update on management of acute ischemic stroke. · update on management of acute ischemic stroke....
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UPDATE ON
MANAGEMENT OF ACUTE
ISCHEMIC STROKE.Himanshu Chokhawala, MD
Vascular Neurology fellow,
Ochsner Clinic Foundation.
No Conflict of interest
No Discosures!
Objectives
• Extending window for thrombectomy to 24 hours
• Treating WAKE – UP stroke.
• When to NOT administer IV – tPA in Acute Ischemic stroke
DAWN and DEFUSE III trial
• Thrombectomy benefitted in carefully selected patients
• Window for treatment of AIS extended to 24 hours
• Time is just another factor in decision for treatment options
• TIME = BRAIN NOW COLLATERALS = BRAIN
Copyright © 2017 Stryker NP001713 v1.0 | Slide 5 of 29
DAWN™ TrialDWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo® Retriever
Purpose of the DAWN Trial?
Compare the benefit of treatment
with the Trevo® Retriever + medical
management vs. medical
management alone within 6-24
hours after last seen well (TSLW).
Design
Unblinded open label randomized multicenter international clinical
trial
Funding
Stryker Neurosciences
Population
Inclusion criteria:
• Age >= 18
• Acute ischemic stroke
• Failed IV t-PA or treatment with IV t-PA contraindicated
• Last known to be normal 6-24 hours previously
• Baseline modified Rankin Scale (mRS) of 0 or 1
• Occlusion of ICA and/or (M1 MCA)
• Mismatch between severity of clinical deficit and infarct volume
• Group A: > 80 yrs, NIHSS 10+, infarct volume < 21 ml
• Group B: < 80 yrs, NIHSS 10+, infarct volume < 31 ml
• Group C: < 80 yrs, NIHSS 20+, infarct volume 31-51 ml
Exclusion criteria:
Clinical
• Pregnancy, major hemorrhage, prior thrombectomy use
• Seizures at stroke onset
• Sustained hypertension (systolic >185 or diastolic >110)
Imaging
• Intracranial hemorrhage
• Infarct > 1/3rd MCA territory at baseline
• Cerebral vasculitis
• carotid dissection, high grade stenosis,
• Intracranial stenting in treatment area from pre-existing intervention
Demographics
Treatment arm N=107
Control arm N=99
Age (years) (mean) 69.4 + 14.1 70.7 + 13.2
80 or over (%) 23% 29%
NIHSS, baseline (median, [IQR]) 17 [13-21] 17 [14-21]
NIHSS 10-20 (%) 73% 73%
Sex, male (%) 39% 52%
IV-tPA administered 5% 13%
Nogueira R.G. et. al., NEJM 2017
Medical history
Treatment arm N=107
Control arm N=99
Hypertension 78% 76%
Atrial fibrillation* 40% 24%
Diabetes mellitus 24% 31%
Previous ischemic stroke or TIA 11% 11%
* p=0.01
Nogueira R.G. et. al., NEJM 2017
Baseline clot locations – core lab adjudicated
Clot locationTreatment arm
N=107 Control arm
N=99
ICA 21% 19.2%
M1 78% 78%
M2 2% 3%
Nogueira R.G. et. al., NEJM 2017
Workflow times and mode of stroke presentationTreatment arm
N=107 Control arm
N=99
Time last seen well to randomization –hours median [IQR]
12.2 (10.2, 16.3) 13.3 (9.4, 15.8)
Time symptoms observed to randomization – hours, median [IQR]
4.8 [3.6 – 6.2] 5.6 [3.6 – 7.8]
Time last seen well to revascularization (TICI 2b/3) –hours median [IQR]
13.6 [11.3 – 18.0] NA
Mode of stroke presentation
Wake up stroke* 63% 47%
Witnessed stroke 10% 14%
Un-witnessed stroke 27% 38%
* P=0.04
Nogueira R.G. et. al., NEJM 2017
Primary endpoint
Nogueira R.G. et. al., NEJM 2017
48 %v/s
13 %5
mRS 0 - 2
mRS 5 – 6
38 %v/s
70 %
Primary endpoint
Nogueira R.G. et. al., NEJM 2017
Primary endpoint
Nogueira R.G. et. al., NEJM 2017
Safety outcomes
Subgroup analyses
of the first primary
endpoint
Nogueira R.G. et. al., NEJM 2017
Conclusions
• DAWN-eligible patients treated with Thrombectomy is associated with better clinical outcomes and with higher rates of functional independence (mRS 0-2) compared to standard medical therapy (48.6% vs 13.1%, probability of superiority >0.999, NNT = 2.8)
• Treatment effect persisted throughout 24 hours from TLKW; however, earlier treated patients do better.
• DAWN eligible patients presenting beyond 6 hours of TLSW had comparable safety profile to thrombectomy performed within 6 hours.
Nogueira R.G. et. al., NEJM 2017
And mismatch ratio > 1.8
IV Thrombolysis in WAKE – UP stroke
Objective
• IV Alteplase is a standard of care for AIS within 4.5 hours of symptom onset
• Time of symptom onset in not known in 14 – 27% of strokes.
• Reasons – Wake up strokesAphasia, confusion
• MRI brain can help assist with gauging time of symptom onset
• Ischemic lesion on DWI sq with no hyperintensity on FLAIR seq predicts symptom onset 4.5 hours from imaging.
DWIADC
FLAIRHemo / SWI
MRI brain
Trial Design
Investigator – initiated, multicenter, randomized, double blinded, placebo
controlled clinical trial.
Inclusion criteria
• Clinical signs of Acute stroke
• Age > 18 – 80 < years old
• No known time of onset
• Last known well more than atleast 4.5 hours
• Mismatch on DWI / FLAIR lesion with GRE/ SWAN seq and MRA
Exclusion Criteria
• MRI showed intracranial hemorrhage
• Lesion > 1/3rd of the MCA territory
• Pt getting thrombectomy
• NIHSS > 25
• Any other contraindication for tPA.
Demographics
Treatment arm N=245
Control arm N=249
Age (years) (mean) 65.3 + 11.2 65.2 + 11.9
Sex, male (%) 65% 64.3%
Median NIHSS score 6 (4 - 9) 6(4 - 9)
Reason for unknown time of onset
Nighttime sleep 227 (89) 222 (89.2)
Day time sleep 12(4.7) 11(4.4)
Aphasia (Confusion) 15(5.9) 16(6.4)
Treatment arm N=245
Control arm N=249
Any 84 (33) 84(34.1)
Intracranial ICA 24 (9.6) 11(4.5)
MCA stem 35 (14.1) 37(15.0)
MCA branch 32 (12.9) 36(14.6)
Others 12(4.8) 12(4.9)
Vessel Occlusion on MRA
Medical history
Treatment arm N=254
Control arm N=249
Hypertension 135(53) 131(52)
Diabetes Mellitus 43(16.9) 39(15.7)
Atrial fibrillation 93(36) 85(34.1)
Hypercholesterolemia 30(11.8) 29(11.6)
Nogueira R.G. et. al., NEJM 2017
Hx of Ischemic stroke 37(14.6) 131(52)
Primary Outcomes
74
65
GROTTA BAR
Safety Outcomes
Conclusion
• MRI selected patients with unkown time of onset of symptoms
benefitted from IV tPA
• Availability of MRI still a restricting factor
• Thrombectomy eligible patients were excluded so benefit with IV
tPA unknown
When NOT to give IV tPA in AIS
PRISMS - The Potential of rtPA for Ischemic Strokes with Mild
Symptoms
Published - July 10, 2018
Journal - JAMA
Funding - Genentech Inc.
Design - Phase IIIb, Multicenter, randomized, double blinded
Clinical Trial
Background
• Mild stroke burden (NIHSS (0-5)) > 60% of all ischemic strokes
• There is no RCT for efficacy of Alteplase in Minor non- disabling AIS.
• Large Landmark trials for tPA - NINDS, ECASS, ECASSI I , ECASS I I I, ATLANTIS, EPITHET) excluded patients with low NIHSS.
Population
Inclusion Criteria
• Age > 18
• NIHSS 0 - 5 and neuro deficit not disabling
• Able to perform basic ADL (bathing, ambulating, toileting
hygiene and eating)
• Pt able to walk unassisted
• Treatment initiated within 3 hours of symptom onset
Exclusion Criteria
• Pre - stroke disability (mRS 2 - 6)
• Dysphagia, ICH and other standard contraindications for tPA
Study Intervention
• Group 1 - IV Alteplase and Placebo oral ASA
• Group 2 - Placebo IV Alteplase and Oral ASA
• IV study treatment was administered within 3 hrs of symptom
onset
• Oral study treatment administered within 24 hours of symptom
onset (75% got < 3h)
Demographics
Medical History
Time from symptom onset
Baseline NIHSS
Primary Outcome
Safety Outcomes
Conclusion
• MINOR + NON disabling AIS treatment with Alteplase
compared with ASA DID NOT increase the likelihood of
favorable outcome at 90 days.
SYNOPSIS
• DAWN and DEFUSE III eligible patients benefits with
thrombectomy upto 24 hours from LKN.
• Pt with Unkown time of onset benefits with IV tPA when
eligible with MRI brain.
• Low NIHSS and non - disbaling stroke can be treated with
ASA instead of IV tPA.