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Is there even a time window? A brief summary of key 2018 trials: DAWN and DEFUSE-3 For Neurosciences Update Conference, February 22, 2018 Maxim D. Hammer, M.D.
Is there even a time window?
A brief summary of key 2018 trials: DAWN and DEFUSE-3
For Neurosciences Update Conference, February 22, 2018
Maxim D. Hammer, M.D.
Executive Summary
Based on DAWN and DEFUSE-3, we now have proof that some patients with large vessel occlusion will benefit from endovascular therapy well beyond 6 hours.
The patients who are proven to benefit are those with small core infarction and large area of tissue at risk.
From 0-6 hours, we should maintain our focus on rapid treatment with IV-tPA and endovascular therapy.
From 6-24 hours, we can now treat selected patients who meet clinical and imaging criteria.
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Terminology
LVO: Large vessel occlusion.
Refers to occlusion of a major vessel of the Circle of Willis, such as ICA (intracranial), MCA, BA
CIM: Clinical Imaging Mismatch.
Refers to the discrepancy between a neurological examination that shows malfunction of a large region of the brain and imaging that shows only partial infarction of that region. Suggests potentially reversible ischemia.
IM: Imaging mismatch
Refers to a significant discrepancy between the size of the core infarction and size of the tissue at risk, as determined by perfusion imaging.
RAPID: Rapid Processing of Perfusion and Diffusion.
Refers to imaging software (CT and MR) that automatically calculates brain tissue core infarction versus tissue at risk using consensus-derived, medically validated standards.
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Example of RAPID
N Engl J Med. 2018 Jan 4;378(1):11-21 N Engl J Med. 2018 Jan 24
DAWN DEFUSE 3
Trial Designs
DAWN
Multicenter
Prospective
Randomized
Blinded end points
Sponsored by Stryker Neurovascular
Halted early (prespecified interim
analysis)
DEFUSE-3
Multicenter
Prospective
Randomized
Blinded end points
Sponsored by NIH (StrokeNet)
Halted early (prespecified
interim analysis)
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Inclusion criteria, abbreviated
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Trial DAWN DEFUSE-3
Time 6-24 hours 6-16 hours
NIHSS ≥10 ≥6
mRS 0-1 0-2
IVtPA Allowed Allowed
LVO Intracranial ICA and/or MCA Intracranial ICA and/or MCA
CIM 3 strata:
Core 0-21cc, NIHSS≥10, age≥80
Core 0-31cc, NIHSS≥10, age<80
Core 31-51cc, NIHSS≥20, age<80
1 stratum, fulfilling:
• Core <70cc
• Mismatch ratio >1.8
• Mismatch volume ≥ 15cc
Target Small core infarct
Large CIM
Accept larger core,
Large IM
Endpoints, abbreviated
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Trial DAWN DEFUSE-3
Primary • utility-weighted mRS at day 90
• Functional independence
(mRS 0-2)
mRS at day 90
Secondary Functional independence
(mRS 0-2)
The mRS vs “utility-weighted” mRS
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mRS
0 No symptoms
1 No significant disability Able to carry out all usual activities despite some symptoms.
2 Slight disability Able to look after own affairs without assistance, but unable to carry out all
previous activities.
3 Moderate disability Requires some help, but able to walk unassisted.
4 Moderately severe disability Unable to attend to own bodily needs without assistance, and unable to walk
unassisted.
5 Severe disability Requires constant nursing care and attention, bedridden, incontinent.
6 Dead
The mRS vs “utility-weighted” mRS
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mRS
0 No symptoms
1 No significant disability
2 Slight disability
3 Moderate disability
4 Moderately severe disability
5 Severe disability
6 Dead
The mRS vs “utility-weighted” mRS
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mRS Utility weighted mRS
0 No symptoms 10
1 No significant disability 9.1
2 Slight disability 7.6
3 Moderate disability 6.5
4 Moderately severe disability 3.3
5 Severe disability 0
6 Dead 0
Endpoints, abbreviated
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Trial DAWN DEFUSE-3
Primary • utility-weighted mRS at day 90
• Functional independence
(mRS 0-2)
mRS at day 90
Secondary * Functional independence
(mRS 0-2)
Baseline characteristics DAWN
DEFUSE-3
Key Baseline Features: CIM comparison
15
DAWN DEFUSE-3
median NIHSS
T/E
Control
17
17
16
16
Core cc
T/E
Control
7.6 (2.0-18.0)
8.9 (3.0-18.1)
9.4 (2.3-25.6)
10.1 (2.1-24.3)
DAWN - Efficacy
DAWN
DAWN
DEFUSE-3
DEFUSE-3
DEFUSE-3
Outcomes comparison
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DAWN DEFUSE-3
mRS
Treatment
Control
Utility weighted
5.5 (+/-3.8)
3.4 (+/- 3.1)
mRS
3 (1-4)
4 (3-6)
mRS 0-2
Functional outcome
Treatment
Control
Number Needed to Treat=
52 (49%)
13 (13%)
2.8
41(45%)
15(17%)
3.6
Infarct growth at 24h
(median, cc)
1(0-28)
13(0-42)
23(10-75)
33(18-75)
DAWN: Safety
DEFUSE-3 - Safety
Safety Comparison
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DAWN DEFUSE-3
Death at 90 days
n(%)
17(16)
18 (18)
Tx
Cx
13(14)
23(26)
Early sICH
n(%)
20(19)
18(18)
Tx
Cx
6(7)
4(4)
Early Neurological
Deterioration n(%)
6(6)
3(3)
Tx
Cx
8(9)
1(12)
Clinical-Imaging Mismatch (CIM) vs Imaging Mismatch (IM)
Within a “late” time window:
DAWN aimed for CIM
DEFUSE aimed for IM
They ended up with similar patients:
Small Core
CIM and IM
CIM = IM !
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Executive Summary
Based on DAWN and DEFUSE-3, we now have proof that some patients with large vessel occlusion will benefit from endovascular therapy well beyond 6 hours.
The patients who are proven to benefit are those with small core infarction and large area of tissue at risk, which are definable using advanced imaging techniques.
• Core can be defined using RAPID software for CT or MRI
• Tissue at risk can be defined by RAPID or by CIM
From 0-6 hours, we should maintain our focus on rapid treatment with IV-tPA and endovascular therapy.
From 6-24 hours, we can now treat selected patients who meet clinical and imaging criteria.
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