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Title

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Therapeutic Management Options for

Acute Ischemic Stroke Anna Rosenbaum, MD

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Title

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Epidemiology

• Epidemiology

– 4th leading cause of death in the United States1

– Leading cause of disability

– Increase in projected stroke related medical costs 2012 - 2030 from 71.55 billion to $183.13 billion2

1 Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245

2 Ovbiagele B, et al. Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013;44:2361–2375

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Acute Reperfusion Therapy

• IV Thrombolysis

– IV rTPA

• Mechanical embolectomy/endovascular therapy

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IV TPA • Tissue plasminogen activator

– Mechanism: serine protease that inhibits plasmin degradation of fibrin

– FDA approved in 1995

– Number needed to treat to prevent 1 death/disability:

• 8 – within 3 hour window3

• 14 – within 4.5 hour window4

• Overall absolute benefit of treatment is a 13% lower rate of significant disability

3 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NEJM, 1995;333(24): 1581-1587.

4 Hacken, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet

2004;363(9411):768-774.

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IV TPA

• FDA approved for use within 3 hours

• Not FDA approved for 3-4.5 hour window, but recommended based on available evidence (ECASS III)5

• Every 30 minute delay in administration leads to 10% reduction in good outcome

• Treatment times beyond 270 minutes have no benefit

5 Hacke, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008; 359:1317-1329

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Door to Needle Time Timeline Inclusion/Exclusion

- ED physician:

10 minutes of arrival

- Stroke consultant is notified within

15 minutes of arrival

- CT scan is completed within 25

minutes of arrival

- CT is interpreted within 45

minutes of arrival

Marler JR, et al. Proceedings of a national symposium on rapid identification and

treatment of acute stroke. Bethesda, MD: The National Institute of Neurologic

Disorders and Stroke (NINDS), National Institutes of Health, 1997;97:4239

- Last known normal (“wake up”

strokes excluded)

- Any significant medical history

- NIHSS

- Glucose level (finger stick)

- Other significant laboratory results

- Current blood pressure

- Results of acute brain imaging

(CT scan +/- CTA)

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Title

Date

Exclusion Criteria

• Evidence of intracranial hemorrhage on pretreatment CT scan

• Minor or rapidly improving symptoms

• Symptoms of subarachnoid hemorrhage, even with normal head CT

• Active internal bleeding: Gastrointestinal or urinary bleeding within last 21 days

• Platelet count less than 100,000/mm3

• Heparin during the preceding 48 hours associated with elevated aPTT

• Currently taking oral anticoagulants (e.g. Warfarin sodium) or recent use with an elevated prothrombin time (PT) greater than 15 seconds or INR greater than 1.7

• Major surgery or other serious trauma during preceding 14 days

• Stroke, serious head trauma or intracranial surgery during preceding 3 months

• Recent arterial puncture at a non-compressible site

• Recent lumbar puncture during preceding 7 days

• Systolic BP > 185 mm of Hg or diastolic BP > 110 mm of Hg at the time of t-PA infusion and/or patient requires aggressive treatment to reduce blood pressure

• Any history of intracranial hemorrhage, neoplasm, arteriovenous malformation, or aneurysm

• Recent Acute Myocardial Infarction

• Observed seizure at stroke onset

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Exclusion criteria (con’t)

Relative Contraindications:

• Early signs of a large cerebral infarction: edema, hypodensity, mass effect, and obliteration of sulci in > 1/3 of middle cerebral artery territory on CT scan.

• NIHSS greater than 22

• Glucose less than 50 mg/dL or greater than 400 mg/dL.

• Pregnant female

• Difficult to control hypertension

• Age greater than 75

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Exclusion criteria: 3-4.5 hour window

• History of stroke AND diabetes mellitus

• NIHSS score >25

• > 80 years old

• Any warfarin use (regardless of INR value)

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Candidate selection: Exclusion criteria

Rapidly improving deficits/low stroke scales - Not necessarily a contraindication to tpa (unless minor deficit)

- complete hemianiopsia

- severe aphasia

- visual/sensory extinction

- any weakness limiting sustained effort against gravity

Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force, Stroke. ahajournals.org/content/44/9/2500.abstract.

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Early ischemic changes on CT

Early ischemic changes on CT scan are not contraindications: • loss of grey-white matter differentiation

• Hypoattenuation

• loss of insular ribbon

• hyperdense artery signs (MCA)

• sulcal effacement

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Date

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Date

Completed stroke

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Date

ICH

• Symptomatic intracranial hemorrhage

– NINDS 6.4% (3 hr. window)

– ECASS III 7.9% (4.5 hour window)

• Stroke mimics (seizure, migraine)

– risk of ICH is less than 1%

Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke

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Stroke Mimics - not a contraindication

• Extremely low rate of symptomatic ICH (<1%)

– Complicated migraine (migraine with focal deficits)

– Seizure (Todd’s paralysis)

Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and pooled analysis of reported series. Stroke 2011;42(6):1771-1774

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For every 100 patients treated with tPA

Hours from

symptom onset

0-1.5 1.5-3 3-4.5

Excellent outcome 12 13 6

Number helped 28 23 17

Number harmed 1.5 3 3

Liklihood of help

vs. harm

18 9 6

Pooled data from 7 trials (NINDS 1&2, ECASS I, II, II, ATLANTIS A&B)

Figure 1-2

Figure 1-2 Changes in final outcome as a result of intravenous recombinant tissue-type plasminogen activator (IV rtPA) treatment within 3 hours of onset. Reprinted from Saver JL, Medscape.7emedicine.medscape.com/article/1160840-overview.

P. Kaatri. CONTINUUM: Lifelong Learning in Neurology.

Copyright © 2014 American Academy of Neurology . Published by Lippincott Williams & Wilkins. 17

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Mechanical Thrombectomy Who should be considered?

• Patients ineligible for IV rTPA – 3 hr. time window: on coumadin with INR >1.7

– 3-4.5 hr time window: any coumadin

– Any of the newer oral anticoagulants (rivoroxaban/Xarelto, dagibatran/Pradaxa, apixiban/Eliquis)

• significant stroke deficits (NIHSS > 8)

• if treatment can be initiated within 6 hours (based on PROACT II, MELT)1

• comparable safety and efficacy between IV rtPA within 3 hours versus endovascular therapy within 62

1 Furlan A, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in

acute cerebral thromboembolism. JAMA 1999;282(21):2003Y2011; Ogawa A, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007;38(10)

2 Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368(10):904-913 (SYNTHESIS)

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FDA Approved devices

• Revascularization rates > 80%

– Stentrievers:

• Solitaire

• Trevo

– Penumbra Aspiration

Figure 1-4 Devices cleared by the US Food and Drug Administration for acute stroke clot removal: A, Merci Retriever; B, Solitaire stent retriever; C, Penumbra aspiration system; and D, TREVO2 stent retriever.Panel A courtesy of Concentric Medical, Inc; Panel B courtesy of Covidien; Panel C courtesy of Penumbra, Inc; Panel D courtesy of Stryker. Khatri, Pooja

CONTINUUM: Lifelong Learning in Neurology. 20(2, Cerebrovascular Disease):283-295, April 2014. doi: 10.1212/01.CON.0000446101.44302.47

Copyright © 2014 American Academy of Neurology . Published by Lippincott Williams & Wilkins. 20

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IMS III • IV rTPA + endovascular therapy

vs.

IV rTPA alone

• Results:

– endovascular therapy + TPA not superior to TPA alone within 6 hours

• Comparable safety Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368(10)

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IMS III

• Subgroups may benefit:

– NIHSS >20

– Large proximal occlusions

• Carotid terminus

• Clots > 8 mm

– Better recanalization than with tpa alone

– Studies ongoing

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Title

Date

Beyond 6 hours?

Trials ongoing in regard to imaging criteria:

• MR RESCUE

–penumbral imaging1

1 Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368(10):914-923

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Endovascular Therapy Possible candidates for consideration for endovascular therapy beyond 6 hours:

– Moderate-to-severe deficit (e.g. NIHSS ≥ 8)

– last seen normal or unknown time of symptom onset

– 24 hour anterior circulation ischemic syndrome

– 36 hours posterior circulation ischemic syndrome

• Must have:

– CT head with < well demarcated hypodensity < 1/3 of the territory

– MRI (ideally within 1-2 hours of recognition) with DWI abnormality < 1/3 of territory (anterior circulation) or

– lack of large brainstem DWI abnormality (posterior circulation)