3. Acute Ischemic Stroke (AIS)
AIS is an interruption in blood flow to a part of the brain. This should be distinguished from
intracerebral hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, and epidural
hemorrhage.
Ischemic strokes that are caused by occlusion of the internal carotid artery or proximal anterior
cerebral, middle cerebral, or basilar artery, may be broadly termed large vessel occlusions (LVOs).
Rapid administration of intravenous tPA has been the standard of care for ischemic stroke (both
small-vessel and large-vessel), for over 20 years (NINDS trial, 1995). Any patient arriving within 4.5
hours of “last known well time” should be considered for IV tPA – hence the mantra “time is brain.”
Over the past 20 years, the Stroke community has been investigating whether endovascular
reperfusion (recanalization) of LVOs may benefit this subtype of strokes.
4. The Modified Rankin Scale (MRS):
A commonly used stroke outcome measure
0: No symptoms at all.
1: No significant disability despite symptoms; able to carry out all usual duties and activities.
2: Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance.
3: Moderate disability; requiring some help, but able to walk without assistance.
4: Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without
assistance.
5: Severe disability; bedridden, incontinent and requiring constant nursing care and attention.
6 Dead.
5. LVO endovascular trials:
Early 2000s
1999
PROACT II
(intra-arterial
thrombolysis)
2005
MERCI
(corkscrew
retriever)
2009
Penumbra
(aspiration
system)
6. LVO endovascular
therapies: 2010-2014
• In 2012, two new devices were approved for use in
the USA for stroke due to LVO: Trevo and Solitaire.
• Termed stent-retrievers or “stentrievers,” these
devices consist of an expandable stent which pushes
through the clot, then expands to retrieve it
• These new devices improved revascularization rates
and had lower rates of hemorrhage compared with
Merci and Penumbra
• Even so, multiple 2013 studies (IMS-III, SYNTHESIS
Expansion, and MR RESCUE) showed no benefit of
endovascular treatment over IV tPA
7. The results of five randomized
controlled trials (RCTs) showed
improved efficacy of endovascular
thrombectomy (ET) for large vessel
occlusion (LVO), when compared
with IV tPA alone.
MR CLEAN
ESCAPE
REVASCAT
SWIFT PRIME
EXTEND-IA
2015: A very good year for endovascular thrombectomy
MRS 0-2: 26.5%
MRS 0-2: 46%
RR: 1.7 (1.41-2.05); p<0.0001
8. What changed in 2015?
Only new devices
(stentrievers)
Experienced
proceduralists
More stringent
patient selection
Patients without LVO
were excluded
Patients with
completed strokes at
arrival were excluded
Alberta Stroke Program Early
CT Score (ASPECTS)
Stat MRI
CT Perfusion Scan
We dichotomize this scale broadly into two categories: Independent (MRS 0, 1, or 2) and dependent on others (3+). Most of the stroke trials of the past 15 years have used the dichotomization of the Modified Rankin Scale as their primary endpoint.
Although all three of these early trials increased reperfusion of LVOs, there was not a significant clinical benefit in the MERCI and Penumbra trials, and the clinical benefits seen in PROACT II were countenanced by a significantly increased risk of intracranial hemorrhage.
There were some drawbacks of these three trials. MR RESCUE trial was restricted by the undersized sample and use of less effective thrombectomy devices. In the IMS-3 and Synthesis trials, criteria for inclusion of patients were poor, since these studies also included patients with no arterial occlusion and without endovascular treatment into the endovascular arm. Moreover, the recanalization rates attained in these studies were too low to actually investigate the effect of arterial recanalization and tissue reperfusion.
There was a collaboration between all the investigators of these trials, the HERMES collaboration, and the results of HERMES are shown above as change in MRS. This format of showing change in MRS is reproduced in our paper under discussion today – the DAWN trial.
These trials enrolled patients who presented between 4.5 and 12 hours from their last known well time. EXTEND-IA and SWIFT PRIME pts got IV tPA so presented within 4.5h, MR CLEAN within 6.5h, REVASCAT within 8h, ESCAPE within 12h.
The 5 2015 trials were different from older studies in that they were performed with newer-generation devices (stentrievers), and more careful patient selection. Patients were excluded if they had imaging evidence of already having completed their infarct at the time of arrival. Imaging modalities such as noncontrast CT (ASPECTS), DWI on MRI, and CT Perfusion were used to determine if a patient already had a “core” infarct which was above a certain volume threshold.
As we imaged patients for these trials, trying to find good candidates for reperfusion, we realized there was a lot of heterogeneity in terms of how quickly people progressed from LVO to completed infarction. Some patients have excellent collateral circulation that keeps the tissue in a state of “penumbra” for hours, whereas others have very poor collateral flow, and they tend to complete their infarcts very quickly, within minutes. This idea lead us from the “time is brain” paradigm to the “perfusion is brain” paradigm – which begs the question, how far out can we push the time, as long as the tissue is perfused?
Mismatch – the patient comes in with significant deficits, eg right hemiplegia and aphasia, without evidence of a matched completed infarct on ASPECTS, MRI, or CTP. They defined this by including patients with relatively high NIH Stroke Scales, and introducing a maximal completed infarct volume. (the NIHSS is a 0-42 point scale indicating stroke severity by symptoms) There were three groups: A, pts over 80 with NIHSS 10+ and infarct vol <21cc / B, pts under 80 with NIHSS 10+ and infarct vol <31cc, and / C pts under 80 with NIHSS 20+ and infarct vol < 21cc. Patients over 80 would be expected to have worse outcomes based on age, and needed to have smaller infarct volumes to justify taking them. Patients with NIHSS 20+ would be expected to have huge strokes and they would tolerate a higher infarct volume at presentation, with the presumption that there was significantly more tissue “at risk.” All patients also needed to have pre-stroke Rankin score of 0 or 1 (able to carry out all usual duties).
Utility-weighted values were 10 for mRS level 0; 9.1 for mRS level 1; 7.6 for mRS level 2; 6.5 for mRS level 3; 3.3 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. This was going to be the first trial using this as a primary end point, but FDA didn’t love this, and wanted them to add rate of MRS 0-2 as a coprimary end point (was initially secondary end point).
Point out ICA and M1 segment of MCA
Patients were similar in terms of age, NIHSS, and infarct volume, the 3 most important predictive characteristics for how people do after a stroke.
No difference in mortality
Difference in 24h deterioration – most likely led by large ischemic strokes causing edema at 24h
