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Controversies in Neurocritical Care
Paul Vespa, MD, FCCM, FAAN, FNCS Professor of Neurology and Neurosurgery
Director of Neurocritical Care
UCLA David Geffen School of Medicine
Agenda
• Carotid Intervention in Carotid Artery Stenosis
– CEA vs CAS ?
• Acute Stroke Thrombectomy in 2014
– Should we be doing it?
• Blood Pressure control in Intracerebral hemorrhage
– What is the best number?
Carotid Stenosis
Options: CEA and CAS
Outcome of CEA based on degree of
stenosis
Indications for CEA based on NASCET
Carotid Angioplasty and Stenting
(CAS) in carotid stenosis
• N = 167 CAS vs N = 167 CEA
• Carotid ultrasound to make stenosis
• 1:1 randomization
• 81 or 325 mg ASA
• Nitinol stent with emboli prevention
device
• Little details about CEA – “ surgeons
used their customary techniques”
SAPPHIRE
SAPPHIRE
Critique of SAPPHIRE
• Mixture of Asx and Symptomatic
• Outcome is a gamish of all M+M
• No functional outcome data
– No QOL or mRS, etc
• CEA arm may not have been well controlled,
outcome is not comparable with NASCET
CREST 2010
CREST 2010
Summary of published trials in CAS vs CEA
Safety of CEA is better than CAS Silver et al Stroke 2011
CEA CAS Symptomatic
CEA CAS Asymptomatic
Abbott et al
Cerebral Hyperperfusion after CEA
Komorobashyi JCBFM 2005
Controversy regarding Thrombectomy in acute stroke
• Within 4.5 hours, IV tpa is reasonable for most patients
– Old age >80, diabetes and hypertension, warfarin
• Beyond 4.5 hours, the possibility of intra-arterial therapy exists
– IA tpa
– Thrombectomy
Synthesis Results Italian study using the Penumbra Device
ET (n=181) IVT (n=181)
Onset to randomization 2:28 (2:04-3:10 2:25 (1:59-2:59)
Onset to treatment* 3:45 (3:14-4:20) 2:45 (2:20-3:20)
UCLA Stroke Center
MR Rescue Trial – thrombectomy in mismatch cohort
Tmax PWI Predictive
Map
Day 7
Infarct
Favorable
Penumbral
Pattern
Non-Penumbral
Pattern
DWI
Favorable = predicted infarct core ≤ 90 cc & ratio of predicted infarct tissue
within at-risk region ≤ 70% (voxel-based multivariate MRI and CT models)
Kidwell et al, Stroke 2012
MR Rescue results
Primary Hypothesis: Test for Interaction between treatment assignment and
penumbral pattern by shift analysis
E/Pen n=34
S/Pen n=34
E/Non-Pen n=30
S/Non-Pen n=20
p value
Mean (95% CI) Day 90 mRS 3.9
(3.3-4.4) 3.4
(2.8-4.0) 4.0
(3.4-4.6) 4.4
(3.6-5.2) 0.14
As such, the trial failed to demonstrate that penumbral imaging identifies
patients who will differentially benefit from endovascular therapy for acute
ischemic stroke
JL Saver, R Jahan, E Levy, T G Jovin, B Baxter, R Nogueira, W Clark, R Budzik, OO Zaidat, for
the SWIFT Trialists
Lancet, Aug 26, 2012
Clinical Outcomes
Outcomes Among
Randomized Patients
Randomized
Solitaire FR
N=58
Randomized
Merci
N=55
Non-
inferiority
P value1
Superiority
P value1
Good neurologic outcome
at 90d2 58.2% (32/55) 33.3% (16/48) 0.0001 0.017
Mortality at 90 days 17.2% (10/58) 38.2% (21/55) 0.0001 0.020
1. Noninferiority by Wald’s method, superiority by Fisher’s Exact test
2. Good neurological outcome defined as mRS ≤ 2, or equal to the prestroke mRS if the prestroke mRS was higher than 2, or NIHSS score improvement ≥ 10
Tim
e to
Dea
th
P=0.014
(Days)
Blood Pressure control in ICH
Stroke 2007; Stroke 2010
ICH patient with hypertension, instability early on
0
50
100
150
200
250
8:0
0
10:0
0
12:0
0
14:0
0
16:0
0
18:0
0
20:0
0
22:0
0
0:0
0
2:0
0
4:0
0
6:0
0
8:0
0
Hour
SB
P m
m H
g
Interact 1: median 4 hours to start of treatment
Interact 1 results
Interact results
INTERACT 2 - Slides are courtesy of Craig Anderson Feb 15, 2014
Protocol schema from INTERACT1 (Lancet Neurol 2008) and INTERACT 2 (Int J Stroke 2010)
Acute spontaneous ICH confirmed by CT/MRI
Definite time of onset within 6 hours
Systolic BP 150 to 220 mmHg
No indication/contraindication to treatment
In-hospital vital signs, NIHSS, GCS and BP over 7 days
Intensive BP lowering
SBP <140 mmHg
Standard BP management
Guidelines SBP <180 mmHg)
R
36
Independent 90 day outcome with modified Rankin scale (mRS)
POWER CALCULATION FOR INTERACT 2
N=2800 gives 90% power for 7% absolute (14% relative) decrease (50% standard vs 43% intensive) in outcome
Patients were excluded with large ICH, poor prognosis, early surgery
Lots of patients got mannitol ATC
INTERACT2 – Small hematomas were studied
0 10 20 30 40 50 60 70 80 90 100
0.6
0.4
0.2
0
Density
Baseline hematoma volume (ml)
median Surgery
threshold
Systolic BP time trends 1 hour - Δ14 mmHg (P<0.0001) 6 hour - Δ14 mmHg (P<0.0001)
Systolic BP control Median (iqr) time to treatment, hr - intensive 4 (3-5), standard 5 (3-7)
Intensive group to target (<140mmHg) 462 (33%) at 1 hour 731 (53%) at 6 hours
Me
an
Systo
lic B
loo
d P
ressu
re (
mm
H
g)
0
110
120
130
140
150
160
170
180
190
200
R 15 30 45 60 6 12 18 24 2 3 4 5 6 7
Standard Intensive
// //
Minutes Hours Days / Time
164
153
150
139
am pm am pm am pm am pm am pm am pm
P<0.0001
beyond 15mins
Target level
38
Primary clinical outcome
Death or major disability (mRS 3-6) at 90 days
12.0 12.0
40.0 43.6
0
10
20
30
40
50
60
Intensive Standard
Major Disability
(3-5)
Death (6)
%
(N=1399) (N=1430)
52.0% 55.6%
Odds ratio 0.87 (95%CI 0.75 to 1.01) P=0.06
39
Key secondary outcome Ordinal shift in mRS scores (0-6)
Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04
40
18.0%
18.8%
16.6%
19.0%
\
12.0%
8.0%
0 1 2 3 4 5 6
Intensive
Standard
Major disability Death Disability but independent
18.7% 15.9% 18.1% 6.0% 21.1% 8.1% 12.0%
7.6%
Interact 2 – hemorrhagic expansion was the same in both groups
Systo
lic B
lood P
ressure
(m
mH
g)
21.5
20.1 19.2
19.7 18.7 19.4 19.3 19.3 19.1
18.9 19.2 19.3 18.9 18.5 18.1 18.6 18.5 20.8
18.4 17.7 17.6 16.9 16.7
17.2 18.1 17.6 17.4 16.9
17.5 16.7 16.4 16.4 16.3 16.6
12
0
14
0
16
0
18
0
20
0
1 6 12 18 24 am pm am pm am pm am pm am pm am pm
Guideline group
Intensive group
Hour Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
BP variability is associated with worsened outcome in INTERACT 2
Interpretation of Interact 2
• Study of variable BP reduction
– 140 -145 mm Hg vs 150-155 range
• Primary outcome was negative (p =0.06)
• Secondary outcomes appear to be better in the intervention group (p < 0.04)
– Strong trend towards benefit across all categories
• BP variability is important
– less variability of BP correlates to better outcomes
Conclusions
• CEA is best for carotid stenosis
– CAS may be reasonable alternative
• Thrombectomy for acute stroke is unproven
– Novel devices now being tested
• BP control for ICH 100-150 seems reasonable based on data
– Special attention to avoiding BP fluctuations
Recommended