Presenter name Title Date Therapeutic Management Options for Acute Ischemic Stroke Anna Rosenbaum, MD
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Therapeutic Management Options for
Acute Ischemic Stroke Anna Rosenbaum, MD
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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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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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Completed stroke
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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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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)