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Acute Stroke Management

5. Acute Ischemic Stroke Treatment

June 2018 - 2018 UPDATE

5.1 Patient Selection for Acute Ischemic Stroke Treatments

Box 5A Criteria for Stroke Centres Providing Acute Ischemic Stroke Treatment

Note: treatment benefits from revascularization decreases over time as an estimated 1.9 million brain cells die every minute following stroke onset (Saver 2006); therefore, all patients with stroke should be treated as fast as possible to maximize potential for the best outcomes, and the new extended time windows should not be interpreted to mean that time to treatment can be slowed down in any way.

  1. All patients with disabling acute ischemic stroke within 24 hours of stroke symptom onset or last known well should be rapidly screened clinically and with neurovascular imaging [Evidence Level B].
  2. All patients with disabling acute ischemic stroke who can be treated within the indicated time windows must be screened without delay by a physician with stroke expertise (either on-site or by telemedicine/telestroke consultation) to determine their eligibility for both intravenous alteplase (within 4.5 hours from stroke symptom onset) and/or interventional treatment with endovascular thrombectomy (within a 6 hour window from stroke symptom onset). [Evidence Level A].
  3. Patients meeting criteria in 5.1 (i) (within 6 hours) should immediately undergo neurovascular imaging with non-contrast computed tomography (NCCT) and including CT angiography (CTA) then considered for treatment on the basis of imaging [Evidence Level A].
  4. There are randomized controlled trials which indicate that highly selected patients with disabling stroke symptoms may benefit from endovascular thrombectomy up to 24 hours from the time they were last known well, including patients with stroke on awakening, and patients should be considered for eligibility within the extended time window on a case-by-case basis [Evidence Level A]. Note, these patients were selected using CTP or diffusion-weighted criteria (as defined in Box 5C below) (new for 2018)
  5. Highly selected patients being considered for endovascular thrombectomy beyond 6 hours will require additional advanced neurovascular imaging [Evidence Level A]. Refer to Box 4D for additional Imaging Selection Criteria.

Clinical considerations:

  1. One recent multi-centre randomized double-blind placebo controlled trial compared alteplase to placebo for ischemic stroke patients with unknown time of onset, using MRI selection criteria (DWI/FLAIR mismatch). It included ischemic stroke patients who were not candidates for endovascular thrombectomy, and who would otherwise have met the criteria for acute intravenous alteplase administration 46 (refer to Box 5B for alteplase criteria)
    • This trial demonstrates a clinical benefit of intravenous alteplase administered more than 4.5 h from the time the patient was last known well in patients where onset time is unknown (no upper time limit defined).
    • If intravenous alteplase is considered after 4.5 h, a consultation with a physician with stroke expertise should be obtained. Selection of patients for intravenous alteplase in patients presenting after 4.5 hours on the basis of CT, CTA and CTP remains unproven at this time.
    • MRI scanning can be challenging to obtain urgently in an Emergency Department setting. This must be considered in decision-making and not delay decisions regarding endovascular thrombectomy eligibility.
5.2 Imaging Criteria

Refer to Section 4.2 for detailed recommendations and Boxes 4A, 4B, 4C and 4D for selection criteria for neuroimaging.

  1. Patients should be considered for revascularization treatment when there is no evidence of extensive early infarct changes [Evidence Level B], in consultation with physicians with stroke expertise. Note: one possible tool to assess infarct change is the ASPECT score:
    1. Timely access to CT or MR perfusion scanning can also be used to demonstrate a perfusion mismatch and to determine the extent of the ischemic core [Evidence Level A], especially in patients beyond 6 hours from last known well, including patients with stroke on awakening.
  2. For endovascular thrombectomy, patients should have a proximal occlusion in the anterior circulation [Evidence Level A]. Refer to Box 5C for endovascular thrombectomy inclusion and exclusion criteria.
5.3 Intravenous Thrombolysis with Alteplase
  1. All eligible patients with disabling ischemic stroke should be offered intravenous alteplase [Evidence Level A]. Eligible patients are those who can receive intravenous alteplase within 4.5 hours of the onset of stroke symptoms [Evidence Level A]. Refer to Section 4.2 and Boxes 4A – 4D for detailed recommendations on neuroimaging; Refer to Box 5B for inclusion and exclusion criteria for intravenous alteplase eligibility. Refer to Section 5.1 Clinical Considerations for patients who arrive beyond the 4.5 hour time window.
    1. When it is unclear whether or not a patient should be treated with alteplase, urgently consult with a stroke specialist within the institution or through telestroke services [Evidence Level C].
    2. If there is uncertainty regarding CT imaging interpretation, consult a radiologist in your institution [Evidence Level C].
  2. All eligible patients should receive intravenous alteplase as soon as possible after hospital arrival [Evidence Level A], with a target door-to-needle time of less than 60 minutes in 90% of treated patients, and a median door-to-needle time of 30 minutes [Evidence Level B].
    1. Treatment should be initiated as soon as possible after patient arrival and CT scan [Evidence Level B]; every effort should be made to ensure door-to-needle times are routinely monitored and improved [Evidence Level C].
    2. Alteplase should be administered using a dose of 0.9 mg/kg to a maximum of 90 mg total dose, with 10 percent (0.09 mg/kg) given as an 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].
      Caution: the dosing of alteplase for stroke is not the same as the dosing protocol for administration of alteplase for myocardial infarction.
  3. Hospital inpatients who present with a sudden onset of new stroke symptoms should be rapidly evaluated by a specialist team and provided with access to appropriate acute stroke treatments (including thrombolysis and endovascular thrombectomy) [Evidence Level B]. Note: once stroke occurs to an existing inpatient, all other sections of the Canadian Stroke Best Practice modules apply to these patients for assessment, diagnosis, management, and recovery.
  4. Management of complications from alteplase administration:
    1. For patients with angio-edema, a staged response using antihistamines, glucocorticoids and standard airway management should be used as per local protocol [Evidence Level C].
    2. There is insufficient evidence to support the routine use of cryoprecipitate, fresh frozen plasma, prothrombin complex concentrates, tranexamic acid, factor VIIa, or platelet transfusions for alteplase – associated bleeding [Evidence Level C]. Use of these medications should be decided on an individual case basis.

Clinical Considerations for Alteplase Administration: (new for 2018)

  1. Consent – Intravenous thrombolysis and endovascular therapy are considered the standard of care for acute stroke treatment. Routine procedures for emergency consent apply.
  2. Intravenous alteplase is considered the standard of care and is currently the only approved thrombolytic agent for acute ischemic stroke treatment. There are other drugs being investigated; however, at this time are not approved for use in stroke patients.
  3. Alteplase administration for patients on direct oral anticoagulants (DOACs): alteplase should not routinely be administered to patients on DOACs presenting with acute ischemic stroke. Endovascular thrombectomy may be considered in in these cases for eligible patients, and decisions should be based on individual patient factors and assessment of benefit and risk.
    1. In comprehensive stroke centres with access to specialized tests of DOAC levels and reversal agents, thrombolysis could be considered, and decisions should be based on individual patient characteristics, in consultation with hematology specialists, patients and their families.
  4. There remain situations in which clinical trial data to support the use of intravenous thrombolytic therapy is more limited. In these situations urgent consultation with a stroke expert is recommended alongside the clinical judgment of the treating physician and discussion with the patient or substitute decision maker.
    1. This may apply to: pediatric stroke (newborn to age 18 years); and pregnant women who experience an acute ischemic stroke. Refer to Canadian Stroke Best Practices Management of Acute Stroke during Pregnancy Consensus Statement for further information
5.4 Acute Endovascular Thrombectomy Treatment (EVT)

Refer to Section 4.2 and Boxes 4B, 4C and 4D for detailed recommendations on neuroimaging-based selection criteria.

  1. Endovascular thrombectomy should be offered within a coordinated system of care including agreements with emergency medical services, access to rapid neurovascular (brain and vascular) imaging, coordination between emergency medical services, the Emergency Department, the stroke team and radiology, local expertise in neurointervention, and access to a stroke unit for ongoing management [Evidence Level A].
  2. Endovascular thrombectomy is indicated in patients based upon imaging selection with non-contrast CT head and CT angiography (including extracranial and intracranial arteries) [Evidence Level A]. Refer to Box 5C for Inclusion Criteria for endovascular thrombectomy.
  3. Endovascular thrombectomy is indicated in patients who have received intravenous alteplase and those who are not eligible for intravenous alteplase [Evidence Level A].
  4. Patients eligible for intravenous alteplase as well as endovascular thrombectomy should also be treated with intravenous alteplase, which can be initiated while simultaneously preparing the angiography suite for endovascular thrombectomy [Evidence Level A].
  5. Eligible patients who can be treated with endovascular thrombectomy within 6 hours of symptom onset (i.e., arterial access within 6 hours of onset) should receive endovascular thrombectomy [Evidence Level A]. Refer to Box 4B for Imaging Inclusion Criteria for endovascular thrombectomy.
  6. Highly selected patients with large vessel occlusion who can be treated with endovascular thrombectomy within 24 hours of symptom onset (i.e., arterial access within 24 hours of onset) and those patients with stroke discovered on awakening should receive endovascular thrombectomy [Evidence Level A]. Refer to for Imaging Inclusion Criteria for endovascular thrombectomy beyond 6 hours from onset.
  7. For large artery occlusions in the posterior circulation (e.g. basilar artery occlusion) the decision to treat with endovascular thrombectomy should be based on the potential benefits and risks of the treatment for the individual patient, and made by a physician with stroke expertise in consultation with the patient and/or substitute decision-makers. [Evidence Level C]. Note: randomized trials are currently ongoing and guidance will be reviewed when trial results are available.
  8. Sedation: For endovascular procedures, procedural sedation is generally preferred over general anaesthesia and intubation in most patients when necessary [Evidence Level B].
    1. General anaesthesia and intubation is appropriate if medically indicated (e.g. for airway compromise, respiratory distress, depressed level of consciousness, severe agitation, or any other indication determined by the treating physician) and in such cases, excessive and prolonged hypotension and time delays should be avoided [Evidence Level B].

Clinical Considerations for Endovascular Thrombectomy (new for 2018)

  1. For patients transferred to an EVT-enabled hospital, in order to ensure patient remains a candidate for EVT, consider doing repeat NCCT immediately on arrival if most recent CT was completed more than 60 minutes prior to arrival at the EVT–enabled site.
  2. Device selection should be at the discretion of the interventionalists based on clinical and technical factors during the procedure.
  3. For patients undergoing EVT following administration of alteplase, there should not be a delay in proceeding to EVT to determine clinical effectiveness of alteplase.

Box 5B Criteria for Acute Thrombolytic Therapy with Intravenous Alteplase

Box 5C Inclusion Criteria for Endovascular Thrombectomy

The recommendations from this module have been published in International Journal of Stroke by SAGE Publications Ltd. Copyright © 2018 World Stroke Organization.

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.

Endovascular treatment for large artery ischemic stroke has clearly demonstrated efficacy with numbers needed to treat (NNT) of approximately four to achieve functional independence at 90 days. Recent data from the DAWN trial (Nogueira et al. 2017) suggest the NNT may be as low as three, while pooled results from a series of older trials, indicated the number was higher, closer to five (HERMES, Goyal et al. 2016). This therapy has profound impact on patients who suffer the most devastating ischemic strokes; patients who, if left untreated, will place a more significant burden on the healthcare system, long term care and family caregivers.

(Note: to obtain mRS of 0-2 at 90 days (49% vs. 13%=NNT of 2.8); HEREMES 2016 meta-analysis to obtain mRS score of 0-2 at 90 days (46% vs. 26.5%=NNT of 5.1))

System Implications +-
  1. Local protocols should prioritize stroke patients for immediate access to appropriate diagnostics such as CT imaging and neurovascular imaging with CTA. This should include patients with known times of stroke symptom onset (or time last seen well), and patients who are discovered with stroke symptoms on wakening.
  2. Coordinated and integrated systems of care involving all relevant personnel in the prehospital and emergency care of stroke patients, including paramedics, Emergency Department staff, stroke teams, radiologists and neurointerventionists. Protocols should be in place in partnership with EMS agencies and treating hospitals, and between hospitals within stroke systems to ensure rapid transport to centres providing advanced stroke services within treatment time windows
  3. Considerations should be given to northern, rural, remote and Indigenous residents to ensure immediate access to appropriate diagnostics and treatment is not delayed.
  4. Health regions and stroke systems should examine and determine the possible resource impact of the EVT time window extension (up to 24 hours in highly selected cases). Demand for imaging will increase especially at comprehensive stroke and EVT-enabled centres. Staffing, service hours and capacity should be considered to ensure efficiency and effectiveness of services. 
  5. System planners and patient flow specialists should plan for significant challenges associated with diversion of potential EVT candidates to EVT-enabled centres. This will affect Emergency Departments, Radiology Departments and acute inpatient units, where occupancy rates are already stretched (over 100% in many hospitals).
  6. Stroke neurology and neurointerventional expertise should be regionalized, with a system in place across regions for rapid access to physicians experienced in acute thrombolysis and endovascular therapies, including through telemedicine. This includes protocols for contacting physicians with stroke expertise for administration of intravenous alteplase, as well as transport to higher levels of stroke care, as needed, for intravenous alteplase or endovascular thrombectomy.
  7. Build capacity for trained neurointerventionists within health regions and academic institutions to ensure sufficient availability to meet regional and provincial EVT healthcare needs.
  8. Hyperacute protocols in place and well-communicated to all healthcare practitioners within the hospital regarding management of in-hospital stroke patients, ensuring access to CT imaging of the brain and CTA of the extracranial and intracranial vessels as soon as possible after stroke symptom onset.
  9. Access to specialized acute stroke units where staff are experienced in managing patients who have received alteplase or endovascular thrombectomy.
  10. Endovascular interventional programs are in evolution across Canada; decisions around appropriate site, transfer and bypass protocols, and timelines will be determined at the provincial or regional level.  Decisions about when those services are fully operational, and who should be transferred by paramedics to those facilities should be made at the provincial/regional level and communicated to all relevant stakeholders.
  11. Availability of helical CT scanners with appropriate programming for CT angiography (multiphase or dynamic CTA) and CT perfusion sequences, and appropriate post-processing software optimized for the production of high-quality imaging.
  12. A consistent, comprehensive data collection protocol for EVT across Canada should be established to monitor patient outcomes.
Performance Measures +-
  1. Overall proportion of all ischemic stroke patients who receive treatment with intravenous alteplase (core).
  2. Median time (in minutes) from patient arrival in the Emergency Department to administration of intravenous alteplase.
  3. Median time from hospital arrival to groin puncture, and from CT scan (first slice of the non-contrast CT) to groin puncture for patients undergoing endovascular thrombectomy.
  4. Proportion of ischemic stroke patients who receive treatment with intravenous alteplase within 3.0 and 4.5 hours of symptom onset.
  5. Proportion of all thrombolyzed stroke patients who receive alteplase within 30 minutes of hospital arrival (core).
  6. Overall proportion of all ischemic stroke patients who receive treatment with endovascular thrombectomy (core).
  7. Median time from hospital arrival to first reperfusion for patients undergoing endovascular thrombectomy. Time of first reperfusion is defined as the first angiographic image showing partial or complete reperfusion of the affected arterial territory (* CIHI project 440 Indicator).
  8. For patients with stroke while in hospital for other medical reasons (in-hospital strokes), median time from last known well to brain imaging.
  9. For patients with stroke while in hospital for other medical reasons (in-hospital strokes), median time from last known well to acute thrombolysis or endovascular thrombectomy (groin puncture).
  10. Final reperfusion status for patients undergoing endovascular reperfusion therapy, quantified using the modified Thrombolysis in Cerebral Infarction (mTICI) system. (* CIHI 440 Indicator)
  11. Proportion of patients with symptomatic subarachnoid or intracerebral hemorrhage following intravenous alteplase (defined as any PH1, PH2, RIH, SAH, or IVH associated with a four-point or more worsening on the NIHSS within 24 hours).
  12. Proportion of patients with symptomatic subarachnoid or intracerebral hemorrhage following endovascular thrombectomy (defined as any PH1, PH2, RIH, SAH, or IVH associated with a four-point or more worsening on the NIHSS within 24 hours).
  13. Proportion of patients in rural or remote communities who receive alteplase through the use of telestroke technology (as a proportion of all ischemic stroke patients in that community and as a proportion of all telestroke consults for ischemic stroke).
  14. Modified Rankin Scale (mRS) score of all stroke patients who receive intravenous alteplase or endovascular thrombectomy at time of hospital discharge and at 90 days post-hospital discharge.
  15. In-hospital mortality rates (overall and 30-day) for ischemic stroke patients stratified by those who receive alteplase or endovascular thrombectomy and those who do not.

Measurement Notes

  1. Refer to Core Indicator Reference Document for indicator calculations, all process timelines and outcome measures for intravenous acute thrombolysis and EVT.
  2. In 2018, the Canadian Institute of Health Information is launching a new stroke quality of care special project (#440) as part of the Discharge Abstract Database extraction that enables data collection on six performance measures for endovascular thrombectomy. Identified above with * (CIHI Stroke Special Project for EVT440)
  3. Data may be obtained from patient charts, through chart audit or review.
  4. 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 alteplase administration noted in the patient chart (nursing notes, Emergency Department record, or medication record).
  5. For performance measures 4 and 5, calculate all percentiles and examine 50th and 90th percentiles and inter-quartile range.
  6. When recording if alteplase is given, include times for both the administration of the bolus, and the time when the infusion is started there are often delays between bolus and infusion which may decrease alteplase efficacy. The route of administration should also be recorded, as there are different times to administration benchmarks for intravenous and endovascular routes.
  7. For endovascular thrombectomy, treatment time should be time of first groin puncture.
Summary of the Evidence +-

Evidence Table A and Reference List
Evidence Table B and Reference List

Intravenous Thrombolysis

The weight of evidence from many large, international trials over a time frame of 20 years, clearly indicate that treatment with intravenous alteplase reduces the risk of death or disability following ischemic stroke, at 3 to 6 months post treatment. The NINDS trial (1995) was one of the earliest, large trials, which was conducted in the USA. Patients were randomized to receive alteplase or placebo within 3 hours of symptom onset. At 3 months, significantly more patients in the rt-PA group had experienced a good outcome (using any one of the study’s 4 metrics), with no difference in 90-day mortality between groups. In contrast, patients who received alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group. 

In the first ECASS trial (1995) 620 patients received alteplase or placebo within 6 hours of event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with alteplase and placebo were 40.3% vs. 36.6%, respectively, absolute difference =3.7%, p=0.277. In subgroup analysis of patients treated < 3 hours and 3-6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%.  Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the alteplase group experienced a favourable outcome, defined as mRS scores <2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009).  At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score ≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic ICH associated with treatment with alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality. 

The Third International Stroke Trial (2012), is the largest (n=3,035) and most recent trial of alteplase, in which patients were randomized to receive a standard dose of alteplase (0.9 mg/kg) or placebo.  Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and to determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advance age or time to treatment. Unlike all previous, large trials, which excluded them, IST-3 included patients >80 years. In fact, the majority of patients (53%) were >80 years. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the sub groups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the t-PA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001). The 3-year risk of mortality (2016) was similar between groups (47% vs. 47%, 95% CI 3.6%, 95% CI -0.8 to 8.1); however, patients who received rt-PA had a significantly lower risk of death between 8 days and 3 years (41% vs. 47%; HR= 0.78, 95% CI 0·68–0·90, p=0·007).

Although it is known that the optimal timing of administration of intravenous alteplase is <3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the 3-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002-2007 to compare the outcomes of patients who had been treated with alteplase within 3 hour of symptom onset (n=11,865) and those treated from 3-4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the 3-hour treatment window. Patients in the <3-hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3-4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). Emberson et al. (2014) used data from 6,756 patients from 9 major t-PA trials (NINDs a/b, ECASS I/II, III, ATLANTIS a/b, EPITHET, IST-3) to more closely examine the effect of timing of administration. Earlier treatment was associated with the increased odds of a good outcome, defined as an (mRS score of 0-1 (≤3.0 h: OR=1.75, 95% CI 1.35-2.27 vs. >3 to ≤4.5 h: OR=1.26, 95% CI 1.05-1051 vs. >4.5 h: OR=1.15, 95% CI 0.95-1.40). Framed slightly differently, when patient-level data from the same 9 major RCTs were recently pooled, Lees et al. (2016) reported that for each patient treated within 3 hours, significantly more would have a better outcome (122/1,000, 95% CI 16-171), whereas for each patient treated >4.5 hours, only 20 patients/1,000 (95% CI -31-75, p=0.45) would have a better outcome. Wardlaw et al. (2013), including the results from 12 RCTs (7,012 patients), concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective. Most recently, the results from the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-Up) trial (Thomalla et al. 2018) suggest that highly-selected patients with mild to moderate ischemic strokes and an unknown time of symptom onset, treated with alteplase may also benefit from treatment. Patients in this trial were not eligible for treatment with mechanical thrombectomy and were selected based on a pattern of "DWI-FLAIR-mismatch. A significantly higher proportion of patients in the alteplase group had a favourable clinical outcome (mRS 0-1) at 90 days (53.3% vs. 41.8%, adj OR=1.61, 95% CI 1.06-2.36, p=0.02), although the risk of parenchymal hemorrhage type 2 was significantly higher compared with placebo (4% vs. 0.4%, adj OR=10.46, 95% CI 1.32 to 82.77, p=0.03).

The standard treatment dose of rt-PA is established to be 0.9 mg/kg, with a maximum dose of 90 mg. The non-inferiority of a lower dose (0.6 mg/kg) was recently examined in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial (Anderson et al. 2016). The primary outcome (death or disability at 90 days) occurred in 53.2% of low-dose patients and 51.1% in standard dose patients (OR=1.09, 95% CI 0.95-1.25, p for non-inferiority=0.51), which exceeded the upper boundary set for non-inferiority of 1.14. The risks of death within 90 days or serious adverse events did not differ significantly between groups (low dose vs. standard dose: 8.5% vs. 10.3%; OR=0.80, 95% CI 0.63-1.01, p=0.07 and 25.1% vs. 27.3%; OR=0.89, 95% CI 0.76-1.04, p=0.16, respectively), although the risk of symptomatic ICH was significantly higher in patients that received the standard dose of rt-PA.

Although not yet approved in Canada for the use in stroke, results from several recent studies, indicate that tenecteplase, which has some pharmacokinetic advantages over alteplase, may be non-inferior to alteplase. In the NOR-TEST Logallo et al. (2017) recruited 1,100 patients from 13 stroke units. Patients were randomized to receive intravenous tenecteplase 0.4 mg/kg (maximum of 40 mg) or alteplase 0.9 mg/kg (maximum of 90 mg).  At 90 days, a similar proportion of patients had an excellent outcome (mRS 0-1, 64% vs. 63%). Similar percentages of patients in each group experienced an ICH within 24-48 hours (9%) and had died by 90 days (5%). Results from the phase II ATTEST Trial, (Huang et al. 2015) also suggest that tenecteplase is non-inferior to alteplase. In this trail, 104 patients were randomized to receive tenecteplase (0.25 mg/kg, 25 mg max) or alteplase (0.9 mg/kg, 90 mg max) within 4.5 hours of ischemic stroke. Safety and efficacy outcomes were non-significantly different between groups. 

The use of mobile stroke units, ambulances which are equipped with specialized equipment, such as on-site laboratories and CT scanners, and are staffed with additional personnel with stroke expertise, are now appearing in large, urban cities. The feasibility and effectiveness of these vehicles has yet to be established. Kunz et al. (2016) compared the outcomes of patients who received thrombolysis therapy using the mobile stroke unit, STEMO from 2011-2015 with patients who received thrombolysis, but arrived at hospital via traditional emergency medical services. A significantly higher proportion of patients in the STEMO group were treated ≤ 90 minutes of stroke (62% vs. 35%, p<0.0005) and were living without severe disability at 3 months (83% vs. 74%, p=0.004). The 3-month mortality was also significantly lower in the STEMO group (6% vs. 10%, p=0.022). However, there was no significant difference in the primary outcome, the number of patients who achieved an excellent outcome (mRS 0-1) at 3 months (53% STEMO vs. 47% conventional, p=0.14). There were no significant differences in the safety outcomes between the 2 groups (sICH 3% vs. 5%, p=0.27 and 7-day mortality 2% vs. 4%, p=0.23). Adjusting for baseline characteristics, STEMO was an independent predictor of living without severe disability at 3 months (OR=1.86, 95% CI 1.20-2.88, p=0.006), but not for the primary outcome (OR=1.40, 95% CI 1.00-1.97, p=0.052). In an earlier study examining the use of STEMO, (Ebinger et al. 2014), among patients for whom STEMO was deployed, the mean alarm-to-treatment time for patients who received thrombolysis was reduced by 25 minutes, compared with control weeks. Of the eligible patients, t-PA was used in 32.6% of STEMO deployment cases, 29% during STEMO weeks, and 21.1% during control weeks.  

The use of thrombolytic therapy in patients who are younger than 18 years and in women at any stage of pregnancy has not been evaluated empirically. The evidence base for the safety and effectiveness of the use of thrombolysis during pregnancy and the puerperium is derived from a series of case reports. The results from a total of 15 previous cases (10 intravenous and 5 intra-arterial), in addition to the presentation of their own case were summarized by Tversky et al. (2016). The neurological outcomes of these women were described as similar to (non-pregnant) patients who met the eligibility criteria. Most of the women who experienced significant recovery went on to deliver healthy babies. The evidence in terms of thrombolytic treatment for patients <18 years comes primarily from the International Pediatric Stroke Study, (IPSS) an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial Alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died and the remainder had moderate or severe neurological deficits.  The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al. 2009) is currently recruiting subjects for 5-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial t-PA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.

Endovascular Therapy

Re-vascularization can also be achieved through mechanical dislodgement with specialized devices (+/- intra-arterial and/or intravenous rt-PA). To date, 10 major RCTs have been completed for which results have been published, in which endovascular therapies were compared with best medical management. Several trials are still ongoing, or have yet to report their findings. The recent results from most of these trials indicate that rapid endovascular therapy may be a safe and more effective treatment than intravenous rt-PA alone, for patients with anterior circulation ischemic strokes in selected regions, when performed within 6-12 hours of symptom onset.  

In the largest trial, MR CLEAN (Berkhemer et al. 2014), included 500 patients who were ≥18 years, with a baseline NIHSS score of 2 or greater, and were treatable within 6 hours of stroke onset. Patients were randomized to receive endovascular treatment with rt-PA or urokinase, and/or mechanical treatment with retrievable stents, which were used in 81.5% of patients, or other available devices, versus best medical management. The median time from stroke onset to groin puncture was 260 minutes. The majority of patients in both groups were treated with intravenous t-PA (87.1% intervention group, 90.6% control group). There was a significant shift in the distribution towards more favourable mRS scores among patients in the intervention group at 90 days (adj common OR=1.67, 95% CI 1.21-2.30). The odds of both a good (mRS 0-2) and excellent (mRS 0-1) recovery at day 90 were also significantly higher among patients in the intervention group (adj OR=2.07, 95% CI 1.07-4.02 and adj OR=2.16, 95% CIU 1.39-3.38, respectively). Patients in the intervention group were more likely to show no evidence of intracranial occlusion on follow-up CTA (adj OR=6.88, 95% CI 4.34-10.94, n=394) and to have a lower median final infarct volume (-19 mL, 95% CI 3-34, n=298). At two-year follow-up (van den Berg et al. 2017), the odds of an mRS score of 0-2 remained significantly higher in the intervention group (37.1% vs. 23.9%, adj OR= 2.21, 95% CI 1.30−3.73, p=0.003). The ESCAPE trial (Goyal et al. 2015) enrolled 316 patients ≥18 years, with stroke onset less than 12 hours, a baseline NIHSS score of > 5 and moderate-to-good collateral circulation. Patients were randomized to receive endovascular mechanical thrombectomy, using available devices or best medical management. The median time from stroke onset to first reperfusion was 241 minutes. 72.7% of patients in the intervention group and 78.7% of those in the control group received intravenous t-PA. The odds of improvement in mRS scores by 1 point at 90 days were significantly higher among patients in the intervention group (adj OR=3.2, 95% CI 2.0-4.7). The odds of good outcome (mRS score 0-2) at 90 days were also higher in the intervention group (adj OR=1.7, 95% CI 1.3-2.2), as were the odds of a NIHSS score of 0-2 and a Barthel Index score of 95-100 (adj OR=2.1, 95% CI 1.5-3.0 and 1.7, 95% CI 1.3-2.22, respectively). The risk of death was significantly lower in the intervention group (adj RR=0.5, 95% CI 0.-0.8). In neither MR CLEAN nor ESCAPE, was there an increased risk of symptomatic ICH associated with endovascular therapy. No interaction effects were found in subgroup analyses of age, stroke severity, time to randomization, or baseline ASPECTS in either of the trials.

The THRACE trial (Bracard et al. 2016) had broader eligibility criteria and included 414 patients aged 18-80 years with an occlusion in the intracranial carotid, the MCA (M1) or the upper third of the basilar artery with onset of symptoms <4 hours and NIHSS score of 10-25 at randomization. Patients were randomized to receive dual intravenous rt-PA therapy + intra-arterial mechanical clot retrieval with the Merci, Penumbra, Catch or Solitaire devices or treatment with IV rt-PA only. The median time from symptom onset to thrombectomy was 250 minutes. The odds of achieving mRS score of 0-2 at 90 days were increased significantly in the thrombectomy group (53% vs. 42.1%, OR=1.55, 95% CI 1.05-2.3, p=0.028, NNT=10). There were no significant differences between groups in the number of patients with symptomatic or asymptomatic hemorrhages at 24 hours. Three trials evaluated the efficacy of the use of a specific retriever device (Solitaire FR Revascularization Device). In the EXTEND IA trial (Campbell et al. 2015), there were no inclusion criteria related to stroke severity. Seventy patients ≥18 years, with good premorbid function and an anterior circulation acute ischemic stroke, with criteria for mismatch, who could receive intra-arterial treatment within 6 hours of stroke onset, were included. All patients received intravenous rt-PA, while 35 also underwent intra-arterial mechanical clot retrieval. A significantly greater proportion of patients in the endovascular group experienced early neurological improvement (80% vs. 37%, p<0.001), >90% reperfusion without ICH at 24 hours (89% vs. 34%, p<0.001) and were functionally independent at day 90 (71% vs. 40%, p=0.009). The SWIFT-PRIME trial (Saver et al. 2015) randomized 196 patients, aged 18-80 years with NIHSS scores of 8-29 with a confirmed infarction located in the intracranial internal carotid artery, MCA, or carotid terminus who could be treated within 6 hours of onset of stroke symptom, to receive intravenous rt-PA therapy + intra-arterial mechanical clot retrieval, or rt-PA only. The likelihood of successful reperfusion (>90%) at 27 hours was significantly higher in the endovascular therapy group (82.8% vs. 40.4%, RR=2.05, 95% CI 1.45-2.91, p<0.001) and a significantly higher percentage of patients were independent at day 90 (mRS 0-2) (60.2% vs. 35.5%, RR=1.70, 95% CI 1.23-2.33, p=0.001). Finally, in the REVASCAT trial (Jovin et al. 2015), 206 patients with NIHSS scores of 6 or greater who could be treated within 8 hours of stroke onset were randomized to receive mechanical embolectomy + best medical management or best medical management only, which could include intravenous t-PA (78%). The odds of dramatic neurological improvement at 24 hours were increased significantly in the intervention group (adj OR=5.8, 95% CI 3.0-11.1). The odds for improvement by 1 mRS point at 90 days were increased significantly in the intervention group (adj OR=1.7, 95% CI 1.05-2.8), as were the odds of achieving an mRS score of 0-2 at 90 days (adj OR=2.1, 95% CI 1.1-4.0). At one-year follow-up (Davalos et al. 2017), the proportion of patients who were functionally independent (mRS score 0–2) was significantly higher for patients in the thrombectomy group (44% vs. 30%; OR=1.86, 95% CI 95% CI 1.01-3.44). No treatment effects were noted based on sub group analyses in either SWIFT-PRIME or REVASCAT, based on age, baseline NIHSS score, site of occlusion, time to randomization, or ASPECTS score. There was no increased risk of symptomatic ICH in any of these trials. 

Two trials (THERAPY and PISTE) halted recruitment prematurely following the presentation of the MR CLEAN trial, resulting in much smaller sample sized than planned. These trials generally reported improved outcomes for patients undergoing mechanical thrombectomy, although the smaller sample sizes were not powered to meet the primary endpoints. As a result, statistical significance was not always achieved. 

The results of the DAWN (Nogueira et al. 2017) and DEFUSE-3 (Albers et al. 2018) trials suggest that the treatment window for mechanical thrombectomy is wider than previously thought. The DAWN trial included 206 patients, last been known to be well 6 to 24 hours earlier, with no previous disability (mRS 0-1) and who met clinical mismatch criteria who had either failed intravenous t-PA therapy, or for whom its administration was contraindicated, because of late presentation. Patients were randomized to treatment with thrombectomy with Trevo device + medical management or medical management alone. The trial was terminated early after interim analysis when efficacy of thrombectomy was established. The median intervals between the time that a patient was last known to be well and randomization was 12.2 hours in the thrombectomy group and 13.3 hours in the control group. The mean utility weighted mRS score was significantly higher in the thrombectomy group (5.5 vs. 3.4, adj difference =2.0, 95% Cr I 1.1-3.0, prob of superiority >0.999). There were no interactions in sub group analysis (mismatch criteria, sex, age, baseline NIHSS score, occlusion site, interval between time that patient was last known to be well and randomization and type of stroke onset). A significantly higher proportion of patients in the thrombectomy group experienced an early response to treatment, had achieved recanalization at 24 hours and were independent (mRS 0-2) at 90 days (49% vs. 13%, NNT=3). The admission criteria for the DEFUSE-3 trial were broader and included those who had remaining ischemic brain tissue that was not yet infarcted. The median time from stroke onset to randomization was just under 11 hours for patients in the endovascular group. A significantly higher proportion of patients in the endovascular group were independent (mRS 0-2) at 90 days (45% vs. 17%, OR=2.67, 95% CI 1.60–4.48, p<0.001, NNT=4). 

The positive results from these 7 trials contrast with those of 3 earlier RCTs examining endovascular therapy using first generation devices, which are no longer on the market or in use in Canada. In the SYNTHESIS trial, Ciccone et al. (2013) randomized 362 patients to receive either pharmacological or mechanical thrombolysis, or a combination of these approaches or intravenous rt-PA within 4.5 hours of symptom onset. At 90 days, the percentages of patients alive, living without disability were similar between groups (30.4% vs. 34.8%, adjusted OR=0.71, 95% CI 0.44 to 1.14, p=0.16). The IMS III trial (Broderick et al. 2013), which also randomized patients to receive mechanical or pharmacological endovascular treatment, or intravenous t-PA was stopped early due to a lack of efficacy. Finally, the MR RESCUE trial (Kidwell et al. 2013). randomized 188 patients, within 8 hours of symptom onset to undergo mechanical embolectomy with the Merci Retriever or Penumbra System or standard care, grouped according to penumbra pattern vs. nonpenumbra pattern. At 90 days, there were no significant differences between groups (embolectomy vs. standard care) in the mean mRS score, the proportion of patients with a good outcome (mRS 0-2) or death among patients with penumbral or nonpenumbral patterns. 

The results from several meta-analyses, indicated the odds of a favourable outcome were all significantly increased with mechanical thrombectomy. Goyal et al. (2016) included the results from 5 trials, using second generation devices.  The odds of achieving a mRS score of 0-1 or 0-2 at 90 days were significantly higher for patients in the endovascular group. The NNT for a one-point reduction in mRS was 2.6. Using data from these same trials, Saver et al. (2017) conducted pooled analysis to examine the timeframe in which endovascular treatment is associated with benefit. Compared with medical therapy, the odds of better disability outcomes at 90 days associated with endovascular therapy declined with longer time from symptom onset to arterial puncture. The point at which endovascular therapy was not associated with a significantly better outcome was 7 hours and 18 minutes. Campbell et al. (2016), included the results of 4 trials in which the Solitaire device was used. Treatment with Solitaire device was associated with both a significantly greater likelihood of independence, and of excellent functional outcome at 90 days compared with best medical management. Flynn et al. (2017) included the results from 8 trials and reported that mechanical thrombectomy was associated with significantly higher odds of functional independence (unadjusted OR=2.07, 95% CI 1.70-2.51, p<0.0001). Time series analysis demonstrated robust evidence for a 30% relative benefit for mechanical thrombectomy for this outcome. While there was no evidence that mechanical thrombectomy was associated with increased risks of mortality or symptomatic ICH, robust evidence to demonstrate a 30% relative risk reduction was lacking.

Evidence from several trials and meta-analyses have examined the outcomes of patients undergoing mechanical thrombectomy using general anesthesia versus conscious sedation. Generally, the findings indicate that conscious sedation is preferred.  Using the results from 7 RCTs including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE and THRACE, Campbell et al. (2018) performed a patient-level meta-analysis comparing the outcomes of patients randomized to the mechanical thrombectomy groups who had received general anesthesia or non-general anesthesia.  The odds of improved outcome using non-general anesthesia were significantly higher in ordinal analysis of mRS scores. The authors estimated for every 100 patients treated under general anesthesia (compared with non-general anesthesia), 18 patients would have worse functional outcome, including 10 who would not achieve functional independence. There was no increased risk of 90-day mortality associated with general anesthesia. The results from a meta-analysis including the results of 22 studies (Brinjikiji et al. 2017), also indicated that conscious sedation (i.e., non-general anesthesia) was associated with better outcomes. The odds of a favorable functional outcome at 90 days were significantly lower for patients who received general anesthesia (OR=0.58; 95% CI, 0.48–0.64), while the odds of 90-day mortality were significantly increased (OR=2.02, 95% CI 1.66–2.45). In contrast to these findings, Löwhagen Hendén et al. (2017) reported no significant differences between groups (general anesthesia vs conscious sedation)
in the proportion of patients with a good outcome at 3 months (42% vs. 40%, p=1.00), or in the distribution of mRS scores at 90 days. In the SIESTA trial (Schönenberger et al. 2016), a significantly higher percentage of patients in the general anesthesia group had a good outcome (mRS 0-2) at 3 months (37% vs. 18.2%, p=0.01), compared with conscious sedation.

Many hospitals do not have the in-house expertise to perform endovascular procedures. As a result, patients who are potential candidates for treatment will need to be transported from receiving hospitals to a centre that provides interventional neuroradiologic services.  Although the additional transportation involved will inevitably cause treatment delays, particularly the time from symptom onset to groin puncture, results from several recent studies suggest that patient outcomes may not be worse.  Gerschenfeld et al. (2017) compared the outcomes of 159 patients who received mechanical thrombectomy following t-PA, using a drip and ship model and those who received the same procedure at the mother ship. Although the median process times from patients in the mothership group were all significantly shorter, there were no significant differences between groups in the proportion of patients with a favourable outcome (mRS 0-2) at 3 months, or who experienced a symptomatic ICH, and discharge NIHSS scores were similar. Weber et al. (2016) reported similar results in a study involving 643 patients consecutively admitted to 17 stroke units, 8 of which offered in-house endovascular procedures. Compared with stroke units which did not offer this service and were required to transfer patients to one that did, the frequency of in-hospital and 3-month mortality were similar. Median periprocedural times were significantly shorter for in-house group.

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