Acute Ischemic Stroke: The Role for Endovascular Therapy

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Original Studies
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Keywords

Take Home Points:

Endovascular therapy, as an adjunct to standard stroke therapy, may be beneficial for a very select population of patients that present with an acute ischemic stroke and have a proven large, proximal occlusion on imaging.

Endovascular therapy includes any one or more of the following:

Intra-arterial thrombolytic therapy
Clot and stent retrieval
Thrombectomy with mechanical devices

Endovascular therapy should be considered in patients with a clinical stroke who fulfill the following criteria:

Age ≥ 18 years
National Institute of Health Stroke Scale (NIHSS) ≥ 6
Have received intravenous tissue plasminogen activator (IV tPA), alteplase (Activase) within 4.5 hours of onset of symptoms
Have a demonstrated large, proximal (middle cerebral artery, internal carotid artery, or anterior cerebral artery) occlusion on imaging
Are eligible to receive endovascular therapy within 6 hours of a clinical stroke

Summary:

The administration of IV tPA, specifically alteplase (Activase), is currently the only FDA-approved treatment for acute ischemic stroke. While tPA is considered the Gold Standard therapy for acute stroke care, its use is limited by:

Multiple contraindications
Narrow therapeutic time window (up to 4.5 hours for some eligible patients)
Reduced efficacy with large clot burden or proximal occlusions of the major intracranial arteries.

Alternative interventions to IV tPA include:

Intra-arterial thrombolytic therapy
Endovascular (intra-arterial) thrombectomy
Endovascular (intra-arterial) thromboaspiration

Despite previous large, randomized controlled trials using first generation endovascular devices (MR RESCUE, IMS III, SYNTHESIS EXPANSION) suggesting no large magnitude benefit and even potential harm with endovascular therapy, critical reviews of these trials have suggested that a possible benefit may exist in a more select patient population using latest generation endovascular devices.

Several subsequent randomized controlled trials (MR CLEAN, EXTEND-IA, ESCAPE) investigated endovascular intervention a smaller subset of acute ischemic stroke patients, including only those with large proximal occlusions confirmed by neuroimaging. The percentage of patients independent at 90 days (modified Rankin score of 0-2) in control (usual care) and intervention (usual care plus endovascular therapy) groups was compared. Key findings of these studies include:

Dramatic improvements in neurologic outcomes in favor of intra-arterial intervention following standard stroke care with IV tPA.
Demonstration of a 14% (MR CLEAN), 33% (EXTEND-IA), and 24% (ESCAPE) absolute benefit in independence at 90 days.
Mortality benefit noted in one trial (7% absolute benefit, ESCAPE trial)

Other observations from this literature:

All three trials included only patients with proven large, proximal occlusions on imaging, and two trials (EXTEND-IA, ESCAPE) additionally required imaging-based evidence of salvageable tissue as identified by an ischemic penumbra, further narrowing the select group of patients to which these results apply, and who are likely to benefit from thrombolytic therapy based on current data.
EXTEND-IA and ESCAPE were terminated early based on highly positive interim efficacy analysis, which was conducted after the MR CLEAN trial was published reporting an absolute benefit of endovascular therapy.
Almost all patients enrolled in the intervention groups of these trials received IV tPA prior to endovascular intervention. Those that did not receive IV tPA prior to endovascular intervention were too few to allow for extrapolation of significant results.
While intra-arterial therapy was defined as either intra-arterial tPA or mechanical intervention in some of these trials, the vast majority of patients underwent mechanical intervention with latest generation retrievable stents and interpretations of patient outcomes should consider this.
Two additional studies (REVASCAT, SWIFT) further upheld the reported benefit of intra-arterial interventions in conjunction with the standard of care for acute stroke patients with equally dramatic results. Both of these trials were also stopped early.

Conclusions:

While three initial trials of endovascular therapy for acute CVA that utilized first generation endovascular devices in patients that had also received IV-tPA reported neutral to negative outcomes, subsequent trials (MR CLEAN, EXTEND-IA, ESCAPE) that carefully selected patients with large, proximal occlusions and evidence of salvageable brain tissue and used newer generation retrievable stents almost exclusively reported improved reperfusion rates and positive neurologic outcomes.
Current evidence suggests that in tPA eligible patients presenting with an acute ischemic event and a proven large proximal arterial occlusion on imaging, endovascular therapy following IV tPA administration in this very select patient population may have a significant morbidity benefit and a possible mortality benefit.
It is important to note that the results of these trials (MR CLEAN, EXTEND-IA, ESCAPE) should not be generalized beyond their strict inclusion criteria, as potential harm has been reported with endovascular interventions for less select patient populations.

Author: Karolina DeAugustinis, MD
Editor(s): Anthony J. Busti, MD, PharmD, FNLA, FAHA; Jeremiah Hinson, MD, PhD
Last Reviewed: August 2015

Supporting Guidelines
American Stroke Association (2015) Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered. Patients should receive endovascular therapy with a stent retriever if they meet all the following criteria. Prestroke modified Rankin Scale score 0 to 1 Acute ischemic stroke receiving intravenous r-tPA within 4.5 hours of onset according to guidelines from professional medical societies Causative occlusion of the internal carotid artery or proximal MCA (M1) Age ≥18 years NIHSS score of ≥6 Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of ≥6 Treatment can be initiated (groin puncture) within 6 hours of symptom onset Guideline Rating: Class I; Level of Evidence A Reference:2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015 Jun 29. [Epub ahead of print] PubMed

Supporting Guidelines

American Stroke Association (2015)
- Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered.
- Patients should receive endovascular therapy with a stent retriever if they meet all the following criteria.
- Guideline Rating: Class I; Level of Evidence A
- Reference:2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015 Jun 29. [Epub ahead of print] PubMed

Original Studies

Berkhemer et al (MR CLEAN investigators). A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. PubMed

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Level of Evidence	1b
Study Design	Prospective, Randomized, Open-label, Blinded end-point, Multi-center
Sample Size	n = 500
Population	Patients with acute ischemic stroke and a proximal intracranial occlusion of the anterior circulation confirmed on imaging (CTA, MRA, or DSA)
Inclusion Criteria	Age ≥ 18 years NIHSS ≥6 Occlusion of the distal intracranial carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery (A1 or A2), established by imaging Treatment initiation within 6 hours of stroke onset
Exclusion Criteria	General exclusion criteria for intra-arterial treatment (arterial blood pressure exceeding 185/110 mmHg, blood glucose less than 2.7 or over 22.2 mmol/L (48 to 400 mg/dL), treatment with IV thrombolysis in a dose exceeding 0.9 mg/kg or 90 mg, cerebral infarction in the distribution of the relevant occluded artery in the previous 6 weeks) Coagulation abnormalities Specific exclusion criteria for intra-arterial thrombolysis (history of cerebral hemorrhage, severe head injury in < 4, treatment with oral thrombin or factor X antagonists)
Interventions	N = 267 (53.4%): Control Group = Usual care alone vs. N = 233 (46.6%): Intervention Group = Intra-arterial treatment (delivery of thrombolytic, mechanical thrombectomy, or both) plus usual care: Thrombolytic therapy included 1 of 2 options: 1) maximum of 90 mg alteplase loading dose if no prior alteplase was given or restricted to 30 mg if a prior dose was used. 2) max dose of 1,200,000 IU of urokinase if no prior alteplase was given or 400,000 IU if alteplase was already given.
Follow Up	90 days
Primary Endpoint	Modified Rankin score at 90 days Score ranges from 0 (no symptoms) to 6 (death) with a score of less than or equal to 2 being functional independence.
Secondary Endpoint	Imaging parameter vessel recanalization at 24 hours (Clot Burden score and collateral score) Infarct size at 5 days assessed with ASPECTS Final infarct volume calculation NIHSS and NIH supplemental motor scale at 24 hours and at 1 week or discharge
Results	233 were assigned to intra-arterial treatment group and 267 to usual care alone. The median age was mid 60s, 58% being males, and having a median NIH stroke scale of 17. The median time to groin puncture was 4 hours and 20 minutes. 445 patients (89.0%) were treated with IV tPA before randomization. There were too few that were not treated with IV tPA prior to endovascular intervention to draw any statistically significant conclusions. Retrievable stents were used in 190 of the 233 patients (81.5%). Patients with a modified Rankin score of 0-2 at 90 days in the intervention group was 32.6% vs. 19.1% in the usual care group - absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2). The adjusted common odds ratio (OR) was 1.67 (95% CI, 1.21 to 2.30). There were no significant difference in mortality. Complication rate was 6% with no significant differences in symptomatic intracerebral hemorrhage. However, the intervention group experienced more new ischemic strokes involving a different vascular territory (5.6% vs 0.4%, p < 0.001).
NNT/NNH	= 7
Conclusions	Intra-arterial therapy in conjunction with IV tPA is safe and effective in patients presenting with an acute ischemic stroke secondary to a large, proximal occlusion of the anterior circulation.
Location	16 medical centers in the Netherlands
Funding	Dutch Heart Foundation and others
Trial Registries	Netherlands Trial Registry Number, NTR1804 and Current Controlled Trials Number, ISRCTN10888758
Comments	While MR CLEAN did conduct imaging to identify a proximal occlusion in the anterior circulation, it did not require evidence of an ischemic penumbra with an infarcted core for enrollment. Urokinase is also not a treatment option in the United States like alteplase (Activase). Patients were not enrolled until after the administration of IV tPA suggesting that non-responsive patients may have been preferentially selected. 90 day modified Rankin Score was calculated by a telephone interview and subjective report by the patient and/or representative.

Campbell et al (EXTEND-IA Investigators). Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med 2015 Mar 12;372(11):1009-18. PubMed

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Level of Evidence	1b
Study Design	Prospective, Randomized, Open-label, Blinded end-point, Multicenter Trial
Sample Size	N = 70 (study was terminated early)
Population	Patients with ischemic stroke who were receiving IV tPA within 4.5 hours after onset of anterior circulation ischemic stroke due to large, proximal occlusion with evidence of an ischemic penumbra.
Inclusion Criteria	Patients presenting with anterior circulation acute ischemic stroke eligible using standard criteria to receive IV tPA within 4.5 hours of stroke onset Patient, family member or legally responsible person depending on local ethics requirements has given informed consent Patient's age is ≥18 years (no restriction on age) Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset Arterial occlusion on CTA or MRA of the internal carotid artery, proximal middle cerebral artery, distal middle cerebral artery Mismatch - Using CT or MRI with a Tmax >6 second delay perfusion volume and either CT-rCBF or DWI infarct core volume. a) Mismatch ratio of greater than 1.2; and b) Absolute mismatch volume of greater than 10 ml; c) Infarct core lesion volume of less than 70mL
Exclusion Criteria	Intracranial hemorrhage, rapidly improving symptoms, pre-stroke modified Rankin score of ≥ 2 inability to access the cerebral vasculature, stenosis proximal to the thrombus site, carotid dissection, terminal illness with less than 1 year life expectancy, pregnant women, previous stroke within last three months, recent past history or clinical presentation of intracranial hemorrhage, subarachnoid hemorrhage, arterio-venous malformation, aneurysm, or cerebral neoplasm, current use of anticoagulants with coagulation prolongation, use of glycoprotein IIb - IIIa inhibitors within the past 72 hours, hypoglycaemia, blood pressure > 185/110, hemorrhagic diathesis, gastrointestinal or urinary bleeding within the preceding 21 days, major surgery within the preceding 14 days, exposure to a thrombolytic agent within the previous 72 hours.
Interventions	All patients received alteplase IV at a dose of 0.9 mg/kg per standard of care and then randomized into one of two groups: Control Group = Usual care only vs. Intervention Group = Intra-arterial treatment with a stent retriever (Solitaire FR retrievable stent by Covidien) plus usual care
Follow-Up	90 days
Primary Endpoint	Co-primary end points: Median percentage reperfusion at 24 hours Early neurologic improvement (≥8 point reduction in NIHSS or reaching 0-1 at 3 days)
Secondary Endpoint	Reperfusion at 24 hrs post stroke without symptomatic intracerebral hemorrhage Recanalization at 24 hrs post stroke Infarct growth within 24 hrs Stroke severity (NIHSS) at 24hrs Symptomatic intra-cranial hemorrhage Death due to any cause Modified Rankin Scale (mRS) 0-1 at 3 months Modified Rankin Scale (mRS) 0-2 at 3 months Categorical shift in mRS at 3 months NIHSS reduction ≥8 points or reaching 0-1 at 3 months
Results	The median age was 69 years. The median NIH stroke scale was 15. The median stroke to puncture time was 210 minutes. Reperfusion at 24 hours for the endovascular intervention group was 89% as compared with the alteplase-only group at 34% (P<0.001). Early neurologic improvement at 3 days was 80% for endovascular intervention group vs the 37% for the alteplase-only group (adjusted P < 0.001). 71% of patients in the endovascular treatment group had functional independence (modified Rankin score of 0-2) as compared to 40% in the alteplase-only group - absolute difference of 33% (P = 0.01). Although not statistically significant, at the time of early termination of the study more deaths occurred in the alteplase only group compared to the endovascular plus alteplase group (20% vs 9%). The median infarct growth at 24 hr was also less with the intervention group (35.3 mL vs 10.9 mL; P = 0.007). The rate of symptomatic intracerebral hemorrhage was 6% the alteplase only group vs 0% for the intervention group.
NNT/NNH	= 3
Conclusions	In patients receiving IV tPA for acute ischemic stroke with identified salvageable tissue on CT perfusion imaging, adjunctive endovascular therapy with a retrievable stent improves reperfusion, neurologic recovery and functional outcome.
Location	14 centers in Australia and New Zealand
Funding	Funded by the Australian National Health and Medical Research Council and others
Trial Registeries	EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTR N12611000969965
Comments	This study had no upper limit age restrictions This study had no restrictions based on NIHSS score. The investigators had originally planned to enroll 100 patients. The EXTEND-IA trial was terminated early after the release of the MR CLEAN results and an unplanned interim efficacy analysis was conducted based on the Haybittle-Peto stopping rule

Goyal et al (ESCAPE Trial investigators). Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. N Engl J Med 2015 Mar 12;372(11):1019-30. PubMed

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Level of Evidence	1b
Study Design	Prospective, Randomized, Open-label, Blinded end-point, Multicenter Trial
Sample Size	n=315 (this study was terminated early)
Population	Patients with disabling acute stroke due to a proximal intracranial artery occlusion of the anterior circulation with collateral flow to an ischemic penumbra surrounding an ischemic core.
Inclusion Criteria	Acute ischemic stroke Age 18 or greater Onset (last-seen-well) time to randomization time < 12 hours. Disabling stroke defined as a baseline NIHSS > 5 at the time of randomization. Pre-stroke (24 hours prior to stroke onset) independent functional status Confirmed symptomatic intracranial occlusion at the internal carotid artery, proximal middle cerebral artery, distal middle cerebral artery. Time to puncture within 60 minutes of baseline non-contrast CT with target CT to first recanalization of 90 minutes.
Exclusion Criteria	Confirmation of a moderate/large core in the territory of symptomatic intracranial occlusion via non contrast CT, CTA or CT perfusion. Groin puncture is not possible within 60 minutes No femoral pulses or very difficult endovascular access Pregnancy Suspected intracranial dissection as a cause of stroke. Severe or fatal comorbid illness precluding follow-up or rendering intervention ineffective
Interventions	N = 150; Control Group = Usual acute stroke care per guidelines N = 165; Intervention Group = Endovascular thrombectomy or thrombolysis plus usual care
Follow Up	90 days
Primary Endpoint	A shift of one or more categories (proportional odds analysis) on the modified Rankin scale.
Secondary Endpoint	NIHSS 0-2 Modified Rankin Score of 0-2 Mortality at 90 days EQ-5D (EuroQoL)Cognitive outcomes (Trailmaking A, B; MoCA; Boston Naming test; Sunnybrook hemi-spatial neglect battery) Barthel Index > 90 (≥95) Barthel Index shift analysis (ordinal logistic regression) miFUNCTION score Economic (cost-effectiveness) analysis
Results	Median age was 70 years with an NIH stroke scale of 17 Time to puncture was approximately 4 hours 53% of patients in the intervention group had a modified Rankin score of 0-2 at 90 days as compared to 29.3% in the control group giving an absolute difference of 23.7% Mortality was reduced from 13% to 6% Retreivable stents were used in 130 of the 151 participants (86%) in the intervention group There were no significant differences in symptomatic intracerebral hemorrhage or perforations of the middle cerebral artery
NNT/NNH	NNT for good neurologic outcome = 4 NNT to save a life = 15
Conclusions	In patients with an acute ischemic stroke due to a proximal vessel occlusion with a small infarct core and moderate to good collateral circulation, intra-arterial intervention as an adjunct to the standard of care improves neurologic status and mortality at 90 days.
Location	22 centers in Canada, the United States, South Korea, Ireland, and the UK
Funding	Covidien
ClinicalTrials.gov	NCT01778335
Comments	This is the first randomized control trial to show a mortality benefit from reperfusion for ischemic stroke. A planned interim analysis was accelerated after the MR CLEAN results were published and conducted after 243 patients had completed their 90 day follow up. Early termination of trial recruitment for efficacy was recommended. The trial had originally planned to enroll 500 patients through 90 days of follow up.

Related Articles
Kidwell et al (MR RESCUE Investigators). A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013 Mar 7;368(10):914-23.PubMed Broderick et al (IMS-III Investigators). Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013 Mar 7;368(10):893-903. PubMed

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