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Section 3.4

Acute Thrombolytic Therapy

All patients with disabling acute ischemic stroke who can be treated within 4.5 hours of symptom onset should be evaluated without delay to determine their eligibility for treatment with intravenous tissue plasminogen activator (alteplase).

  1. Eligible patients are those who can receive intravenous alteplase within 4.5 hours of the onset of stroke symptoms in accordance with criteria adapted from National Institute of Neurological Disorders and Stroke (NINDS) tPA Stroke Study and the European Cooperative Acute Stroke Study (ECASS III)207 [Evidence Level A].
  2. All eligible patients should receive intravenous alteplase as soon as possible after hospital arrival, with a target door-to-needle time of less than 60 minutes [Evidence Level C].
  3. Administration of alteplase should follow the American Stroke Association guidelines: total dose 0.9 mg/kg with 10 percent (0.09 mg/kg) given as intravenous bolus over one minute and the remaining 90 percent (0.81 mg/kg) given as an intravenous infusion over 60 minutes [Evidence Level A].
  4. Features on the initial CT brain scan of an otherwise alteplase-eligible ischemic stroke patient that modify the response to treatment remain poorly defined. Some of the trials of alteplase excluded patients with severe hemispheric stroke if the initial CT scan showed early signs of infarction involving more than one-third of the territory of the middle cerebral artery (i.e., a score of less than five on the Alberta Stroke Program Early CT Score [ASPECTS]). 232 In clinical practice, the decision to treat such a patient with alteplase should be based on the clinical judgment of the treating physician, and the wishes of the patient and family, until such time as additional data from randomized controlled trials are made available [Evidence Level B].
  5. There remain situations where there are sparse or no clinical trial data to support the use of thrombolytic therapy: paediatric stroke, stroke in patients over the age of 80 years with diabetes, adults who present within the first few hours of onset of an acute ischemic stroke but do not meet current criteria for treatment with intravenous alteplase, and intra-arterial thrombolysis. In clinical practice, the decision to use alteplase in these situations should be based on the clinical judgment of the treating physician, and the wishes of the patient and family, until such time as additional data from randomized controlled trials are available [Evidence Level A].

 

Note on this recommendation:

In Canada, alteplase is currently approved by Health Canada for use in adults with acute ischemic stroke within three hours after the onset of stroke symptoms. Exemptions may apply; e.g., a “Letter of No Objection” from Health Canada is required for clinical trials examining the use of intravenous alteplase for other treatment protocols.

    Criteria for Acute Thrombolytic Therapy

    Criteria adapted in accordance with the criteria identified in National Institute of Neurological Disorders and Stroke (NINDS) 233 tPA Stroke Study and the European Cooperative Acute Stroke Study (ECASS III) 207

    Treatment Criteria

    • Diagnosis of ischemic stroke causing measurable neurologic deficit in a patient who is18 years of age or older
    • Onset of symptoms more than one hour and less than 4.5 hours before alteplase administration

     

    Exclusion Criteria

    Historical

    • History of intracranial hemorrhage
    • Stroke or serious head or spinal trauma in the preceding three months
    • Recent major surgery
    • Arterial puncture at a non-compressible site in the previous seven days
    • Any other condition that could increase the risk of hemorrhage after alteplase administration

     

    Clinical

    • Symptoms suggestive of subarachnoid hemorrhage
    • Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo- or hyperglycemia
    • Hypertension refractory to antihypertensives such that target blood pressure

     

    Laboratory

    • Blood glucose concentration below 2.7 mmol/L or above 22.2 mmol/L
    • Elevated activated partial-thromboplastin time
    • International Normalized Ratio greater than 1.7
    • Platelet count below 100,000 per cubic millimetre

    CT or MRI Findings

    • Any hemorrhage on brain CT or MRI
    • CT or MRI signs of acute hemispheric infarction involving more than one-third of the middle cerebral artery territory (Alberta Stroke Program Early CT Score (ASPECTS)
    Rationale

    Meta-analyses of the randomized controlled trials of intravenous alteplase for acute ischemic stroke have shown that thrombolytic treatment can reduce the risk of disability and death, despite the risk of serious bleeding. The latest time for alteplase administration after stroke onset remains imprecisely defined, but currently available data show clear evidence of benefit when given up to 4.5 hours after the onset of symptoms. The available evidence demonstrates a strong inverse relationship between treatment delay and clinical outcome; eligible patients should be treated without delay, regardless of when they present within the treatment window.

    System Implications
    • Local protocols for prioritizing stroke patients for rapid access to appropriate diagnostics such as CT scans and duplex ultrasound, communicated to all relevant personnel such as emergency department, imaging, and stroke teams.
    • A system for rapid access to physicians experienced in administration of acute thrombolysis, including through telemedicine, which includes protocols for contacting physicians and for administration of tissue plasminogen activator.
    • Access to specialized stroke units where staff are experienced in managing patients who have received tissue plasminogen activator for stroke.
    Performance Measures
    1. Proportion of all ischemic stroke patients who receive treatment with alteplase (core).
    2. Proportion of all eligible ischemic stroke patients who receive treatment with alteplase.
    3. Proportion of all thrombolyzed stroke patients who receive alteplase within one hour of hospital arrival (core).
    4. Median time (in minutes) from patient arrival in the emergency department to administration of alteplase.
    5. Proportion of patients with symptomatic intracerebral hemorrhage following alteplase treatment.
    6. Proportion of patients in rural or remote communities who receive alteplase through the use of telestroke technology (as a proportion of all ischemic stroke cases in that community and as a proportion of all telestroke consults for ischemic stroke cases).

    Measurement Notes

    • Data may be obtained from patient charts, through chart audit or review.
    • Time interval measurements should be taken from the time the patient is triaged or registered at the hospital (whichever time comes first) until the time of medication administration noted in the patient chart (nursing notes, emergency department record, or medication record).
    • When recording if tissue plasminogen activator is given, the route of administration should also be recorded, as there are different times to administration benchmarks for intravenous versus intra-arterial routes.
    Implementation Resources and Knowledge Transfer Tools
    • National Institutes of Health Stroke Scale (NIHSS) and Canadian Neurological Scale (CNS) pocket cards available at www.heartandstroke.ca/profed
    • National Stroke Nurses Council: Best Practice Nursing Care Across the Acute Stroke Continuum: Modules 1&2
    Summary of the Evidence

    The release of the Third European Cooperative Acute Stroke Study (ECASS III) trial in 2008 resulted in an extension of the treatment time window for acute thrombolysis from three hours to four and one half hours.207 The 2009 update of the Cochrane systematic review of thrombolysis for acute ischemic stroke reflected these changes in practice.234 The systematic review included 26 trials involving 7,152 patients. Not all trials contributed data to each outcome. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration; the rest used the intravenous route. Most data came from trials that started treatment up to six hours after stroke; three trials started treatment up to nine hours and one small trial up to 24 hours after stroke. About 55 percent of the data was from trials of intravenous tissue plasminogen activator alone. Very few of the patients (0.5%) were aged over 80 years.

    Many trials had some imbalances in key prognostic variables. Several trials did not have complete blinding of outcome assessment. Thrombolytic therapy, mostly administered up to six hours after ischemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.81, 95% confidence interval (CI) 0.73 to 0.90). Thrombolytic therapy increased the risk of symptomatic intracranial hemorrhage (OR 3.49, 95% CI 2.81 to 4.33) and death by three to six months after stroke (OR 1.31, 95% CI 1.14 to 1.50). Treatment within three hours of

    stroke appeared more effective in reducing death or dependency (OR 0.71, 95% CI 0.52 to 0.96) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials in part attributable to concomitant antithrombotic drug use (P = 0.02), stroke severity and time to treatment. The analysis also found antithrombotic drugs given soon after thrombolysis may increase the risk of death. The authors concluded thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. This overall benefit was apparent despite an increase both in deaths (evident at seven to 10 days and at final follow up) and in symptomatic intracranial hemorrhages. The findings of this review also confirm that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which thrombolysis may best be given in routine practice.

    The Third European Cooperative Acute Stroke Study (ECASS III) examined the use of intravenous alteplase 3–4.5 hours after the onset of ischemic stroke.207 Of a total of 821 patients, 418 were randomly assigned to receive alteplase at a dose of 0.9 mg/kg and 403 to receive placebo. The median time for the administration of alteplase was three hours and 59 minutes after stroke onset. More patients had a favorable outcome (modified Rankin score 0 or 1) with alteplase than with placebo (52.4% v. 45.2%; OR 1.34, 95% CI 1.02–1.76; p = 0.04; NNT = 14). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% v. 17.6%, p = 0.001; for symptomatic intracranial hemorrhage, 2.4% v. 0.2%, p = 0.008 [number need to harm 45]). Mortality did not differ significantly between the alteplase and placebo groups (7.7% v. 8.4%; p = 0.68). There was no significant difference in the rate of other serious adverse events.

    ECASS III excluded patients older than 80 years, patients with severe stroke (National Institutes of Health Stroke Severity Score > 25 or imaging evidence of involvement of more than one-third of the middle cerebral artery territory) and patients with a history of the combination of previous stroke and diabetes. These factors most likely contributed to the low death rate, low hemorrhage rate and excellent placebo outcome rate relative to previous trials, and should be taken into consideration when treating patients 3–4.5 hours after stroke onset.

    These results were consistent with the benefit predicted by a model derived from a pooled analysis of individual patient data from previous randomized trials of intravenous alteplase versus placebo.236 The analysis found that earlier administration of alteplase improved the odds ratio of having a favorable outcome by 2.8 for 0–90 minutes, 1.55 for 90– 180 minutes and 1.4 for 180–270 minutes, highlighting the importance of initiating treatment without delay.

    Post marketing surveillance studies in Canada and Europe have suggested that intravenous alteplase is safe and effective in routine clinical practice when it is administered in accordance with the protocols used in the clinical trials.237-240 The Canadian Alteplase for Stroke Effectiveness Study (CASES) assessed the effectiveness of alteplase therapy for ischemic stroke in a prospective national cohort study.237 Data were collected over 2.5 years between 1999 and 2001 from centres capable of administering alteplase according to Canadian guidelines.241 A total of 1135 adults were enrolled at 60 hospitals across Canada (an estimated 84 percent of all treated ischemic stroke patients in the country) with follow up at 3 months. An excellent clinical outcome was observed in 37 percent of the patients. Symptomatic intracranial hemorrhage occurred in 4.6 percent of the patients (95% CI 3.4%–6.0%); however, 75 percent of these patients died in hospital. No differences in outcomes were observed between rural and urban settings.

    In Europe, the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), involving 6483 adults in 14 countries, showed that the rates of symptomatic intracerebral hemorrhage, mortality and independence in activities of daily living for patients treated with intravenous alteplase in routine clinical practice in accordance with the licensing specifications of the European Medicines Evaluation Agency were similar to the outcomes reported in randomized controlled trials.239 Comparison of a cohort of 11 865 patients treated within three hours and a cohort of 664 patients treated 3–4.5 hours after stroke onset showed no significant differences in outcome (symptomatic intracerebral hemorrhage, mortality and functional independence).240