stroke - what's new wsns 2 · – nihss ≥8 and ≤30 – ineligibility for or failure to...
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What’s New in Strokethe evidence
and letting go of what we thought we knew
Kyra Becker, MD, FAHA
University of Washington School of Medicine
Harborview Medical Center
outline
• stroke Center certification
• timing of tPA therapy
• endovascular therapy
• acute imaging (diffusion/perfusion mismatch)
• intracranial stenosis
• EC‐IC bypass
• PFOs
Det Norske Veritas
timing of IV tPA
www.thelancet.com Published online May 23, 2012 DOI:10.1016/S0140‐6736(12)60768‐5
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www.thelancet.com Published online May 23, 2012 DOI:10.1016/S0140‐6736(12)60768‐5
endovascular therapy
Penumbra
Trevo
Merci
Solitaire
SWIFT
• MERCI vs. Solitaire• inclusion criteria:
– age 22‐85
– RX within 8 hours of symptom onsetRX within 8 hours of symptom onset
– NIHSS ≥8 and ≤30
– ineligibility for or failure to respond to tPA
• non‐inferiority trial
• primary endpoint: TIMI 2 or 3 flow without SICH
Lancet. Published online August 26, 2012
Tomsick AJNR 28 Feb 2007 www.ajnr.org
TIMI flow
• TIMI 0 (no perfusion): absence of any antegradeflow beyond occlusion
• TIMI 1 (penetration without perfusion): faint antegrade flow beyond the occlusion with incomplete filling of the distal bed.
• TIMI 2 (partial reperfusion): delayed or sluggish antegrade flow with complete filling of the distal territory.
• TIMI 3 (complete perfusion): normal flow which fills the distal bed completely
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TICI flow
• Grade 0: No Perfusion. No antegrade flow beyond the point of occlusion.
• Grade 1: Penetration With Minimal Perfusion.
• Grade 2: Partial Perfusion. – Grade 2a: Only partial filling (<2/3) of the entire vascular territory is visualized.
– Grade 2b: Complete filling of all of the expected vascular territory is visualized, but the filling is slower than normal.
• Grade 3: Complete Perfusion.
SWIFT
SolitaireN=58
MERCIN=55
OR (95% CI)
non‐inferiority
superiority
successful recanalization without SICH
primary endpoint
61% (34/56) 24% (13/54)4.87
(2.14‐11.10)<0.0001 0.0001
clinical efficacy at 90 daysclinical efficacy at 90 days
good outcome (mRS≤2)
58% (32/55) 33% (16/48)2.78
(1.25‐6.22)0.0001 0.017
independent 36% (20/55) 29% (14/48)1.39
(0.61‐3.18)0.0312 0.53
MERCIMulti‐MERCI
SWIFTMERCI arm
SWIFT SOLITAIRE
armTREVO
N=141 N=164 N=55 N=58 N=60
median age (yrs) 67±16 68±16 67 65
h/o AF (%) ??? ??? 67 45 42
time to therapy (hrs)
4.3 4.3 5.3 4.9 3.5(hrs)
median NIHSS 19 19 17 18
IV tPA RX (%) 0 29 40 60
recanalization (%) 48 68 30 68 78 (92)
90 day mortality (%) 44 34 38 17 20
symptomatic ICH (%)
8 10 11 2 5
90 day mRS 2 (%) 28 36 33 58 55
endovascular rescue
• IMS I and IMS II– single arm studies with historic controls
– modified dose of tPA within 3 hours of symptom onset (0 6 mg/kg over 30 mins) for patients with NIHSS≥10(0.6 mg/kg over 30 mins) for patients with NIHSS≥10
– endovascular therapy with IA tPA (up to 22 mg) and/or mechanical thrombectomy
– recanalization rates of 56%‐73%
Stroke 2007;38;2127‐2135.
IMS III
• age: 18‐82 years
• IV tPA within 3 hrs of stroke onset
• NIHSSS ≥ 10 at the time that IV tPA is begun or SSS d 0 i h d dNIHSSS >7 and <10 with documented
occlusion of M1, ICA or basilar artery on CTA
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IMS III
• RX– standard dose tPA (0.9 mg/kg over 1 hr)
– modified dose tPA (0.6 mg/kg over ½ hr) followed by endovascular rescue
• outcome– mRS score of 0‐2 at 3 months
• design– predicated on the belief that IV/IA RX would be at least 10% better (absolute) than IV tPA alone
IMS III
• RX– standard dose tPA (0.9 mg/kg over 1 hr)
– modified dose tPA (0.6 mg/kg over ½ hr) followed by endovascular rescue
• outcome– mRS score of 0‐2 at 3 months
• design– predicated on the belief that IV/IA RX would be at least 10% better (absolute) than IV tPA alone
Penumbra “THERAPY” Trial
full dose IV tPA versus full dose IV tPA followed by endovascular RX
endovascular therapy:unintended consequences
00 g
m/m
in
normotensive Individuals
100
50
hypertensive Individuals
-
-
pressure autoregulation
CB
F m
l/10 -
0
50
0 50 100 150 200
ischemia
Cerebral Perfusion Pressure (mm Hg)
-
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Stroke. 2010; 41:1175‐1179 poor outcome = mRS≥3
Stroke. 2010; 41:1175‐1179
23 yo with MCA occlusion
• 75 yo with sudden onset right HP and aphasia
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100
75
50
PaCO2
PaO2
CPP
Blo
od
Flo
wti
ss
ue
/min
)
25
050 100 150 200
Cer
ebra
l B(m
L/1
00
gm
Pressure (mmHg)
acute imaging
http://www.nuigalway.ie/psychiatry/research/neuroimaging_lab/index.html
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DEFUSE “profiles”
• no mismatch: PWI <120% of DWI volume
• small lesion: DWI and PWI volume both <10ml
• malignant profile: baseline DWI ≥100ml and/or a PWI ≥ 100mland/or a PWI ≥ 100ml
• “target” mismatch: PWI ≥10ml and ≥120% of the DWI volume
MR based stroke studies
• DEFUSE 1– observational– IV tPA from 3‐6 hrs after stroke onset
• DEFUSE 2– observational– endovascular therapy within 12 hrs after stroke onset
patients with mismatch do better
py
• DIAS 2– desmoteplase vs. placebo b/t 3‐9 hrs– NIHSS of 4 to 20– DWI/PWI mismatch >20%– increased mortality without increased IPH
• EPITHET– tPA given 3—6 h after stroke did not attenuate infarct growth in
patients with diffusion‐perfusion mismatch
an analogy cerebrovascular occlusive disease
TIA or non-disabling stroke within 30 daysculprit vessel: 70-99% stenosis
SAMMPRIS interventions
• ASA 325 mg/day
• clopidogrel 75 mg/day for 90 days
• high dose statin to target LDL <70 mg/dL
• BP control to goal <140/90 (or <130/80 if diabetic)
PTAS
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SAMMPRIS
estimated stroke/death rate:
based on historical controls
(from WASID): 11%
actual stroke/death rate:
PTAS + best medical
therapy: 14%
best medical therapy: 6%best medical therapy: 6%
similar rate of stroke in the territory of the stenoticartery after 30 days
N Engl J Med. 365:993‐1003, 2011.
AMM in SAMMPRIS
Do anti‐thrombotic “failures” have a differential benefit from PTAS?
antithrombotic failures and AMM
• In the medical treatment arm, outcome event rates were similar among patients who had “failed” ATT and those who did not.
– ie. antithrombotic failures were not at higherie. antithrombotic failures were not at higher risk of recurrent stroke
• Patients on ATT at the time of the index TIA/stroke (63%) were still more likely to benefit from medical therapy than PTAS (P<0.0009 at 30 days and P=0.028 for long‐term follow up).
is there ever a role for PTAS
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COSS study
• based on observation that patients with recent carotid occlusion and increased OEF had high risk of stroke
• patients randomized to EC IC bypass vs• patients randomized to EC‐IC bypass vs. best medical RX within 120 days of last symptom
EC‐IC bypass
http://www.downstate.edu/neurosurgery/diseases/extra_intra_bypass.html
COSS study
Hypothesis: STA‐MCA bypass will decrease the risk of ipsilateral stroke by 40% at 2 yrs (despite an assumed peri‐operative risk of 12%)
– patients randomized to EC‐IC bypass vs bestpatients randomized to EC IC bypass vs. best medical RX within 120 days of last symptom
COSS results
estimated stroke rate:
based on historical
controls: 40%
actual stroke rates:
STA‐MCA bypass: 23%
best medical therapy: 21%
PFO
http://www.escardio.org/communities/cardio‐tomorrow/congresses‐events/abstracts/Pages/surgical‐treatment‐entrapped‐thrombus.aspx
http://library.med.utah.edu/WebPath/CVHTML/CV115.html
http://www.riversideonline.com/health_reference/Disease‐Conditions/DS00728.cfm
N Engl J Med 2012;366:991‐9.
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N Engl J Med. 366:991‐999, 2012.
PFO closure
N Engl J Med. 366:991‐999, 2012.
shunt characteristics
STARFlexN=400
MedicalN=451
P value
Trace
shunt7.0%
(n=8/114)
8.0%(n=10/126)
0.75
Moderate 5 3% 8 4%Moderate
shunt5.3%
(n=7/132)
8.4%(n=12/143)
0.31
Substantial
shunt3.6%
(n=3/84)
5.3%(n=3/57)
0.62
No atrial septal aneurysm
6.4%(n=15/236)
8.5%(n=20/236)
0.38
Atrial septal aneurysm
4.9%(n=7/142)
6.5%(n=9/139)
0.58
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RESPECT RESPECT
Patient population• age 18‐60 years
• cryptogenic stroke and PFO
• enrollment within 270 days of last stroke
RandomizationRandomization• PFO closure versus “current medical standard‐of‐care”
End Points• recurrence of nonfatal stroke, post‐randomization death and fatal
ischemic stroke
Enrollment• 980 patients with more than 2,700 patient years of experience
“In stark contrast to prior randomized trials of competitive PFO devices for mitigation of risk in cryptogenic stoke patients, we are confident our trial will demonstrate greater benefit and less risk in the device arm of the trial.”
“…obviously we’re no longer blinded to the data and that was the basis for the level of confidence we’ve expressed that when the full trial results are reported at the TCT, we are optimistic that these will be favorable results.”
more technology failures
ICP monitoring in TBI
• study done in South America where there was clinical equipoise regarding the utility of ICP monitoring
• patients randomized to placement of an ICP• patients randomized to placement of an ICP monitor for ICP directed care or to clinically directed care without an ICP monitor
no difference in outcome
summary: acute stroke
• There is clear clinical benefit to IV tPA in a 3 hour time window.– available data are less clear about the benefit after 3 hours
• The utility of endovascular therapy as a primaryThe utility of endovascular therapy as a primary therapy for stroke remains to be proven.– available data do not support endovascular rescue
• Diffusion/Perfusion mismatch identifies patients who are likely to have better outcomes.– the role of diffusion/perfusion mismatch for choosing patients likely to benefit from therapy is unclear
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summary: stroke prevention
• medical therapy is a lot better than assumed
• interventions carry higher risk than assumed
RCTs are invaluable
“…there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns ‐‐ the ones we don't know we don't know."
D.H.Rumsfeld
http://www.peteykins.com/sparklepony/Rumsfeld60105b.jpg