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
|Level of Evidence
Randomized, Open-label, Blinded end-point, Multi-center
||n = 500
with acute ischemic stroke and a proximal intracranial occlusion of the
anterior circulation confirmed on imaging (CTA, MRA, or DSA)
- 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
- General exclusion criteria for intra-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)
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
- Modified Rankin score at 90
- Score ranges from 0 (no symptoms) to 6 (death)
with a score of less than or equal to 2 being functional independence.
- 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
- 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
- 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).
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
||16 medical centers in
Foundation and others
Trial Registry Number, NTR1804 and Current Controlled Trials Number,
- 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
|Level of Evidence
Randomized, Open-label, Blinded end-point, Multicenter Trial
70 (study was terminated early)
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.
presenting with anterior circulation acute ischemic stroke eligible using
standard criteria to receive IV tPA within 4.5 hours of stroke onset
family member or legally responsible person depending on local ethics
requirements has given informed consent
age is ≥18 years (no restriction on age)
clot retrieval treatment can commence (groin puncture) within 6 hours of stroke
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
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.
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
Intervention Group = Intra-arterial treatment
with a stent retriever (Solitaire FR retrievable stent by Covidien) plus usual
percentage reperfusion at 24 hours
- Early neurologic improvement (≥8 point reduction
in NIHSS or reaching 0-1 at 3 days)
at 24 hrs post stroke without symptomatic intracerebral hemorrhage
at 24 hrs post stroke
growth within 24 hrs
severity (NIHSS) at 24hrs
due to any cause
Rankin Scale (mRS) 0-1 at 3 months
Rankin Scale (mRS) 0-2 at 3 months
shift in mRS at 3 months
- NIHSS reduction ≥8 points or reaching 0-1 at 3
median age was 69 years. The median NIH stroke scale was 15. The median stroke
to puncture time was 210 minutes.
at 24 hours for the endovascular intervention group was 89% as compared with
the alteplase-only group at 34% (P<0.001).
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
- 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.
||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.
centers in Australia and New Zealand
||Funded by the
Australian National Health and Medical Research Council and others
ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical
Trials Registry number, ACTR N12611000969965
- 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
|Level of Evidence
Randomized, Open-label, Blinded end-point, Multicenter Trial
(this study was terminated early)
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.
- 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.
of a moderate/large core in the territory of symptomatic intracranial occlusion
via non contrast CT, CTA or CT perfusion.
puncture is not possible within 60 minutes
femoral pulses or very difficult endovascular access
intracranial dissection as a cause of stroke.
- Severe or fatal comorbid illness precluding
follow-up or rendering intervention ineffective
- N = 150; Control Group =
Usual acute stroke care per guidelines
- N = 165; Intervention Group = Endovascular
thrombectomy or thrombolysis plus usual care
shift of one or more categories (proportional odds analysis) on the modified
- 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
age was 70 years with an NIH stroke scale of 17
to puncture was approximately 4 hours
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
was reduced from 13% to 6%
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 for good neurologic
outcome = 4
NNT to save a life = 15
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.
||22 centers in Canada, the United States, South Korea, Ireland, and the
- 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.