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