Transcript Update on Cochrane Systematic Review on thrombolysis

Thrombolysis in acute ischaemic stroke –
Updated Cochrane Thrombolysis metaanalysis
JM Wardlaw, V Murray, PAG Sandercock
University of Edinburgh and Karolinska Institutet, Stockholm
Brenda Thomas, Greg del Zoppo, Eivind Berge, Take Yamaguchi
Thrombolysis Systematic Review
• Continuously updated since 1990
• All randomised controlled trials of any
thrombolytic drug versus control
• Last update 2003:
– 18 trials (n=5675)
– Drugs: rt-PA, streptokinase, uro-kinase,
rPro-urokinase,
– Time windows:
0-3, 0-6 hrs
– Brain Imaging : CT
– Age over 80 :
42 patients
Methods
• Material
– New trials
– New data from existing trials
• Methods
–
–
–
–
Multiple overlapping ascertainment methods
Two independent reviewers extracted data
Odds Ratios (ORs), 95% CI, heterogeneity
Metaregression on some key variables
Methods – data sought
Previous outcomes :
– Intracranial haemorrhage - asymptomatic, symptomatic and
fatal
– Death early and late,
– Poor functional outcome
– Infarct early swelling,
Previous subgroups :
–
–
–
–
Time to treatment,
antithrombotic treatment,
stroke severity,
mRS cut point,
New subgroups :
– type of imaging, CT or MR
– CT infarct signs,
– stroke subtype, large artery/lacunar
What’s new in 2008?
2008:
– 8 new trials (n=+1477, total: n=7152)
– Drugs: 3 rt-PA; 2 UK; 3 desmoteplase
– Route: 2 intra-arterial, 6 intravenous
– Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs
– Imaging pre randomisation:
• CT: 5
• MR: 3 (+1) DWI/PWI mismatch
– Age over 80: ≈42
Death or dependency at the end of follow-up
IV urokinase
IV streptokinase
0.91 (0.64, 1.42)
0.94 (0.72, 1.24)
IV rt-PA
0.77 (0.47, 0.89)
IV streptokinase
+ aspirin
1.09 (0.49, 1.72)
IA pro-urokinase
0.55 (0.31, 1.00)
IA urokinase
0.57 (0.28, 1.14)
IV desmoteplase
0.85 (0.53, 1.38)
Total
0.82 (0.73, 0.91)
ECASS 3
Inclusion:
3-4.5 hours
Age 18-80 yrs
Excluded :
NIHSS>25 or CT infarct signs >1/3MCA
diabetes and prior stroke
stroke in previous 3 months
Outcomes:
SICH: “any apparently extravascular blood in the brain or within
the cranium that was associated with clinical deterioration, as
defined by an increase of 4 points or more in the score on the
NIHSS, or that led to death and that was identified as the
predominant cause of the neurologic deterioration”
Good functional outcome: mRS 0-1 vs 2-6
ECASS 3
Baseline imbalances
Age
NIHSS
Diabetes
Prior
stroke
rt-PA
64.9
10.7
9
14.8
PLA P
65.6 0.36
11.6 0.03
10
16.6 0.47
7.7 14.1 0.03
All drugs and rt-PA
Summary of effects, 2008; ORs (95% CI)
SICH
(incl fatal)
Late
Death
All drugs
n=7152
3.3
2.7 - 4.1
p<0.00001
1.3 *
1.1 - 1.5
p=0.06
0.8 *
0.7 - 0.9
p<0.0001
rt-PA
n=3977
3.1
2.3 - 4.0
p<0.00001
1.1
1.0 - 1.4
p=0.16
0.8 *
0.7 - 0.9
p<0.0001
* Significant heterogeneity confounds interpretation
Death or
Dependency
rt-PA trials: 2003 versus 2008
ORs (95% CI)
SICH
(incl fatal)
Late
Death
Death or
Dependency
2003
n=2955
3.1
2.3 - 4.2
p<0.00001
1.2 *
0.9 - 1.5
p=0.14
0.8 *
0.7 - 0.9
p=0.003
2008
n=3977
3.1
2.3 - 4.0
p<0.00001
1.1
1.0 - 1.4
p=0.16
0.8 *
0.7 - 0.9
p<0.0001
* significant heterogeneity confounds interpretation
rt-PA trials: 2008
N per 1000 treated, 95% CI
Outcome
all
0-3 hrs
3-6 hrs
SICH
60
50, 80
70
40, 100
60
50, 80
Death
10
10, 40
0
50, 50
20
0, 50
Death or
Depend.
60
100, 30
110
170, 50
40
80, 10
X = decrease
X = increase
mRS 2-6 or 3-6 (rt-PA): Similar overall result
Modified Rankin:
2 to 6
3 to 6
IV tPA vs control
Mori
NINDS
ECASS
ECASS 2
ECASS 3
Atlantis A
Atlantis B
rt-PA subtotal
0.1
0.78 1
thrombolysis better
5
100.1
0.77 1
5
10
thrombolysis worse
CDSR Oct 2004
Death or dependency: subgroups
OR (95% CI)
n Trials n patients
Latest time to treatment, all drugs (hours)
3
4.5
6
9
1
2
9
3
624
1161
3463
325
0.62 (0.45, 0.85)
0.85 (0.68, 1.07
0.84 (0.73, 0.96)
0.85 (0.52, 1.39)
Treatment time rt-PA (hours)
0-3
3-6
5
6
0.64 (0.5. 0.8)
0.83 (0.7, 0.9)
930
2766
0.1 0.2
0.5
favours treatment
1
2
5
10
favours control
Subgroups : Imaging (all drugs, all times)
OR (95% CI)
n Trials n patients
Death or dependency
CT
MR DWI/PWI
10
4808
0.79 (0.8, 0.9)
4
425
0.87 (0.6, 1.3)
SICH
CT
4.55 (3.31, 6.27)
MR DWI/PWI
7.51 (1.39, 40.54)
CT
1.18 (1.01, 1.40)
MR DWI/PWI
2.18 (1.09, 4.36)
Death
0.1 0.2
0.5
favours treatment
1
2
5
10
favours control
Other results, 2008
CT infarct signs and thrombolysis (3 trials): no clear
interaction
Infarct swelling (5 trials):
reduced with rt-PA (OR 0.78, 0.62, 1.00, p=0.05)
Metaregression on
–
–
–
–
–
–
Time to treatment (2 methods)
Antithrombotic therapy
Selection by MR DWI/PWI vs CT
”Stroke severity” (2 methods)
Dose – MI equivalent vs ”stroke” dose
Trial size
did not explain differences between trials
Conclusion, Update 2008
•
•
•
•
•
Heterogeneity still confounds interpretation
ECASS 3 consistent with existing rt-PA meta-analysis.
Potential for benefit to at least six hours
Limited new knowledge on latest time windows.
Almost complete lack of data on older patients;
antithrombotic use; stroke severity/subtype, diabetes
• Outcome following selection on MR mismatch not
apparently different to CT.
• No material change in main outcomes since 2003.
Implications
• Further data on i.v. rt-PA needed from
randomised trials :
– Out to at least six hours
– Older patients, diabetes, hypertension,
stroke subtypes
– Clarifying risk factors for haemorrhage and
death
Competing interests
• SITS-MOST Steering and CT
adjudication
• ECASS 3 CT reading Committee
• IST3 Trial Steering Committee and
Imaging lead
rt-PA 2008- OR and events per 1000 treated
rt-PA Effect
per 1000
Symptomatic ICH :
<3 hrs
3-6 hrs
+70
+60
Death by three months :
<3 hrs
3-6 hrs
0
+20
Dead or Dependent :
<3 hours
-110
- 40
3-6 hours
0.1
better
CDSR 2008
0.66
0.84 1.0
1.33
thrombolysis
3.37
10 OR
worse