R.E.B.E.L. EM – Endovascular Therapy for Acute Ischemic Stroke

Originally published at R.E.B.E.L. EM on March 15, 2018. Reposted with permission.

Follow Salim R. Rezaie at @srrezaie

Background: Approximately 80% of strokes are ischemic in origin leading to significant morbidity and mortality worldwide.  In ischemic stroke, there is usually a core infarct and an ischemic penumbra.  The penumbra is the area that we try to salvage with reperfusion therapy. Currently, systematic intravenous alteplase administered within 4.5hrs after symptom onset is the mainstay of therapy, however many question its risk/benefit ratio in ischemic stroke. 4.5 hours is a narrow therapeutic time window and many contraindications such as recent surgery, coagulation abnormalities, and history of intracranial hemorrhage inhibit many patients from receiving systemic thrombolysis.  There have been many studies evaluating endovascular therapy in the management of ischemic stroke published in the past few years.  This post will serve as a review of those studies.

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Physician
Greater San Antonio Emergency Physicians

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Associate Editor – REBEL EM

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Study #1 – IMS-III [1]:

What They Did:

• International, phase 3, randomized, open-label clinical trial with a blinded outcome
• Patients receiving systemic IV tPA within 3 hours after stroke symptom onset received either: Additional endovascular therapy or IV tPA alone in a 2:1 ratio

Outcomes:

• Primary: Proportion of patients with modified Rankin scale (mRs) score of ≤2 at 90 days

Inclusion:

• 18 – 82 years of age
• Receipt of IV tPA within 3 hours after symptom onset
• Moderate to severe neuro deficit (NIHSS score ≥10) or NIHSS >7 but <10 with CTA confirmed proximal occlusion
• Written informed consent

Exclusion:

• History of stroke past 3 months
• Previous intracranial hemorrhage, neoplasm, SAH, or AVM
• Clinical presentation suggests a SAH, even if initial CT scan is normal
• HTN at the time of treatment: SBP >185 of DBP > 110mmHg or aggressive measures to lower blood pressure to below these limits was required
• Presumed septic embolus or suspicion of bacterial endocarditis
• Presumed pericarditis including pericarditis after AMI
• Suspicion of aortic dissection
• Recent (within 30d) surgery or biopsy of parenchymal organ
• Recent (within 30d) trauma, with internal injuries or ulcerative wounds
• Recent (within 90d) severe head trauma or head trauma with loss of consciousness
• Any active or recent (within 30d) hemorrhage
• Patients with known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency or oral anticoagulant therapy
• INR > 1.7
• Pregnancy or breastfeeding
• Glucose <50 mg/dL or >400mg/dL, platelets <100,000, or Hct <25
• Patients requiring hemodialysis or peritoneal dialysis or have contraindication to angiogram
• Patients who have received heparin or a direct thrombin inhibitor within the last 48 hours
• Arterial puncture at a non-compressible site or LP in previous 7 days
• Patients with seizure at onset of stroke
• Patients with pre-existing neurological or psychiatric dz that would confound neuro evaluations
• Terminal illness

Results:

• 656 patients randomized (Stopped early due to futility)
  • Endovascular Therapy = 434 patients
  • Systemic IV tPA = 222 patients
• mRs of ≤2 (Functional Independence) at 90d
  • Endovascular therapy: 40.8%
  • Systemic IV tPA: 38.7%
  • 95% CI: -6.1 – 9.1
• No statistically significant differences in secondary outcomes or safety outcomes between groups with one exception:
  • Asymptomatic ICH within 30hrs:
    • Endovascular Therapy: 27.4%
    • Systemic IV tPA: 18.9%
    • P = 0.01

Strengths:

• Multicenter, randomized clinical trial
• Pre-specified primary efficacy and subgroup analyses and safety data
• No industry sponsors were involved in the study design, conduct, manuscript review, or protocol review
• All neuro assessments at 90 days were performed by study investigators blinded to treatment assignment of patients

Limitations:         

• CTA and MRA used infrequently to assess anatomy of proximal vascular occlusions and instead an NIHSS score of ≥10 was used
• Need 900 patients to provide an effect size of 10%. The authors planned to enroll 900 patients, but trial stopped early due to futility. This can minimize finding harm or benefit in a smaller patient population
• The investigators changed their inclusion criteria at some point during the study to patients with no imaging and NIHSS score ≥10 to patients with CTA imaging and NIHSS score ≥8
• Extensive exclusion criteria limiting enrollment of patients and generalizability
• Randomization was required within 40 minutes after the initiation of the infusion again limiting generalizability to many medical systems
• Newer stent retrievers were only used in a small number of patients in this trial

Discussion:

• Its important to note that although reperfusion rates were higher with endovascular therapy compared to systemic tPA alone, there was no significant clinical benefit in neurological outcomes. In other words if there is no viable tissue, then revascularization will not fix this.  Like placing a stent in a coronary artery when the myocardium is already dead.
• In subgroup analyses of patients with more severe stroke (NIHSS ≥20), which is the population you would think has more proximal occlusions, there was still no difference in patients who ended up with a mRs of ≤2 when comparing endovascular treatment to systemic IV tPA

Author Conclusion: “This trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone.”

Clinical Take Home Point: There is probably a subset of ischemic stroke patients who may benefit from endovascular therapy, however one thing is for sure…improved reperfusion is not a guarantee of clinical efficacy (i.e. good neurologic outcomes)

Study #2 – MR RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy) [2]:

What They Did:

• Multicenter, phase 2b, randomized, controlled, open-label, clinical trial assigning patients within 8hrs after onset of large vessel, anterior-circulation strokes
• Mechanical embolectomy vs standard care
• All patients had pretreatment CT or MRI of brain

Outcomes:

• Primary: Mean 90d modified Rankin scale (mRs) score
• Secondary:
• Patients with mRs 0 – 2 were evaluated for mean 90d mRs score
• Successful revascularization
• Successful reperfusion on 7d CT or MRI (≥90% of volume of original perfusion lesion from baseline)

Inclusion:

• Patients between the ages of 18 – 85 years of age
• NIHSS scores of 6 – 29
• Large-vessel, anterior-circulation ischemic stroke
• Clot retrieval within 8 hours after onset of initial symptoms
• Favorable penumbral pattern defined as: infarct core of ≤90mL and predicted infarct tissue within the at-risk region of ≤70%

Exclusion:

• NIHSS ≥30
• Acute ICH
• Coma
• Rapidly improving neuro signs prior to randomization
• Pre-existing medical, neurological, or psychiatric disease that would confound neuro functional or imaging evaluations
• Pregnancy
• Known allergy to iodine previously refractory to pretreatment medications
• CTA or MRA with proximal ICA occlusion, proximal carotid stenosis >67%, or dissection
• INR > 3.0
• PTT >3x normal
• Renal failure: serum Cr >2.0 or GFR <30
• MRI Contraindication

Results:

• 118 eligible patients
  • Mean time to enrollment = 5.5hrs
  • 58% of patients with large salvageable tissue and small infarct core (vs large infarct core and small/absent penumbra)
  • Overall 90d mortality = 21% (No difference between groups)
  • Overall Symptomatic ICH = 4% (No difference between groups)
• Mean 90d mRs Score:
  • Embolectomy = 3.9
  • Standard Care = 3.9
  • P = 0.99
  • No difference whether patients had a large salvageable tissue and small core or small salvageable tissue with large core

Strengths:

• Multicenter randomized clinical trial
• Core laboratories completed primary neuroimaging analyses blinded to treatment assignment
• Concentric medical (who provided medical devices) had no involvement in the study design or in the analysis or interpretation of the data

Limitations:

• Small patient population
• Low rate of revascularization with embolectomy
• CT evaluation had larger predicted core volumes than patients evaluated with MRI
• Took 8 years to complete this trial, and during this time there were advances in techniques and clinical practices (i.e. new stent retrievers)
• Time to access was >6 hours after onset of symptoms (i.e. ?increased core infarct size)
• Follow-up imaging not available for all patients

Author Conclusion: “A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care.”

Clinical Take Home Point: In patients with acute ischemic stroke interventional embolectomy did not lead to better 90d neurological outcomes when extended out to 8 hours from symptom onset compared to standard care.

Study #3 – SYNTHESIS [3]:

What They Did:

• Pragmatic, multicenter, open-treatment, randomized clinical trial of 362 patients with acute ischemic stroke, within 4.5 hours after onset
• Endovascular therapy vs Systemic IV t-PA

Outcomes:

• Primary: survival free of disability (mRs of 0 – 1)
• Secondary:
  • Portion of pts with mild neurologic deficit or none (NIHSS score ≤6)
  • Fatal and non-fatal symptomatic ICH at day 7
  • Fatal and non-fatal symptomatic edema from original brain infarction at day 7
  • Fatal and nonfatal recurrent ischemic stroke at day 7
  • Death from any cause at day 7
  • Neurologic deterioration (defined as a increase of ≥4 on NIHSS score) on day 7
  • Fatal and non-fatal extracerebral events on day 7

Inclusion:

• Acute ischemic stroke
• Age 18 – 80 years
• Initiation of treatment within 4.5hrs after symptom onset for systemic t-PA
• Initiation of treatment within 6hrs after symptom onset for endovascular therapy
• Availability of interventional neuroradiologist

Exclusion:

• Known contrast sensitivity
• Women of childbearing ate potential or known to be breastfeeding
• Prognosis very poor regardless of therapy (likely to be dead within months)
• Disability preceding stroke (i.e. mRs >1)
• Unlikely to be available for follow-up)
• Refused consent
• Any other condition which the investigator feels could pose a hazard in terms of risk/benefit to the patient, or if the therapy proves impracticable
• Intracranial tumors (Except small meningioma)
• Hemorrhage of any degree
• Acute infarction (since this may be an indicator that the time of symptoms onset is not correct)

Results:

• 362 patients
  • Median time to start treatment = 3.75hrs (Endovascular Therapy)
  • Median time to start treatment = 2.75hrs (Systemic t-PA)
  • Non-fatal symptomatic ICH within 7d = 6% in both groups
• Survival Free Disability (mRs of 0 – 1)
  • Endovascular Therapy = 30.4%
  • Systemic t-PA = 34.8%
  • OR 0.71
  • 95% CI 0.44 – 1.14
  • P = 0.16
• Death at 90 Days:
  • Endovascular Therapy = 14.4%
  • Systemic t-PA = 9.9%
  • P = 0.22
• Stroke Caused by Dissection on Day 7:
  • Endovascular Therapy = 8%
  • Systemic t-PA = 2%
  • P = 0.03

Strengths:

• Multicenter randomized clinical trial
• No industry support or industry involvement in the trial
• All analyses performed by statistician who was not aware of treatment assignments
• Patients baseline characteristics were similar between groups with the exception of more atrial fibrillation in the systemic t-PA group (16% vs 8%)

Limitations:

• Evaluation of secondary end points were done by neurologists aware of treatment assignments
• Study was set up to verify or refute absolute difference of 15%, meaning smaller differences could be present and not statistically significant
• Demonstration of vessel occlusion was not a requirement for inclusion in this trial

Author Conclusion: “The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA.”

Clinical Take Home Point: It is important to note that although there was no benefit to endovascular therapy vs systemic t-PA, there was more death at 90 days (not statistically significant) and strokes due to dissection (statistically significant) in the endovascular therapy group.

After 3 trials of no difference, some key points are worth mentioning about subsequent trials:

• Proximal occlusion required radiologically proven intracranial occlusion (i.e. CTA, MRA)
• Using retrievable stents as opposed to first-generation Merci devices

Study #4 – MR CLEAN (Multicenter Randomized clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) [4]:

What They Did:

• Pragmatic, phase 3, multicenter, randomized clinical trial of intraarterial treatment plus usual care or usual care alone
• Intraarterial treatment (intraarterial thrombolysis, mechanical treatment, or both) plus usual care (which could include intravenous administration of alteplase) vs usual care alone

Outcomes:

• Primary: modified Rankin scale (mRs) at 90 days
• Secondary:
  • NIHSS score at 24 hours
  • NIHSS score at 5 – 7 days or discharge if earlier
  • Activities of daily living measured by the Barthel index
  • Health-related quality of life measurement measured with the EuroQol Group 5-Dimention Self-Report Questionnaire at 90 days
  • Arterial recanalization measured with CTA or MRA at 24 hours
  • Final infarct volume on noncontrast CT at 5 – 7 days
• Safety Variables:
  • Hemorrhagic complications
  • Progression of ischemic stroke
  • New ischemic stroke into a different vascular territory
  • Death

Inclusion:

• Age ≥18 years (no upper limit of age)
• CT or MRI scan ruling out intracranial hemorrhage
• Proximal arterial occlusion in anterior cerebral circulation confirmed on vessel imaging (CTA, MRA or Digital subtraction angiography (DSA))
• NIHSS score of ≥2
• Ability to treat intraarterially within 6 hours after symptom onset

Exclusion:

• Arterial blood pressure > 185/100mmHg
• Blood glucose <2.7 or >22.2 mmol/L
• Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9mg/kg alteplase or 90mg
• Intravenous treatment with thrombolytic therapy despite contra-indications (i.e. major surgery, gastrointestinal bleeding or urinary tract bleeding within the previous 2 weeks, or arterial puncture at a non-compressible site within the previous 7 days)
• Exclusion Criteria for Mechanical Thrombectomy
  • Laboratory evidence of coagulation abnormalities (i.e. platelet count <50 x10⁹/L, aPTT >50 sec, or INR > 3.0
• Exclusion Criteria for Intra-Arterial Thrombolysis
  • Cerebral infarction in the distribution of relevant occluded artery in the previous 6 weeks
  • History of ICH
  • Severe head injury (contusion) in the previous 4 weeks
  • Clinical or laboratory evidence of coagulation abnormalities (i.e. platelet count <90 x 10⁹/L, aPTT > 50 sec , or INR > 1.7)

Results:

• Enrolled 500 patients at 16 medical centers in the Netherlands
  • Intaarterial treatment = 233 (46.6%)
  • Usual care = 267 (53.4%)
  • Mean age = 65 years (range: 23 – 96)
• Modified Rankin Scale Score at 90 days (Median)
  • Intervention = 3 (range 2 – 5)
  • Control = 4 (range 3 – 5)
  • 95% CI 1.66 (1.21 – 2.28)
• Modified Rankin Scale Score of ≤2:
  • Intervention = 44.2%
  • Control = 25.1%
• No significant differences in serious adverse events during 90 day follow-up period (p = 0.31) but:
  • Embolization into new territories outside the target downstream territory on DSA (20/233 patients = 8.6%)
  • Procedure related vessel dissections = 4 patients (1.7%)
  • Vessel perforation = 2 patients (0.9%)
  • New ischemic stroke in a different vascular territory
    • Intervention 5.6%
    • Control 0.4%
    • P < 0.001

Strengths:

• Multicenter, randomized clinical trial
• Randomization was web passed with permuted blocks
• Investigators, unaware of treatment groups assignments, conducted follow-up interviews at 90 days
• All neuroimaging was evaluated by two neuroradiologist unaware of treatment-group assignments
• All treatment-effects were explored in prespecified subgroups of patients to evaluate statistical significance of possible differences
• Used an intention to treat analysis to provide unbiased comparisons among treatment groups
• Groups were balanced not skewing results toward intervention or control

Limitations:

• Neurologists were aware of the treatment-group assignments which could add bias to the results of the trial
• Unbalanced randomization resulting in more patients in the control group
• Reperfusion rate was low (58.7%) when compared to previous studies (80%)
• 9% of patients in the intervention group had embolization into new vascular territories on DSA
• Low proportion of patients in the control group had a mRS of 0 – 2 at the 90 day follow up assessment biasing the results toward intervention
• Patients were aware of treatment group assignments which could influence their opinions about health and functional outcomes

Discussion:

• 445 patients (89.0%) were treated with IV alteplase before randomization
• Retrievable stents used in 190/233 patients (81.5%)

Author Conclusion: “In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.”

 Clinical Take Home Point: Although intrarterial treatment administered within 6 hours after stroke did improve neurological outcomes compared to usual care, it is important to remember this was a limited population of patients (i.e. proximal occlusions with salvageable brain tissue) and that there was a real increase in embolization and new strokes in the intervention arm of this study.

Study #5 – ESCAPE (Endovascular treatment for Small Core and Anterior Circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times) [5]:

What They Did:

• Multicenter, prospective, randomized, open-label, controlled trial of patients with acute ischemic stroke with small infarct core, proximal intracranial arterial occlusion, and goo collateral circulation
• Randomized to standard care vs standard care + endovascular treatment up to 12 hours after symptom onset

Outcomes:

• Primary: mRs at 90 days
• Secondary:
• Early recanalization and reperfusion
• ICH
• Angiographic complications
• Neuro disability at 90d
• Death

Inclusion:

• Adults age ≥18 years
• Up to 12 hour after onset of stroke symptoms
• NIHSS > 5 at time of randomization
• Had a CT and CTA brain to identify participants with a small infarct core, occluded proximal artery in the anterior circulation, and moderate to good collateral circulation
• Independent functional status in activities of daily living prior to stroke

Exclusion:

• Large infarct core
• Poor collateral circulation
• Pregnancy
• Severe contrast allergy
• Suspected intracranial dissection

Results:

• 316 patients randomized
  • Median time from CT head to 1^st reperfusion = 84 minutes
• Functional Independence at 90 Days:
  • Endovascular Therapy = 53%
  • Standard Care = 29.3%
  • P<0.001
  • 95% CI 1.4 – 2.4
• Mortality at 90d:
  • Endovascular Therapy = 10.4%
  • Standard Care = 19.0%
  • P = 0.04
  • 95% CI 0.3 – 1.0
• Symptomatic ICH:
  • Endovascular Therapy = 3.6%
  • Standard Care = 2.7%
  • P = 0.75

Strengths:

• Blinded outcome evaluation
• Trial monitored by an independent data and safety monitoring board
• Study funders not involved in design or conduct of study, preparation or review of protocol, collection or analysis of data, or preparation of the manuscript
• Baseline characteristics of patient populations were similar
• Non heterogeneity of treatment effect across any of the prespecified subgroups

Limitations:

• Trial stopped early which may affect the magnitude of results for or against endovascular therapy
• No required screening of logs showing how many patients were ineligible on the basis of imaging criteria that were included in the study
• Majority of patients were enrolled at endovascular centers making it difficult to generalize results to community settings without endovascular treatment options

Discussion:

• Important to note that the median time from noncontrast CT brain to first reperfusion was 84 minutes in this trial
• Another important note is that although patients could be enrolled up to 12 hours after symptom onset, the median time from symptom onset to first reperfusion was only 241 minutes
• Only 49 patients (15.5%) underwent randomization ≥6 hours after symptom onset and study was not powered to evaluate this cohort of patients

Author Conclusion: “Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality.”

Clinical Take Home Point: In a subgroup of patients with acute ischemic stroke, imaging excluding large infarct core and poor collateral circulation, endovascular therapy improves functional independence when compared to standard care alone.

Study #6 – EXTEND IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial) [6]:

What They Did:

• Multicenter, prospective, randomized, open-labeled, blinded-endpoint, controlled trial
• Randomized to 0.9mg/kg alteplase <4.5hrs after onset of ischemic stroke plus endovascular thrombectomy with Solitaire FR stent retriever or systemic thrombolysis alone

Outcomes:

• Primary:
  • Reperfusion at 24 hours
  • Early neuro improvement (≥8 point reduction on NIHSSS or score of 0 – 1 at day 3)
• Secondary:
  • mRs at 90d
  • Symptomatic ICH
  • Death due to any cause

Inclusion:

• Age ≥ 18 years
• Receive IV alteplase within 4.5hrs after onset of ischemic stroke
• Imaging proven occlusion of internal carotid or middle cerebral artery
• Salvageable brain
• Ischemic core <70mL on CT perfusion imaging
• Endovascular therapy had to be initiated within 6 hours after stroke onset and completed within 8 hours after onset
• Functional independence before stroke (i.e. mRs <2)

Exclusion:

• ICH
• Rapidly improving symptoms
• Pre-stroke mRs ≥2
• Carotid dissection
• Contraindication to imaging with contrast agents
• Hypersensitivity to nickel-titanium
• Terminal illness with expectation to not survive more than 1 year
• Pregnancy
• Previous stroke past 3 months
• Past history of SAH, AV M, aneurysm, cerebral neoplasm
• Current use of anticoagulants and INR >1.6
• Use of glycoprotein IIb-IIIa inhibitors within past 72 hours
• Hypoglycemia
• Uncontrolled HTN (SBP > 185mmhg or DBP > 110mmhg)
• Hereditary or acquired hemorrhagic diathesis
• GIB or Urinary bleeding previous 21 days
• Major surgery within preceding 14 days

Results:

• 70 patients randomized
  • Median time from stroke onset to initiation of alteplase: 145 min (Alteplase only) vs 127 min (Endovascular Therapy)
  • Median time to initiation of endovascular therapy = 210 minutes
• Median Percentage of Ischemic Territory Undergoing Reperfusion at 24hrs:
  • Endovascular Group = 100%
  • Alteplase Only Group = 37%
  • P<0.001
• Functional Independence at 90 Days:
  • Endovascular Group = 71%
  • Alteplase Only Group = 40%
  • P = 0.01
• No difference in mortality or symptomatic ICH

Strengths:        

• Covidien supplied the Solitaire FR device, but the company was not involved in the preparation of manuscript
• Multicenter, randomized trial
• Patient selection based on imaging to find patients most likely to benefit from reperfusion
• 24 hour interval assessment to provided assurance that re-occlusion was uncommon

Limitations:

• Yet another interventional trial stopped early again limiting patient population and therefore magnitude of results (i.e. small sample size of 70 patients)
• Inability to provide subgroup analyses
• 25% of patient excluded due to large ischemic core on imaging not included in the analysis making it impossible to see possibility of benefit or harm with endovascular therapy

Discussion:

• This trial was unique in that it used CT perfusion imaging to select patients with the greatest potential to benefit from endovascular therapy. Only 65% of patients in the MR CLEAN trial received this type of imaging
• Initiation of alteplase and randomization was only 30 minutes in this trial compared to 100minutes in MR CLEAN
• An important point is that time from stroke onset to initiation of endovascular procedure was a median of 50 minutes shorter than MR Clean
• Finally the reperfusion rate in this study was 58% higher than MR CLEAN, but reperfusion does not guarantee functional outcomes

Author Conclusion: “In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome.” 

Clinical Take Home Point: As technology and comfort with endovascular therapy improve it appears in patients with acute ischemic stroke with proximal arterial occlusions and salvageable tissue on CT imaging results in improved reperfusion, early neurologic recovery and functional outcome.  It is unclear what the benefits would be in patients in later time windows (i.e. >6hrs).

Study #7 – SWIFT PRIME (Solitaire With the Intention For Thrombectomy as PRIMary Endovascular Treatment) [7]:

What They Did:

• International, multicenter, prospective, randomized open controlled trial
• Systemic IV t-PA (control) vs Endovascular thrombectomy within 6 hours after symptom onset (intervention)
• Confirmed occlusions in the proximal arterial intracranial circulation (Intracranial internal carotid artery and/or first segment of the middle cerebral artery)
• Absence of large ischemic core lesions

Outcomes:

• Primary: modified Rankin scale at 90 days
• Secondary:
  • Mortality at 90d
  • Rate of functional independence (mRs Score ≤2) at 90d
  • Change in the NIHSS score at 27 hours after randomization
  • Safety outcomes: intracranial hemorrhage at 27 hours after randomization

Inclusion:

• Age 18 – 80 years
• Pre-stroke mRs ≤1
• Acute ischemic stroke
• Moderate to severe neurological deficits (NIHSS ≥8 and <30)
• Imaging confirmed occlusion of the intracranial internal carotid artery and/or first segment of the middle cerebral artery
• Receiving or had received IV t-PA within 4.5hrs of onset of stroke
• Able to undergo initiation of endovascular treatment within 6 hours after the time of onset of acute stroke symptoms

Exclusion:

• Contraindication to IV t-PA per national guidelines
• Pregnant or lactating females
• Prisoners
• Rapid neurological improvement
• Serious sensitivity to radiographic contrast agents
• Sensitivity to Nickel, Titanium metals
• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency
• Renal failure with a baseline serum Cr >2mg/dL or GFR ≤30
• Life expectancy <90days
• SAH
• Aortic dissection
• Current or recent use of illicit drugs, alcohol
• Intracranial tumor

Results:

• 196 patients underwent randomization
  • Median time from stroke onset to groin puncture = 224 minutes (Range: 165 – 275min)
  • Reperfusion Rate = 88%
  • Median modified Rankin Scale Score at 90d:
    • Intervention: 2
    • Control: 3
  • Rate of Functional Independence (mRs at 90d)
    • Intervention: 60%
    • Control: 35%
    • P <0.001
  • No difference in 90 day mortality or symptomatic intracranial hemorrhage

Strengths:

• International, multicenter, prospective, randomized controlled trial
• Trial was monitored by an independent data and safety committee
• Balanced demographic and clinical characteristics in the two treatment groups limiting bias
• Used worst case and best case scenarios to account for missing data

Limitations:

• Another study stopped early, and again affecting the magnitude of results (i.e. 196 patients included in analysis)
• Trial was funded by Covidien (maker of the Solitaire retriever)
• This trial evaluated only patients who had received systemic IV t-PA but did not evaluate patients who were ineligible for systemic IV t-PA
• This trial did not evaluate patients with more than 6 hours of symptoms
• All enrolling sites were tertiary care centers with experienced neruointerventionalists and results may not be generalizable to sites without neurointerventional expertise

Discussion:

• For every 3 patients who were treated 1 additional patient had an improved disability outcome
• For every 4 patients who were treated 1 additional patient was functionally independent at 90 day follow-up
• This trial had a high reperfusion rate of 88% that was better than earlier trials

Author Conclusion: “In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes as 90 days.”

Clinical Take Home Point: In patients receiving systemic IV t-PA, ≤6 hours of symptoms of stroke, due to large-vessel occlusions and small to moderate ischemic cores, thrombectomy with a stent retriever improved functional independence at 3 months after stroke. 

Study #8 – REVASCAT (Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) [8]:

What They Did:

• Multicenter, sequential, open-label phase 3 randomized controlled trial with blinded evaluation of patients with stroke symptoms within 8 hours
• Medical therapy (Systemic IV alteplase when eligible) vs Endovascular therapy with the Solitaire stent retriever
• All patients with confirmed proximal anterior circulation occlusion and absence of a large infarct

Outcomes:

• Primary: modified Rankin score at 90 days
• Secondary:
• Infarct volumes on CT or MRI at 24 hours
• Vessel revascularization on CTA or MRA at 24 hours
• Decrease in NIHSS score of ≥8 from baseline at 24 hours
• Mortality at 90d
• Symptomatic ICH at 90d

Inclusion:

• Age 18 – 85 years
• Occlusion in the proximal anterior circulation
• Could be treated within 8 hours after symptom onset
• Prestroke functional ability of 1 or less on mRs score
• Baseline score of at least 6 on NIHSSS

Exclusion:

• Known hemorrhagic diathesis, coagulation factor deficiency, or on oral anticoagulant therapy with INR >3.0
• Baseline platelet count <30,000
• Baseline blood glucose <50 or >400mg/dL
• Severe HTN (SBP >185mmHg or DBP > 100mmHg)
• Patients in coma
• Seizures at stroke onset
• Serious advanced or terminal illness with anticipated life expectancy of < 1 year
• History of life threatening allergy to contrast medium
• Renal insufficiency with Cr ≥3.0mg/dL
• Pregnancy or breast feeing
• Cerebral vasculitis
• Pre-existing neurological or psychiatric diagnosis that would confound neurological or functional evaluation
• Large ischemic core
• ICH
• Intracranial tumor (Except small meningioma)

Results:

• 206 patients included in trial
  • Successful revascularization = 66%
  • Median time from stroke onset to revascularization = 355min
• Functional Independence (mRs ≤2) at 90d)
  • Endovascular Arm: 43.7%
  • Medical Therapy Arm: 28.2%
  • Adjusted OR 2.1
  • 95% CI 1.1 – 4.0
• No difference in rate of ICH or mortality

Strengths:

• Multicenter, randomized controlled trial
• Monitored by an independent data and safety monitoring board
• Local and external certified assessors were unaware of study group assignments separately evaluated the primary outcome
• All analyses were performed in a intention to treat population
• No crossovers occurred in this trial
• All patients were available for evaluation at 90 days for the primary outcome
• Baseline characteristics were similar between the two study groups

Limitations:

• Trial was stopped early, and requiring a sample size of 690 patients and only recruited 206 patients, again minimizing magnitude of results
• Study was funded by Covidien, the manufacturer of the Solitaire FR stent retriever
• There were significant discrepancies between central and investigator ASPECTS (Quantitative topographic CT scan score used in patients with MCA stroke) scores and occlusion sites
• Used ASPECTS scores instead of perfusion imaging to estimate ischemic core which is less accurate in estimating core volume
• Sample size not sufficient to permit assessments of the effects of thrombectomy in prespecified groups

Discussion:

• For every 6.5 patients treated with thrombectomy one case of functional dependency would be achieved (NNT = 6.5)

Author Conclusion: “Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post stroke disability and increased the rate of functional independence.”

Clinical Take Home Point: In patients with anterior circulation stroke who could be treated with thrombectomy within 8 hours after symptom onset there was a reduced severity of disability at 90days.

Study #9 – THRACE (THRombectomie des Arteres CErebrales) [9]:

What They Did:

• Randomized controlled trial in patients aged 18 – 80 years with acute ischemic stroke and proximal cerebral artery occlusion
• IV thrombolysis started within 4hr and thrombectomy within 5hr of stroke symptom onset
• IV thrombolysis alone (AVT group) or IV thrombolysis + mechanical thrombectomy (IVTMT group)

Outcomes:

• Primary: functional independence at 90d (mRs ≤2)
• Secondary:
  • NIHSS Score at 24hrs, discharge or day 7, and 3months
  • Mortality at 90d
  • Symptomatic ICH at 24hrs

Inclusion:

• Age 18 – 80 years
• NIHSS score of 10 – 25
• Occlusion of intracranial internal carotid artery, M1 segment of middle cerebral artery, or the superior third of the basilar artery
• IV thrombolysis could be administered within 4 hours of symptom onset
• Thrombectomy could be initiated within 5 hours of symptom onset

Exclusion:

• Contraindications to alteplase
• Treatment initiated >4hrs after stroke symptom onset
• Unable to have patient follow-up
• History of iliofemoral surgery
• Occlusion of preocclusive stenosis of the cervical segment of the ICA ipsilateral to the lesion
• ICH
• Intracranial tumors other than small meningiomas

Results:

• 414 patients randomized
  • Stroke symptom onset to thrombectomy: 250min (Range 210 – 290 min)
  • Reperfusion rate = 69%
  • Functional Independence (mRs ≤2) at 3 Months:
    • IVT: 42%
    • IVTMT: 53%
    • OR 1.55
    • 95% CI 1.05 – 2.30
    • P = 0.028
  • No difference in mortality at 90d or symptomatic ICH at 24 hours

Strengths:

• Study funder had no role in study design, data collection, data analysis, data interpretation, or writing the manuscript
• No baseline characteristic differences in two groups

Limitations:

• Trial stopped early recruiting only 414 patients, yet again minimizing magnitude of results
• Modified Rankin score estimated by vascular neurologists not blinded to treatment arms
• Protocol changes occurred during the course of the study (i.e. IV t-PA window increased from 3hr to 4hrs)
• Only two patients with occlusions of the superior third of the basilar artery limiting any conclusions about this subset of patients

Discussion:

• Median delay from IV thrombolysis to randomization was <20min (This is fast). Other trials ranged from 47 – 121 minutes.
• The time from randomization to groin puncture was 82 minutes which is a lot higher than prior trials and could be one reason there is a reduced difference in functional independence between groups

Author Conclusion: “Mechanical thrombectomy combined with standard intravenous thrombolysis improves functional independence in patients with acute cerebral ischaemia, with no evidence of increased mortality.  Bridging therapy should be considered for patients with large-vessel occlusions of the anterior circulation.”

Clinical Take Home Point: In patients with anterior circulation ischemic strokes, selected by imaging based criteria, combining mechanical thrombectomy with standard IV thrombolysis improved functional independence at 3 months with no increase in mortality or symptomatic ICH

Study #10 – THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke) [10]:

What They Did:

• International, multicenter, prospective, randomized, open label, blinded end point, controlled clinical trial
• Aspiration thrombectomy after IV alteplase vs IV alteplase alone in patients with large vessel ischemic stroke

Outcomes:

• Primary:
  • Percent of patients achieving functional independence (mRs ≤2) at 90d
  • Severe adverse reactions at 90days
• Secondary:
  • Severity of 90d disability
  • Proportion of patients with improvement, defined as mRs of 0 – 2 at 30d
  • ≥10 point NIHSS improvement from baseline to 24 hours or NIHSS of 0 – 1 at discharge
  • 24 hour infarct volume
  • Rate of symptomatic ICH
  • Mortality at 90d

Inclusion:

• 18 – 85 years of age
• Intracranial internal carotid artery or middle cerebral artery occlusion on CT angiography
• NIHSS ≥8
• ≥8mm clot length

Exclusion:

• >1 of 3 of the affected middle cerebral artery territory with established infarction
• Cervical ICA stenosis/occlusion requiring treatment before thrombectomy
• Prestroke disability (mRs >1)

Results:

• 108 patients of 692 planned included in analysis
  • Onset to groin puncture = 227min (Range 184 – 263)
• Functional Independence (mRs ≤2) at 90d:
  • Endovascular Therapy: 38%
  • Systemic IV Alteplase Alone: 30%
  • OR 1.4; 95% CI 0.6 – 3.3
  • P = 0.52
• Severe Adverse Reactions at 90d:
  • Endovascular Therapy: 42%
  • Systemic IV Alteplase Alone: 48%
  • OR 1.3; 95% CI 0.6 – 2.7
  • P = 0.55
• Symptomatic ICH:
  • Endovascular Therapy: 9.3%
  • Systemic IV Alteplase Alone: 9.7%
  • P = 1.0
• 90d Mortality
  • Endovascular Therapy: 12%
  • Systemic IV Alteplase Alone: 23.9%
  • P = 0.18

Strengths:

• Multicenter, international randomized controlled trial
• The primary outcome was assessed by blinded adjudicators

Limitations:

• Trial halted early and therefore not adequately powering the study outcomes
• Imbalances in baseline characteristics between two treatment arms (i.e. fewer intracranial ICA occlusion patients in the IV arm)
• Very specific patient population (i.e. ≥8mm of clot) may limit generalizability

Author Conclusion: “THERAPY did not achieve its primary endpoint in this underpowered sample. Directions of effect for all prespecified outcomes were both internally and externally consistent toward benefit.  It is possible that an alternate method of thrombectomy, primary aspiration, will benefit selected patients harboring large vessel occlusions.  Further study on this topic is indicated.”

Clinical Take Home Point: This was an underpowered study and due to the early termination of the trial it is difficult to draw definitive conclusions from this one trial alone.

Study #11 – DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) [11]

What They Did:

• Multicenter, prospective, randomized, open-label trial clinical trial
• Patients with occlusion of intracranial ICA or proximal MCA last known to be well between 6 – 24hrs with mismatch in clinical deficit and infarct volume
• Thrombectomy plus standard care vs standard care

Outcomes:

• Primary:
  • Mean score for disability (mRs) at 90d
  • Rate of functional independence (mRs ≤2) at 90d
  • Stroke related mortality at 90d
• Secondary:
  • Early therapeutic response (Decrease in NIHSS ≥10 from baseline or NIHSS of 0 – 1 on day t, 6, or 7 of hospitalization or discharge if before day 5)
  • Mortality at 90d
  • Infarct volume and change from baseline infarct volume at 24hours
  • Recanalization of occluded vessel on CTA or MRA at 24hrs
  • Symptomatic ICH

Inclusion:

• Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:
  • Subject has failed IV t-PA therapy (defined as a confirmed persistent occlusion 60 min after administration)
  • Subject is contraindicated for IV t-PA administration
• Age ≥18
• Baseline NIHSS ≥10 (assessed within one hour of measuring core infarct volume)
• Could be randomized between 6 – 24 hours of last known well
• No significant pre-stroke disability (pre-stroke mRs = 0 or 1)
• Anticipated life expectancy of at least 6 months
• Able to attend follow up visits
• <1/3 MCA territory involved, as evidenced by CT or MRI
• Occlusion of the intracranial ICA and/or MCA-M1 as evidenced by MRA or CTA
• Clinical Imaging Mismatch (CIM) defined by MR-DWI or CTP

Exclusion:

• History of severe head injury within past 90 days and residual neurological deficits
• Rapid improvement in neurological status to an NIHSS<10 or evidence of vessel recanalization prior to randomization
• Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations
• Seizures at stroke onset
• Baseline blood glucose 50mg/dL or >400mg/dL
• Baseline Hb <7mmol/L
• Baseline platelet count <50k
• Abnormal baseline electrolyte parameters (Na <130mmol/L, potassium <3mEq/L or >6mEq/L)
• Renal failure (Serum Cr >3.0mg/dL) – patients on dialysis can be treated regardless of serum creatinine
• Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant with INR > 3.0 or PTT > 3x normal
• Any active or recent hemorrhage within the past 30d
• History of severe allergy to contrast medium
• Severe, sustained HTN (SBP >185mmHg or DBP > 110mmHg) – If BP can be successfully reduced and maintained at acceptable level using medication then patients were enrolled
• Pregnancy or Breast feeding
• Presumed septic embolus (i.e. bacterial endocarditis)
• ICH on CT/MRI
• CTA or MRA evidence of flow limiting carotid dissection, high-grade stenosis, or complete cervical carotid occlusion
• Occlusions in multiple vascular territories
• Significant mass effect with midline shift
• Intracranial tumor (except small meningioma)

Results:

• 206 patients enrolled into the study
  • Interval from time that patient was last known to be well and randomization was approximately 13.6hrs in this trial
  • 84% of patients had reperfusion
• Rate of functional independence (mRs ≤2) at 90d:
  • Thrombectomy Arm: 49%
  • Standard Care Arm: 13%
  • Absolute Difference = 36%; 95% CI 24 0 47
  • P <0.001
• Rate of Symptomatic ICH:
  • Thrombectomy Arm: 6%
  • Standard Care Arm: 3%
  • P = 0.50
• 90d Mortality:
  • Thrombectomy Arm: 19%
  • Standard Care Arm: 18%
  • P = 1.00
• No difference in stroke-related death at 90 days, and symptomatic ICH

Strengths:

• Multicenter randomized clinical trial
• No heterogeneity in prespecified subgroup analyses
• Blinded assessment of end points

Limitations:

• Trial stopped early due to prespecified superiority of thrombectomy limiting the power of some of the analyses
• Randomization stratified according to prognostic variables that investigators determined to be most pertinent
• Trial restricted to patients with infarcts of small or medium volume (Extent of tissue injury is a determinant of risk of ICH after reperfusion therapy)

Discussion:           

• An interesting point is that the percentage of patients who had onset of stroke symptoms on awakening were higher in the thrombectomy group than the control group (63% vs 47%)

Author Conclusion: “Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.”

Clinical Take Home Point: In patients with acute anterior ischemic stroke, last known well between 6 – 24hrs, and had a perfusion mismatch on imaging, it appears that thrombectomy improved functional independence at 90days.

Study #12 – DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) [12]

What They Did:

• Multicenter, randomized, open-label trial with blinded outcome assessment
• Thrombectomy + medical therapy vs medical therapy alone in patients 6 – 16hrs after stroke symptoms with remaining ischemic brain tissue
• Proximal middle cerebral artery or internal carotid artery occlusion
• Initial infarct size of <70mL
• Ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of ≥1.8

Outcomes:

• Primary:
  • modified Rankin scale score at 90d
  • 90d mortality
  • Symptomatic ICH at 36hrs
• Secondary:
  • Functional independence (mRs ≤2) at 90d
  • Infarct volume at 24hrs after randomization
  • Reperfusion (i.e. greater than 90% reduction in region of perfusion delay) at 24hr
  • Complete recanalization of primary arterial occlusive lesion at 24hr on CTA or MRA

Inclusion:

• Signs and symptoms consistent with diagnosis of an acute anterior circulation ischemic stroke
• Age 18 – 90 years
• Baseline NIHSS ≥6
• Ability to undergo endovascular therapy between 6 – 16hrs after time last known well (including patients who had awakened from sleep with with symptoms of stroke)
• Ability to perform perfusion imaging
• Initial infarct volume (ischemic core) <70mL
• Ratio of volume of ischemic tissue to initial infarct volume of ≥1.8
• Potential reversible ischemia (penumbra) of ≥15mL
• Occlusion of cervical or intracranial internal carotid artery or proximal middle cerebral artery on CTA or MRA

Exclusion:

• Serious, advanced, or terminal illness or life expectancy <6mo
• Pre-existing medical, neurological, or psychiatric disease that would confound neurological or functional evaluations
• Pregnancy
• Unable to get contrast brain perfusion scan with either MRI or CT
• Known allergy to iodine that precludes endovascular procedure
• Treated with tPA >4.5hrs after time last known well
• Treated with tPA 3 – 4.5hrs after last known well AND any of the following: age>80, current anticoagulant use, history of diabetes AND prior stroke, NIHSS >25
• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, recent oral anticoagulation with INR >3
• Seizures at stroke onset if precludes obtaining an accurate baseline NIHSS
• Baseline blood glucose <50mg/DL or >400mg/dL
• Platelet count <50k
• Severe, sustained HTN (SBP > 180mmHg or DBP >110mmHg)
• Presumed septic embolus; suspicion of bacterial endocarditis
• Evidence of intracranial tumor except small meningioma, ICH, or AVM
• Significant mass effect with midline shift
• Internal carotid dissection
• Intracranial stent in same vascular territory

Results:

• 182 patients included in randomization
• Median time from symptom onset to imaging 10hrs 29min
• Median time from randomization ot femoral puncture = 28min
  • Functionally Independent at 90d (mRs ≤2)
    • Endovascular Therapy: 45%
    • Medical Therapy Alone: 17%
    • RR 2.67; 95% CI 1.60 – 4.48
    • P <0.001
  • 90d Mortality Rate:
    • Endovascular Therapy: 13%
    • Medical Therapy Alone: 23%
    • OR 0.55; 95% CI 0.30 – 1.02
    • P = 0.05
  • No significant difference in symptomatic intracranial hemorrhage or serious adverse events

Strengths:

• Multicenter, randomized controlled trial
• Two trial groups were balanced
• Only 3 patients lost to follow up
• Assessors of neurological outcomes were unaware of any imaging or clinical data

Limitations:

• Another trial stopped early minimizing the beneficial results of the trial
• Subgroup analysis was limited due to the lower than anticipated number of patients

Author Conclusion: “Endovascular thrombectomy for ischemic stroke 6 – 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle cerebral artery or internal carotid artery occlusion and a region of tissue that was ischemic but not yet infarcted.”

Clinical Take Home Point: In patients with acute ischemic stroke due to large-vessel occlusion with perfusion imaging showing potentially salvageable brain tissue within 6 – 16hrs after stroke onset led to a higher rate of functional independence at 90days with endovascular therapy + medical therapy vs medical therapy alone

2018 AHA Guidelines for Endovascular Therapy in Acute Ischemic Stroke [13]

New recommendations of note, regarding endovascular therapy, are listed below:

1. Systems should be established so that brain imaging studies can be performed within 20 minutes of arrival in the ED in at least 50% of patients who may be candidates for IV alteplase and/or mechanical thrombectomy – Level I
2. Multimodal CT and MRI, including perfusion imaging, should not delay administration of IV alteplase – Level III (Harm)
3. For patients who otherwise meet criteria for endovascular therapy, it is reasonable to proceed with CTA if indicted in patients with suspected intracranial large vessel occlusion before obtaining a serum creatinine concentration in patients without a history of renal impairment – Level IIa
4. In selected patients with acute ischemic stroke within 6 – 24 hours of last known normal who have large vessel occlusion in the anterior circulation, obtaining CT perfusion, Diffusion weighted MRI, or MRI perfusion is recommended to aid in patient selection for mechanical thrombectomy, but only when imaging and other eligibility criteria from RCTs showing benefit are being strictly applied in selecting patients for mechanical thrombectomy – Level IA
5. In selected patients with acute ischemic stroke within 6 – 16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended – Level IA
6. In selected patients with acute ischemic stroke within 6 – 24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable – Level IIa
7. In patients who undergo mechanical thrombectomy, it is reasonable to maintain the BP ≤180/105mmHg during and for 24 hours after the procedure – Level IIa
8. In patients who undergo mechanical thrombectomy with successful reperfusion, it might be reasonable to maintain BP at a level <180/105mmHg – Level IIb 

Summary of All RCTs to Date on Endovascular Therapy for Acute Ischemic Stroke

Clinical Take Home Point:    

• Systemic IV thrombolysis can have limited responsiveness (13 – 50%) to large thrombi in the central circulation, a narrow time window for administration (4.5hrs), and increases the risk of cerebral/systematic hemorrhage
• The initial 3 trials showing no difference in 90d mRs scores were most likely due to:
  • Proximal occlusion not radiologically proven with intracranial occlusions (i.e. CTA, MRA)
  • The use of first-generation Merci devices as opposed to retrievable stents
  • It is also important to note that in many of the earlier trials there were more new strokes and vessel dissections compared to systemic therapy
• In the studies reviewed, recruitment averaged about 1 patient per month, meaning this was a very specific and particular patient that was recruited
• As more and more trials have been performed, the efficiency, the type of imaging, and technology have all also improved, minimizing complications and improving efficacy of endovascular therapy
• Endovascular therapy for ischemic stroke is suitable for patients with ischemic stroke within 24hrs of symptom onset, with:
  • Proof of proximal intracranial vessel occlusion
  • Imaging methods to exclude large infarct cores
  • Efficient workflow to achieve fast recanalization and high reperfusion rates
  • Workflow: Ischemic Stroke Symptoms ≤24hrs -> CT/CTA -> If CTA positive for large anterior (ICA/MCA) stroke -> CT or MR Perfusion Scan to determine eligibility for Endovascular Therapy
• Later trials included patients with “wake up” strokes, which have not previously been included in systemic t-PA trials
• One final note: It is important to realize that many trials were stopped early, and because of this the magnitude of benefit for endovascular therapy may be over inflated in many of these trials 

References:

1. Broderick JP et al. Endovascular Therapy After Intravenous t-PA versus t-PA Alone for Stroke. NEJM 2013. PMID: 23390923
2. Kidwell JR et al. A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke. NEJM 2013. PMID: 23394476
3. Ciccone A et al. Endovascular Treatment for Acute Ischemic Stroke. NEJM 2013. PMID: 23387822
4. Berkhemer OA et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. NEJM 2015. PMID: 25517348
5. Goyal M et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM 2015. PMID: 25671798
6. Campbell BCV et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. NEJM 2015. PMID: 25671797
7. Saver JL et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs t-PA Alone in Stroke. NEJM 2015. PMID: 25882376
8. Jovin TG et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. NEJM 2015. PMID: 25882510
9. Bracard S et al. Mechanical Thrombectomy After Intravenous Alteplase Versus Alteplase Alone After Stroke (THRACE): A Randomised Controlled Trial. Lancet 2016. PMID: 27567239
10. Mocco J et al. Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone. Stroke 2016. PMID: 27486173
11. Nogueira RG et al. Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct. NEJM 2017. PMID: 29129127
12. Albers GW et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM 2018. PMID: 29364767
13. Powers WJ et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018. PMID: 29367334

For More Thoughts on This Topic Checkout:

• Justin Morgenstern at First 10 EM: Interventional Therapy for Acute Ischemic Stroke – The Evidence
• Salim Rezaie at REBEL EM: Ischemic Stroke Treatment Archive
• EM Docs: 2018 AHA/ASA Ischemic Stroke Updates

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