Download 3rd-annual-stroke-symposium-CTP-and-PLEASENoCTP - TRAC-V

Ameer E. Hassan DO,
Clinical Director of Endovascular Surgical Neuroradiology,
Neurocritical care and Clinical Neuroscience Research,
Valley Baptist Medical Center
Assistant professor, Neurology and Radiology
University of Texas Health Science Center – San Antonio
*
Financial:
Consultant for GE Healthcare, Microvention
and Covidien.
Conflicts of interest: none
Background
Non-contrast cranial computed tomographic (CT) scan
findings in acute ischemic stroke patients have been
classically used to select patients for intravenous and
endovascular thrombolysis therapy in the:
European Cooperative Acute Stroke (ECASS) I1,II2 and III3,
Interventional Management of Stroke (IMS) I4,II5 and III6,
Prolyse in Acute Cerebral Thromboembolism (PROACT) II7,
Mechanical Embolus Removal in Cerebral Ischemia
(MERCI)8 trials.
Background
Studies have found that dynamic CT-P images were more
accurate than non-enhanced cranial CT in the detection of
ischemic stroke in patients presenting with symptoms less
than 12 hours in duration.
Another study found that CT perfusion (CT-P) imaging was
more sensitive [100%] and specific [92%] than non contrast
CT [93% sensitive and 67% specific] for the detection of
large ischemic infarcts (affecting greater than one third of
the affected lobe).
Subsequently, new emphasis has been placed on using CTP imaging to select patients with acute ischemic stroke
who can benefit from an expanded time window with
intravenous or endovascular treatment.
Expanding the time window
after 4.5 hours
???
Expanding the time window
after 4.5 hours
Arrival
15
25
minute
s
minute
s
45
minutes
60 minutes & within
4.5 hours of onset
Endovascular
time window
Not
defined
Trend of thrombolytic use in the
United States
3.5
3.0
3.4
Use of endovascular
Use of Intravenous
2.5
2.0
2.0
1.5
1.2
0.1
2.3
1.4
1.0
0.5
2.6
0.3
0.5
2006
0.4
0.6
0.6
2007
2008
2009
0.0
2004
2005
Hassan AE, Chaudhry SA, Grigoryan M, Tekle WG, Qureshi AI. Stroke. 2012
Nov;43(11):3012-7.
Trend of thrombolytic use in the
United States (Hassan et al. Stroke 2012)
Based on analysis of the Nationwide Inpatient Sample
database from 2005 to 2008:
intra-arterial thrombolysis has steadily increased by
17%, 22%, 25% and 35% respectively.
However the proportion of patients who are disabled or
dead has not changed over the years.
Patients discharged to a nursing facility are still around
49% and approximately 14% of patients die in the
hospital.
Endovascular Thrombolysis
While endovascular treatment has reduced the
rate of death and disability compared with no
treatment
The relatively high rate and expense associated
with such treatment mandates a more effective
strategy for patient selection.
Endovascular Thrombolysis
In order to increase the rates of good
outcomes, new emphasis has been placed on
using advanced neuroimaging to select patients
with acute ischemic stroke who can benefit
from endovascular treatment.
The potential of CTP is based on high
prevalence of use among patients with acute
stroke to confirm the diagnosis of ischemia
without delaying treatment.
CTP Selection of Penumbra
The presence of ischemic penumbra on CT-P
can be identified based on:
increased mean transit time (MTT),
decreased cerebral blood flow (rCBF), and
normal or increased cerebral blood volume
(rCBV)
11
All potentially used to select acute ischemic
stroke patients for intravenous or endovascular
treatment.
12
increased mean transit time (MTT),
decreased cerebral blood flow (rCBF), and
normal or increased cerebral blood volume (rCBV)
Limitations of CTP
There are limitations to acquisition and interpretation of CT-P
imaging.
Multi-slice CT scanners provide 2 to 4 cm of coverage per
acquisition which do not always allow the evaluation of the exact
perfusion deficit volumes if they exceed the volume studied.12
The variation in reconstruction of CT-P images and qualitative
interpretation of salvageable tissue may lead to selection of a
relatively heterogeneous population, leading to the inclusion of
patients with limited salvageable tissue which may obscure the
benefit of endovascular treatment.
False negatives and un-interpretable imaging can be obtained
when using CT-P imaging largely due to a patient’s low cardiac
output, inappropriate slow rate of bolus administration, contrast
extravasation in the subcutaneous tissue, patient movement, and
operator inexperience.11
Current Endovascular Protocol
• Endovascular treatment patient selection:
–≤ 4.5 hours
• NIHSS of ≥10
–4.5-6 hours
• NIHSS of ≥10
• NIHSS <9 with mismatch on perfusion
–6-24 hours
• NIHSS of ≥10
– Anterior circulation
» if large perfusion mismatch is present
– All basilar artery occlusions within the first 24 hours
Protocol for acute ischemic stroke treatment
Time dependent loss of benefit
0-3 hrs
salvageable brain
Ischemic
stroke
3-6 hrs
Value of
Additional
imaging
>6 hrs
Salvageable tissue
Time dependent value of additional imagingIdentify presence of salvageable tissue.
(Hassan AE. Stroke. 2010 Aug;41(8):1673-8)
rCBF-rCBV mismatch on CTP
Time
Salvageable tissue
Time dependent value of additional imagingIdentify presence of salvageable tissue.
(Hassan AE. Stroke. 2010 Aug;41(8):1673-8)
Diffusion-perfusion mismatch on MRI
OR rCBV-rCBF mismatch on CTP
rCBV +
Time
rCBF↓
CTP Guided and Time Guided Endovascular Treatments
(Re: Hassan AE. Stroke. 2010 Aug;41(8):1673-8)
Outcomes
CTP
Time guided
p-
guided treatment
treatment
value
n=69
23 (32%)
n=127
41 (33%), 125
Favorable
outcome at
CTP guided endovascular treatment did
discharge not increase the rate of short-term
Early neurological
46 (64%)
69 (64%), 108
favorable outcomes among acute
improvement
0.90
Symptomatic ICH
Partial/complete
recanalization
0.59
0.52
0.94
ischemic stroke patients
6 (8%)
61 (88%)
8 (6%)
103 (81%)
Limitations of CTP
So if CTP should select patients for
endovascular treatment more
appropriately, what happened?
Agreement and variability in the interpretation of presenting CT and CTPerfusion Imaging changes in Ischemic Stroke Patients qualifying for
endovascular therapy.
(Hassan et al. Neurocrit Care. 2012 Feb;16(1):88-94.)
• Kappa values for the treatment decisions based on CT images
was 0.43 (range 0.14-0.8) (moderate agreement), and for the
decisions based on CTP images was 0.29 (range 0.07-0.67)
(fair agreement) among the five subjects.
• There was substantial variability within the group and
between images interpretation.
• Observed agreement on decision to treat with endovascular
therapy was found to be 75% with CT images and 59% with CTP images (with no adjustment for chance). Kappa values for
intra-rater agreement were -0.14 (ranged -0.27-0.27) (poor
agreement).
• In conclusion, there is considerable lack of agreement, even
among stroke specialists, in selecting acute ischemic stroke
patients for endovascular treatment based on CT-P changes.
This mandates a careful evaluation of CT-P for patient
selection before widespread adoption.
Agreement and variability in the interpretation of presenting CT and CTPerfusion Imaging changes in Ischemic Stroke Patients qualifying for
endovascular therapy.
(Hassan et al. Neurocrit Care. 2012 Feb;16(1):88-94.)
* CT-P example of a Right MCA stroke with
the majority of reviewers deciding to treat
with endovascular therapy
Agreement and variability in the interpretation of presenting CT and CTPerfusion Imaging changes in Ischemic Stroke Patients qualifying for
endovascular therapy.
(Hassan et al. Neurocrit Care. 2012 Feb;16(1):88-94.)
* CT-P and CT scan example of a Left MCA
stroke with the majority of reviewers
deciding NOT to treat endovascularly.
A trial of imaging selection and endovascular treatment for
ischemic stroke.
(MR RESCUE Investigators, NEJM, March 2013)
A randomized multicenter trial (22 stroke centers)
with a total of 118 patients from 2004 to 2011.
 Embolectomy was not superior to standard care
in patients with either a favorable penumbral
pattern (mean score, 3.9 vs. 3.4; P=0.23) or a
nonpenumbral pattern (mean score, 4.0 vs. 4.4;
P=0.32).
In the primary analysis of scores on the 90-day
modified Rankin scale, there was no interaction
between the pretreatment imaging pattern
and treatment assignment (P=0.14).
A trial of imaging selection and endovascular treatment for
ischemic stroke.
(MR RESCUE Investigators, NEJM, March 2013)
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.
*
- Interventional Management of Stroke III
(IMS III) – Broderick JP et
al. N Engl J Med. 2013 Mar 7;368(10):893-903.
* Phase III, randomized, multi-center, open-label clinical
trial
* Purpose: To determine whether a combined IV/IA approach
to recanalization is superior to standard IV rt-PA alone
when initiated within 3 hours of stroke onset.
* Primary outcome measure: Favorable outcome in terms of
functional independence as measured by a Modified Rankin Scale
score of 0-2 at 3 months.
Prematurely terminated because it passed
the point of significance even if the trial
was completed
Endovascular Interventions - Interventional
Management of Stroke III (IMS III)
* RCT of 656 patients with documented large-artery occlusions,
NIHSS 8 or higher:
* 434 randomized to EST after bridging (low-dose) IV t-PA;
* 222 randomized to full dose IV t-PA;
* Results: no difference in outcomes between the two groups
overall, despite a hint of the appropriate shift in mRS favoring
EST:
Endovascular Interventions - Interventional
Management of Stroke III (IMS III)
* Good reperfusion (TICI 2b or 3) was achieved in only 44% of
patients with an M1 occlusion, and at a similar or lower rate for
other sites of occlusion;
* In keeping with previous literature reports, IV TPA does not
seem to work well for stroke due to carotid terminus occlusions
or tandem extracranial ICA/M1 occlusions.
* In IMS3 the rate of good outcome in these patients was 4%.
With IV/IA outcomes a bit better (26%) but overall remain poor.
At our center, about 20-30% of patients we treat fall into this
category. This is not a small minority of patients!
Endovascular Interventions - Interventional
Management of Stroke III (IMS III)
* EST used IA t-PA or any approved thrombectomy device the
treating physician chose to use:
* IA t-PA only (n=151)
* MicroSonic SV system (n=14)
*20% with no lesion to treat
* Merci (n=77)
* Penumbra (n=39)
* Solitaire (n=4)
{ <18% of total EST patients}
{ <10% of total EST patients}
{ <1% of total EST patients}
Endovascular Interventions - Interventional
Management of Stroke III (IMS III)
* Learning points (ISC 2013, Honolulu HI ):
* Largest signals in favor of EST are: Terminal ICA occlusions, severe
deficits (NIHSS>20) and early time to treatment.
* Reperfusion is a good thing, but it is TIME dependent, for every 30
minute delay in reperfusion there is a 10% lower chance of a good
outcome
* MERCI has more associated complications than other EST
approaches.
* Centers like University of Cincinnati (PI of IMS I, II, & III) still
practice the same approach prior to IMS III results.
* Majority of EST at large centers includes IV TPA excluded patients
(recent major surgery, INR > 1.7, previous intracranial pathology,
etc.), posterior circulation occlusions, and OUTSIDE of the time
window; AS WELL AS patients with M1 occlusions who are not
improving within first 30 minutes of IV TPA.
Endovascular Interventions - Interventional
Management of Stroke III (IMS III)
*
Comparing EST to proven MI treatment:
* In acute MI, many of the original trials comparing endovascular
therapy to IV lytics were negative and even the latest trials comparing
endovascular therapy to IV fibrin-specific lytics had a difference of
1% mortality (which required pooled analyses and large sample
sizes).
* The reality of endovascular acute stroke care (including at top
academic centers in the US) during IMS3 was conducted is one of
long delays from hospital presentation to groin puncture (mean 81
min from iv t-PA administration to groin puncture and another 42 min
from groin to treatment start in IMS3).
* Contrast this to the mandatory door to ballon time of 90 minutes in
acute coronary syndromes beyond which Medicare does not
reimburse acute coronary interventions for MI and you can
appreciate where we stand compared to our cardiology colleagues.
* In fact whenever a cardiologist asks me why all those trials published
in the New England Journal of Medicine were negative my answer is
"imagine a percutaneous coronary revascularization trial against IV
lytics in which the door-to-balloon time is 3 hours and you will
understand why."
Advanced modality imaging evaluation in acute ischemic
stroke may lead to delayed endovascular reperfusion therapy
without improvement in clinical outcomes.
(Sheth et al. JNIS, May 2013)
A recent retrospective multicenter analysis
(10 stroke centers) with a total of 556
treated with endovascular thrombolysis
showed that multimodal imaging was
associated with delays in treatment
without reducing hemorrhage rates or
improving clinical outcomes.
286 (51%) patients had a non-contast CT,
190 (34%) patients had CT-P, and 80 (14%)
patients had MRI.
Advanced modality imaging evaluation in acute ischemic
stroke may lead to delayed endovascular reperfusion therapy
without improvement in clinical outcomes.
(Sheth et al. JNIS, May 2013)
Non contrast CT had significantly lower
median times to groin puncture (61 min,
IQR 40-117), compared with CTP (114
min, 81-152) or MRI (124, 87-165).
They concluded that a prospective trial is
warranted to support advanced imaging.
Evidence based guidelines
2013 AHA/ASA Guidelines for
Early Management of Patients With Acute Ischemic Stroke
*
CT perfusion and MRI perfusion and diffusion imaging, including
measures of infarct core and penumbra, may be considered for
the selection of patients for acute reperfusion therapy beyond the
time windows for intravenous fibrinolysis. (Class IIb; Level of
Evidence B)”
Definitions
Class IIb:Usefulness/efficacy is less well established by evidence or opinion
Evidence B: Greater conflicting evidence from single randomized trial or
nonrandomized studies
Objective
To demonstrate that non-contrast
computed tomography imaging within 8
hours of acute ischemic stroke symptom
onset is comparable to computed
tomography perfusion imaging.
Methods
We will prospectively study all
consecutive acute ischemic stroke
patients who are treated within 8 hours
of symptom onset with an endovascular
intervention. In the setting of wake up
strokes, time of symptom onset is
identified by time last seen normal.
Methods
*All the patients will undergo, non-contrast
computed tomography imaging, computed
tomography angiography and computed tomography
perfusion imaging.
*The endovascular treatment team will be blinded to
the results of the computed perfusion imaging.
*Every patient will undergo non-contrast computed
tomography 24 hours and 48 hours post
endovascular intervention as well as after any
suspected deterioration in neurologic function.
Methods
Additional Data Collected:
age and gender
pre-admission vascular risk factors (hypertension,
dyslipidemia, diabetes mellitus, cigarette smoking,
atrial fibrillation, congestive heart failure, history of
stroke/TIA and coronary artery disease)
race/ethnicity
Pre- and intra- procedural intubation status will be
obtained.
Data regarding severity of stroke will be quantified
by the admission National Institutes of Health Stroke
Scale (NIHSS) score and discharge functional outcome
was ascertained using the modified Rankin Scale
(mRS) score.
CT Protocol - ASPECTS
 The stroke team will use the ASPECTS method to read the
CT scans.
 The ASPECTS is determined from two standardized axial CT
cuts, one at the level of the thalamus and basal ganglion
and one adjacent to the most superior margin of the
ganglionic structures, such that they were not seen.
 On these two sections, which are, by definition, not
continuous, the MCA territory is allotted 10 points.
 A single point is subtracted for an area of early ischemic
change, such as focal swelling or parenchymal
hypoattenuation, for each of the defined regions.
 A normal CT scan receives an ASPECTS of 10 points. A score
of zero indicated diffuse ischemic involvement throughout
the MCA territory.
CT Protocol - ASPECTS
Inclusion Criteria
New focal
neurological signs in the Internal carotid
artery, Middle Cerebral Artery, or Anterior Cerebral
artery distribution allowing initiation of treatment
within 8 hours of the onset of symptoms;
A minimum National Institutes of Health Stroke Scale
(NIHSS) score of 8
Age greater than or equal to 18 years.
Exclusion Criteria
* NIHSS score greater than 30
* coma
* Rapidly improving neurological signs at any point prior to endovascular intervention
* Seizures at onset
* Clinical presentation suggestive of subarachnoid hemorrhage
* Septic embolism
* Suspected lacunar stroke
* Active or recent hemorrhage within 30 days
* Known hemorrhagic diathesis
* Baseline international normalized ratio greater than 3
* Receipt of heparin within 48 hours with a partial thromboplastin time greater than two
*
*
*
times the lab normal
Platelets less than 30,000
Sustained severe hypertension
Evidence of intracranial hemorrhage, significant mass effect with midline shift, or an
obvious infarction of greater than one third (100mls) of the Middle Cerebral Artery
vascular territory on non-contrast head computed tomography scan
Primary Outcomes
*24 hour NIHSS score following treatment
*7 day or discharge NIHSS score
*Discharge modified Rankin score
*In-hospital mortality
*Symptomatic intracranial hemorrhage, and
asymptomatic intracranial hemorrhage rates.
CTP analysis
*The perfusion scans obtained will be generated
using both Gaussian Fit and single value
deconvolution methods using Vitrea software
(Vital Images), yielding the following perfusion
parameters: time to peak, MTT, rCBF, and rCBV.
* The CT-P scans will be retrospectively reviewed
by a neuro-radiologists and two endovascular
interventionalists to determine which patients
have a penumbra (preserved rCBV, decreased
rCBF and increased MTT) and would have been
appropriate for an endovascular intervention.
* Inter-observer agreement will be determined.
CTP analysis
* Based on qualitative analysis of the cerebral blood volume maps,
we will define salvageable tissue (penumbra) amenable to
endovascular intervention, to be present when the total ischemic
territory is at least 20% greater than the infarcted area and the
ischemic zone involved the cortex.
* In the case of an MCA vascular territory infarction, the patient will
be excluded from intervention if the infarct burden is greater than
or equal to one third of the vascular territory on qualitative analysis
of the CT-P cerebral blood volume (CBV) map.
* The CT-P infarct core and ischemic penumbra will be automatically
calculated by the software using the appropriate MTT and rCBV
thresholds (CT-P penumbra: MTT >145% of the contralateral side
values, rCBV > 2 mL/100 g; CT-P infarct: MTT >145% of the
contralateral side values, rCBV <2 mL/100 g).
Results
 A total of 102 patients have been
screened for this trial over a 2 year
period at 2 stroke centers.
A total of 55 patients have been
enrolled
47 patients were excluded:
 Posterior circulation
 No CTP performed
 Not consentable or did not want to sign consent
 Last seen normal >8 hours
 NIHSS<8
*
Acute ischemic stroke Comprehensive treatment growth
Number of Patients Discharged with diagnosis of Ischemic
Stroke
2010
2011
2012
2013
343
337
394
464
(390)
(457)
45
(9.8%)
(Total number without transferred patients)
% of Patients Treated with IV rt-PA at VBMC
% of Patients Treated with IV rt-PA all
(includes Drip & Ship)
% of Patients Receiving any Endovascular Intervention
% of Patients Receiving any Recanalization Therapy
11
18
18
(3.2 %)
(5.3%)
(4.6%)
3.2%
5.3%
22
(5.5%)
15
52
(11.2%)
(3.8%)
57
(12.2%)
37
109
(9.3%)
(23.4%)
Conclusion
Time is brain, The availability of
endovascular interventions
should not preclude the IV TPA in eligible patients
CTP guided endovascular treatment has not been associated with
improved outcomes among acute ischemic stroke patients in the
current literature (most likely due to delay in treatment).
Prospective studies are required to validate the CTP criteria and
protocols currently in use, while using the latest stroke devices
(Solitaire, Trevo, and Penumbra) prior to incorporating CTP as a
routine patient selection modality for acute ischemic stroke
treatments.
*