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Welcome to Family Medicine Grand Rounds’ series: Recognition and Acute Management of Stroke This program includes a video, test and evaluation modules. After viewing the video, you will be asked to complete a five question test and a brief evaluation in order to be eligible for your CME credits. The estimated time to complete this entire activity is 1 hour and 15 minutes. This program requires: Windows Microsoft Windows 2008 (required Desktop experience), Windows 7, Windows Vista, Windows XP, Windows 2003 Microsoft Internet Explorer 7.0 or later, Firefox 3.6 or later or Google Chrome Windows Media Player 9.0 or later Media Silverlight 5.0 or later Broadband internet connection MAC MAC OS X or later Safari 4.0 or later or Firefox 3.6 or later Microsoft Silverlight 5.0 or later (viewers are prompted to install this when attempting to view a presentation) Broadband internet connection (256 Kbps or more)

Welcome to Family Medicine Grand Rounds’ series: New Oral Anticoagulants: Are they better than what we have? Heather Harle, MD Attending Neurologist, Neurology Associates of Lancaster Recorded Wednesday, September 17, This program will be available for CMEs until September 17, 2015.

Objectives Following the completion of this program, participants should be able to: 1) Classify the clinical symptoms consistent with acute ischemic and hemorrhagic strokes 2) Recognize basic radiologic (CT and MRI) findings consistent with ischemic and hemorrhagic strokes 3) Assess localization of stroke, in particular signs/symptoms associated with lacunar versus large vessel stroke. 4) Compare situations in which TPA would be considered to be used, either IV or through neurointervention, and general exclusions to its use. 5) Review basic in-hospital management of acute ischemic and hemorrhagic stroke

Disclosure: None of the faculty/planners have revealed any significant commercial interests that may bias his/her presentation. Accreditation Statement The Lancaster General Hospital is accredited by the Pennsylvania Medical Society to provide continuing medical education for physicians. Designation Statement The Lancaster General Hospital designates this live activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with extent of their participation in the activity. Conflict of Interest Statement Faculty and all others who have the ability to control content of continuing medical education activities sponsored by Lancaster General Hospital are expected to disclose to the audience whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s).

Heather Harle, MD September 17, 2013

 ISCHEMIC  (85%)  HEMORRHAGIC  (15%)

 Probability of dying much higher with hemorrhagic  30 day mortality for ischemic is 7.6% vs. 37.5% for hemorrhagic  Risk factor profile quite different between the two  Ischemic – diabetes, a fib, previous stroke or MI, PVD  Hemorrhagic – smoking, alcohol  Age, sex, hypertension does not predict stroke type

 TIA - Brief episode of neurologic dysfunction caused by focal retinal or brain ischemia, with clinical symptoms lasting usually less than one hour, and no evidence of acute infarction  Albers et al, NEJM,  STROKE – Neurologic dysfunction caused by focal retinal or brain ischemia with symptoms longer than 1 hour or evidence of acute infarction on MRI.

 Sudden onset of symptoms referrable to the brain  Since the brain is topographically organized, ischemic strokes fall into a discrete pattern of syndromes primarily including some combination of Aphasia, neglect, face/arm/leg weakness or numbness, dysarthria, diplopia, dysphagia, vertigo, gait changes.

 ACA – leg weakness, apathy, urinary incontinence  MCA – face, arm +/- leg weakness, aphasia or neglect, hemianopsia  PCA – hemianopsia, memory loss

 Lipohyalinosis of small blood vessels of brain (microvascular disease)  Thalamus, basal ganglia, pons, cerebellum  Smoking, hypertension, hyperlipidemia, diabetes are major risk factors

 December 5, 1913 – April 12, 2012  Lacunar syndromes - Pure motor, pure sensory, sensorimotor, ataxic hemiparesis

 Tissue plasminogen activator is a naturally occurring enzyme, that breaks plasminogen into plasmin, causing clot breakdown.  Costs about 1500 dollars/dose  Approved for MI, PE, and acute ischemic stroke

 NINDS, 624 pts were treated with TPA (0.9 mg/kg) vs. placebo within 3 hours  ½ were treated within 90 minutes  Primary efficacy outcome was complete or near complete recovery 3 months after stroke. Favorable outcomes were achieved in 31 – 50% of pts who were treated, compared with 20 to 38% given placebo.

 Risk of bleeding with stroke is about 0.6% without TPA, 6.4% if TPA is given  Odds ratio for good outcome if treated within 90 minutes – 2.11  If treated within 180 minutes  In general, we say you are 30% more likely to be functionally independent at 3 months if you receive TPA  TPA, approved in 1996, is now standard of care, you technically don’t need to get consent

 Inclusion  Clear time of onset (within 3 hours)  Symptoms consistent with stroke (acute onset, localizing to a vascular territory...)  CT negative for blood, ischemic changes, unless early  Exclusion  0.9 mg/kg, 10% infused over 1 minute, the other 90% over 1 hr  BP’s less than 180/105 (labetalol pushes, nicardipine gtt)  Assess q 15 minutes during infusion, q30 minutes next 7 hours, and q1 hour next 16 hours  Stop infusion if there’s a clinical change for the worse  Platelets, cryoprecipitate if there’s a bleed

 Admitted to Trauma neuro first 24 hours  Close monitoring and blood pressure control  No aspirin, DVT proph for 24 hours  Watch for neurological decline which could signify hemorrhage

 821 pts, Age 18-80, were randomized to received IV- TPA hours  Excluding NIHSS >25  Excluding combination of diabetes and previous stroke  52.4% vs. 45.2% had a favorable outcome (Rankin 0-1 at 3 months); odds of a favorable outcome  The risk of bleeding goes up (27% vs 17%), but risk of death the same between groups

 Select patient who look like they’re having a stroke from a clot in a large artery but who aren’t a candidate for IV-TPA (ie. Are outside the 3 hour, (or 4.5 hr) time window, may be a candidate for IA-TPA.  Not done currently at LGH, we would ship these patients to Hershey or Jefferson

 PROACT II – 474 pts between 3 and 6 hours post stroke underwent angiogram. 180 pts were randomized to receive IV- prourokinase.  90 day mortality rates were the same (25 treated and 27% control)  ICH was seen more commonly in the treated pts, 35% vs 13%. 10% were symptomatic  40% of treated pt vs 25% control pts had a Rankin score of 2 or less at 90 days. NNT=7  Results extended to TPA as that’s the equivalent available in the US.  This is the only trial actually showing that intra- arterial approach is better than aspirin alone.

 Every other trial looking at devices uses “recanalization” as the primary end point, not actual patient improvement  MERCI pts enrolled, primary outcome measures were recanalization- which was 46% with device vs. 18% control and good Rankin score (<2) at 90 days – 46% vs. 10%  Symptomatic ICH in 7.8% (less than PROACTII)

 Wire mesh similar to cardiac stents. Deployed inside a clot where it expands, then is retracted.  58% have good outcomes compared to 33% with MERCI  17% treated with Solitaire died, compared to 38% treated with MERCI

 NEJM Feb 2013  118 patients were randomized within 8 hours of large vessel stroke to received aspirin only, or go on to intra-arterial therapy, embolectomy.  No difference in outcomes  We now await large randomized trials evaluating the efficacy of intra-arterial therapy, is the cost worth it?

 So they don’t get IV-TPA, or intervention, now what?  Aspirin  BP management  Admission and w/u to determine etiology (in order to prevent another stroke)  Address risk factors to prevent another stroke

 CAST and IST established the effectiveness of aspirin for acute stroke  CAST used 160 mg, IST used 300 mg, both within 48 hours of onset, 40,000 pts.  Combined, they showed a reduction of 9 fewer deaths or non-fatal strokes per 1000 treated patients, NNT 111.  As of now, no large randomized trials evaluate the usefulness of any other anti-platelet in acute stroke.

 Early  Current recommendations are not to lower the bp for the first 24 hours if bp is less than 220/120.  Really we don’t have good data to support this  In the IV-TPA patient, we lower below 180/105 for the first 24 hours, there is good data that sICH is more common in the pts with higher bp’s.  If BP is less than 120 systolic, consider laying head of bed flat, and administering saline  Late  Reduces risk of recurrence 30-40%  JNC-7 - <140 systolic or <130 with DM, CKD

 Evaluation for cause in order to prevent recurrence includes:  Brain and vessel imaging  Echo, possibly TEE  Fasting lipids, possibly A1c  Swallow screening

 Modifiable risk factors  High blood pressure (risk increased 4x, treatment reduces likelihood by 40%), smoking (double the risk, stopping reduces risk in 2-4 years), high cholesterol, atrial fibrillation, diabetes, excessive alcohol, recreational drugs, obesity, physical inactivity, carotid disease  Non-modifiable risk factors  Age, race, heredity, sex

 Aspirin – reduces risk of recurrence by 30%  Plavix, Aggrenox  Coumadin (risk of stroke reduced from 5% to 1.5% / year)  Pradaxa, xarelto  Statin (zocor/simvastatin, lipitor/atorvastatin, crestor etc) – reduces risk by ~30% (LDL goal less than 100, or less than 70)

 Randomized, blinded, placebo controlled trial in China  5170 pts with recent tia or small stroke were randomized to receive 300 mg loading dose of plavix and 75 to 300 mg aspirin daily (or placebo in place of plavix)  Outcome measure was stroke or death at 90 days  Plavix plus aspirin group – 8.2%  Aspirin group – 11.7%  Bleeds were no different (0.3%)

 Currently recruiting  Placebo or Plavix loading dose of 600 mg, within 12 hours of small stroke/TIA  With mg of aspirin daily  Outcome measure is stroke/MI, death at 90 days

(spontaneous intracerebral hemorrhage) Not sdh,sah, epidurals

 More frequently: headache, vomiting, decreased level of consciousness, very high blood pressures, progression of deficit

 BP control stat - Acute management includes labetalol, nicardipine gtt, systolic less than 150 (our practice here)  Reversal of anti-coagulants  Repeat imaging (including blood vessels), ie. MRI/MRA of brain

 If pt scanned early, less than 3 hours, 1/3 may progress and have increase in hematoma size of 1/3 or more  This is the biggest prognosticator for morbidity/mortality  How to prevent growth  Reversal of anti-coagulants  BP control

 Check Starnet – Physicians – Pharmacy – choose the anti-coagulant to reverse  Warfarin = Vitamin K and FFP  Heparin (low molecular weight heparin)= protamine  Pradaxa/xarelto – No real reversal agents, consider Factor VIIa or aPCC

 INTERACT, Chinese trial, 2008, 400 patients randomized to bp’s lower than 140 by 6 hours in, vs lower than 180. There was less hematoma growth with aggressive bp reduction, and neuro outcomes were equivalent  ATACH replicated this  INTERACT 2 – NEJM JUNE 2013 – ~700 pts with aggressive bp reduction (<140) vs <180 – no difference in death or severe disability but at 3 months patients aggressively treated had better Rankin scores  ATACH 2 is pending

 Neurosurgery  Consult for “infratentorial”  (Brainstem or cerebellar locations)  High risk for herniation, hydrocephalus  Intraventricular blood  High risk for hydrocephalus  Large lobar or basal ganglia bleed  Greater than 2 cm  Clinical worsening  AVM other malformation

 Most due to hypertension related changes in the blood vessels “Charcot aneurysms”  Basal ganglia  Thalamic  Pontine  Cerebellar  Elderly patients with dementia and lobar hemorrhages may have a condition called cerebral amyloid angiopathy which leads to ischemic and hemorrhagic strokes and seizures  Atypical locations, pt with hx of dementia

 Amyloid angiopathy  Elderly patients with recurrent TIA’s, strokes, hemorrhages, seizures, dementia Radiology.casereports.net

 ALCOHOL, DRUG USE, HTN, SMOKING

 Adams Harold P, et al. Guidelines for the Early Management of adults with ischemic stroke, Stroke, 38;  Anderson, Craig et al. Intensive blood pressure reduction in acute intracerebral hemorrhage trial (INTERACT), Lancet, May  Anderson, Craig et al. Rapid Blood Pressure Lowering in Patients with Acute Intracerebral Hemorrhage (INTERACT2), NEJM, June  Chinese Acute Stroke Trial (CAST). Randomized placebo controlled trial of aspirin use in 20,000 pts with acute ischemic stroke, Lancet, 349:1997.  Furlan Anthony, et al. Intra-arterial Prourokinase for Acute Ischemic stroke, JAMA, 282; 21,  Gubitz G et al. Anticoagulants for acute ischemic stroke, Cochrane Database Syst Rev, 2;  Hacke, Werner et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECAS III), NEJM 359;13,  International Stroke Trial Collaborative Group (IST), Lancet, 349;  Morganstern, Lewis et al. Guidelines for the management of spontaneous intracerebral hemorrhage, Stroke  NINDS study group. TPA for acute ischemic stroke, NEJM, 333;  Qureshi, Al. Antihypertensive treatment of acute cerebral hemorrhage, (ATACH), Neurocrit care, 2007, (6)  Smith, Wade S, et al. Safety and Efficacy of Mechanical Embolectomy in acute ischemic stroke (MERCI), Stroke,  Wang, Yongjun et al. Clopidigrel with aspirin in acute minor ischemic stroke or TIA. NEJM, July 4, 2013.

 Dipyradimole plus aspirin was shown in ESPS 2 and Esprit to be better than aspirin alone for secondary prevention.  Multiple European trials previous to these failed to show benefit of the combination  JASAP and PROFESS failed to show noninferiority to plavix.  Given that we have good evidence that plavix may not be better than aspirin in patients with previous stroke, my personal belief is it may not be better, and certainly costs substantially more (and at least 25% will discontinue due to headache).

 Plavix does not actually reach maximum anti- platelet effect for 5 days. In ACS, a loading dose of 300 – 600 mg is given. In stroke, this has been evaluated in a few small overseas trials, and was shown safe.  CAPRIE showed plavix superior to aspirin in preventing stroke, MI, or vascular death in patients with PVD and MI, but not those with previous stroke.  My practice, if a patient fails aspirin, may be to switch to plavix, particularly if pt has PVD or hx of MI

Aspirin plus plavix - The combination of aspirin and plavix in three separate trials of secondary stroke prevention (MATCH, CHARISMA, SPS III) has been shown to lead to more hemorrhagic complications with no reduction in recurrent strokes However, CHANCE POINT is currently enrolling

Thank you for viewing the video. In order to receive your CME credit, please click the “links” icon at the bottom right hand side of your computer screen to take a post test quiz and evaluation and receive your CME credits. For technical questions about this program, please contact For questions about the content, please contact Dr. Harle at