Therapeutic Management Options for Acute Ischemic Stroke Anna Rosenbaum, MD
Epidemiology Epidemiology 4 th leading cause of death in the United States 1 Leading cause of disability Increase in projected stroke related medical costs 2012-2030 from 71.55 billion to $183.13 billion 2 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
Acute Reperfusion Therapy IV Thrombolysis IV rtpa Mechanical embolectomy/endovascular therapy
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 window 3 14 within 4.5 hour window 4 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.
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
Door to Needle Time Timeline - 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 Inclusion/Exclusion - 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)
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, Presenter or aneurysm name Recent Acute Myocardial Infarction Observed seizure at stroke onset
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
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)
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.
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
Completed stroke
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
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
For every 100 patients treated Hours from symptom onset with tpa 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 tissuetype plasminogen activator (IV rtpa) treatment within 3 hours of onset. Reprinted from Saver JL, Medscape.7emedicine.medscape.com/arti cle/1160840-overview. P. Kaatri. CONTINUUM: Lifelong Learning in Neurology. Copyright 2014 American Academy of Neurology. Published by Lippincott Williams & Wilkins. 17
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 6 2 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)
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
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)
IMS III Subgroups may benefit: NIHSS >20 Large proximal occlusions Carotid terminus Clots > 8 mm Better recanalization than with tpa alone Studies ongoing
Beyond 6 hours? Trials ongoing in regard to imaging criteria: MR RESCUE penumbral imaging 1 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
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)