Update on management of Acute ischemic stroke. · UPDATE ON MANAGEMENT OF ACUTE ISCHEMIC STROKE. Himanshu Chokhawala, MD Vascular Neurology fellow, Ochsner Clinic Foundation.

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.