Time is Brain: Optimal Management of Acute Stroke

1
Time is BrainOptimal Management of Acute Stroke

• Keith W Muir
• Division of Clinical Neurosciences, University of
  Glasgow

2
Evolution of Ischaemic Damage
3h
24h
11 days
CT
SPECT
3
The Ischaemic Penumbra
CBF
Normal
Hypoperfusion
Penumbra
Infarction
Time
Jones TH et al J Neurosurg 1981
4
(No Transcript)
5
Stroke Management Pathways

• Recognition
• Prioritisation
• Diagnosis
• Clinical
• Radiological (define pathology, localisation,
  mechanism)

TIA or Minor Stroke
Disabling Stroke

• Immediate treatment
• IV rtPA if lt4.5h
• Aspirin
• Stroke Unit care
• Avoid complications
• Swallowing assessment
• Treat infection, pyrexia, hypoxia, ?other
  physiological derangements

• Define mechanism
• Initiate secondary prevention
• Aspirin Dipyridamole MR
• Statin (? Atorvastatin 80mg)
• ? Other antiplatelets?
• ? Blood pressure
• Carotid endarterectomy

6
Public Education
7
Diagnostic Accuracy of Hospital-Referred Stroke
Harbison et al. Stroke. 20033471-76
8
Stroke Mimics
Newcastle, UK 2000
New York, USA 1990-92
Harbison et al. Stroke. 20033471-76
Libman et al. Arch Neurol 1995521119-22.
9
CT in Acute Stroke
Haemorrhage
Ischaemic
Non-Stroke
10
Hyperacute CT Sensitivity
11
Predictive Value of EICECASS 2 Results
Sensitivity and Positive Predictive Values with
Baseline CT for Ischemic Infarcts at Intervals
after Stroke Onset
Median NIHSS Score 12.5 12.0 11.0 10.0 9.0 9.0
Positive Predictive Value () 100 95 98 96
93 80
Sensitivity () 58 66 65 64 66 38
Interval h 0-1 1-2 2-3 3-4 4-5 5-6
Von Kummer et al. Radiology 2001 21995100.
12
(No Transcript)
13
NINDS IV rtPA lt3h3 Month Outcome
rtPA
Placebo
NINDS rtPA Study Group. NEJM 19953331581-7.
14
ASIST StudyTime to Presentation after Stroke
Nursing Triage lt15mins Seen by Junior Dr
lt15mins Seen by Consultant lt3h CT lt3h
86 22 5 8

• n739
• unselected acute stroke patients
• 22 UK hospitals

Harraf et al. BMJ 200232517
15
South Glasgow IV rtPA Treatments 1996 - 2007
16
pCT L MCA Occlusion
TTP
CBV
Penumbragram
17
SITS-MOST Outcomes
Pooled RCTs
n465
n463
n6136
Wahlgren et al. Lancet 2007 369 27582
18
Thrombolysis by PostcodeUK SITS-MOST 2002-06
n614 (Approximately 0.15)
Lees et al QJM 2008
19
ThrombolysisBenefit v Time to Treatment All
rtPA Trials
Lancet 2004363 (9411) 768-774.
20
(No Transcript)
21
Primary Endpoint (ITT)
Day 90 mRS 0,1 Excellent recovery
0.5 1 1.5
Favours Placebo Favours Alteplase
? For unadjusted data
Hacke et al N Engl J Med 20083591317-29.
22
Primary Endpoint (ITT)
Day 90 mRS 0,1 Excellent recovery
Favours Placebo Favours Alteplase
Adjusted for prognostic variables treatment,
baseline NIHSS, smoking history, stroke onset to
treatment time, and prior hypertension
Hacke et al N Engl J Med 20083591317-29.
23
ECASS 3Distribution (shift) analysis day 90
ITT
mRS score
1
2
3
0
4
5
6
Alteplase (n418)
27.5
9.3
14.1
24.9
9.3
6.7
8.1
p0.024
Placebo (n403)
23.3
21.8
16.4
13.7
8.2
11.4
5.2
Patients
100
0
20
40
60
80
stratified on CochranMantelHaenszel
test,adjusted for baseline NIHSS scores and
time-to-treatment onset
Lees et al. N Engl J Med 2006354588-600
Hacke et al N Engl J Med 20083591317-29.
24
Early Treatment Remains Essential

• The effect size (OR 1.4) at 3-4.5h is confirmed
  by ECASS III, and the confidence intervals will
  significantly narrow in the new pooled analysis,
  however, the difference in effect size compared
  with early treatment (OR 2.8) remains

OR 2.8
OR 1.5
OR 1.4
OR 1.2
4.0
3.5
3.0
2.5
Adjusted odds ratio
2.0
1.5
1.0
0.5
0.0
60
120
180
240
300
360
1.5h
3h
4.5h
6h
OTT Time (mins)
Hacke et al N Engl J Med 20083591317-29.
Hacke et al. Lancet 2004 363 76874
25

• having more time does not mean we should take
  more time
• There may be more time for the patients,but not
  for the treating physicians

Hacke et al N Engl J Med 20083591317-29.
26
SITS-ISTR 3-4.5h Data
Wahlgren et al Lancet 2008 372 130309
27
Intracerebral Haemorrhage
SICH Rate (95 CI)
SITS-MOST 1.7 (1.4-2.0) ECASS 4.5
(4.1-5.1) NINDS 7.3 (6.6-8.0) Fatal 0.28
(0.17-0.45)
Wahlgren et al. Lancet 2007 369 27582
28
(No Transcript)
29
Stroke Unit CareSummary of Effects
Intervention n/N
Control n/N
OR (95 CI)
ARR
NNT
Death
0.82 0.71, 0.94
4.1
24
522/2515
596/2396
Death or Dependence
0.78 0.68, 0.89
4.7
21
1117/2000
1171/1935
Death or Institutional Care
0.80 0.71, 0.90
5.4
19
994/2486
1077/2373
0.5
1
2
Cochrane Database of Systematic Reviews 2003
30
Stroke UnitsPeople or Geography ?
1 Year Disability (modified Rankin Scale)
Kalra et al. Lancet 2000 356 894-9.
31
When Do Stroke Units Work?Cumulative Survival
Advantage
8
6
Cumulative Survival Advantage ()
4
2
0
0
1
2
4
6
12
16
26
52
Time (weeks)
Stroke Unit Trialists Collaboration. Stroke
1997 28 2139-44.
32
Aspirin in Acute StrokeSummary of Effects (IST,
CAST, MAST-I)
OR (95 CI)
ARR
NNT
Death
0.92 0.87, 0.98
0.8
121
Death or Dependence
0.95 0.91, 0.98
1.3
78
Recurrent Stroke
0.87 0.78, 0.96
0.7
195
Complete Recovery
1.06 1.01, 1.11
-1.1
-95
0.5
1
2
Cochrane Database of Systematic Reviews 2000
33
Physiological Variables and OutcomeCase-Control
Study
p0.03
p0.001
p0.10

• 28 controls
• 28 Abnormal
• O2 saturation lt93
• blood glucose gt10mmol/l
• temperature gt37.5C
• serum osmolarity gt300mOsm/kg
• during first 72h after admission

Langhorne et al. Stroke 2000312526-7.
34
TIARisk Factors and Prognosis
No of Risk Factors
0
Stroke-free Survival
1
2
3
4
5
Days after TIA
Risk Factors for Stroke agegt60, weakness, speech
loss, durationgt10mins, diabetes
Johnston et al. JAMA 20002842901-6.
35
ABCD2 (Age, Blood pressure, Clinical features,
Duration, Diabetes)
A
Age ?60 years 1 Blood pressure Systolic ?140
mmHg and/or Diastolic ?90 mmHg) 1 Clinical
features Unilateral weakness 2 Speech
disturbance without weakness 1 Duration of
symptoms in minutes ?60 mins 2 1059
mins 1 Diabetes 1
B
C
D
D2
Johnston, Rothwell et al Lancet 2007 369 28392
36
Risk of Stroke After TIA ABCD2 Score Prognosis
Johnston, Rothwell et al Lancet 2007 369 28392
37
TIA Permanent Damage?
Transient sensory disturbance
Transient speech slurring and face tingly
Blurred vision, headache, transient facial
numbness
38
DWI Lesions and TIA Duration
Kidwell et al Stroke 1999301174-80.
39
TIA Minor Stroke Imaging Predictors
p0.02
DWI
MRA
1.0
-
-

-
0.9
0.8


0.7
0.6
0.5
0
30
60
90
Days After Acute TIA or Minor Stroke
Coutts et al. Ann Neurol 200557848-54.
40
Carotid EndarterectomyEffect and Time after
Event
50.0
32.7
70-99
50-69
40.0
16.0
30.0
9.4
11.2
8.8
20.0
3.4
ARR (), 95 CI
0.0
-1.9
10.0
0.0
-10.0
-20.0
0-2
2-4
4-12
12
Weeks between symptomatic event and randomisation
41
EXPRESS StudyRisk of Stroke After First Seeking
Medical Attention (Clinic-referred population)
Rothwell et al. Lancet 20073701432-1442.
42
EXPRESSProcess of Care Indicators
Rothwell et al. Lancet 20073701432-1442.
43
Hospital Admission for TIA?SOS-TIA Study
Lavallée et al. Lancet Neurol 2007 6 95360
44
Event onset to Referral to ASU
Median 3h 45min
45
Referral to Arrival in ASU

• Time of Referral to Arrival (n 38 documented)
• Median 1h 15m (Range 15m 3h 5m)

10
n
8
6
4
2
0
151-180min
91-120min
61-75min
31-45min
0-15min
181-210min
121-150min
76-90min
46-60min
16-30min
Time of Referral to Arrival
46
Admission to Imaging Time
62
38
47
Time Intervals
Median times (mins)
48
Summary