 95% CI 1.25-2.92)
      • Reference - Stroke 2015 Sep;46(9):2681

Eligibility

Overview of eligibility for IV alteplase

  • eligibility criteria recommended by professional organizations vary
  • an overview of generally agreed-upon criteria is below; see organization-specific recommendations for additional details
    • age ≥ 18 years old
    • acute ischemic disabling stroke onset within previous 3 hours (some organizations extend this to 4.5 hours)
    • blood pressure can be safely lowered and maintained to < 185/110 mm Hg
    • no current or substantially increased risk of major bleeding such as
      • intracranial hemorrhage on brain imaging
      • signs and symptoms of subarachnoid hemorrhage
      • coagulopathy (do not delay alteplase for laboratory tests, but terminate administration if results show coagulopathy)

American Heart Association / American Stroke Association (AHA/ASA) recommendations (2018)

  • if decision is made to administer IV alteplase, administer as soon as possible; time to treatment is strongly associated with outcomes (AHA/ASA Class I, Level A)(1)
  • indications for IV alteplase (given at 0.9 mg/kg, maximum dose 90 mg over 60 minutes, with initial 10% of dose given as bolus over 1 minute)(1)
    • administration within 3 hours of acute ischemic stroke symptom onset or time since last known well
      • recommended
      • may be considered if mild ischemic stroke symptoms that are nondisabling, but more study is needed determine risk-benefit ratio (AHA/ASA Class IIb, Level C-LD)
    • administration 3-4.5 hours after acute ischemic stroke symptom onset or time since last known well
      • recommended if all of (AHA/ASA Class I, Level B-R)
        • age 18-80 years old
        • no history of both diabetes mellitus and prior stroke
        • NIHSS score ≤ 25 points
        • no current use of oral anticoagulants
        • without imaging evidence of ischemic injury in > 1/3 of MCA territory
      • may also be beneficial in patients
      • has uncertain benefits for patients with very severe stroke symptoms (NIHSS score > 25) (AHA/ASA Class IIb, Level C-LD)
    • blood pressure (BP) can be safely lowered to < 185/110 mm Hg with antihypertensive agents and stabilized (AHA/ASA Class I, Level B-NR)
    • initial blood glucose levels > 50 mg/dL (AHA/ASA Class I, Level A)
  • contraindications(1)
  • additional considerations for specific patient populations and clinical situations(1)
    • IV alteplase may be reasonable for patients with
      • blood glucose levels that are initially < 50 400 mg/dL or > 400 mg/dL but are subsequently normalized (AHA/ASA Class IIb, Level C-LD)
      • dural puncture, including lumbar dural puncture within previous 7 days (AHA/ASA Class IIb, Level C-EO)
      • potential stroke mimic (the possibility has not been excluded); stroke mimic has low risk of symptomatic intracranial hemorrhage and starting IV alteplase is probably recommended in preference over delaying treatment to pursue additional diagnostic studies (AHA/ASA Class IIa, Level B-NR)
      • gastrointestinal and genitourinary bleeding > 21 days previous; the risk of bleeding with IV alteplase is reported to be low (AHA/ASA Class IIb, Level C-LD); (alteplase administration within 21 days of gastrointestinal event is a contraindication)
    • IV alteplase may also be reasonable, with careful consideration, for patients with
      • major trauma not involving the head within previous 14 days, but increased risk of bleeding from trauma-related injuries must be weighed against severity and potential disability from the ischemic stroke (AHA/ASA Class IIb, Level C-LD)
      • major surgery within previous 14 days, but increased risk of surgical-site hemorrhage must be weighed against anticipated reduction in stroke-related neurological deficits (AHA/ASA Class IIb, Level C-LD)
    • IV alteplase has uncertain benefits if arterial puncture of noncompressible vessel within previous 7 days (AHA/ASA Class IIb, Level C-LD)
    • for some conditions, appropriateness of IV alteplase depends on the severity of the condition or stroke
      • antithrombotic use or coagulopathy
        • IV alteplase recommended if pre-stroke use of antiplatelet drug monotherapy (AHA/ASA Class I, Level A) or antiplatelet drug combination therapy (AHA/ASA Class I, Level B-NR); benefit of outweighs small increased risk of symptomatic intracerebral hemorrhage
        • IV alteplase may be reasonable if history of warfarin use and international normalized ratio ≤ 1.7 or prothrombin time < 15 seconds (AHA/ASA Class IIb, Level B-NR)
        • if clinical history of potential bleeding diathesis or coagulopathy, alteplase has uncertain benefits and should be considered on a case-by-case basis (AHA/ASA Class IIb, Level C-EO)
      • arterial dissection
        • if known or suspected extracranial cervical arterial dissection; IV alteplase administered within 4.5 hours of stroke onset is reasonably safe and probably recommended (AHA/ASA Class IIa, Level C-LD)
        • if known or suspected intracranial arterial dissection, IV alteplase has unknown risks and benefits (AHA/ASA Class IIb, Level C-LD)
      • if cerebral microbleed
        • if history of ≤ 10 cerebral microbleeds on MRI, IV alteplase is reasonable (AHA/ASA Class IIa, Level B-NR)
        • if history of > 10 cerebral microbleeds on MRI, IV alteplase has uncertain benefits and an increased risk of symptomatic intracerebral hemorrhage; IV alteplase may be reasonable if potential for substantial benefit (AHA/ASA Class IIb, Level B-NR)
  • see Specific patient populations for additional recommendations in other patient populations

Canadian Stroke Best Practice Recommendations (CSBPR) (2018)

  • indications(6)
    • symptom onset or time since last known well < 4.5 hours
    • ischemic stroke causing disabling neurologic deficits
    • age ≥ 18 years old; for adolescents, use clinical judgement and consult with pediatric stroke specialist if possible
  • if considering IV alteplase > 4.5 hours after stroke onset, consult with physician with stroke experience(6)
  • absolute contraindications(6)
    • active hemorrhage or condition associated with increased risk of major hemorrhage after alteplase administration
    • any hemorrhage on brain imaging
  • if prestroke use of direct oral anti-coagulants (DOACs), alteplase should not routinely be administered(6)
    • endovascular therapy may be considered in eligible patients
    • decisions should be based on individual patient factors and assessment of benefit and risk
    • thrombolysis can be considered in comprehensive stroke centers with access to specialized tests of DOAC levels and reversal agents; base decisions on individual patient in consultation with hematology specialists, patients, and their families
    • no evidence to support routine reversal of anticoagulation
  • other relative contraindications (use clinical judgement)(6)
    • history of intracranial hemorrhage
    • stroke or serious head or spinal trauma within previous 3 months
    • major surgery within previous 14 days
    • arterial puncture in non-compressible site within previous 7 days
    • symptoms that suggest subarachnoid hemorrhage
    • stroke-like symptoms due to non-ischemic stroke conditions such as seizure with post-ictal Todd's paralysis or hypo- or hyperglycemia-induced focal neurological signs
    • hypertension refractory to aggressive treatment in which blood pressure < 180/105 mm Hg cannot be achieved or maintained; treat blood pressure rapidly and aggressively to minimize delays to thrombolysis
    • treatment with direct non-vitamin K oral anticoagulant
    • early signs of extensive infarction on CT scan
    • blood glucose < 2.7 mmol/L or > 22.2 mmol/L
    • elevated activated partial-thromboplastin time
    • international normalized ratio > 1.7
    • platelet count < 100,000/mm3
  • consult with experts if eligibility not clear(6)
    • if appropriateness of alteplase is unclear, urgently consult with a stroke specialist within the institution or via telestroke services (CSBPR Evidence Level C)
    • if CT imaging results are not clear, consult with radiologist within the institution (CSBPR Evidence Level C)

Stroke Foundation (Australia) recommendations (2017)

  • eligibility criteria(5)
    • potentially disabling ischemic stroke
    • stroke onset within previous 4.5 hours
  • absolute contraindications(5)
    • acute intracranial hemorrhage
    • extensive frank hypodensity on CT scan (> 1/3 of middle cerebral artery territory or equivalent)
      • if met, reassess stroke onset time
      • subtle ischemic changes (loss of gray-white differentiation) are not a contraindication but do indicate irreversible injury
    • active non-compressible systemic bleeding
    • systemic coagulopathy (but do not delay thrombolysis for laboratory testing unless clinical suspicion), including any of
      • platelet count < 100,000 mm3
      • international normalized ratio > 1.7 including warfarin use
      • unfractionated heparin within previous 48 hours and elevated activated partial thromboplastin time
      • low molecular weight heparin (including prophylactic doses) within previous 24 hours and with abnormal anti-factor Xa activity
      • direct oral anticoagulant use (such as apixaban, dabigatran, or rivaroxaban) within previous 48 hours and medication-specific abnormal coagulation parameters, unless a specific reversal agent is available
    • infective endocarditis, which is associated with an increased risk of symptomatic intracerebral hemorrhage
    • thoracic aortic dissection
  • relative contraindications (carefully consider risks and benefits)(5)
    • severe uncontrolled high blood pressure (BP)
      • attempt to lower elevated BP to < 185/110 mm Hg prior to thrombolysis and maintain this level
      • if BP cannot be lowered, thrombolysis should not be commenced
    • previous intracerebral hemorrhage not including cerebral microbleeds on MRI
    • major head trauma or cranial or spinal surgery within previous 3 months
    • other major surgery or trauma within previous 14 days; consider discussion with the surgeon involved
    • recent gastrointestinal or genitourinary tract bleeding within previous 21 days
    • central nervous system intra-axial neoplasm
    • ischemic stroke within previous 3 months (consider the size of the previous infarct and severity of current stroke)
  • additional considerations(5)
    • cervical artery (extra-cranial) dissection is not a contraindication
    • lumbar puncture within 7 days of alteplase has limited evidence on safety

The Royal College of Physicians Intercollegiate Stroke Working Party recommendations (2016)

  • Royal College of Physicians Intercollegiate Stroke Working Party recommends(3)
    • if ischemic stroke onset within previous 3 hours, consider IV alteplase regardless of age or stroke severity
    • if stroke onset 3-4.5 hours previous
      • consider alteplase in patients < 80 years old
      • for patients ≥ 80 years old, alteplase can be considered on an individual basis; benefits are less than if treated earlier, but no increased risk of complications
    • lower blood pressure to < 185/110 mm Hg before administering alteplase
    • consider combination IV thrombolysis and intra-arterial clot extraction with stent retriever and/or aspiration if both of the following conditions are met
    • patient has proximal intracranial large vessel occlusion causing a disabling neurological deficit (NIHSS ≥ 6 points)
    • arterial puncture can begin ≤ 5 hours after stroke onset
  • if stroke due to cervical arterial dissection, alteplase still recommended in otherwise eligible patients(3)

Japan Stroke Society (JSS) recommendations (2012)

  • give IV alteplase if ischemic stroke onset within previous 4.5 hours (JSS Grade A, Level Ia)(4)
  • absolute contraindications(4)
    • ischemic stroke onset > 4.5 hours previous (JSS Grade D, Level Ia)
    • brain imaging shows evidence of
    • current clinical findings
      • strong suspicion of thoracic aortic dissection (JSS Grade D, Level III)
      • suspected subarachnoid hemorrhage
      • concurrent hemorrhage such as intracranial, gastrointestinal, urinary tract, or retroperitoneal
      • hemoptysis
      • blood pressure > 185/110 mm Hg despite antihypertensive therapy
      • significant hepatic disorder
      • acute pancreatitis
    • blood test results
      • abnormal blood glucose (< 50 mg/dL or > 400 mg/dL)
      • platelet count ≤ 100,000/mm3
      • for patients on anticoagulant therapy or those with abnormal coagulation, INR > 1.7, aPTT > 1.5 times baseline (about 40 seconds)
    • history of
      • history of nontraumatic intracranial hemorrhage (JSS Grade D, Level III)
      • stroke within previous month (excluding transient ischemic attack)
      • significant head/spinal injury or surgery within previous 3 months
      • gastrointestinal or urinary tract bleeding within previous 21 days
      • major surgery or significant trauma other than head injury within previous 14 days
      • hypersensitivity to alteplase
    • suspected development of epilepsy based on medical history
  • use increased caution in some patients (if potential benefits outweigh increased risks and after patient or his representatives provide informed consent ) (JSS Grade C1, Level IIa)(4)
    • age > 80 years old
    • severe neurologic benefit (NIHSS score ≥ 26 points)
    • minor severity or rapidly improving symptoms
    • current clinical findings
      • thoracic aortic aneurysm
      • gastrointestinal ulcer, diverticulitis, or colitis
      • active tuberculosis
      • poorly controlled diabetes
      • infective endocarditis
    • currently taking thrombolytic or antithrombotic therapy (especially oral anticoagulant therapy)
    • history of
      • myocardial infarction within previous 3 months
      • biopsy or trauma within previous 10 days
      • stroke (especially if concurrent diabetes)
      • allergy to proteins
  • see Specific patient populations for additional recommendations in other patient populations

Eligibility by Activase (alteplase) drug label (2018)

  • IV alteplase FDA approved for acute ischemic stroke
    • before initiating treatment, exclude intracranial hemorrhage as primary cause of stroke
    • initiate treatment as soon as possible and ≤ 3 hours after stroke onset
    • recommended dose: 0.9 mg/kg (total dose ≤ 90 mg) IV, with first 10% of total dose given as IV bolus over 1 minute and remainder infused over 60 minutes
  • contraindications (risk of bleeding is greater than potential benefits)
    • current intracranial hemorrhage
    • subarachnoid hemorrhage
    • active internal bleeding
    • intracranial or intraspinal surgery or serious head trauma within previous 3 months
    • presence of intracranial conditions that may increase the risk of bleeding such as some neoplasms, arteriovenous malformations, or aneurysms
    • bleeding diathesis
    • current severe uncontrolled hypertension
  • if recent history of oral anticoagulants or heparin, do not delay alteplase for coagulation study, but discontinue if studies show international normalized ratio > 1.7 or elevated activated partial thromboplastin time (aPTT)
  • Reference - FDA DailyMed 2018 March

Timing of IV Alteplase

Recommendations from professional organizations

Overview of recommendations

  • IV alteplase is recommended as soon as possible and within 3 hours of stroke onset
  • some but not all organizations extend the recommendation if onset occurred 3-4.5 hours previously, but strengths of recommendations and additional criteria are not consistent among organizations
  • no organization recommends alteplase if onset occurred > 4.5 hours previously

American Heart Association / American Stroke Association (AHA/ASA) recommendations (2018)

Canadian Stroke Best Practice Recommendations (CSBPR) recommendations (2018)

  • if disabling ischemic stroke and patient eligible for IV alteplase (stroke onset within previous 4.5 hours), give IV alteplase (CSBPR Evidence Level A) as soon as possible after hospital arrival and CT scan (CSBPR Evidence Level B)
  • if considering IV alteplase > 4.5 hours after stroke onset, consult with physician with stroke experience
  • do not delay decisions regarding thrombolysis in order to
    • take chest x-ray to investigate possible acute heart or pulmonary disease
    • evaluate swallowing
    • insert of indwelling urethral catheter

American College of Emergency Physicians (ACEP) recommendations (2015)

  • offer IV t-PA to selected patients with stroke onset within previous 3 hours at institutions that can safely administer t-PA; consider the increased risk of symptomatic intracerebral hemorrhage (ACEP Level B)(2)
  • IV t-PA may also be offered to carefully selected patients with stroke onset 3-4.5 hours previous at institutions that can safely administer t-PA (ACEP Level B)(2)

Stroke Foundation (Australia) recommendations (2017)

  • give thrombolysis as soon as possible in eligible patients with stroke onset within previous 4.5 hours (SF Strong recommendation)(5)
  • do not delay thrombolysis for laboratory testing for coagulopathy unless clinical suspicion(5)

The Royal College of Physicians recommendations (2016)

  • if stroke onset within previous 3 hours, consider alteplase regardless of age or stroke severity(3)
  • if stroke onset 3-4.5 hours previous(3)
    • consider alteplase in patients < 80 years old
    • for patients ≥ 80 years old, alteplase can be considered on an individual basis; benefits are less than if treated earlier, but no increased risk of complications

Japan Stroke Society (JSS) recommendations (2012)

Activase (alteplase) package insert (2018)

  • initiate IV alteplase as soon as possible and within 3 hours of acute ischemic stroke onset (FDA DailyMed 2018 March)

Evidence for effect of time to alteplase administration on outcomes

  • in patients eligible for IV alteplase, benefit of therapy is time dependent, and treatment should be started as quickly as possible (AHA/ASA Class I, Level A; CSBPR Evidence Level A )(1, 6)
  • recommended goal of door-to-needle time is < 60 minutes ( CSBPR Evidence Level B)(1 , 6)
  • earlier treatment with recombinant tissue plasminogen activator following acute ischemic stroke associated with increased likelihood of favorable outcome in clinical practice (level 2 [mid-level] evidence)
    • based on retrospective cohort study
    • 84,439 patients (mean age 74 years, 49% female) with acute ischemic stroke in Germany were analyzed
    • 12% received rt-PA within 12 hours of stroke onset and 88% did not
    • favorable outcome (modified Rankin Scale score 0-1) at discharge in 37.7% without rt-PA
    • compared to no rt-PA, likelihood of favorable outcome was increased with rt-PA treatment
      • at < 1.5 hours from stroke onset (adjusted odds ratio [OR] 2.5, 95% CI 2.1-2.9)
      • at 1.5-3 hours (adjusted OR 1.9, 95% CI 1.7-2)
      • at 3-4.5 hours (adjusted OR 1.3, 95% CI 1.1-1.5)
      • at > 4.5 hours (adjusted OR 1.3, 95% CI 1-1.6)
    • rt-PA treatment at > 4.5 hours associated with increased risk of death compared to no rt-PA (adjusted odds ratio 1.5, 95% CI 1.1-1.9)
    • Reference - BMJ 2014 May 30;348:g3429 full-text
  • reduced time to treatment with t-PA associated with decreased hospital mortality and increased discharge to home in patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on retrospective cohort study from 1,395 hospitals participating in Get With The Guidelines-Stroke Program
    • 58,353 patients (mean age 72 years and 50% women) with acute ischemic stroke who received t-PA IV within 4.5 hours of symptom onset were analyzed
    • median time to treatment was 144 minutes with
      • 9.3% within < 90 minutes
      • 77.2% within 91-180 minutes
      • 13.6% within 181-270 minutes
    • median pretreatment National Institutes of Health Stroke Scale score 11 (assessed in 88%)
    • 33.4% achieved independent ambulation at hospital discharge, 38.6% were discharged to home, 8.8% died in hospital, and 4.9% had intracranial hemorrhage
    • shorter onset to treatment (per 15-minute increment) associated with (in adjusted analyses)
      • increased independent ambulation at discharge (odds ratio [OR] 1.04, 95% CI 1.03-1.05)
      • increased discharge to home (OR 1.03, 95% CI 1.02-1.04)
      • decreased in-hospital mortality (OR 0.96, 95% CI 0.95-0.98)
      • decreased symptomatic intracranial hemorrhage (OR 0.96, 95% CI 0.95-0.98)
    • Reference - JAMA 2013 Jun 19;309(23):2480
  • as time from stroke onset to t-PA administration increases, apparent benefit (in terms of increasing likelihood of functional independence) decreases and apparent harm (in terms of increasing mortality and risk for intracerebral hemorrhage) increases (level 2 [mid-level] evidence)
    • based on meta-analysis of randomized trials with differences in inclusion criteria
    • meta-analysis of individual patient data from 3,670 patients who had treatment started within 6 hours of stroke onset in 8 randomized placebo-controlled trials of t-PA
    • trials individually had inconsistent results for functional outcome
      • 3 trials independently found significant improvement in functional outcome with t-PA
        • NINDS 1 + 2 trials with t-PA given 0-3 hours after stroke onset
        • ECASS III trials with t-PA given 3-4.5 hours after stroke onset
        • all these trials included patients with minor stroke
      • 5 trials independently found no improvement in functional outcome with t-PA; these 5 trials excluded patients with minor stroke
        • ECASS trial with t-PA given 0-6 hours after stroke onset
        • ECASS II trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS A trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS B trial with t-PA given 0-5 hours after stroke onset (changed to 3-5 hours after NINDS 2 trial published)
        • EPITHET trial with t-PA given 3-6 hours after stroke onset
    • in analysis of effect of t-PA in relation to time from stroke onset as continuous variable
      • good functional outcome (modified Rankin Scale score 0-1 at 90 days)
        • significantly increased with t-PA from 0 to 4.5 hours (0 to 270 minutes)
        • magnitude of increase declined with increasing time from stroke onset
      • mortality significantly increased with t-PA after 4-4.5 hours (240-270 minutes)
      • intracerebral hemorrhage significantly increased at all time points with increasing magnitude as time from stroke onset increased
    • in analysis of effect of t-PA in relation to time from stroke onset as categorical variable
      • comparing t-PA vs. placebo given at 0-1.5 hours (0-90 minutes) in analysis of 312 patients
        • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 41.6% vs. 29.1% (p = 0.0013, odds ratio 2.55, 95% CI 1.44-4.52) (NNT 5 in adjusted analysis)
        • mortality 18.6% vs. 20.5% (odds ratio 0.78, 95% CI 0.41-1.48)
        • intracerebral hemorrhage in 3.1% vs. 0% (odds ratio not evaluable due to 0 events in control group) (NNH 32 in crude analysis)
      • comparing t-PA vs. placebo given at 1.5-3 hours (91-180 minutes) in analysis of 618 patients
        • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 41.9% vs. 28.9% (p = 0.0116, odds ratio 1.64, 95% CI 1.12-2.4) (NNT 9 in adjusted analysis)
        • mortality 16.8% vs. 15.6% (odds ratio 1.13, 95% CI 0.7-1.82)
        • intracerebral hemorrhage in 5.6% vs. 1% (p < 0.0008, odds ratio 8.23, 95% CI 2.39-28.32) (NNH 21 in crude analysis)
      • comparing t-PA vs. placebo given at 3-4.5 hours (180-270 minutes) in analysis of 1,620 patients
        • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 44.6% vs. 37.7% (p = 0.0135, odds ratio 1.34, 95% CI 1.06-1.68) (NNT 15 in adjusted analysis)
        • mortality 11% vs. 10.1% (odds ratio 1.22, 95% CI 0.87-1.71)
        • intracerebral hemorrhage in 4.3% vs. 1.2% (p < 0.0004, odds ratio 3.61, 95% CI 1.76-7.38) (NNH 32 in crude analysis)
      • comparing t-PA vs. placebo given at 4.5-6 hours (270-360 minutes) in analysis of 1,118 patients
        • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 37.4% vs. 35.6% (p = 0.16, odds ratio 1.22, 95% CI 0.92-1.61)
        • mortality 15% vs. 10.2% (p = 0.0501, odds ratio 1.49, 95% CI 1-2.21) (NNH 20 in crude analysis)
        • intracerebral hemorrhage in 6.8% vs. 0.9% (p < 0.0001, odds ratio 4.32, 95% CI 2.84-18.9) (NNH 17 in crude analysis)
    • Reference - Lancet 2010 May 15;375(9727):1695, editorial can be found in Lancet 2010 May 15;375(9727):1667
    • estimated increase of 1.8 days of disability-free life for every 1-minute decrease in time from stroke onset to treatment
      • based on extrapolation of these meta-analysis results to a retrospective cohort of 2,258 patients with stroke treated with IV thrombolytics
      • Reference - Stroke 2014 Apr;45(4):1053

Evidence for IV alteplase 0-3 hours after stroke

Efficacy and safety overview (0-3 hours)

  • for patients with stroke onset within previous 3 hours, professional organizations recommend IV alteplase
  • t-PA given within 3 hours of acute ischemic stroke may increase functional independence without affecting overall mortality at 3-6 months, but associated with increased risk for symptomatic (and fatal) intracranial hemorrhage within 7 days (level 2 [mid-level] evidence)
    • based on systematic reviews of randomized trials with heterogeneity and methodologic limitations
    • consistent results reported across
      • 2014 Cochrane review analyses of 7 trials with about 1,800 patients (limited by heterogeneity and trials with methodologic limitations)
      • 1995 NINDS trial with 624 patients (limited by allocation concealment not stated and baseline differences favoring tissue plasminogen activator [t-PA] in 91-180 minutes subgroup)
      • 2012 IST-3 trial with subgroup of 849 patients randomized within 3 hours of stroke onset (limited by lack of blinding)
      • 2010 individual patient data meta-analysis of 8 randomized trials (not including IST-3 trial) with 930 patients treated within 3 hours of stroke onset
      • 2014 individual patient data meta-analysis of 9 randomized trials (including IST-3 trial) with 1,549 patients treated within 3 hours of stroke onset
  • estimated effects of using t-PA within 3 hours, based on NINDS trial
    Effect of t-PA at 0-3 Hours*:
    Outcome Likelihood with PlaceboLikelihood with t-PA
    Good functional outcome (mRS score 0-1) at 3 months26.5%42.5% (NNT 7)
    Symptomatic intracranial hemorrhage (NINDS definition) at 36 hours0.6%6.4% (NNH 17)
    Mortality at 3 months21%17% (not significant)
    Abbreviations: mRS, modified Rankin Scale; NINDS, National Institute of Neurological Disorders and Stroke; t-PA, tissue plasminogen activator.

    * based on NINDS trial

2014 Cochrane review (0-3 hours)

  • recombinant tissue plasminogen activator (rt-PA) given within 3 hours of acute ischemic stroke may increase functional independence without affecting overall mortality, but associated with increased risk for symptomatic intracranial hemorrhage (level 2 [mid-level] evidence)
    • based on Cochrane review limited by heterogeneity and trials with methodologic limitations
    • systematic review of 27 randomized trials comparing thrombolytic agents vs. control in 10,187 patients with acute ischemic stroke
    • thrombolytic agents included rt-PA (70% of patients), urokinase, recombinant prourokinase, streptokinase, and desmoteplase
    • control group included placebo, no treatment, or aspirin
    • 23 trials evaluated IV thrombolytic agents, 4 trials evaluated intra-arterial thrombolytic agents
    • IV rt-PA evaluated in 12 trials with 7,012 patients
    • in analyses of IV rt-PA given via randomized assignment 0-3 hours after stroke onset
      • decreased death or dependency (odds ratio [OR] 0.65, 95% CI 0.54-0.8) in analysis of 6 trials with 1,779 patients
      • no significant difference in overall mortality (OR 0.91, 95% CI 0.73-1.13) in analysis of 7 trials with 1,806 patients
      • increased symptomatic intracranial hemorrhage (OR 4.25, 95% CI 2.53-7.16) in analysis of 5 trials with 1,155 patients
      • these analyses largely determined by IST-3 trial which was unblinded and NINDS trial which had allocation concealment not stated and baseline differences
      • analyses of rt-PA given within 3 hours (regardless of time randomization) had consistent results
    • Reference - Cochrane Database Syst Rev 2014 Jul 29;(7):CD000213
    • comparing IV rt-PA vs. control in patients treated within 3 hours
      • favorable outcome (modified Rankin Scale score 0-1) in 31.6% vs. 22.9% (odds ratio [OR] 1.61, 95% CI 1.3-1.99)
      • favorable outcome (modified Rankin Scale score 0-2) in 40.7% vs. 31.7% (OR 1.53, 95% CI 1.26-1.86)
      • Reference - subgroup reporting of Cochrane review (Lancet 2012 Jun 23;379(9834):2364 full-text)
    • DynaMed commentary -- efficacy data reporting outcomes for patients treated from 0 to 6 hours after stroke onset is no longer reported in DynaMed because effect on time from symptom onset to t-PA administration appears to highly influence the efficacy results such that conclusions combining data from 0 to 3 hours and 3 to 6 hours are not valid

1995 NINDS trial (0-3 hours)

  • t-PA within 3 hours of ischemic stroke onset may reduce disability at 3 months but increases rate of symptomatic and fatal intracerebral hemorrhage (level 2 [mid-level] evidence)
    • based on randomized trial with allocation concealment not stated and with baseline differences (NINDS trial)
    • considerable inclusion and exclusion criteria
      • inclusion criteria
        • ischemic stroke with clearly defined time of onset
        • t-PA (or placebo) given within 180 minutes
        • no evidence of hemorrhage on computed tomography (CT) scan
      • exclusion criteria
        • stroke or serious head trauma within preceding 3 months
        • major surgery within 14 days
        • history of intracranial hemorrhage
        • systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg
        • gastrointestinal or urinary tract hemorrhage within 21 days
        • arterial puncture at noncompressible site within 7 days
        • seizure at onset of stroke
        • anticoagulants within 48 hours
        • elevated partial thromboplastin time, prothrombin time > 15 seconds or platelet count < 100,000/mm3
        • glucose < 50 mg/dL (2.7 mmol/L) or > 400 mg/dL (22.2 mmol/L)
    • 624 patients randomized to t-PA 0.9 mg/kg IV vs. placebo within 3 hours of onset of acute ischemic stroke
      • t-PA dosing
        • alteplase (Activase), a recombinant t-PA, 0.9 mg/kg (up to 90 mg)
        • 10% given as IV bolus, then 90% as constant infusion over 60 minutes
      • other protocol considerations
        • no anticoagulants or antiplatelet agents for 24 hours after treatment
        • blood pressure maintained within prespecified values
    • comparing t-PA vs. placebo in all 624 patients
      • proportion of patients with improvement in National Institutes of Health Stroke Scale (NIHSS) stroke severity score at 3 months 47% vs. 39% (p = 0.06)
      • favorable outcome (≤ 1) in NIHSS stroke severity score in 34% vs. 20.5% (p ≤ 0.008, NNT 8)
      • favorable outcome (≤ 1) in modified Rankin Scale in 42.5% vs. 26.5% (p ≤ 0.035, NNT 7)
      • favorable outcome (95-100) in Barthel index in 52% vs. 38% (p ≤ 0.026, NNT 8)
      • any intracranial hemorrhage within 36 hours in 10.9% vs. 3.5% (NNH 13)
      • symptomatic intracranial hemorrhage within 36 hours in 6.4% vs. 0.6% (p < 0.001, NNH 17)
      • fatal intracranial hemorrhage within 36 hours in 2.9% vs. 0.3% (NNH 38)
      • mortality at 3 months 17% vs. 21% (not significant)
    • comparing t-PA vs. placebo in 302 patients treated within 90 minutes after stroke onset at 3 months
      • proportion of patients with improvement in NIHSS stroke severity score 55% vs. 42% (p = 0.02, NNT 8)
      • favorable outcome (≤ 1) in NIHSS stroke severity score in 34% vs. 20% (p = 0.008, NNT 8)
      • favorable outcome (≤ 1) in modified Rankin Scale in 40% vs. 28% (p = 0.035, NNT 9)
      • favorable outcome (95-100) in Barthel index in 53% vs. 38% (p = 0.01, NNT 7)
    • comparing t-PA vs. placebo in 322 patients treated 91-180 minutes after stroke onset at 3 months
      • proportion of patients with improvement in NIHSS stroke severity score 39% vs. 37% (not significant)
      • favorable outcome (≤ 1) in NIHSS stroke severity score in 34% vs. 21% (p = 0.008, NNT 8)
      • favorable outcome (≤ 1) in modified Rankin Scale in 45% vs. 25% (p < 0.001, NNT 5)
      • favorable outcome (95-100) in Barthel index in 51% vs. 38% (p = 0.026, NNT 8)
    • higher rates of favorable outcome at 3 months with t-PA than with placebo appeared consistent among subgroups of
      • 81 patients with small-vessel occlusive stroke
      • 252 patients with large-vessel occlusive stroke
      • 273 patients with cardioembolic stroke
    • Reference - NINDS trial (N Engl J Med 1995 Dec 14;333(24):1581 full-text), editorial can be found in N Engl J Med 1995 Dec 14;333(24):1632, commentary can be found in N Engl J Med 1996 May 23;334(21):1405, ACP J Club 1996 May-Jun;124(3):58, J Fam Pract 1996 May;42(5):458
    • baseline differences
      • more patients in t-PA group had been receiving aspirin prior to stroke event and more patients in t-PA group had less severe, small-vessel occlusions but statistical analysis shows benefit of t-PA upon accounting for these variables (letters can be found in N Engl J Med 1996 May 23;334(21):1405)
      • baseline differences favored t-PA group within subgroup of patients treated within 91-180 minutes of stroke onset, with most patients with mild stroke at baseline in t-PA group and most patients with worse stroke at baseline in placebo group (BMJ 2004 329:820 [web-only content])
    • using modified Rankin Scale score 0-2 (no or slight disability but not requiring assistance for activities of daily living) at 90 days, this outcome was achieved by 157 of 312 patients with t-PA (50.3%) vs. 120 of 312 patients with placebo (38.5%) (adjusted odds ratio 1.62, 95% CI 1.18-2.23, NNT 9) (Stroke 2007 Dec;38(12):3205 full-text)
  • noted that CT must be examined carefully to exclude any signs of hemispheric brain ischemia, which may increase risk for deterioration after thrombolytic therapy (N Engl J Med 1995 Dec 14;333(24):1632)
  • reanalysis of NINDS trial data reported to support benefits with t-PA (Stroke 2004 Oct;35(10):2418 full-text), commentary can be found in Stroke 2005 Feb;36(2):230, Stroke 2005 Mar;36(3):529, but criticized for many reasons including inadequate statistical power (BMJ 2004 329:820 [web-only content])
  • 1-year outcome suggests increased likelihood of minimal or no disability for patients treated with t-PA within 3 hours (level 2 [mid-level] evidence)
    • based on NINDS trial
    • favorable outcome defined as minimal or no disability on several scales
    • comparing t-PA vs. placebo at 12 months
      • favorable outcome using Barthel index in 50% vs. 38% (p = 0.005, NNT 9)
      • favorable outcome using modified Rankin Scale in 41% vs. 28% (p = 0.001, NNT 8)
      • favorable outcome using Glasgow Outcome scale in 43% vs. 32% (p = 0.006, NNT 9)
      • mortality 24% vs. 28% (not significant)
    • Reference - N Engl J Med 1999 Jun 10;340(23):1781 full-text, commentary can be found in N Engl J Med 1999 Oct 14;341(16):1240
    • DynaMed commentary -- authors of article received financial support from drug manufacturer

2012 IST-3 trial (0-3 hours)

  • rt-PA given within 3 hours after stroke onset may increase likelihood of independent functioning but increase risk of symptomatic hemorrhage at 7 days, with no overall effect on death at 6 months (level 2 [mid-level] evidence)
    • based on subgroup analyses of randomized trial without blinding (IST-3 trial)
    • 3,035 adults with acute ischemic stroke randomized to rt-PA 0.9 mg/kg IV vs. usual care within 6 hours of symptom onset
    • 1,617 patients (53%) were > 80 years old
    • IST-3 protocol designed to enroll patients with "uncertainty" regarding use of rt-PA, so most patients < 80 years old meeting guideline-supported criteria for rt-PA within 3 hours of stroke onset were given rt-PA and not enrolled in IST-3 trial
    • time from symptom onset to randomization was
      • < 3 hours in 849 patients (28%)
      • 3-4.5 hours in 1,177 patients (39%)
      • 4.5-6 hours in 1,007 patients (33%)
    • comparing rt-PA vs. usual care in subgroup of patients randomized within 3 hours of symptom onset
      • independent functioning (measured by Oxford Handicap Score 0-2) at 6 months in 30.6% vs. 22.7% (adjusted odds ratio 1.64, 95% CI 1.03-2.62, NNT 13)
      • no other outcomes reported in this subgroup
    • comparing rt-PA vs. usual care in overall cohort
      • fatal or nonfatal symptomatic intracranial hemorrhage at 7 days in 7% vs. 1% (p < 0.0001, NNH 16)
      • death at 7 days in 11% vs. 7% (p = 0.001, NNH 25)
      • death at 6 months in 27% vs. 27% (not significant)
    • Reference - IST-3 trial (Lancet 2012 Jun 23;379(9834):2352 full-text), correction can be found in Lancet 2012 Aug 25;380(9843):730, editorial can be found in Lancet 2012 Jun 23;379(9834):2320
    • comparing rt-PA vs. usual care in subgroup of 849 patients randomized within 3 hours of symptom onset
      • increased likelihood of any improvement in Oxford Handicap Score (adjusted ordinal analysis across entire scale) (adjusted odds ratio 1.5, 99% CI 1.03-2.19)
      • death within 7 days in 11% vs. 9% (adjusted odds ratio 1.43, 99% CI 0.77-2.66)
      • symptomatic intracranial hemorrhage within 7 days in 7% vs. 1% (adjusted odds ratio 8.8, 99% CI 2.11-35.1, NNH 16)
      • Reference - Stroke 2015 Mar;46(3):746
  • 18-month outcomes reported to support increase in independent functioning with rt-PA (35% vs. 31.4%, p = 0.024, NNT 28) and no significant effect on mortality (34.9% vs. 35.1%), based on subgroup of 2,348 patients from IST-3 trial who completed 18-month follow-up (Lancet Neurol 2013 Aug;12(8):768 full-text),
    • DynaMed commentary - results not reported by subgroups of time to randomization
  • reduced risk of poor functional outcomes with rt-PA limited to high-risk patients in post hoc subgroup analysis of IST-3 trial (Stroke 2014 Apr;45(4):1000)

2010 individual patient data meta-analysis (0-3 hours)

  • t-PA given within 3 hours of stroke onset may increase likelihood of functional independence and risk for intracerebral hemorrhage without increasing mortality (level 2 [mid-level] evidence)
    • based on meta-analysis of randomized trials with differences in inclusion criteria
    • meta-analysis of individual patient data from 3,670 patients who had treatment started within 6 hours of stroke onset in 8 randomized placebo-controlled trials of t-PA
    • trials individually had inconsistent results for functional outcome
      • 3 trials independently found significant improvement in functional outcome with t-PA; these 3 trials included patients with minor stroke
        • NINDS 1 + 2 trials with t-PA given 0-3 hours after stroke onset
        • ECASS III trial with t-PA given 3-4.5 hours after stroke onset
      • 5 trials independently found no improvement in functional outcome with t-PA; these 5 trials excluded patients with minor stroke
        • ECASS trial with t-PA given 0-6 hours after stroke onset
        • ECASS II trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS A trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS B trial with t-PA given 0-5 hours after stroke onset (changed to 3-5 hours after NINDS 2 trial published)
        • EPITHET trial with t-PA given 3-6 hours after stroke onset
    • comparing t-PA vs. placebo given at 0-1.5 hours (0-90 minutes) in analysis of 312 patients
      • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 41.6% vs. 29.1% (p = 0.0013, odds ratio 2.55, 95% CI 1.44-4.52) (NNT 5 in adjusted analysis)
      • mortality 18.6% vs. 20.5% (odds ratio 0.78, 95% CI 0.41-1.48)
      • intracerebral hemorrhage in 3.1% vs. 0% (odds ratio not evaluable due to 0 events in control group) (NNH 32 in crude analysis)
    • comparing t-PA vs. placebo given at 1.5-3 hours (91-180 minutes) in analysis of 618 patients
      • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 41.9% vs. 28.9% (p = 0.0116, odds ratio 1.64, 95% CI 1.12-2.4) (NNT 9 in adjusted analysis)
      • mortality 16.8% vs. 15.6% (odds ratio 1.13, 95% CI 0.7-1.82)
      • intracerebral hemorrhage in 5.6% vs. 1% (p < 0.0008, odds ratio 8.23, 95% CI 2.39-28.32) (NNH 21 in crude analysis)
    • Reference - Lancet 2010 May 15;375(9727):1695, editorial can be found in Lancet 2010 May 15;375(9727):1667

2014 individual patient data meta-analysis (0-3 hours)

  • t-PA given within 3 hours after stroke onset may increase risk for fatal intracranial hemorrhage within 7 days but may not affect 90-day mortality (level 2 [mid-level] evidence)
    • based on updated meta-analysis of individual patient data with wide confidence intervals
    • individual patient data meta-analysis of 9 randomized trials with 6,756 patients randomized to t-PA vs. no t-PA within 6 hours of stroke onset (same 8 trials in meta-analysis reported above [Lancet 2010 May 15] plus IST-3 trial reported above [Lancet 2012 Jun 23])
    • comparing t-PA vs. control in subgroup of 1,549 patients treated within 3 hours after stroke onset
      • fatal intracranial hemorrhage within 7 days in 2.8% vs. 0.3% (adjusted odds ratio 10.86, 95% CI 2.54-46.41)
      • 90-day mortality 22.2% vs. 21.8% (hazard ratio 1, 95% CI 0.81-1.24)
    • Reference - Lancet 2014 Nov 29;384(9958):1929 full-text, protocol for meta-analysis in Int J Stroke 2013 Jun;8(4):278 full-text
    • DynaMed commentary -- functional outcome data not reported here due to uncertainty in validity of this outcome analysis

2018 PRISMS trial (mild stroke at 0-3 hours)

  • IV alteplase within 3 hours after stroke onset may not improve functional outcome (level 2 [mid-level] evidence) and increases risk of symptomatic intracerebral hemorrhage (level 1 [likely reliable] evidence) compared to aspirin in patients with NIHSS score ≤ 5 and no clearly disabling deficits at presentation
    • based on randomized trial with early termination affecting functional outcome
    • 313 adults (mean age 62 years) presenting within 3 hours of acute ischemic stroke were randomized to alteplase 0.9 mg/kg IV plus oral placebo vs. aspirin 325 mg orally plus IV placebo and followed for 90 days
    • all patients had NIHSS score 0-5 at presentation (median score 2), and current deficits that would not affect ability to return to work or perform basic activities of daily living
    • primary efficacy outcome was modified Rankin Scale (mRS) score at 90 days
    • primary safety outcome was symptomatic intracerebral hemorrhage (ICH) defined as any neurological decline attributed to ICH at ≤ 36 hours
    • statistical power for primary efficacy outcome was limited due to early termination for slow recruitment at 33% of planned enrollment
    • 89% had primary outcome data at 90 days, all patients included in analysis
    • comparing IV alteplase vs. aspirin
      • mRS score 0-1 (good functional outcome) at 90 days in 78.2% vs. 81.5% (not significant)
      • symptomatic ICH at ≤ 36 hours in 3.2% vs. 0% (p < 0.05, NNH 31)
      • serious adverse events at ≤ 90 days in 26% vs. 13.1% (p < 0.05, NNH 7)
    • Reference - PRISMS trial (JAMA 2018 Jul 10;320(2):156, editorial can be found in JAMA 2018 Jul 10;320(2):141)

Evidence for IV alteplase 3-4.5 hours after stroke

Efficacy and safety overview (3-4.5 hours)

  • for patients with stroke onset 3-4.5 hours previous, some but not all professional organizations recommend IV alteplase; strengths of recommendations and additional eligibility criteria vary
  • t-PA given 3-4.5 hours after stroke onset increases risk of symptomatic intracranial hemorrhage and risk of fatal intracranial hemorrhage within 7 days (level 1 [likely reliable] evidence) and might increase 90-day mortality (level 2 [mid-level] evidence) while effect on improving functional outcomes is uncertain and inconsistent across trials
    • based on subgroup data from 9 randomized trials
    • effect on functional outcome was inconsistent
      • no effect reported in randomized trial with 613 patients treated 3-5 hours after stroke onset (ATLANTIS) done in 1993-1998
      • benefit (increase in good functional outcome defined as modified Rankin Scale score 0-1 at 90 days, NNT 14) reported in randomized trial with 821 patients treated 3-4.5 hours after stroke onset (ECASS III) done in 2003-2007, but trial had baseline differences in history of prior stroke and results not significant in subgroup of 89% of patients without history of prior stroke
      • harm (decrease in good functional outcome defined as modified Rankin Scale score 0-2 at 6 months, NNH 16) reported in subgroup of 1,177 patients randomized at 3-4.5 hours after stroke onset in IST-3 trial done in 2000-2011, trial was not blinded
      • benefit (increase in good functional outcome defined as modified Rankin Scale score 0-1 at 90 days, NNT 15) reported in 2010 meta-analysis of subgroup data from 1,620 patients in 8 trials (including ECASS III and ATLANTIS but not including IST-3 trial)
      • 2014 meta-analysis including IST-3 trial has uncertain validity for analysis for functional outcome
    • results from all these analyses consistently found increased risk for symptomatic intracranial hemorrhage, fatal intracranial hemorrhage, and 7-day mortality where reported
    • results for 90-day mortality were not statistically significant but consistent with clinically important increase in ATLANTIS trial and 2014 meta-analysis
    • best estimates of effects of tissue plasminogen activator (t-PA) given 3-4.5 hours after stroke onset from analysis of ECASS III, IST-3, Cochrane review, and 2014 individual patient data meta-analysis
      • for 90-day mortality, NNH 49 (95% CI NNH 19 to ∞ to NNT 137)
      • for fatal intracranial hemorrhage, NNH 44 (95% CI 18-136)
      • for symptomatic intracranial hemorrhage
        • using parenchymal type 2 definition, NNH 33 (95% CI 14-112)
        • using National Institute of Neurological Disorders and Stroke (NINDS) definition, NNH 22 (95% CI 13-80)
      • for functional outcome, results are inconsistent and do not support a single numerical estimate of effect
      • Reference - BMJ 2015 Mar 17;350:h1075

1999 ATLANTIS trial (3-5 hours)

  • alteplase given 3-5 hours after stroke onset increases rate of symptomatic and fatal intracranial hemorrhage without apparent benefit in functional outcomes (level 1 [likely reliable] evidence)
    • based on randomized trial (ATLANTIS trial)
    • 613 patients aged 18-79 years with acute ischemic stroke treated within 3-5 hours of symptom onset were randomized to recombinant tissue plasminogen activator (rt-PA), alteplase 0.9 mg/kg vs. placebo IV over 1 hour
    • comparing t-PA vs. placebo in 547 patients in per-protocol analysis
      • excellent neurologic recovery (National Institutes of Health Stroke Scale [NIHSS] score 0 or 1) at 90 days in 33.8% vs. 32% (p = 0.65)
        • 28% vs. 31% in subgroup of 111 patients treated 3-4 hours after symptom onset (p = 0.84)
        • 34% vs. 33% in subgroup of 436 patients treated 4-5 hours after symptom onset (p = 0.92)
      • mortality at 90 days 11% vs. 6.9% (p = 0.09)
      • symptomatic intracranial hemorrhage in 7% vs. 1.1% (p < 0.001, NNH 17)
      • fatal intracranial hemorrhage in 3% vs. 0.3% (p < 0.001, NNH 37)
    • similar results in intention-to-treat analysis (which included 63 patients not enrolled in 3- to 5-hour time frame)
    • study funded by drug manufacturer
    • Reference - ATLANTIS trial (JAMA 1999 Dec 1;282(21):2019), editorial can be found in JAMA 1999 Dec 1;282(21):2068, commentary can be found in ACP J Club 2000 Jul-Aug;133(1):18
    • benefit for t-PA found in small subgroup of patients who received t-PA within 3 hours of stroke onset in ATLANTIS trial
      • 61 such patients were found to have both significant benefit and significant risk with t-PA
      • t-PA-treated patients were more likely to have very favorable outcome (score of 1 or less on NIHSS) at 90 days (p = 0.01) even with significant increase in rate of symptomatic intracranial hemorrhage
      • Reference - Stroke 2002 Feb;33(2):493 full-text , editorial can be found in Stroke 2002 Feb;33(2):495

2008 ECASS III trial (3-4.5 hours)

  • alteplase given 3-4.5 hours after nonsevere stroke onset might reduce disability at 90 days (NNT 14) (level 2 [mid-level] evidence) but increases risk of symptomatic intracranial hemorrhage (NNH 22) (level 1 [likely reliable] evidence)
    • based on randomized trial with confidence intervals for efficacy outcome including small effects without clinical relevance, and baseline differences favoring alteplase group
    • 821 patients aged 18-80 years with acute ischemic stroke randomized to alteplase 0.9 mg/kg (up to 90 mg) vs. placebo IV within 3-4.5 hours of symptom onset
    • exclusion criteria prior to randomization
      • severe stroke (NIHSS score > 25)
      • intracranial hemorrhage on computed tomography (CT)
      • major ischemic infarction on CT
    • CT or magnetic resonance imaging (MRI) done 22-36 hours after treatment and again if clinically indicated
    • 10.3% alteplase and 11.9% placebo patients had protocol violations (did not receive treatment, did not meet age or imaging inclusion criteria, or received treatment outside of time window) but were included in intention-to-treat analysis
    • baseline differences comparing alteplase group vs. placebo group
      • mean NIHSS score 10.7 vs. 11.6 (median 9 vs. 10, p = 0.03)
      • history of prior stroke in 7.7% vs. 14.1% (p = 0.003)
    • 13 (3.1%) alteplase and 10 (2.5%) placebo patients were lost to follow-up but were included in intention-to-treat analysis using worst possible outcome
    • 90-day outcomes comparing alteplase vs. placebo
      • disability score 0-1 on modified Rankin Scale in 52.4% vs. 45.2% (p = 0.04, NNT 14 [95% CI 6-204], odds ratio 1.34, 95% CI 1.02-1.76)
      • disability score 2-3 on modified Rankin Scale in 23.4% vs. 27.8%
      • disability score 4-5 on modified Rankin Scale in 17.4% vs. 18.9%
      • death in 6.7% vs. 8.2% (not significant)
    • safety outcomes comparing alteplase vs. placebo
      • any intracranial hemorrhage in 27% vs. 17.6% (p = 0.001, NNH 10)
      • symptomatic intracranial hemorrhage by ECASS III definition (increase of ≥ 4 points on NIHSS score and hemorrhage identified as predominant cause of neurologic deterioration) in 2.39% vs. 0.25% (p = 0.008, NNH 46)
      • symptomatic intracranial hemorrhage by NINDS definition (hemorrhage on imaging, clinical suspicion of hemorrhage or any decline in neurologic status, and no hemorrhage on prior CT scan) in 7.9% vs. 3.5% (p = 0.006, NNH 22, 95% CI for NNH 9-119)
      • fatal intracranial hemorrhage in 0.7% vs. 0% (not significant)
    • Reference - ECASS III trial (N Engl J Med 2008 Sep 25;359(13):1317), editorial can be found in N Engl J Med 2008 Sep 25;359(13):1393, commentary can be found in N Engl J Med 2008 Dec 25;359(26):2839, Ann Intern Med 2009 Jan 20;150(2):JC1
    • analyses limited to 89% patients in ECASS III trial without history of prior stroke find no significant difference in favorable outcome (modified Rankin Scale score 0-1) at 90 days (odds ratio 1.19, 95% CI 0.89-1.59) (J Emerg Med 2014 Mar;46(3):385)
  • patients ≥ 65 years old may have increased risk of symptomatic intracranial hemorrhage (NNH 11) without functional benefit (level 2 [mid-level] evidence), while patients < 65 years old may have reduced disability (NNT 9) without increase in symptomatic intracranial hemorrhage (level 2 [mid-level] evidence)
    • based on subgroup analysis of ECASS III trial
    • in 481 patients ≥ 65 years old, comparing alteplase vs. placebo at 90 days
      • disability score 0-1 on modified Rankin Scale in 49% vs. 45% (not significant)
      • symptomatic intracranial hemorrhage in 11% vs. 2% (p < 0.05, NNH 11)
      • mortality 11% vs. 9% (not significant)
    • in 339 patients < 65 years old, comparing alteplase vs. placebo at 90 days
      • disability score 0-1 on modified Rankin Scale in 57% vs. 45% (p < 0.05, NNT 9)
      • symptomatic intracranial hemorrhage in 4% vs. 6% (not significant)
      • mortality 3% vs. 8% (not significant)
    • Reference - Lancet Neurol 2009 Dec;8(12):1095
  • review comparing ECASS III results to other trials of IV t-PA can be found in J Emerg Med 2010 Jan;38(1):99

2012 IST-3 trial (3-4.5 hours)

  • rt-PA given 3-4.5 hours after stroke onset may decrease likelihood of independent functioning at 6 months and increase risk for symptomatic intracranial hemorrhage and death within 7 days (level 2 [mid-level] evidence)
    • based on subgroup analyses of randomized trial without blinding (IST-3 trial)
    • 3,035 adults with acute ischemic stroke randomized to rt-PA 0.9 mg/kg IV vs. usual care within 6 hours of symptom onset
    • 1,617 patients (53%) were > 80 years old
    • time from symptom onset to randomization was
      • < 3 hours in 849 patients (28%)
      • 3-4.5 hours in 1,177 patients (39%)
      • 4.5-6 hours in 1,007 patients (33%)
    • comparing rt-PA vs. usual care in subgroup of patients randomized 3-4.5 hours after symptom onset
      • independent functioning (measured by Oxford Handicap Score 0-2) at 6 months in 31.5% vs. 37.7% (adjusted odds ratio 0.73, 99% CI 0.5-1.07)
      • DynaMed commentary -- in unadjusted analysis using 95% CI the summary statistic is odds ratio 0.76, 95% CI 0.6-0.97, NNH 16, 95% CI for NNH 9-146)
      • no other outcomes reported in this subgroup
    • comparing rt-PA vs. usual care in overall cohort
      • fatal or nonfatal symptomatic intracranial hemorrhage at 7 days in 7% vs. 1% (p < 0.0001, NNH 16)
      • death at 7 days in 11% vs. 7% (p = 0.001, NNH 25)
      • death at 6 months in 27% vs. 27% (not significant)
    • Reference - IST-3 trial (Lancet 2012 Jun 23;379(9834):2352 full-text), correction can be found in Lancet 2012 Aug 25;380(9843):730, editorial can be found in Lancet 2012 Jun 23;379(9834):2320
    • comparing rt-PA vs. usual care in subgroup of 1,177 patients randomized 3-4.5 hours after symptom onset
      • no significant effect on likelihood of any improvement in Oxford Handicap Score (adjusted ordinal analysis across entire scale) (adjusted odds ratio 1.06, 99% CI 0.78-1.44)
      • death within 7 days in 13% vs. 7% (adjusted odds ratio 1.82, 99% CI 1.07-3.1, NNH 16)
      • symptomatic intracranial hemorrhage within 7 days in 7% vs. 1% (adjusted odds ratio 6.3, 99% CI 2.16-18.34, NNH 16)
      • Reference - Stroke 2015 Mar;46(3):746
    • DynaMed commentary -- good functional outcome measured as modified Rankin Scale score 0-1 not reported in subgroup of patients randomized 3-4.5 hours after symptom onset

2010 individual patient data meta-analysis (3-4.5 hours)

  • t-PA given 3-4.5 hours after stroke onset might increase likelihood of functional independence and risk for intracerebral hemorrhage without increasing mortality (level 2 [mid-level] evidence)
    • based on meta-analysis of randomized trials with differences in inclusion criteria
    • meta-analysis of individual patient data from 3,670 patients who had treatment started within 6 hours of stroke onset in 8 randomized placebo-controlled trials of t-PA
    • trials individually had inconsistent results for functional outcome
      • 3 trials independently found significant improvement in functional outcome with t-PA; these 3 trials included patients with minor stroke
        • NINDS 1 + 2 trials with t-PA given 0-3 hours after stroke onset
        • ECASS III trial with t-PA given 3-4.5 hours after stroke onset
      • 5 trials independently found no improvement in functional outcome with t-PA; these 5 trials excluded patients with minor stroke
        • ECASS trial with t-PA given 0-6 hours after stroke onset
        • ECASS II trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS A trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS B trial with t-PA given 0-5 hours after stroke onset (changed to 3-5 hours after NINDS 2 trial published)
        • EPITHET trial with t-PA given 3-6 hours after stroke onset
    • comparing t-PA vs. placebo given at 3-4.5 hours (180-270 minutes) in analysis of 1,620 patients
      • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 44.6% vs. 37.7% (p = 0.0135, adjusted odds ratio 1.34, 95% CI 1.06-1.68) (NNT 15 in adjusted analysis, 95% CI for NNT 8-73)
      • 90-day mortality 11% vs. 10.1% (adjusted odds ratio 1.22, 95% CI 0.87-1.71) (NNH 51 for point estimate for 90-day mortality from adjusted analysis, not statistically significant)
      • clinically relevant parenchymal hemorrhage in 4.3% vs. 1.2% (p < 0.0004, adjusted odds ratio 3.61, 95% CI 1.76-7.38) (NNH 33 in adjusted analysis, 95% CI for NNH 14-112)
    • Reference - Lancet 2010 May 15;375(9727):1695, editorial can be found in Lancet 2010 May 15;375(9727):1667

2014 individual patient data meta-analysis (3-4.5 hours)

  • t-PA reported to increase likelihood of functional independence if given within 4.5 hours after stroke onset (level 3 [lacking direct] evidence) but increases risk for fatal intracranial hemorrhage within 7 days (level 1 [likely reliable] evidence) and may increase 90-day mortality (level 2 [mid-level] evidence)
    • based on updated meta-analysis of individual patient data with uncertainty in compatibility of efficacy data being combined
    • individual patient data meta-analysis of 9 randomized trials with 6,756 patients randomized to t-PA vs. no t-PA within 6 hours of stroke onset (same 8 trials in meta-analysis reported above [Lancet 2010 May 15] plus IST-3 trial reported above [Lancet 2012 Jun 23])
    • DynaMed commentary -- reliability of how IST-3 data was combined with other trials for efficacy data (outcome of functional independence) is uncertain because
      • outcomes were determined differently - 3-month assessment used in most trials, but 6-month assessment from postal questionnaire used for IST-3 trial
      • outcomes not reported for individual trials, but positive outcome from 2010 meta-analysis combined with negative outcome from IST-3 trial would be expected to have summary conclusion of no overall effect, or high degree of heterogeneity questioning reliability of meta-analysis
      • approach to statistical analysis not designed to analyze efficacy (of t-PA vs. no t-PA) by time
        • prespecified analyses designed to minimize the potential for IST-3 results to "dilute substantially" the results from the prior meta-analysis
        • "the primary interest is not in the 'main effect' of treatment estimated across all the trials but rather the extent to which the treatment effect varies according to these three baseline characteristics (time from symptom onset to treatment, patient age, stroke severity)"
        • only adjusted analyses reported
      • argument made that IST-3 data could be nonrepresentative by overselecting patients with uncertainty (IST-3 eligibility criteria stated "if the patient had a clear indication for IV thrombolysis with rt-PA, they were to be treated in accordance with local guidelines") but this concern may only apply to data up to 3 hours after stroke onset, as local guidelines generally limited clear indications to that time frame
    • comparing t-PA vs. control in subgroup of 2,812 patients treated 3-4.5 hours after stroke onset
      • fatal intracranial hemorrhage within 7 days in 2.5% vs. 0.5% (adjusted odds ratio 5.63, 95% CI 2.49-12.76; NNH 44, 95% CI 18-136)
      • 90-day mortality 16.9% vs. 15.9% (hazard ratio 1.14, 95% CI 0.95-1.36; NNH 49, 95% CI NNH 19 to NNT 137)
    • Reference - Lancet 2014 Nov 29;384(9958):1929 full-text, protocol for meta-analysis in Int J Stroke 2013 Jun;8(4):278 full-text

Evidence for IV alteplase ≥ 4.5 hours after stroke or if unknown time of onset

Efficacy and safety overview (4.5-6 hours)

IST-3 trial (4.5-6 hours)

  • rt-PA given 4.5-6 hours after stroke may not affect likelihood of independent functioning but may increase risk for symptomatic intracranial hemorrhage (level 2 [mid-level] evidence)
    • based on subgroup analyses of randomized trial without blinding (IST-3 trial)
    • 3,035 adults with acute ischemic stroke randomized to recombinant tissue plasminogen activator (rt-PA) 0.9 mg/kg IV vs. usual care within 6 hours of symptom onset
    • 1,617 patients (53%) were > 80 years old
    • time from symptom onset to randomization was
      • < 3 hours in 849 patients (28%)
      • 3-4.5 hours in 1,177 patients (39%)
      • 4.5-6 hours in 1,007 patients (33%)
    • comparing rt-PA vs. usual care in subgroup of patients randomized 4.5-6 hours after symptom onset
      • independent functioning (measured by Oxford Handicap Score 0-2) at 6 months in 47.3% vs. 42.6% (adjusted odds ratio 1.31, 95% CI 0.89-1.93)
      • no other outcomes reported in this subgroup
    • comparing rt-PA vs. usual care in overall cohort
      • fatal or nonfatal symptomatic intracranial hemorrhage at 7 days in 7% vs. 1% (p < 0.0001, NNH 16)
      • death at 7 days in 11% vs. 7% (p = 0.001, NNH 25)
      • death at 6 months in 27% vs. 27% (not significant)
    • Reference - IST-3 trial (Lancet 2012 Jun 23;379(9834):2352 full-text), correction can be found in Lancet 2012 Aug 25;380(9843):730, editorial can be found in Lancet 2012 Jun 23;379(9834):2320
    • comparing rt-PA vs. usual care in subgroup of 1,007 patients randomized 4.5-6 hours after symptom onset
      • possibly increased likelihood of any improvement in Oxford Handicap Score (adjusted ordinal analysis across entire scale) (adjusted odds ratio 1.35, 99% CI 0.99-1.85)
      • death within 7 days in 8% vs. 5% (adjusted odds ratio 1.55, 99% CI 0.77-3.12)
      • symptomatic intracranial hemorrhage within 7 days in 6% vs. 1% (adjusted odds ratio 6.33, 99% CI 1.8-22.2, NNH 20)
      • Reference - Stroke 2015 Mar;46(3):746

2010 individual patient data meta-analysis (4.5-6 hours)

  • t-PA given 4.5-6 hours after stroke onset may increase mortality and risk for intracerebral hemorrhage without increasing likelihood of functional independence (level 2 [mid-level] evidence)
    • based on meta-analysis of randomized trials with differences in inclusion criteria
    • meta-analysis of individual patient data from 3,670 patients who had treatment started within 6 hours of stroke onset in 8 randomized placebo-controlled trials of tissue plasminogen activator (t-PA)
    • trials individually had inconsistent results for functional outcome
      • 3 trials independently found significant improvement in functional outcome with t-PA
        • NINDS 1 + 2 trials with t-PA given 0-3 hours after stroke onset
        • ECASS III trials with t-PA given 3-4.5 hours after stroke onset
        • all these trials included patients with minor stroke
      • 5 trials independently found no improvement in functional outcome with t-PA; these 5 trials excluded patients with minor stroke
        • ECASS trial with t-PA given 0-6 hours after stroke onset
        • ECASS II trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS A trial with t-PA given 0-6 hours after stroke onset
        • ATLANTIS B trial with t-PA given 0-5 hours after stroke onset (changed to 3-5 hours after NINDS 2 trial published)
        • EPITHET trial with t-PA given 3-6 hours after stroke onset
    • comparing t-PA vs. placebo given at 4.5-6 hours (270-360 minutes) in analysis of 1,118 patients
      • good functional outcome (modified Rankin Scale score 0-1 at 90 days) in 37.4% vs. 35.6% (p = 0.16, odds ratio 1.22, 95% CI 0.92-1.61)
      • mortality 15% vs. 10.2% (p = 0.0501, odds ratio 1.49, 95% CI 1.00-2.21) (NNH 20 in crude analysis)
      • intracerebral hemorrhage in 6.8% vs. 0.9% (p < 0.0001, odds ratio 4.32, 95% CI 2.84-18.9) (NNH 17 in crude analysis)
    • Reference - Lancet 2010 May 15;375(9727):1695, editorial can be found in Lancet 2010 May 15;375(9727):1667

2014 individual patient data meta-analysis (4.5-6 hours)

  • t-PA given > 4.5 hours after stroke onset may increase risk for fatal intracranial hemorrhage within 7 days and may increase 90-day mortality (level 2 [mid-level] evidence)
    • based on updated meta-analysis of individual patient data with wide confidence intervals
    • individual patient data meta-analysis of 9 randomized trials with 6,756 patients randomized to t-PA vs. no t-PA within 6 hours of stroke onset (same 8 trials in meta-analysis reported above [Lancet 2010 May 15] plus IST-3 trial reported above [Lancet 2012 Jun 23])
    • comparing t-PA vs. control in subgroup of 2,395 patients treated > 4.5 hours after stroke onset
      • fatal intracranial hemorrhage within 7 days in 2.8% vs. 0.3% (adjusted odds ratio 8.16, 95% CI 2.88-23.11)
      • 90-day mortality 16.4% vs. 13.8% (hazard ratio 1.22, 95% CI 0.99-1.25)
    • Reference - Lancet 2014 Nov 29;384(9958):1929 full-text, protocol for meta-analysis can be found in Int J Stroke 2013 Jun;8(4):278 full-text
    • DynaMed commentary -- functional outcome data not reported here due to uncertainty in validity of this outcome analysis

2014 Cochrane review (3-6 hours)

  • DynaMed commentary -- unable to make conclusions regarding outcomes specific to 3-4.5 or 4.5-6 hour time frames from Cochrane review, because data was combined to 3-6 hour time frame and not separately reported
  • recombinant tissue plasminogen activator (rt-PA) given 3-6 hours after stroke may increase risk for symptomatic intracranial hemorrhage and might increase overall mortality without increasing likelihood of functional independence (level 2 [mid-level] evidence)
    • based on Cochrane review limited by heterogeneity and trials with methodologic limitations
    • systematic review of 27 randomized trials comparing thrombolytic agents vs. control in 10,187 patients with acute ischemic stroke
    • thrombolytic agents included rt-PA (70% of patients), urokinase, recombinant prourokinase, streptokinase, and desmoteplase
    • control group included placebo, no treatment, or aspirin
    • 23 trials evaluated IV thrombolytic agents, 4 trials evaluated intra-arterial thrombolytic agents
    • IV rt-PA evaluated in 12 trials with 7,012 patients
    • in analyses of IV rt-PA given via randomized assignment 3-6 hours after stroke onset
      • no significant difference in death or dependency (odds ratio [OR] 0.97, 95% CI 0.85-1.09) in analysis of 5 trials with 4,049 patients, results limited by significant heterogeneity
      • nonsignificantly increased overall mortality (OR 1.17, 95% CI 1-1.38) in analysis of 5 trials with 4,044 patients, results limited by significant heterogeneity
      • increased symptomatic intracranial hemorrhage (OR 3.62, 95% CI 2.76-4.76) in analysis of 5 trials with 4,013 patients
      • analyses of rt-PA given within 6 hours (regardless of time of randomization) had consistent results
      • in patients treated 3-6 hours after stroke, no significant difference in favorable outcome (modified Rankin Scale score 0-2) with 47.5% vs. 45.7% (OR 1.07, 95% CI 0.96-1.2) in analysis of 7 trials with 4,971 patients (Lancet 2012 Jun 23;379(9834):2364 full-text)
    • Reference - Cochrane Database Syst Rev 2014 Jul 29;(7):CD000213
    • DynaMed commentary -- efficacy data reporting outcomes for patients treated from 0 to 6 hours after stroke onset is no longer reported in DynaMed because effect on time from symptom onset to t-PA administration appears to highly influence the efficacy results such that conclusions combining data from 0 to 3 hours and 3 to 6 hours is not valid

IV Alteplase with Unknown Time of Stroke Onset

  • American Heart Association / American Stroke Association (AHA/ASA) does not recommend IV alteplase if time last known normal > 3-4.5 hours previous and patient awoke with stroke or has unclear or unwitnessed stroke onset (AHA/ASA Class III No Benefit, Level B-NR)(1)
  • MRI-guided IV alteplase may reduce risk of neurologic disability at 90 days (level 2 [mid-level] evidence) but increases risk of parenchymal hemorrhage (level 1 [likely reliable] evidence) in patients with unknown time of stroke onset but with MRI suggestive of onset within 4.5 hours
    • based on randomized trial with early termination affecting neurologic disability outcome
    • 503 patients aged 18-80 years (mean age 65 years) with unknown time of stroke onset were randomized to magnetic resonance imaging (MRI)-guided alteplase 0.9 mg/kg IV vs. placebo and followed for 90 days
    • all patients had imaging results predictive of symptom onset within 4.5 hours (ischemic lesion visible on diffusion-weighted magnetic resonance imaging but no parenchymal hyperintensity in same region on fluid-attenuated inversion recovery [FLAIR])
    • patients with severe stroke (National Institute of Health Stroke Scale [NIHSS] score ≥ 25) or planned thrombectomy were excluded
    • additional patient/treatment characteristics
      • median interval between symptom recognition and treatment initiation 3.1 hours in alteplase group vs. 3.2 hours in placebo group
      • median interval between time patient last known to be well and treatment initiation 10.3 hours in alteplase group vs. 10.4 hours in placebo group
      • median NIHSS score at baseline 6 in both groups
    • primary efficacy outcome was favorable outcome, defined as score 0 or 1 on modified Rankin scale (mRS)
    • primary safety outcomes were death and composite outcome of death or dependence (mRS score 4-6)
    • trial stopped early due to lack of funding (original enrollment goal 800 patients)
    • comparing IV alteplase vs. placebo
      • favorable outcome in 53.3% vs. 41.8% (p = 0.02, NNT 9)
      • death or dependence in 13.5% vs. 18.3% (not significant)
      • death in 4.1% vs. 1.2% (p = 0.07)
      • parenchymal hemorrhage type 2 in 4% vs. 0.4% (p = 0.03, NNH 27)
      • symptomatic intracranial hemorrhage in 2% vs. 0.4% (not significant)
      • serious adverse events in 22.3% vs. 21.3% (not significant)
    • Reference - WAKE-UP trial (N Engl J Med 2018 Aug 16;379(7):611 full-text, editorial can be found in N Engl J Med 2018 Aug 16;379(7):682)

Management of Patient on IV Alteplase

Monitoring

  • do not delay IV alteplase treatment to monitor further improvement (time of administration has large impact on outcomes) (AHA/ASA Class III Harm, Level C-EO)(1)
  • American Heart Association/American Stroke Association recommendations(1)
    • admit patient to intensive care unit or stroke unit for monitoring
    • delay use of nasogastric tubes, indwelling bladder catheters, or intra-arterial pressure catheters if possible
    • monitor blood pressure and perform neurologic assessment every 15 minutes during and after infusion for 2 hours, then every 30 minutes for next 6 hours, then hourly until 24 hours after treatment
    • if blood pressure ≥ 180/105 mm Hg, increase frequency of blood pressure measurement and give antihypertensive medication to maintain blood pressure ≤ 180/105 mm Hg (see Antihypertensives for additional information)
    • if patient develops severe headache, acute hypertension, nausea, vomiting, or has worsening neurological examination, discontinue alteplase infusion and obtain emergency computed tomography (CT)
    • follow-up CT or magnetic resonance imaging (MRI) at 24 hours and before starting antiplatelets or other antithrombotic therapies
    • be prepared to treat potential adverse events including bleeding complications and angioedema that may obstruct airway (AHA/ASA Class I Harm, Level B-NR)
  • Canadian Stroke Best Practice Recommendations - if bleeding, the is insufficient evidence to support routine use of cryoprecipitate, fresh frozen plasma, prothrombin complex concentrates, tranexamic acid, factor VIIa, or platelet transfusions (CSBPR Evidence Level C); consider use on case-by-case basis

Antihypertensives

  • for patients with blood pressure (BP) > 185/110 mm Hg who are otherwise candidates for IV alteplase
  • no solid data to guide medication selection, but reasonable options include (AHA/ASA Class IIb, Level C-EO)(1)
    • if BP > 185/110 mm Hg
      • labetalol 10-20 mg IV over 1-2 minutes, may repeat once
      • nicardipine 5 mg/hour IV, titrate up by 2.5 mg/hour every 5-15 minutes to maximum 15 mg/hour; when desired BP reached, adjust to maintain
      • clevidipine 1-2 mg/hour IV, titrate by doubling dose every 2-5 min until desired BP reached; maximum 21 mg/hour
    • to maintain BP to ≤ 180/105 mm Hg during or after reperfusion, monitor BP
      • every 15 minutes for 2 hours
      • then every 30 minutes for 6 hours
      • then every hour for 16 hours
    • if systolic BP > 180-230 mm Hg or diastolic BP > 105-120 mm Hg
      • labetalol 10 mg IV followed by continuous IV infusion 2-8 mg/minute
      • nicardipine 5 mg/hour IV, titrate up by 2.5 mg/hour every 5-15 minutes to desired effect; maximum 15 mg/hour
      • clevidipine 1-2 mg/hour IV, titrate by doubling the dose every 2-5 minutes until desired BP reached; maximum 21 mg/hour
    • if BP not controlled or diastolic BP > 140 mm Hg, consider sodium nitroprusside IV
  • American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines - Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults
    • lower blood pressure slowly to < 185/110 mm Hg before initiating thrombolytic therapy in adults with acute ischemic stroke and elevated blood pressure who are eligible for treatment with IV tissue plasminogen activator (ACC/AHA Class I, Level B-NR)
    • attain blood pressure < 185/110 mm Hg before administration of IV tissue plasminogen activator and maintain blood pressure < 180/105 mm Hg for at least the first 24 hours after initiating drug therapy in adults with acute ischemic stroke (ACC/AHA Class I, Level B-NR)
    • Reference - Hypertension 2018 Jun;71(6):e13
  • see Blood pressure management in acute ischemic stroke for additional information

Aspirin and other antithrombotic therapies

  • aspirin and other antiplatelet agents are recommended for most patients, and anticoagulants for select patients, to treat acute ischemic stroke and reduce risk of recurrence (see Antiplatelet therapy for acute stroke, Antiplatelet therapy for secondary prevention of stroke, and Anticoagulation therapy for acute stroke for additional information)
  • for most patients who receive IV alteplase, guidelines recommend aspirin, but delay administration for 24 hours after alteplase started
    • American Heart Association / American Stroke Association (AHA/ASA) recommendations(1)
      • aspirin is generally delayed for 24 hours but may be considered earlier if there are concomitant conditions for which aspirin given in the absence of IV alteplase is known to be beneficial or withholding it is known to cause substantial risk (AHA/ASA Class I, Level A)
      • similarly, antithrombotic therapy in general within first 24 hours of IV alteplase has uncertain risks but might be considered if patient has conditions for which it is known to be beneficial or withholding it is known to increase risk (AHA/ASA Class IIb, Level B-NR)
      • do not give concurrent abciximab (AHA/ASA Class III Harm, Level B-R)(1)
    • Canadian Stroke Best Practice Recommendations (CSBPR) recommends that antiplatelet agents be delayed until intracranial hemorrhage has been excluded by imaging scan conducted 24 hours post-thrombolysis (CSBPR Evidence Level B)(6)
  • aspirin not recommended as substitute for acute stroke treatment in patients otherwise eligible for IV alteplase or mechanical thrombectomy (ASA/AHS Class III No Benefit, Level B-R)(1)
  • for patients who were using antithrombotic therapy before the stroke
    • if the therapy consisted of antiplatelets, IV alteplase is generally still recommended
    • if the therapy consisted of other antithrombotic agents, IV alteplase may be contraindicated or recommended only with careful consideration
    • see Eligibility for specific recommendations
  • eptifibatide plus lower-dose recombinant tissue plasminogen activator (rt-PA) being studied to reduce risk for intracranial hemorrhage compared to standard rt-PA for acute ischemic stroke, but differences in clinical outcomes are not established (level 2 [mid-level] evidence)
    • based on 2 small randomized trials with inadequate statistical power
    • 126 patients in CLEAR-ER trial
      • 126 patients aged 18-85 years with acute ischemic stroke were randomized to combination therapy (rt-PA 0.6 mg/kg, plus eptifibatide 135 mg/kg bolus then 0.75 mg/kg/minute for 2 hours) vs. standard rt-PA (0.9 mg/kg) IV within 3 hours of symptom onset
      • comparing combination therapy vs. standard rt-PA
        • symptomatic intracranial hemorrhage at 36 hours in 2% in vs. 12% (p = 0.053)
        • good functional outcome (modified Rankin Scale score ≤ 1 or return to baseline) at 90 days in 49.5% vs. 30% (not significant)
      • Reference - CLEAR-ER trial (Stroke 2013 Sep;44(9):2381), editorial can be found in Stroke 2013 Sep;44(9):2377
    • 94 patients in CLEAR trial
      • 94 patients aged 18-80 years who were diagnosed with acute ischemic stroke randomized to 1 of 3 treatments within 3 hours of symptom onset
        • rt-PA 0.3 mg/kg plus eptifibatide 75 mcg/kg bolus followed by 0.75 mcg/kg/minute infusion for 2 hours
        • rt-PA 0.45 mg/kg plus eptifibatide 75 mcg/kg bolus followed by 0.75 mcg/kg/minute infusion for 2 hours
        • rt-PA 0.9 mg/kg
      • at 36 hours after treatment intracranial hemorrhage occurred in 1.4% of patients treated with combination therapy compared with 8% of patients treated with conventional rt-PA therapy (not significant)
      • Reference - CLEAR trial (Stroke 2008 Dec;39(12):3268 full-text)

Symptomatic intracranial hemorrhage

  • American Heart Association / American Stroke Association (AHA/ASA) recommendations (AHA/ASA Class IIb, Level C-EO)(1)
    • stop IV alteplase infusion
    • obtain blood tests
      • complete blood count
      • prothrombin time (international normalized ratio)
      • activated partial thromboplastin time
      • fibrinogen level
      • blood type and cross-match
    • obtain nonenhanced head CT scan
    • give cryoprecipitate (includes factor VIII)
      • 10 units infused over 10-30 minutes (onset in 1 hour, peaks in 12 hours)
      • give additional dose for fibrinogen level of < 200 mg/dL
    • give either
      • tranexamic acid 1000 mg IV over 10 minutes OR
      • epsilon-aminocaproic acid 4-5 grams over 1 hour followed by 1 gram IV until bleeding is controlled (peak onset in 3 hours)
    • consult with hematology and neurosurgery
    • give supportive therapy regarding
      • blood pressure
      • intracranial pressure
      • cerebral perfusion pressure
      • mean arterial pressure
      • temperature
      • glucose
  • see Intracerebral hemorrhage for additional information

Orolingual angioedema

  • Canadian Stroke Best Practice Recommendations - if angioedema, use staged response (antihistamines, glucocorticoids, and airway management) per local protocols (CSBPR Evidence Level C)(6)
  • American Heart Association / American Stroke Association (AHA/ASA) recommendations (AHA/ASA Class IIb, Level C-EO)(1)
    • maintain airway
      • if edema is limited to anterior tongue and lips, endotracheal intubation may not be necessary
      • risk of intubation may be higher if edema involving larynx, palate, floor of mouth, or oropharynx with progression within 30 minutes
      • intubation types
        • optimal intubation is fiberoptic intubation while patient is awake
        • nasal-tracheal intubation may be necessary, but it is associated with increased risk of post-alteplase epistaxis
        • cricothyroidotomy is rarely needed and may be problematic after alteplase
    • stop alteplase infusion and hold angiotensin-converting enzyme (ACE) inhibitors
    • give
      • methylprednisolone 125 mg IV
      • diphenhydramine 50 mg IV
      • ranitidine 50 mg IV or famotidine 20 mg IV
    • if further increase in angioedema, give epinephrine (0.1%) 0.3 mL subcutaneously or 0.5 mL by nebulizer
    • additional medications to consider have some benefit for hereditary angioedema and ACE inhibitor-related angioedema
      • icatibant 3 mL (30 mg) subcutaneous injection in abdominal area; also consider up to 2 additional injections of 30 mg every 6 hours (total number of injections should not exceed 3 over 24 hours)
      • plasma-derived C1 esterase inhibitor 20 units/kg
    • also give supportive care
  • see Angioedema and C1 inhibitor deficiency (including hereditary angioedema) for additional information

Specific Patient Populations

Age > 80 years old

Recommendations from professional organizations

  • age > 80 years old is not a contraindication to IV alteplase, but evidence in these patients is limited compared to younger patients and strength of recommendations vary
    • American Heart Association / American Stroke Association (AHA/ASA)(1)
      • if within 3 hours of stroke onset, IV alteplase equally recommended for eligible patients > 80 and 18-80 years old (AHA/ASA Class I, Level A)
        • older age associated with worse prognosis and outcomes, but IV alteplase associated with increased likelihood of being independent at 3 months in all age groups
      • if 3-4.5 hours since stroke onset, IV alteplase appears to be safe and can be as effective for patients > 80 years old as younger patients (AHA/ASA Class IIa, Level B-NR)
    • Royal College of Physicians Intercollegiate Stroke Working Party (2016) national clinical guideline for stroke(3)
      • if ischemic stroke onset within previous 3 hours, consider IV alteplase regardless of age or stroke severity
      • if stroke onset 3-4.5 hours previous and age< 80 years old, IV alteplase should be considered
      • if stroke onset 3-4.5 hours previous and age > 80 years old, IV alteplase should be considered on an individual basis
        • benefits may be less than if treated within 3 hours of stroke onset, but risk of worse outcomes are not increased
    • Japan Stroke Society recommends using increased caution if age > 80 years old (JSS Grade C1, Level IIa)(4)
    • Activase drug label notes that age > 77 years old might be associated with increased risk of intracranial hemorrhage; alteplase still expected to have favorable outcomes in otherwise eligible patients but benefit may be reduced compared to younger patients (FDA DailyMed 2018 March)

Comparing thrombolysis vs. no thrombolysis in patients > 80 years old

  • limited efficacy data comparing thrombolytics vs. no thrombolytics in patients > 80 years old with acute ischemic stroke
    • thrombolysis may reduce disability at 3-6 months in patients > 80 years old with acute ischemic stroke (level 2 [mid-level] evidence), based on statistically significant differences in 1 cohort study and nonsignificant difference in subgroup analysis of 1 randomized trial
    • thrombolysis associated with increased mortality and intracerebral hemorrhage in patients > 80 years old with acute ischemic stroke (level 2 [mid-level] evidence), based on 1 large cohort study
  • in patients > 80 years old with acute ischemic stroke, IV recombinant tissue plasminogen activator (rt-PA) might increase likelihood of independent functioning at 6 months (level 2 [mid-level] evidence)
    • based on subgroup analysis of randomized trial without blinding (IST-3 trial) and without statistical significance
    • 3,035 adults with acute ischemic stroke randomized to rt-PA 0.9 mg/kg IV vs. usual care within 6 hours of symptom onset
    • 1,617 patients (53%) were > 80 years old
    • rt-PA associated with nonsignificant increase in likelihood of independent functioning at 6 months (27.3% vs. 23.5%, adjusted odds ratio 1.35, 95% CI 0.97-1.88) in subgroup analysis of patients > 80 years old
    • Reference - IST-3 trial (Lancet 2012 Jun 23;379(9834):2352 full-text), correction can be found in Lancet 2012 Aug 25;380(9843):730, editorial can be found in Lancet 2012 Jun 23;379(9834):2320
    • DynaMed commentary -- age subgroup results not further reported by time from symptom onset to rt-PA; subgroup data from IST-3 trial by time from symptom onset suggests benefit (increase in functional independence) for use < 3 hours and harm (decrease in functional independence) for use at 3-4.5 hours
  • thrombolysis may reduce disability at 3 months in patients > 80 years old with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on cohort study
    • 23,334 patients with acute ischemic stroke who had thrombolysis were evaluated from Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR)
    • 6,166 patients with acute ischemic stroke who had no thrombolysis were evaluated from patients in neuroprotective drug trials
    • thrombolysis associated with lower scores on modified Rankin Scale at 3 months (p < 0.001)
    • comparing thrombolysis vs. no thrombolysis in 3,472 patients > 80 years old
      • favorable outcomes (modified Rankin Scale score 0-2) at 90 days in 32.9% vs. 20.7% (p < 0.001, NNT 8)
      • mortality at 3 months 32.6% vs. 35.3% (not significant)
      • symptomatic postthrombolysis intracerebral hemorrhage in 11% of 2,087 patients (using definition of any increase in National Institutes of Health Stroke Scale (NIHSS) from baseline and any parenchymal intracerebral hemorrhage)
    • comparing thrombolysis vs. no thrombolysis in 26,028 patients ≤ 80 years old
      • favorable outcomes in 56% vs. 44.4% (p < 0.001, NNT 9)
      • mortality at 3 months 13.6% vs. 14.8% (p < 0.05, NNT 84)
      • symptomatic postthrombolysis intracerebral hemorrhage in 8.3% of 20,220 patients (using definition of any increase in NIHSS from baseline and any parenchymal intracerebral hemorrhage)
    • statistical evaluation of contribution of thrombolysis to intracerebral hemorrhage not reported because posttreatment imaging results unavailable for control group
    • Reference - BMJ 2010 Nov 23;341:c6046 full-text, editorial can be found in BMJ 2010 Nov 23;341:c5891
    • DynaMed commentary -- median time from stroke onset to thrombolysis was 145 minutes in SITS-ISTR, data not reported by time to treatment
  • thrombolysis associated with increased in-hospital mortality and intracerebral hemorrhage in patients > 80 years old with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on cohort study
    • of 524,997 patients admitted for acute ischemic stroke, 158,580 (30%) were > 80 years old
    • among patients > 80 years old, 1,659 (1%) were treated with thrombolysis
    • comparing patients > 80 years old who received thrombolysis vs. no thrombolysis
      • hospital mortality 16.9% vs. 12.75% (odds ratio [OR] 1.38, 95% CI 1.22-1.58, NNH 24)
      • intracerebral hemorrhage in 5.73% vs. 0.53% (OR 11.43, 95% CI 9.19-14.22, NNH 19)
      • endotracheal intubation in 8.38% vs. 4.2% (OR 2.09, 95% CI 1.75-2.49, NNH 24)
      • sepsis in 1.02% vs. 0.47% (OR 2.17, 95% CI 1.33-3.51, NNH 181)
    • Reference - Stroke 2010 Oct;41(10):2259 full-text

Comparing age > 80 years vs. < 80 years in patients who received thrombolysis

  • compared to patients < 80 years old receiving thrombolysis, patients > 80 years old have increased mortality, increased risk for intracerebral hemorrhage, and decreased likelihood of favorable functional outcome (level 2 [mid-level] evidence)
    • based on systematic review of prospective cohort studies and 2 subsequent cohort studies
    • IV thrombolysis with alteplase associated with increased mortality and less favorable functional outcomes in patients ≥ 80 years old compared to patients < 80 years old (level 2 [mid-level] evidence)
      • based on systematic review of prospective cohort studies
      • systematic review of 13 prospective cohort studies (published before September 2010) comparing IV thrombolysis with alteplase in patients ≥ 80 years old vs. patients < 80 years old with acute ischemic stroke
      • alteplase in patients ≥ 80 years old associated with
        • increased mortality (odds ratio [OR] 2.77, 95% CI 2.25-3.4) in analysis of 10 studies
        • decreased risk of favorable functional outcome (OR 0.49, 95% CI 0.4-0.61) in analysis of 8 studies
      • no significant difference in risk of symptomatic intracranial hemorrhage
      • Reference - J Neurol Neurosurg Psychiatry 2011 Jul;82(7):712
    • among patients treated with thrombolytics for acute stroke, patients > 80 years old at increased risk for mortality and intracerebral hemorrhage (level 2 [mid-level] evidence)
      • based on 2 large cohort studies
      • 23,334 patients with acute ischemic stroke who had thrombolysis were analyzed from SITS-ISTR
        • 3,472 patients were > 80 years old
        • comparing patients > 80 years old vs. patients ≤ 80 years old
          • favorable outcomes (modified Rankin Scale score 0-2) in 32.9% vs. 56%
          • mortality 32.6% vs. 13.6%
          • symptomatic intracerebral hemorrhage (using definition of ≥ 4-point increase in NIHSS from baseline) in 2.5% vs. 1.9% (p = 0.07)
          • symptomatic intracerebral hemorrhage (using definition of any increase in NIHSS from baseline) in 11% vs. 8.3% (p < 0.001)
        • Reference - BMJ 2010 Nov 23;341:c6046 full-text, editorial can be found in BMJ 2010 Nov 23;341:c5891
      • 524,997 patients admitted for acute ischemic stroke (27.2% > 80 years old)
        • 7,950 patients were treated with thrombolysis (20.9% > 80 years old)
        • comparing patients > 80 years old vs. patients < 80 years old in overall cohort
          • thrombolysis given in 1.05% vs. 1.72%
          • overall hospital mortality 12.8% vs. 9% (p < 0.0001)
        • comparing patients > 80 years old vs. patients < 80 years old in 7,950 patients who received thrombolysis
          • hospital mortality 16.9% vs. 11.5% (p < 0.05)
          • intracerebral hemorrhage in 5.73% vs. 4.4% (p < 0.05)
        • Reference - Stroke 2010 Oct;41(10):2259 full-text

Comparing age > 90 years vs. 80-89 years in patients who received thrombolysis

  • among patients treated with thrombolytics for acute stroke, patients ≥ 90 years old at increased risk for mortality, intracerebral hemorrhage, and poor functional outcome compared to patients aged 80-89 years (level 2 [mid-level] evidence)
    • based on prospective cohort study of 284 patients ≥ 80 years old receiving thrombolysis for acute ischemic stroke
    • comparing patients aged 80-89 years (mean age 83 years) vs. patients ≥ 90 years old (mean age 92 years, 70% female)
      • mortality 22.1% vs. 45.2% (p = 0.002)
      • favorable outcome in 30.2% vs. 14.3% (p = 0.034)
      • symptomatic intracranial hemorrhage (SICH) using Implementation of Thrombolysis in Stroke-Monitoring Study criteria in 4.7% vs. 13.3% (p = 0.037)
      • SICH using National Institute of Neurological Disorders and Stroke criteria in 5.9% vs. 13.3% (p = 0.106)
    • Reference - Stroke 2011 Jul;42(7):1967 full-text, commentary can be found in Stroke 2011 Oct;42(10):e563

Minor stroke or rapidly improving symptoms

  • ischemic stroke with disabling neurologic deficits is an indication for IV alteplase (see Eligibility section for details)
  • in patients with nondisabling or rapidly improving symptoms, the potential benefit of IV alteplase may not outweigh the risks, but evidence is limited
    • American Heart Association/American Stroke Association (AHA/ASA) recommends(1)
    • Japan Stroke Society recommends using increased caution if minor neurologic deficit or rapidly improving symptoms (JSS Grade C1, Level IIa)(4)
  • in patients with minor stroke and rapidly improving symptoms, IV thrombolysis does not appear to improve functional outcome at 3 months and may reduce likelihood of discharge home from hospital (level 2 [mid-level] evidence)
    • based on systematic review of observational studies
    • systematic review of 13 studies evaluating IV thrombolysis in 2,905 patients with minor stroke and rapidly improving symptoms
    • review included 8 prospective cohort studies, 2 post hoc analyses of clinical trials, 1 nationwide registry study, 1 case series, and 1 retrospective study
    • minor stroke definitions ranged from National Institutes of Health Stroke Scale (NIHSS) ≤ 3 to NIHSS ≤ 6
    • comparing IV thrombolysis vs. no IV thrombolysis
      • IV thrombolysis associated with reduced likelihood of discharge to home (or discharge independently from hospital)
        • odds ratio (OR) 0.5 (95% CI 0.25-0.97) in analysis of 3 studies with 336 patients
        • NNH 3-161 assuming 72% discharge home rate without IV thrombolysis
      • no significant differences in
        • modified Rankin Scale score 0-1 at 3 months (OR 0.99, 95% CI 0.74-1.34) in analysis of 8 studies with 1,940 patients
        • mortality (OR 1.21, 95% CI 0.54-2.72) in analysis of 9 studies with 1,604 patients
    • Reference - Neurol Sci 2014 Sep;35(9):1321

Intracranial vascular malformations, extra-axial neoplasms, or unruptured aneurysms

  • in Activase package insert, intracranial conditions that may increase the risk of bleeding such as some neoplasms, arteriovenous malformations, or aneurysms are contraindications to IV alteplase (FDA DailyMed 2018 March)
  • if unruptured and untreated intracranial vascular malformation
    • AHA/ASA recommendations
      • usefulness and risks of IV alteplase are not well established (AHA/ASA Class IIb, Level C-LD)
      • IV alteplase may be considered if severe neurological deficits and high likelihood of morbidity and mortality; potential benefit in these patients may outweigh the increased risk intracerebral hemorrhage (AHA/ASA Class IIb, Level C-LD)
    • Japan Stroke Society recommends using increased caution (JSS Grade C1, Level IIa)(4)
  • if extra-axial intracranial neoplasm, AHA/ASA and JSS suggest that IV alteplase may be reasonable (AHA/ASA Class IIa, Level C-EO; JSS Grade C1, Level IIa)(1, 4)
  • unruptured intracranial aneurysms might increase the risk of adverse events with IV alteplase, but evidence limited and recommendations vary
    • AHA/ASA recommendations(1)
    • Stroke Foundation (Australia) notes that unruptured aneurysms are not associated with increased risk of complications, but evidence is very limited(5)
    • JSS recommends using increased caution if cerebral aneurysm (JSS Grade C1, Level IIa)(4)
    • symptomatic intracranial hemorrhage reported in 6.7% of patients with acute ischemic stroke and unruptured intracranial aneurysm on systemic thrombolysis (level 3 [lacking direct] evidence)
      • based on systematic review of case series
      • systematic review of 6 case series evaluating systemic thrombolysis in patients with acute ischemic stroke with or without unruptured intracranial aneurysms
      • 120 patients had unruptured intracranial aneurysms
      • rate of symptomatic intracranial hemorrhage in patients with unruptured aneurysm was 6.7% (95% CI 3.1%-13.7%) in analysis of all studies
      • no significant difference in risk of symptomatic intracranial hemorrhage comparing patients with unruptured aneurysm to patients without unruptured aneurysm (risk ratio 1.6, 95% CI 0.54-4.77) in analysis of 5 studies with 1,013 patients
      • Reference - Neurology 2015 Oct 27;85(17):1452

Vertebrobasilar disease

  • IV thrombolytics for vertebrobasilar disease have inconsistent results (level 3 [lacking direct] evidence)
    • based on 3 small case series
    • 12 patients treated with tissue plasminogen activator (t-PA) within 3 hours after onset of stroke
      • 10 patients reported to have favorable outcomes
      • 1 had poor outcome
      • 1 died
    • 5 patients treated with t-PA within 6 hours after onset of stroke
      • 2 patients had minor partial reperfusion
      • 1 had complete reperfusion
      • 1 remained with "locked-in" state (devastating stroke)
      • 3 died
    • 18 patients treated with t-PA within 8 hours after onset of stroke
      • 10 patients capable of self-care at 3-month follow-up
      • 6 patients considered to be in poor condition
      • 2 patients died
    • Reference - N Engl J Med 2005 Jun 23;352(25):2618
  • see Basilar artery occlusion for additional information

Cardiac conditions

  • current or recent myocardial infarction (MI) is not a contraindication, but use increased caution(1, 4)
  • American Heart Association / American Stroke Association (AHA/ASA) suggests that IV alteplase may be reasonable if(1)
  • Japan Stroke Society recommends using increased caution if MI within previous 3 months (JSS Grade C1, Level IIa)(4)
  • if acute pericarditis(1)
  • if left atrial or ventricular thrombus(1)

Stroke after cardiac or cerebral catheterization

  • if ischemic stroke due to cardiac or cerebral angiography, IV alteplase is reasonable (depending on usual eligibility criteria) (AHA/ASA Class IIa, Level A)(1)
  • in patients with ischemic stroke after cardiac catheterization, thrombolysis reported to improve stroke symptoms at 24 hours and 7 days (level 3 [lacking direct] evidence)
    • based on retrospective cohort study with reported differences potentially due to baseline differences
    • 66 patients with ischemic stroke after cardiac catheterization were analyzed
    • 12 patients (18%) had thrombolysis with recombinant tissue plasminogen activator (rt-PA)
      • administration was IV in 7 patients and intra-arterial in 5 patients
      • median time from symptom onset to rt-PA treatment with was 142 minutes (range 54-305 minutes)
    • comparing patients treated with rt-PA vs. no rt-PA
      • median National Institutes of Health Stroke Scale (NIHSS) score at baseline 10.5 points vs. 6 points (p = 0.01)
      • median decrease in NIHSS score from baseline to 24 hours was 6 points vs. 0 points (p < 0.001)
      • either complete resolution (NIHSS of 0) or ≥ 5-point improvement in NIHSS score over first 24 hours in 58% vs. 15% (p < 0.003)
      • median decrease in NIHSS from baseline to 7 days was 6.5 points vs. 1.5 points (p = 0.004)
      • asymptomatic intracerebral hemorrhage in 25% vs. 6% (p = 0.037)
      • no significant differences in
        • mortality during hospital stay (8% vs. 7%)
        • minor puncture site bleeding (8% vs. 7%)
        • discharge without disability (modified Rankin Scale score 0-1) (30% vs. 28%)
      • no episodes of symptomatic intracerebral hemorrhage, retroperitoneal hemorrhage, hemopericardium, other sites of bleeding, or blood transfusions
    • Reference - J Am Coll Cardiol 2008 Mar 4;51(9):906 full-text, editorial can be found in J Am Coll Cardiol 2008 Mar 4;51(9):912, commentary can be found in J Am Coll Cardiol 2008 Jul 22;52(4):317
    • DynaMed commentary -- most of the difference between groups (5-6 points in NIHSS score) may be attributed to baseline differences (4 points); study design cannot distinguish effect of rt-PA from effect of patient selection (giving rt-PA to patients who had transiently higher NIHSS score)

Menstrual and pregnancy/postpartum considerations

  • if menstrual bleeding, IV alteplase may be used, but be aware of potential increased bleeding and use increased caution if recent menorrhagia or vaginal bleeding
    • American Heart Association / American Stroke Association (AHA/ASA) recommendations(1)
      • IV alteplase is reasonable if current menstruation and no history of menorrhagia, but inform patient that alteplase may increase menstrual flow (AHA/ASA Class IIa, Level C-EO)
      • IV alteplase may be considered if recent or active history of menorrhagia without clinically significant anemia or hypotension; potential benefits probably outweigh risk of serious bleeding (AHA/ASA Class IIb, Level C-LD)
      • if active or recent history of vaginal bleeding causing clinically significant anemia, emergency consultation with a gynecologist is probably indicated before deciding on alteplase (AHA/ASA Class IIa, Level C-EO)
    • Stroke Foundation (Australia) suggests that menstrual bleeding should be monitored for 24 hours after alteplase administration(5)
    • Japan Stroke Society (JSS) recommends using increased caution if menstrual bleeding (JSS Grade C1, Level IIa)(4)
  • if pregnancy or recent birth, use increased caution
    • AHA/ASA recommendations(1)
      • if pregnant, stroke is moderate-to-severe, and anticipated benefits outweigh risks of uterine bleeding, IV alteplase may be considered (AHA/ASA Class IIb, Level C-LD)
      • if birth within previous 14 days, safety and efficacy of IV alteplase are not well established (AHA/ASA Class IIb, Level C-LD)
    • Stroke Foundation (Australia) suggests that, for women who are pregnant(5)
      • effect of alteplase on fetus is not known; evidence limited
      • uterine bleeding and fetal death is a potential risk that needs to be taken into account
    • JSS recommends using increased caution if delivery, abortion, or premature labor within the previous 10 days (JSS Grade C1, Level IIa)(4)
    • Activase package insert notes that
      • pregnancy may increase risk of bleeding
      • there is no evidence evaluating effect of alteplase administration on breast milk or maternal lactation
      • Reference - FDA DailyMed 2018 March

iScore stratification

  • IV t-PA may reduce risk of poor outcome in patients with acute ischemic stroke and low- or moderate-risk assessed by iScore, but not in patients with high risk (level 2 [mid-level] evidence)
    • based on retrospective cohort study
    • 12,686 patients with acute ischemic stroke (13.4% treated with tissue plasminogen activator [t-PA]) in the Registry of the Canadian Stroke Network were analyzed
    • patients were stratified by Ischemic Stroke Predictive Risk Score (iScore) to 3 risk strata, and propensity scores for likelihood of t-PA treatment were calculated for patients in each stratum based on multiple baseline demographic and clinical factors
    • 3,380 patients were included in propensity-matched analyses comparing t-PA vs. no t-PA
      • 1,178 at low risk (iScore ≤ 139 points)
      • 1,364 at medium risk (iScore 140-179 points)
      • 838 at high risk (iScore ≥ 180 points)
    • poor outcome defined as death within 30 days of stroke admission or disability at discharge (modified Rankin Scale score 3-5)
    • rates of poor outcome comparing t-PA vs. no t-PA
      • 46.7% vs. 62.8% for low risk (p < 0.05, NNT 7)
      • 75.8% vs. 85.8% for medium risk (p < 0.05, NNT 10)
      • 92.6% vs. 95.2% for high risk (not significant)
    • mean length of stay was significantly lower in t-PA groups in each risk stratum
    • in t-PA group, hemorrhagic complications occurred in 6.4% with low risk, 13.1% with medium risk, and 19.8% with high risk
    • Reference - Stroke 2012 May;43(5):1315 full-text

Other specific populations

  • IV alteplase may be reasonable for patients with
    • early ischemic changes on non-contrast computer tomography of mild to moderate extent (other than frank hypodensity) (AHA/ASA Class I, Level A)(1)
    • renal disease(1, 4)
      • American Heart Association / American Stroke Association (AHA/ASA) recommends IV alteplase in patients with end-stage renal disease on hemodialysis and normal activated partial thromboplastin time (aPTT) (AHA/ASA Class I, Level C-LD); elevated aPTT associated with increased risk of hemorrhagic complications
      • Japan Stroke Society (JSS) recommends using increased caution if significant renal disorder (JSS Grade C1, Level IIa)
    • seizure at stroke onset if evidence that residual impairments are secondary to stroke and not a postictal phenomenon (AHA/ASA Class IIa, Level C-LD; JSS Grade C1, Level IIa)(1, 4)
    • history of diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; increased risk of visual loss should be weighed against reduced stroke-related neurological deficits (AHA/ASA Class IIa, Level B-NR; JSS Grade C1, Level IIa)(1, 4)
    • sickle cell disease (AHA/ASA Class IIa, Level B-NR)(1)
    • illicit drug use and no exclusion criteria (AHA/ASA Class IIa, Level C-LD); treating physician should be aware that illicit drug use may be a contributing factor to incident stroke(1)
    • preexisting disability (mRS score ≥ 2) (AHA/ASA Class IIb, Level B-NR)(1)
      • preexisting disability may not increase risk of symptomatic intracerebral hemorrhage after IV altplase, but may be associated with less neurological improvement and higher mortality than no preexisting disability
      • for treatment decisions, take into account quality of life, social support, place of residence, need for a caregiver, patients’ and families' preferences, and goals of care
    • preexisting dementia; benefit may depend individual considerations such as life expectancy and premorbid level of function (AHA/ASA Class IIb, Level B-NR)(1)
  • if systemic malignancy, safety and efficacy of IV alteplase is not well established (AHA/ASA Class IIb, Level C-LD); IV alteplase may have benefit if life expectancy > 6 months and no contraindications(1)

Dose and Regimen Variations

Dose comparisons

  • IV alteplase is recommended at the following regimens
    • for most patients: 0.9 mg/kg (total dose ≤ 90 mg), with first 10% of total dose given as IV bolus over 1 minute and remainder infused over 60 minutes(1, 6)
    • in Japan: 0.6 mg/kg(4)
  • higher-dose thrombolytic may increase fatal intracranial hemorrhage compared to lower-dose thrombolytic in patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on Cochrane review without significant differences in high-quality trials
    • systematic review of 20 randomized trials evaluating thrombolytics in 2,527 patients with acute ischemic stroke
    • 13 trials with 1,433 patients compared higher-dose thrombolytic to lower dose of same thrombolytic
    • thrombolytics included tissue plasminogen activator (t-PA), urokinase, desmoteplase, and tenecteplase
    • comparing higher vs. lower dose of same thrombolytic
      • higher-dose thrombolytic associated with
        • increase in fatal intracranial hemorrhage in analysis of 10 trials with 1,274 patients
          • odds ratio (OR) 2.71 (95% CI 1.22-6.04)
          • NNH 21-460 with fatal intracranial hemorrhage in 1% of lower-dose thrombolytic group
          • analysis includes 2 high-quality trials, but results in these trials not statistically significant
        • nonsignificant increase in total major extracranial hemorrhage (OR 1.72, 95% CI 0.93-3.21) in analysis of 9 trials with 1,154 patients
      • no significant differences in
        • mortality in analysis of 12 trials with 1,403 patients
        • death or dependency in analysis of 7 trials with 630 patients
    • Reference - Cochrane Database Syst Rev 2013 May 31;(5):CD000514
  • low-dose alteplase within 4.5 hours of acute ischemic stroke appears less effective than standard-dose alteplase for reducing death and disability at 90 days, but may reduce symptomatic intracerebral hemorrhage and 7-day mortality (level 2 [mid-level] evidence)
    • based on randomized noninferiority trial without blinding
    • 3,310 adults (median age 67 years, 62% men, 63% Asian) with acute ischemic stroke eligible for thrombolytic therapy were randomized within 4.5 hours of stroke onset to low-dose alteplase 0.6 mg/kg IV vs. standard-dose alteplase 0.9 mg/kg IV
    • 935 patients with elevated blood pressure were also randomized to early intensive blood pressure management vs. guideline-recommended management in ongoing trial to be published separately
    • primary outcome death or disability (modified Rankin score 2-6) at 90 days
    • noninferiority of low-dose alteplase defined as odds ratio for primary outcome < 1.14 compared to standard-dose alteplase at limit of 95% CI
    • 3.1% had missing outcome data and were excluded from analysis
    • outcome assessors were blinded
    • comparing low-dose alteplase vs. standard-dose alteplase
      • primary outcome in 53.2% vs. 51.1% (odds ratio 1.09, 95% CI 0.95-1.25, noninferiority not met)
      • major symptomatic intracerebral hemorrhage (SITS-MOST criteria) in 1% vs. 2.1% (p = 0.01, NNT 91)
      • 7-day mortality 3.6% vs. 5.3% (p = 0.02, NNT 59)
      • fatal events within 7 days in 0.5% vs. 1.5% (p = 0.01, NNT 100)
      • 90-day mortality 8.5% vs. 10.3% (p = 0.07)
    • no significant difference in overall health-related quality of life, admission to residential care, duration of hospitalization, death or neurologic deterioration at 72 hours, or serious adverse events
    • consistent results in per-protocol analysis including 89.9% of patients
    • Reference - ENCHANTED trial (N Engl J Med 2016 Jun 16;374(24):2313), editorial can be found in N Engl J Med 2016 Jun 16;374(24):2389
  • lower dose of recombinant tissue plasminogen activator (< 0.65 mg/kg) associated with lower risk of poor functional outcomes than higher doses in Chinese patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on prospective cohort study
    • 1,004 Chinese patients with acute ischemic stroke receiving thrombolytic therapy were analyzed
      • all patients received between 0.6 mg/kg and 0.9 mg/kg doses of recombinant tissue plasminogen activator (rt-PA)
      • 97.2% completed 1-month follow-up and 95.6% completed 3-month modified Rankin Scale (mRS)
    • rt-PA dose ≤ 0.65 mg/kg associated with decreased risk of poor functional outcome (mRS score > 1) at 3 months compared to higher doses (adjusted odds ratio 0.67, 95% CI 0.45-0.98)
    • rt-PA dose > 0.86 mg/kg associated with increased risk of symptomatic intracerebral hemorrhage (adjusted odds ratio 2.15, 95% CI 1.19-3.86)
    • in patients > 70 years old, increasing doses of rt-PA associated with
      • increased risk of symptomatic intracerebral hemorrhage
      • decreased risk of good functional outcome at 3 months
      • increased mortality
    • Reference - Stroke 2014 Aug;45(8):2359
  • alteplase (t-PA) 0.72 mg/kg may have better outcomes than alteplase 0.9 mg/kg in Chinese patients ≥ 70 years old with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on prospective cohort study
    • 241 Chinese patients (mean age 66 years) with acute ischemic stroke received alteplase 0.72 mg/kg IV vs. alteplase 0.9 mg/kg IV and were followed for up to 3 months
    • comparing alteplase 0.72 mg/kg vs. 0.9 mg/kg
      • symptomatic intracerebral hemorrhage in 2.6% vs. 8% (not significant)
      • 3-month mortality 6.9% vs. 12.8% (not significant)
    • comparing alteplase 0.72 mg/kg vs. 0.9 mg/kg in subgroup of 112 patients ≥ 70 years old
      • symptomatic intracerebral hemorrhage in 3.3% vs. 15.4% (p = 0.0257, NNT 9)
      • 3-month mortality 5% vs. 21.1% (p = 0.0099, NNT 7)
      • independence rate 53.6% vs. 32.6% (p = 0.0311, NNT 5)
    • Reference - Stroke 2010 May;41(5):885 full-text

Thrombolytics other than alteplase

Tenecteplase

  • tenecteplase (TNKase) FDA approved for acute myocardial infarction but not stroke (FDA DailyMed 2018 March)
  • tenecteplase 0.4 mg/kg IV single bolus may not be superior or noninferior to alteplase, but might be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion (AHA/ASA Class IIb, Level B-R)(1)
  • Canadian Stroke Best Practice Recommendations state IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved for stroke(6)
  • tenecteplase might have similar clinical outcomes compared to alteplase if given within 4.5 hours of onset of acute ischemic stroke (level 2 [mid-level] evidence)
    • based on 3 randomized trials with inconsistent results
    • tenecteplase may have similar radiologic and neurologic outcomes compared to alteplase if given within 4.5 hours of acute ischemic stroke onset (level 2 [mid-level] evidence), but tenecteplase might be associated with increased risk for serious adverse events (level 2 [mid-level] evidence)
      • based on randomized trial without intention-to-treat analysis, and with limited detail for serious adverse events
      • 104 adults with clinical diagnosis of supratentorial acute ischemic stroke eligible for IV thrombolysis within 4.5 hours of symptom onset were randomized to tenecteplase 0.25 mg/kg (maximum 25 mg) vs. alteplase 0.9 mg/kg (maximum 90 mg) and followed for 90 days
      • patients and outcome assessors were blinded to treatment, but treating clinicians were not blinded due to differences in drug administration schedules
      • primary outcome was penumbral salvage of ischemic but viable tissue at 24-48 hours after treatment (estimated as penumbra volume on baseline computed tomography [CT] perfusion minus infarcted penumbra volume at 24-48 hours on noncontrast CT)
      • 92.3% had final diagnosis of stroke, ≤ 92.3% were included in analyses (68.3% were included in penumbral salvage analysis)
      • comparing tenecteplase vs. alteplase
        • mean penumbral salvage 68% vs. 68% (not significant)
        • excellent recovery (modified Rankin Scale score 0-1) at 90 days in 28% vs. 20% (not significant)
        • poor recovery (modified Rankin Scale score 5-6) at 90 days in 21.3% vs. 18.4% (no p value reported)
        • mortality at 90 days 17% vs. 12% (not significant)
        • any intracerebral hemorrhage in 15% vs. 27% (p = 0.09)
        • any parenchymal hemorrhage in 2% vs. 10% (p = 0.12)
        • symptomatic intracerebral hemorrhage (ECASS II definition) in 6% vs. 8% (not significant)
        • any serious adverse event within 7 days in 15% vs. 18% (not significant)
        • any serious adverse event 7-90 days after stroke in 35% vs. 14% (no p value reported, NNH 4)
        • serious adverse events not clearly reported by time of event (0-7 days vs. 7-90 days) and included many different things such as new ischemic stroke, extracranial bleeding, pneumonia, atrial fibrillation, abdominal pain, chest pain, renal impairment, and planned medical procedures
      • Reference - ATTEST trial (Lancet Neurol 2015 Apr;14(4):368)
    • tenecteplase may increase likelihood of good functional recovery (no to slight disability at 90 days) compared to alteplase if given within 4.5 hours of onset of acute ischemic stroke (level 2 [mid-level] evidence)
      • based on small randomized trial
      • 75 patients > 18 years old within 6 hours of acute ischemic stroke and CT imaging criteria suggesting high likelihood of benefit from early reperfusion were randomized to 1 of 3 treatments
        • alteplase 0.9 mg/kg (maximum 90 mg) IV with 10% as initial bolus and 90% over 1 hour
        • tenecteplase 0.1 mg/kg (maximum 10 mg) IV bolus
        • tenecteplase 0.25 mg/kg (maximum 25 mg) IV bolus
      • CT imaging criteria were
        • CT angiographic imaging showing intracranial occlusion of anterior cerebral, middle cerebral, or posterior cerebral artery
        • CT perfusion imaging showing infarct-core lesion < one-third of middle cerebral artery territory or < one-half of anterior cerebral or posterior cerebral artery territory, and hemispheric perfusion lesion ≥ 20 mL and ≥ 20% greater than infarct-core lesion
      • of 2,164 patients screened for trial enrollment, only 604 (22%) were potentially eligible for IV thrombolysis, of whom 127 (5% of original group) met CT imaging criteria
      • baseline differences between groups
        • alteplase group had fewer smokers and lower prevalence of diabetes
        • mean time to treatment 2.7 hours with alteplase vs. 3.1 hours with tenecteplase (both groups combined)
      • treating clinicians were not blinded due to differences in drug administration schedules
      • only 3 patients were treated after 4.5 hours
      • comparing tenecteplase (both groups combined) vs. alteplase
        • good or excellent recovery (modified Rankin Scale score 0-2) at 90 days in 72% vs. 44% (p = 0.02, NNT 4)
        • excellent recovery (modified Rankin Scale score 0-1) at 90 days in 54% vs. 40% (not significant)
        • poor recovery (modified Rankin Scale score 5-6) at 90 days in 10% vs. 28% (p = 0.09)
        • mortality 8% vs. 12% (not significant)
        • mean improvement in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours 8 vs. 3 (p < 0.001)
        • major neurologic improvement (NIHSS score reduced by ≥ 8) at 24 hours in 64% vs. 36% (p = 0.02, NNT 4)
        • mean reperfusion volume at 24 hours 79.3% vs. 55.4% (p = 0.004)
        • large parenchymal hematomas in 4% vs. 16% (p = 0.09)
      • comparing tenecteplase 0.25 mg/kg vs. 0.1 mg/kg
        • mean improvement in NIHSS score at 24 hours 9.6 vs. 6.3 (p = 0.0326)
        • excellent recovery (modified Rankin Scale score 0-1) at 90 days in 72% vs. 36% (p = 0.011, NNT 3)
        • good or excellent recovery (modified Rankin Scale score 0-2) at 90 days in 84% vs. 60% (p = 0.114)
        • poor recovery (modified Rankin Scale score 5-6) at 90 days in 8% vs. 12% (not significant)
        • mortality in 4% vs. 12% (not significant)
      • Reference - N Engl J Med 2012 Mar 22;366(12):1099
    • in randomized trial with early termination
      • randomized trial comparing 3 different doses of tenecteplase (0.1 mg/kg vs. 0.25 mg/kg vs. 0.4 mg/kg) to alteplase 0.9 mg/kg was terminated early due to slow enrolment (112 patients randomized at time of termination)
      • no clear differences in outcomes at 3 months, but trial too small to support reliable conclusions
      • allocation into tenecteplase 0.4 mg/kg group was stopped before trial termination due to increased rates of symptomatic intracranial hemorrhage
      • Reference - Stroke 2010 Apr;41(4):707 full-text
    • no significant difference in death or dependance at 3 months comparing tenecteplase vs. alteplase in meta-analysis of these 3 trials
    • DynaMed commentary -- alteplase given 3-4.5 hours after stroke onset increases risk of symptomatic intracranial hemorrhage and risk of fatal intracranial hemorrhage within 7 days (level 1 [likely reliable] evidence) and might increase 90-day mortality (level 2 [mid-level] evidence) with uncertain effect on functional outcomes; tenecteplase efficacy, safety, and comparative efficacy and safety by time windows (0-3 hours, 3-4.5 hours) not reported

Streptokinase

  • usefulness of IV defibrinogenating agents and of IV fibrinolytics other than alteplase and tenecteplase is not proven; these agents should only be used in setting of a clinical trial (AHA/ASA Class III No Benefit, Level B-R)(1)
  • Canadian Stroke Best Practice Recommendations state IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved in Canada for stroke(6)
  • streptokinase associated with increased mortality in patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on association with increased mortality in 2 of 3 randomized trials
    • streptokinase associated with early mortality in patients with acute ischemic stroke (level 2 [mid-level] evidence)
      • based on early termination of randomized trial without blinding
      • 622 patients with acute ischemic stroke within 6 hours of symptom onset were randomized to streptokinase (1.5 million units IV over 1 hour) vs. aspirin (300 mg/day for 10 days) vs. streptokinase plus aspirin vs. neither
      • comparing streptokinase vs. no streptokinase
        • mortality at 10 days 26.5% vs. 11.5% (p < 0.05, NNH 6)
        • mortality at 6 months 35.8% vs. 24% (p < 0.05, NNH 8)
        • disability at 6 months in 26.8% vs. 39.9% (p < 0.05, NNT 8)
        • death or disability at 6 months in 62.6% vs. 63.9% (not significant)
      • Reference - MAST-I trial (Lancet 1995 Dec 9;346(8989):1509), editorial can be found in Lancet 1995 Dec 9;346(8989):1504, commentary can be found in Lancet 1996 Feb 10;347(8998):391
      • later commentary by same authors suggests that addition of aspirin to streptokinase increased risk of intracranial hemorrhage and streptokinase alone should be studied (Lancet 1998 Sep 12;352(9131):880)
    • streptokinase associated with increased mortality in patients with acute ischemic stroke (level 2 [mid-level] evidence)
      • based on randomized trial with borderline statistical significance
      • 310 patients with acute ischemic stroke and ischemia in middle cerebral artery territory were randomized to streptokinase 1.5 million units vs. placebo IV over 1 hour within 6 hours of stroke onset
      • comparing streptokinase vs. placebo
        • mortality at 10 days 34% vs. 18.2% (p = 0.002, NNH 7)
        • mortality at 6 months 46.8% vs. 38.3% (p = 0.06)
        • primary outcome of death or severe disability (modified Rankin Scale score ≥ 3) at 6 months in 79.5% vs. 81.8% (not significant)
      • Reference - MAST-E trial (N Engl J Med 1996 Jul 18;335(3):145 full-text), editorial can be found in N Engl J Med 1996 Jul 18;335(3):199, commentary can be found in N Engl J Med 1997 Jan 2;336(1):65
    • streptokinase within 4 hours of stroke onset does not appear to reduce mortality or disability (level 2 [mid-level] evidence)
      • based on randomized trial with wide confidence intervals
      • 340 patients aged 18-85 years with stroke randomized to streptokinase 1.5 million units vs. placebo IV in normal saline 100 mL over 1 hour
      • no significant difference in risk of unfavorable outcome (death or disability) at 3 months (relative risk 1.08, 95% CI 0.74-1.58)
      • streptokinase associated with higher rate of hematomas (13.2% vs. 3%, p < 0.01, NNH 9) and symptomatic hematomas (12.6% vs. 2.4%, NNH 9)
      • in subgroup of 70 patients treated within 3 hours after stroke onset, streptokinase associated with nonsignificant reduction in risk of unfavorable outcome (death or disability) at 3 months (relative risk 0.66, 95% CI 0.28-1.58)
      • Reference - ASK trial (JAMA 1996 Sep 25;276(12):961), editorial can be found in JAMA 1996 Sep 25;276(12):995, commentary can be found in JAMA 1997 Jan 1;277(1):19

Desmoteplase

  • usefulness of IV defibrinogenating agents and of IV fibrinolytics other than alteplase and tenecteplase is not proven; these agents should only be used in setting of a clinical trial (AHA/ASA Class III No Benefit, Level B-R)(1)
  • Canadian Stroke Best Practice Recommendations state IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved in Canada for stroke(6)
  • desmoteplase 3-9 hours after ischemic stroke may not improve 90-day functional outcomes in patients with occlusion or high-grade stenosis of cerebral arteries (level 2 [mid-level] evidence)
    • based on randomized trial with confidence intervals including both presence and absence of clinically meaningful differences
    • 492 patients with ischemic stroke plus occlusion or high-grade stenosis in major cerebral artery on magnetic resonance imaging or computed tomography were randomized to desmoteplase 90 mcg/kg IV vs. placebo IV within 3-9 hours of witnessed symptom onset
      • all patients had National Institutes of Health Stroke Scale (NIHSS) score 4-24
      • patients with modified Rankin Scale score > 1 before stroke were excluded
    • median time from stroke onset to treatment was 6.9 hours in desmoteplase group vs. 7 hours in placebo group (not significant)
    • NIHSS response defined as NIHSS score decrease ≥ 8 points or NIHSS ≤ 1 at 90 days
    • 82.3% completed trial and 96.1% were included in analysis
    • comparing desmoteplase vs. placebo at 90 days
      • modified Rankin Scale score 0-2 in 51% vs. 50% (adjusted odds ratio 1.2, 95% CI 0.79–1.81)
      • NIHSS response in 62% vs. 56% (not significant)
      • mortality in 10% vs. 10% (not significant)
      • any serious adverse events in 27% vs. 29% (no p value reported)
      • symptomatic intracranial hemorrhage in 3% vs. 2% (no p value reported)
      • major hemorrhage in 4% vs. 6% (no p value reported)
    • consistent results in per protocol analysis
    • Reference - DIAS-3 trial (Lancet Neurol 2015 Jun;14(6):575)
  • desmoteplase not associated with improved clinical response at 90 days after acute stroke (level 2 [mid-level] evidence)
    • based on randomized trial with inadequate statistical power
    • 193 patients with acute ischemic stroke diagnosed by MRI or CT were randomized to IV desmoteplase 90 mcg/kg vs. desmoteplase 125 mcg/kg vs. placebo within 3-9 hours of onset of stroke symptoms
    • clinical response rates at 90 days 47% with desmoteplase 90 mcg/kg vs. 36% with desmoteplase 125 mcg/kg vs. 46% with placebo
    • pretrial sample size estimates based on assumed 20% clinical response rate in placebo group (larger sample size would be needed to confidently exclude a difference with a 46% clinical response rate in placebo group)
    • Reference - DIAS-2 trial (Lancet Neurol 2009 Feb;8(2):141 full-text), editorial can be found in Lancet Neurol 2009 Feb;8(2):126

Urokinase

  • usefulness of IV defibrinogenating agents and of IV fibrinolytics other than alteplase and tenecteplase is not proven; these agents should only be used in setting of a clinical trial (AHA/ASA Class III No Benefit, Level B-R)(1)
  • IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved in Canada for stroke(6)
  • urokinase may be used for intra-arterial thrombolytics; see Intra-arterial Thrombolytics in Endovascular therapy for acute stroke for additional information

Fibrinogen depleting agents

Ancrod

  • usefulness of IV defibrinogenating agents and of IV fibrinolytics other than alteplase and tenecteplase is not proven; these agents should only be used in setting of a clinical trial (AHA/ASA Class III No Benefit, Level B-R)(1)
  • IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved in Canada for stroke(6)
  • ancrod does not decrease mortality and increases risk of symptomatic intracranial hemorrhage in patients with definite or probable ischemic stroke (level 1 [likely reliable] evidence) but might reduce dependency in surviving patients (level 2 [mid-level] evidence)
    • based on Cochrane review
    • systematic review of 8 randomized trials comparing fibrinogen-depleting agents started within 14 days of stroke onset vs. placebo or control in 5,701 patients with definite or probable ischemic stroke
    • 6 trials with 2,404 patients evaluated ancrod
    • no significant difference in all-cause mortality at end of follow-up (risk ratio [RR] 1.1, 95% CI 0.95-1.29) in analysis of 6 trials with 2,404 patients
    • ancrod associated with
      • nonsignificant decrease in death or dependency at end of follow-up (RR 0.96, 95% CI 0.9-1.02) in analysis of 4 trials with 2,354 patients
      • increase in symptomatic intracranial hemorrhage at end of treatment period in analysis of 6 trials with 2,404 patients
        • RR 3.56 (95% CI 2.15-5.87)
        • NNH 12-54 with 1.6% having symptomatic intracranial hemorrhage at end of treatment period in control group
      • decrease in pulmonary embolism or infarction in analysis of 2 trials with 1,000 patients
        • RR 0.25 (95% CI 0.07-0.88)
        • NNT 45-348 with 2.4% having pulmonary embolism or infarction in control group
    • Reference - Cochrane Database Syst Rev 2012 Mar 14;(3):CD000091
  • summaries of large ancrod trials
    • ancrod has inconsistent results for functional status in 2 randomized trials
      • STAT trial randomized 500 patients within 3 hours of stroke onset in United States and Canada, although some patients were allowed up to 6 hours before treatment
      • ESTAT trial enrolled 1,222 patients within 6 hours of stroke onset in Europe, Australia, and Israel; adapted from STAT trial but with stricter computed tomography (CT) entry criteria and blood pressure modifications
      • both trials enrolled patients with ischemic stroke and acute symptoms lasting at least 30 minutes
      • patients were randomized to ancrod vs. placebo as continuous 72-hour IV infusion, followed by infusions lasting about 1 hour at 96 and 120 hours, infusion rates based on fibrinogen levels with ancrod regimen designed to decrease plasma fibrinogen levels to 1.2-2.1 mcmol/L
      • primary outcome of favorable functional status defined as survival at 90 days with Barthel Index 95 or greater (scale 0-100) or at least equal to prestroke value
      • comparing ancrod vs. placebo in STAT trial
        • 41.1% vs. 35.3% achieved favorable functional status (p = 0.04, NNT 18 but NNT 13 after adjustment for baseline severity)
        • 11.8% vs. 19.8% severely disabled (p = 0.01, NNT 13)
        • 77% vs. 83.3% completed the treatment (difference not statistically significant)
        • no significant differences in mortality rates at 7 days (8.9% vs. 9.5%), 3 months (25.4% vs. 23%), or end of trial (33.5% vs. 32.5%)
        • adverse events within 28 days included 5.2% vs. 2% symptomatic intracranial hemorrhage (p = 0.06, NNH 31), 19% vs. 10.7% asymptomatic intracranial hemorrhage (p = 0.01, NNH 12), 5.2% vs. 9.5% venous thrombotic event (p = 0.05, NNT 24)
        • trial funded by drug manufacturer
        • Reference - JAMA 2000 May 10;283(18):2395 full-text
        • editorial noting that multicenter trial was conducted mostly in community hospitals, many comparisons with tissue plasminogen activator (t-PA) and mention of another ancrod trial with therapy given up to 6 hours that was terminated early due to increased mortality can be found in JAMA 2000 May 10;283(18):2440
        • commentary can be found in JAMA 2000 Sep 20;284(11):1379 and in JAMA 2000 Oct 18;284(15):1926, commentary and comparison with NINDS trial can be found in ACP J Club 2000 Nov-Dec;133(3):91
      • comparing ancrod vs. placebo in ESTAT trial
        • 42% vs. 42% favorable functional outcome at 3 months (no significant difference)
          • 43% vs. 42% in 1,078 patients treated after 3 hours (not significant)
          • 33% vs. 42% in 138 patients treated within 3 hours (not significant)
        • 20% vs. 14% mortality at 3 months (p = 0.023, NNH 16)
        • 25% vs. 21% mortality at 12 months (not significant)
        • neurological recovery in Scandinavian Stroke Scale +3.6 vs. +5.2 points (p = 0.042)
        • 7% vs. 2% symptomatic intracranial hemorrhage (p = 0.007, NNH 20)
        • 5.3% vs. 2% asymptomatic intracranial hemorrhage (p = 0.011, NNH 30)
        • Reference - Lancet 2006 Nov 25;368(9550):1871, editorial can be found in Lancet 2006 Nov 25;368(9550):1845
    • ancrod does not appear to improve 90-day function scores and may increase risk of symptomatic intracranial hemorrhage in patients with acute ischemic stroke (level 2 [mid-level] evidence)
      • based on randomized trial with early termination and inadequate statistical power
      • 508 adults (mean age 70 years) with acute ischemic stroke and able to begin study treatment within 6 hours of symptom onset randomized to ancrod 0.167 units/kg/hour vs. placebo by IV infusion over 2-3 hours
      • study terminated early after interim futility analysis (at 38.5% of targeted recruitment)
      • 82.4% of randomized patients completed study
      • efficacy and safety analyses included 98.4% of randomized patients (anyone infused with any designated treatment material)
      • primary outcome was favorable treatment response at 90 days, defined as any of
        • prestroke modified Rankin Scale (mRS) score 0-1, pretreatment National Institutes of Health Stroke Scale (NIHSS) score 5-15, and 90-day mRS score 0-1
        • prestroke mRS score 0-1, pretreatment NIHSS score ≥ 16, and 90-day mRS score 0-2
        • prestroke mRS score ≥ 2, any pretreatment NIHSS score, 90-day mRS score ≤ prestroke mRS score
      • comparing ancrod vs. placebo at 90 days
        • favorable treatment response in 39.6% vs. 37.2% (not significant)
        • mortality 15.6% vs. 14.1% (not significant)
        • symptomatic intracranial hemorrhage within first 72 hours
          • using Ancrod Stroke Program criteria in 3.9% vs. 2% (not significant)
          • using ECASS II criteria in 3.5% vs. 0.4% (p = 0.021, NNH 32)
        • any serious adverse event in 38% vs. 33.1% (not significant)
      • Reference - Stroke 2009 Dec;40(12):3796 full-text

Defibrase

  • usefulness of IV defibrinogenating agents and of IV fibrinolytics other than alteplase and tenecteplase is not proven; these agents should only be used in setting of a clinical trial (AHA/ASA Class III No Benefit, Level B-R)(1)
  • IV alteplase is the standard of care for thrombolysis and is currently the only approved thrombolytic agent for acute ischemic stroke treatment; other drugs being investigated but are not approved in Canada for stroke(6)
  • defibrase may not reduce mortality but might reduce dependency and may reduce risk of recurrent stroke in patients with definite or probable ischemic stroke (level 2 [mid-level] evidence)
    • based on Cochrane review of trials with methodologic limitations
    • systematic review of 8 randomized trials comparing fibrinogen-depleting agents started within 14 days of stroke onset vs. placebo or control in 5,701 patients with definite or probable ischemic stroke
    • 2 trials with 3,297 patients evaluated defibrase; both had 17%-27% loss to follow-up at 1 year and did not perform intention-to-treat analysis
    • no significant differences in
      • all-cause mortality at end of follow-up (risk ratio [RR] 0.99, 95% CI 0.76-1.29) in analysis of 2 trials with 2,624 patients
      • symptomatic intracranial hemorrhage at end of treatment period (RR 1.15, 95% CI 0.6-2.2) in analysis of 2 trials with 3,000 patients
    • defibrase associated with nonsignificant decrease in death or dependency at end of follow-up (RR 0.93, 95% CI 0.87-1) in analysis of 2 trials with 3,000 patients
    • defibrase associated with decrease in recurrent stroke (ischemic or unknown type) at end of follow-up in analysis of 2 trials with 2,624 patients
      • RR 0.68 (0.5-0.93)
      • NNT 29-204 with 7% having recurrent stroke at end of follow-up in control group
    • Reference - Cochrane Database Syst Rev 2012 Mar 14;(3):CD000091

Ultrasound-enhanced thrombolysis

  • American Heart Association/American Stroke Association (AHA/ASA) does not recommend adjuvant sonothrombolysis (AHA/ASA Class III No Benefit, Level B-R)(1)
  • addition of ultrasound to IV tissue plasminogen activator (t-PA) (sonothrombolysis) might reduce disability compared to t-PA alone in patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on Cochrane review of trials with methodologic limitations
    • systematic review of 5 randomized trials evaluating ultrasound-enhanced IV thrombolysis in 233 patients with definite acute ischemic stroke
    • 4 trials had methodologic limitations including unclear blinding, incomplete outcome data, or selective reporting
    • 1 trial without methodologic limitations had only 15 patients and did not include t-PA in control group
    • compared to t-PA alone, ultrasound plus t-PA associated with
      • decreased death or dependency at 3 months in analysis of 4 trials with 191 patients
        • odds ratio (OR) 0.52 (95% CI 0.28-0.97)
        • NNT 4-146 with death or dependency in 66% in t-PA alone group
        • none of the trials were statistically significant individually in this analysis
        • independence defined as modified Rankin Scale score 0-2 in 3 trials and modified Rankin Scale score 0-1 in 1 trial, so meta-analysis may not be clearly representing a single outcome
      • decreased recanalization failure (OR 0.31, 95% CI 0.17-0.56) in analysis of 4 trials with 215 patients
      • nonsignificant increase in symptomatic or asymptomatic cerebral hemorrhage (OR 2.43, 95% CI 0.89-6.65) in analysis of 4 trials with 214 patients
      • no significant effect on mortality at follow-up (OR 1.01, 95% CI 0.45-2.25) in analysis of 4 trials with 191 patients
    • Reference - Cochrane Database Syst Rev 2012 Oct 17;(10):CD008348
  • high-frequency ultrasound-enhanced thrombolysis may improve recanalization rates (level 3 [lacking direct] evidence) without increasing risk of symptomatic intracerebral hemorrhage (level 2 [mid-level] evidence)
    • based on systematic review without study quality assessment
    • systematic review of 6 randomized trials and 3 nonrandomized studies evaluating ultrasound-enhanced thrombolysis (transcranial Doppler, transcranial color-coded duplex, or low-frequency ultrasound) on t-PA activity in 416 patients with acute cerebral ischemia
    • high-frequency ultrasound-enhanced thrombolysis (transcranial Doppler or transcranial color-coded duplex ultrasound) compared to t-PA alone in analysis of 5 trials
      • no significant difference in risk of symptomatic intracerebral hemorrhage
      • increased likelihood of complete recanalization in high-frequency group (odds ratio 2.99, 95% CI 1.7-5.25)
    • Reference - Stroke 2010 Feb;41(2):280 full-text
  • addition of continuous ultrasound to t-PA improves recanalization rates but no clear effect on clinical outcomes (level 3 [lacking direct] evidence)
    • based on 2 randomized trial without differences in clinical outcomes
    • 126 patients with acute ischemic stroke due to middle cerebral artery occlusion were treated with IV t-PA within 3 hours and randomized to active vs. sham ultrasound treatment
      • ultrasound treatment started before t-PA bolus and provided continuous 2-megahertz (MHz) pulsed-wave ultrasound to occlusion (up to 750 milliwatts [mW]) for 2 hours
      • active ultrasound improved rates of complete recanalization at 2 hours (46% vs. 18%, p < 0.001) but did not significantly affect clinical recovery within 2 hours (29% vs. 21%, p = 0.4)
      • no significant difference in rates of intracerebral hemorrhage (5% in each group)
      • at 3 months, 42% vs. 29% had favorable outcomes based on modified Rankin Scale score 0 or 1 but this result was not statistically significant (p = 0.2) and not based on intention-to-treat analysis
      • worst-case scenario assumptions for dropouts (favorable outcome for control group but not intervention) would result in 35% vs. 44% having favorable outcome (nonsignificantly favoring control group)
      • Reference - CLOTBUST trial (N Engl J Med 2004 Nov 18;351(21):2170 full-text), editorial can be found in N Engl J Med 2004 Nov 18;351(21):2154
    • 37 patients with acute middle cerebral artery main stem occlusion randomized to 1-hour transcranial continuous ultrasound vs. control
      • all patients had standard t-PA thrombolysis
      • comparing ultrasound vs. control
        • complete or partial recanalization after 1 hour in 57.9% vs. 22.2% (p = 0.045, NNT 3)
        • Barthel index ≥ 95 at 90 days in 42% vs. 0% (p = 0.003, NNT 3)
        • modified Rankin Scale score ≤ 1 at 90 days in 21% vs. 0% (p = 0.1)
        • symptomatic intracranial hemorrhage in 15.8% vs. 5.6% (not significant)
      • Reference - Stroke 2008 May;39(5):1470 full-text

Intra-arterial thrombolytics

  • intra-arterial thrombolysis (with agents such as urokinase or prourokinase) does not appear to be safer or more effective than IV thrombolysis for most patients with acute ischemic stroke
    • no drug is FDA approved for intra-arterial use in treatment of stroke
    • intra-arterial thrombolysis may be considered in carefully selected patients with acute middle cerebral artery occlusion or acute basilar occlusion if within 6-hour time window, but endovascular treatment with stent retriever is recommended over intra-arterial fibrinolysis
    • see Endovascular therapy for acute stroke and Basilar artery occlusion for additional information

Ambulance-Based Thrombolysis

  • ambulance-based thrombolysis appears to reduce time to treatment without increasing adverse events (level 2 [mid-level] evidence)
    • based on quasi-randomized trial
    • 6,182 adults (median age 74 years) with suspected acute ischemic stroke and onset within 4 hours were assigned by week to ambulance-based thrombolysis vs. usual ambulance care
      • ambulance-based thrombolysis with tissue plasminogen activator (t-PA) conducted in mobile stroke units equipped with computed tomography (CT) scanner, point-of-care laboratory, telemedicine connection, stroke identification algorithm at dispatcher level, and prehospital stroke team
      • t-PA given prior to hospital transport (≤ 4.5 hours of symptom onset) if ischemic stroke confirmed
    • 34% of patients overall had confirmed ischemic stroke
    • mobile stroke unit was available and deployed for 56% of patients assigned to ambulance-based thrombolysis
    • of patients with confirmed stroke, t-PA received in
      • 29% with ambulance-based thrombolysis overall
      • 32.6% with deployed ambulance-based thrombolysis
      • 21.1% with usual ambulance care
    • mean alarm to t-PA times
      • 61.4 minutes with ambulance-based thrombolysis overall (p < 0.001 vs. usual ambulance care)
      • 51.8 minutes with deployed ambulance-based thrombolysis (p < 0.001 vs. usual ambulance care)
      • 76.3 minutes with usual ambulance care
    • mean onset to t-PA times
      • 110.1 minutes with ambulance-based thrombolysis overall (p = 0.003 vs. usual ambulance care)
      • 102.7 minutes with deployed ambulance-based thrombolysis (p < 0.001 vs. usual ambulance care)
      • 118.5 minutes with usual ambulance care
    • no significant differences in 7-day or in-hospital mortality
    • in patients who received mobile stroke unit care, ambulance-based thrombolysis associated with nonsignificant decrease in risk of intracerebral hemorrhage (odds ratio 0.42, 95% CI 0.18-1.03)
    • Reference - PHANTOM-S trial (JAMA 2014 Apr 23-30;311(16):1622), editorial can be found in JAMA 2014 Apr 23-30;311(16):1615
  • mobile stroke unit reduces time to IV thrombolysis in patients with acute stroke (level 3 [lacking direct] evidence), but insufficient evidence to rule out increase in mortality (level 2 [mid-level] evidence)
    • based on randomized trial with inadequate statistical power for clinical outcomes
    • 100 patients aged 18-80 years having ≥ 1 stroke symptom within 2.5 hours of emergency call randomized to mobile stroke unit vs. hospital-based usual care and followed for 7 days
    • mobile stroke unit described as specialized ambulance with CT scanner, point-of-care laboratory, and telemedicine connection
    • trial discontinued at interim analysis when predetermined criteria met for emergency call-to-decision time
    • comparing mobile stroke unit vs. hospital-based care
      • median time from emergency call to therapy decision 35 minutes vs. 76 minutes (p < 0.0001)
      • median time from symptom onset to therapy decision 56 minutes vs. 104 minutes (p < 0.0001)
      • median time from symptom onset to IV thrombolysis 72 minutes vs. 153 minutes (p < 0.001)
      • 7-day mortality 11% vs. 4% (not significant)
    • Reference - Lancet Neurol 2012 May;11(5):397, editorial can be found in Lancet Neurol 2012 May;11(5):382

Quality Improvement

Medicare/Joint Commission National Hospital Inpatient Quality Measures

  • see Medicare/Joint Commission National Hospital Inpatient Quality Measures for additional information

Physician Quality Reporting System Quality Measures

  • 187. Stroke and Stroke Rehabilitation: Thrombolytic Therapy
    • Percentage of patients ≥ 18 years old with a diagnosis of acute ischemic stroke who arrive at the hospital within 2 hours of time last known well and for whom IV t-PA was initiated within 3 hours of time last known well
    • American College of Physicians (ACP) does not support this performance measure
      • "ACP believes that the measure specification requires further clarification. It is not clinically specific regarding the indications for treatment. There is evidence that the harms of thrombolytic therapy may outweigh the benefit in some cases, especially if the full exclusion criteria published by the National Institute of Neurological Disorders and Stroke and others are not followed. This should be made explicit in the measure exclusion criteria. There also are specific qualifications hospitals must meet in order to provide tPa. The absence of such conditions should also be noted as an exclusion criterion. There may also be regional variations in the availability of qualifying institutions, potentially making this measure inapplicable to all physicians in some areas."
      • Reference - ACP Performance Measure Review 2014 Apr 7 PDF
  • see Physician Quality Reporting System Quality Measures for additional information

Door-to-needle time expectations

Quality improvement evidence

  • national quality improvement initiative associated with decreased time to thrombolytic administration and improved clinical outcomes in patients with acute ischemic stroke (level 2 [mid-level] evidence)
    • based on before-and-after study
    • 71,169 patients with acute ischemic stroke treated with tissue plasminogen activator (t-PA) in United States were evaluated before and after implementation of national quality improvement initiative
      • 27,319 patients (38%) were treated from April 2003 to December 2009 before initiative
      • 43,850 patients (62%) were treated from January 2010 to September 2013 after initiative
    • national quality improvement initiative consisted of 10 care strategies to achieve shorter door-to-needle times for t-PA administration, provided clinical decision support tools, facilitated hospital participation, and encouraged sharing of best practices
    • comparing before vs. after national quality improvement initiative
      • median door-to-needle time for t-PA administration 77 minutes vs. 67 minutes (p < 0.001)
      • door-to-needle time for t-PA administration ≤ 1 hour in 26.5% vs. 41.3% (p < 0.001)
      • in-hospital all-cause mortality 9.93% vs. 8.25% (p < 0.001)
      • symptomatic intracranial hemorrhage at ≤ 36 hours in 5.68% vs. 4.68% (p < 0.001)
      • discharge to home in 37.6% vs. 42.7% (p < 0.001)
    • Reference - JAMA 2014 Apr 23-30;311(16):1632, editorial can be found in JAMA 2014 Apr 23-30;311(16):1615
  • telehealth for acute stroke management (telestroke) reported to improve access to thrombolysis (level 3 [lacking direct] evidence)
  • multicomponent intervention might increase use of alteplase for patients with acute stroke in community hospitals (level 3 [lacking direct] evidence)
    • based on cluster-randomized trial without clinical outcomes and with borderline significance
    • 24 community hospitals with 40,823 patients with acute stroke randomized to multicomponent intervention to increase alteplase use vs. control for 1 year and followed to 3 years
    • multicomponent intervention included qualitative and quantitative assessment of barriers to alteplase use, methods to address barriers, and additional support
    • baseline rate of alteplase use 1.25% in intervention and control hospitals
    • alteplase use in emergency department increased by 1.54% with multicomponent intervention vs. 0.85% with control (p = 0.08)
    • Reference - Lancet Neurol 2013 Feb;12(2):139, editorial can be found in Lancet Neurol 2013 Feb;12(2):120

Guidelines and Resources

Guidelines

United States guidelines

  • American Heart Association/American Stroke Association (AHA/ASA) scientific rationale for inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke can be found in Stroke 2016 Feb;47(2):581 full-text
  • American Heart Association/American Stroke Association (AHA/ASA) scientific statement on treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke can be found in Stroke 2017 Dec;48(12):e343
  • American College of Emergency Physicians (ACEP) clinical policy on use of intravenous tissue plasminogen activator for management of acute ischemic stroke in the emergency department can be found in Ann Emerg Med 2015 Sep;66(3):322
  • American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines (Ninth Edition) on antithrombotic and thrombolytic therapy for ischemic stroke can be found in Chest 2012 Feb;141(2 Suppl):e601S full-text
  • Institute for Clinical Systems Improvement (ICSI) guideline on diagnosis and initial treatment of ischemic stroke can be found at ICSI 2016 Dec PDF
  • American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) statement on emergency interventional stroke therapy (intra-arterial thrombolytic therapy) can be found in J Vasc Interv Radiol 2003 Sep;14(9 Pt 2):S385
  • American Academy of Emergency Medicine (AAEM) position statement on use of intravenous thrombolytic therapy in treatment of stroke can be found at AAEM 2002 Mar 11
  • American Society of Regional Anesthesia and Pain Medicine (ASRA) evidence-based guidelines (fourth edition) on regional anesthesia in patient receiving antithrombotic or thrombolytic therapy can be found in Reg Anesth Pain Med 2018 Apr;43(3):263

United Kingdom guidelines

  • Royal College of Physicians (RCP) national clinical guideline on stroke can be found at RCP 2016 Oct 3 PDF
  • National Institute of Health and Care Excellence (NICE) guidance on alteplase for treatment of acute ischemic stroke can be found at NICE 2012 Sep:TA264 PDF
  • Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on management of patients with stroke or transient ischemic attack (TIA) (assessment, investigation, immediate management, and secondary prevention) can be found at SIGN 2008 Dec PDF

Canadian guidelines

  • Canadian Association of Emergency Physicians (CAEP) position statement on acute ischemic stroke can be found at CJEM 2015 Mar;17(2):217 PDF

European guidelines

  • European Stroke Organisation (ESO) guideline on ischaemic stroke and transient ischaemic attack can be found at ESO 2011 PDF
  • Haute Autorité de Santé conseils pour accident vasculaire cérébral: prise en charge précoce (alerte, phase préhospitalière, phase hospitalière initiale, indications de la thrombolyse) se trouvent sur le site Haute Autorité de Santé 2009 Mai [French], portions also published in English

Asian guidelines

  • Chinese Stroke Therapy Expert Panel (CSTEP) consensus statement on use of intravenous recombinant tissue plasminogen activator to treat acute ischemic stroke can be found in CNS Neurosci Ther 2013 Aug;19(8):543
  • Joint Committee of Japan Stroke Society (JStS) guideline on management of stroke can be found at JStS 2009 PDF [Japanese 日本語]

Australian and New Zealand guidelines

  • Stroke Foundation (SF) (Australia) clinical guideline on stroke management can be found at SF 2017
  • Australasian College for Emergency Medicine (ACEM) statement on IV thrombolysis for ischaemic stroke can be found at ACEM 2018 Mar 7 PDF
  • National Stroke Foundation/Stroke Society of Australasia (NSF/SSA) position statement on implementation of IV tissue plasminogen activator in acute ischemic stroke can be found in Intern Med J 2009 May;39(5):317

African guidelines

Review articles

Patient Information

References

General references used

  • 1. Powers WJ, Rabinstein AA, Ackerson T, et al; American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110, corrections can be found in Stroke 2018 Mar;49(3):e138 and Stroke 2018 Jun;49(6):e233
  • 2. Brown MD, Burton JH, Nazarian DJ, et al; American College of Emergency Physicians (ACEP) Clinical Policies Subcommittee (Writing Committee) on Use of Intravenous tPA for Ischemic Stroke. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015 Sep;66(3):322-333
  • 3. The Royal College of Physicians (RCP) Intercollegiate Stroke Working Party. National clinical guideline for stroke. RCP 2016 PDF
  • 4. Minematsu K, Toyoda K, Hirano T, et al. Guidelines for the intravenous application of recombinant tissue-type plasminogen activator (alteplase), the second edition, October 2012: a guideline from the Japan Stroke Society. J Stroke Cerebrovasc Dis. 2013 Jul;22(5):571-600
  • 5. Stroke Foundation. Clinical Guidelines for Stroke Management 2017. SF 2017 Aug
  • 6. Boulanger JM, Lindsay MP, Gubitz G, et al. Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018. Int J Stroke. 2018 Dec;13(9):949-984

Recommendation grading systems used

  • American Heart Association/American Stroke Society (AHA/ASA) 2018 grading system for recommendations
    • classifications of recommendations
      • Class I - procedure or treatment should be performed or administered
      • Class IIa - reasonable to perform procedure or administer treatment, but additional studies with focused objectives needed
      • Class IIb - procedure or treatment may be considered; additional studies with broad objectives needed, additional registry data would be useful
      • Class III - procedure or treatment should not be performed or administered because it is not helpful or may be harmful
        • Class III ratings may be subclassified as Class III No Benefit or Class III Harm
    • levels of evidence
      • Level A - high-quality evidence from > 1 randomized controlled trial or meta-analysis of high-quality randomized controlled trials
      • Level B-R - moderate-quality evidence from ≥ 1 randomized controlled trial or meta-analysis of moderate-quality randomized controlled trials
      • Level B-NR - moderate-quality evidence from ≥ 1 well-designed nonrandomized trial, observational studies, or registry studies, or meta-analysis of such studies
      • Level C-LD - randomized or nonrandomized studies with methodological limitations or meta-analyses of such studies
      • Level C-EO - consensus of expert opinion based on clinical experience
  • American College of Cardiology/American Heart Association (ACC/AHA) grading system for recommendations
    • classifications of recommendations
      • Class I - procedure or treatment should be performed or administered
      • Class IIa - reasonable to perform procedure or administer treatment, but additional studies with focused objectives needed
      • Class IIb - procedure or treatment may be considered; additional studies with broad objectives needed, additional registry data would be useful
      • Class III - procedure or treatment should not be performed or administered because it is not helpful or may be harmful
        • Class III ratings may be subclassified as Class III No Benefit or Class III Harm
    • levels of evidence
      • Level A - high-quality evidence from > 1 randomized controlled trial or meta-analysis of high-quality randomized controlled trials
      • Level B-R - moderate-quality evidence from ≥ 1 randomized controlled trial or meta-analysis of moderate-quality randomized controlled trials
      • Level B-NR - moderate-quality evidence from ≥ 1 well-designed nonrandomized trial, observational studies, or registry studies, or meta-analysis of such studies
      • Level C-LD - randomized or nonrandomized studies with methodological limitations or meta-analyses of such studies
      • Level C-EO - consensus of expert opinion based on clinical experience
    • Reference
      • ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline on prevention, detection, evaluation, and management of high blood pressure in adults (Hypertension 2018 Jun;71(6):e13)
  • Canadian Stroke Best Practice Recommendations (CSBPR) levels of evidence
    • Evidence Level A
      • meta-analysis of randomized controlled trials or consistent findings from ≥ 2 randomized trials
      • desirable effects clearly outweigh undesirable effects or vice versa
    • Evidence Level B
      • single randomized controlled trial or meta-analysis of non-randomized and/or observational studies or consistent findings from ≥ 2 well-designed nonrandomized trials, uncontrolled trials, or large observational studies
      • desirable effects outweigh or are closely balanced with undesirable effects or vice versa
    • Evidence Level C
      • writing group consensus and/or supported by limited research evidence
      • desirable effects outweigh or are closely balanced with undesirable effects or vice versa (as determined by writing group consensus)
    • Reference - CSBPR on acute stroke management, update 2018 (CSBPR 2018 PDF)
  • American College of Emergency Physicians (ACEP) grades of recommendation
    • levels of recommendation
      • Level A - generally accepted principles for patient care that reflect a high degree of clinical certainty (based on evidence from ≥ 1 Class I study, or multiple Class II studies)
      • Level B - recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (based on evidence from ≥ 1 Class II study, or strong consensus of Class III studies)
      • Level C -
        • recommendations for patient care that are based on evidence from Class III studies, or in the absence of any adequate published literature, based on expert consensus
        • in instances where consensus recommendations are made, “consensus” is placed in parentheses at the end of the recommendation
    • classification of evidence
      • Class I studies
        • for therapy - randomized trial or meta-analysis of randomized trials
        • for diagnosis - prospective cohort using criterion standard or meta-analysis of prospective studies
        • for prognosis - population prospective cohort study or meta-analysis of prospective studies
      • Class II studies
        • for therapy - nonrandomized trial
        • for diagnosis - retrospective observational study
        • for prognosis - retrospective cohort or case-control study
      • Class III studies - case series, case report, or other (for example, consensus, review)
    • Reference - ACEP clinical policy on use of IV tissue plasminogen activator (t-PA) for management of acute ischemic stroke in emergency department (Ann Emerg Med 2015 Sep;66(3):322)
  • Japan Stroke Society (JSS) grades of recommendation
    • grades of recommendation
      • Grade A - strongly recommended
      • Grade B - recommended
      • Grade C1 - may be worth considering, but there is insufficient evidence
      • Grade C2 - not recommended because of a lack of evidence
      • Grade D - recommended against
    • levels of evidence
      • Level Ia - meta-analysis of randomized controlled trials (RCTs)
      • Level Ib - ≥ 1 RCT
      • Level IIa - ≥ 1 well-designed, controlled study but without randomization
      • Level IIb - ≥ 1 well-designed, quasi-experimental study
      • Level III - ≥ 1 well-designed, nonexperimental descriptive study (such as, comparative studies, correlation studies, and case studies)
      • Level IV - expert committee reports, opinions, and/or experience of respected authorities
    • Reference - JSS guideline on IV application of recombinant tissue-type plasminogen activator (alteplase) (J Stroke Cerebrovasc Dis 2013 Jul;22(5):571)
  • Stroke Foundation (SF) (Australia) grades of recommendation
    • Strong recommendation - guideline authors are certain that evidence supports a clear balance toward either desirable or undesirable effects
    • Weak recommendation - guideline authors are not certain about the balance between desirable and undesirable effects
    • Reference - SF clinical guidelines on stroke management (SF 2017 Aug)

DynaMed editorial process

  • DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
  • All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
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Special acknowledgements

  • Alexander Rae-Grant, MD, FRCP(C), FAAN (Deputy Editor, Neurology DynaMed Plus; Neurologist, Cleveland Clinic; Ohio, United States)
  • Dr. Rae-Grant declares no relevant financial conflicts of interest.
  • Amir Qaseem, MD, PhD, MHA, FACP (Vice President of Clinical Policy, American College of Physicians; Pennsylvania, United States; President Emeritus, Guidelines International Network (GIN); Germany)
  • Dr. Qaseem declares no relevant financial conflicts of interest.
  • Alan Ehrlich, MD (Executive Editor; Associate Professor of Family Medicine, University of Massachusetts Medical School; Massachusetts, United States)
  • Dr. Ehrlich declares no relevant financial conflicts of interest.
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