3/22/2017 Overview • Stroke Case Presentation Current Topics in Stroke • Acute Stroke Management at-a-glance Management • Secondary Prevention • New Guidelines for Women Kenneth A. Fox, M.D. Assistant Clinical Professor - UCSF Department of Medicine • Management of Carotid Disease Chief – Department of Neurology Medical Director – J.C.C. Primary Stroke Center Kaiser Permanente San Francisco • Stroke Case Wrap-Up Example Case What’s the next best step for imaging? 69 RHF Obesity, HTN, DM, CAD - BIBEMS 30 minutes after developing: A) Non-contrast Head CT • Slurred speech B) CT Angiogram • R facial droop C) MR Angiogram • R arm and leg weakness D) Catheter Angiography • R visual field cut • R spatial neglect 1
3/22/2017 Imaging – MRI T2 FLAIR Imaging – CTA/CT Perfusion Imaging – MRI Diffusion Weighted Vitals/Systemic Exam • BP 204/99, HR 110, RR 22, SaO2 98%RA • EKG/TELE – atrial fibrillation • Diaphoretic • L carotid bruit • Absent DP pulses • Labs sent (CBC, Coags, Chemistries/BG wnl) 2
3/22/2017 Time Is Brain !!! Currently Available Treatments Time of onset = last time seen normal • 0-4.5 Hours IV-tPA • 0-6 Hours Mechanical Embolectomy • > 8 hours/subacute Anticoagulant/ Antiplatelet Intravenous Tissue Plasminogen Expanding IV t-PA Window Activator (IV t-PA) ECASS III trial (3-4.5 hours) * Pivotal IV t-PA NINDS trial I/II (0-3 hours) * • 821 pts randomized to IV t-PA v. placebo • Part I (24 hrs) 291 pts, randomized to IV tPA v. • primary endpoint was disability at 90 days placebo, no significant differences • favorable outcome in 52% vs 45%, p=0.04 • Part II (90 days) 333 pts, 30% ↑ in 0/minimal • symptomatic ICH: 2.4% vs 0.2%, p=0.008 disability at 90 days, absolute difference ~12% • NO mortality difference • ↑ Symptomatic hemorrhage risk 0.6 to 6.4% • Advisory: avoid in pts >80, Hx Stroke + during 1 st 36 hrs, half were serious and/or fatal DM, Anticoagulation Tx (any INR value) * NEJM 2008 * NEJM 1995 3
3/22/2017 ? IV t-PA ? IV t-PA – Earlier Is Better Inclusion Criteria • Age 18-85 (<80 if beyond 3 hrs) Potential benefit of TPA • Clearly defined time of onset < 4.5 hrs • Measurable neurologic deficit/no rapid rate of improvement ( on NIH Stroke Scale) • Neuroimaging excluding hemorrhage ? IV t-PA ? ? IV t-PA ? Exclusion Criteria Exclusion Criteria (continued) • Recent stroke or serious head trauma • Arterial stick < 7d non-compressible site • Active systemic bleed (GI, hematuria, etc) • Glucose < 50 or > 400 • SBP > 185, DBP > 110 • Seizure at stroke onset • Major surgery < 14 days • Abnormal coags (e.g. INR > 1.4) • History of Intracerebral Hemorrhage • Platelets < 100k • History of Subarachnoid Hemorrhage 4
3/22/2017 Example Stroke Case Treatment Delays/Discrepencies • Only 1-2% of acute strokes occurring in the • Received IV t-PA within 1 hour community receive IV t-PA • New onset atrial fibrillation • Tremendous variation in treatment exists • TTE showed L atrial enlargement depending on hospital and region • LDL 150, HDL 35, TG 108 • CDC-sponsored registry showed that t-PA tx • Fasting glucose 131, HgbA1c 7.2% rate was 3% in GA and 8% in MA, despite 20- • Carotid ultrasound showed bilateral ICA 25% presenting within 3 hrs (10-20% of stenosis at origin - R 40%, L 55%. treated patients received it within 1 hr)* * Stroke 2005 Hypertension Secondary Stroke Prevention • Most important modifiable risk factor • Should begin during acute hospitalization • Predisposes to atherosclerotic disease of intra- and • Vascular/Atherosclerotic Risk Factor extracranial vessels, particularly at bifurcation sites Reduction • Maintaining BP < 120/80, ↓ recurrent stroke risk by *HTN *Diabetes *Atrial Fibrillation 30-40% 1 • Optimal BP regimen has not been established and *Lipids *Smoking *OSA? *Stress? treatment is highly individualized • Antithrombotic Therapy • ACEI and ARBs may ↓ arterial dz progression 2 - Antiplatelet v. Anticoagulation • Lifestyle modifications (e.g. weight loss, exercise, • Carotid Disease Management ↓ salt intake) 1 , 2 Stroke 2004 5
3/22/2017 Hyperlipidemia Diabetes (DM) • ↑ LDL and ↓ HDL linked to athero and heart dz, but direct • ~25% stroke patients have DM, 2-4x risk over relationship to stroke non-DM patients Several trials have shown efficacy in ↓ CV events overall • SPARCL Trial 1 • • ↑ likelihood of recurrent ischemic stroke - atorvastatin 80mg ↓ RR recurrent stroke 16% at 5yr • ↑ morbidity and mortality after stroke Retrospective - statins at discharge lowers the risk of 10-year stroke • recurrence and improves survival 3 • Current AHA/ASA guidelines recommend near Prospective – early statin tx post-stroke improves survival, and • withdrawal, even for a brief period, is associated with worsened normoglycemic levels (Hgaic <7%) for survival. 4 patients with recent ischemic stroke* • Do statins ↑ risk of hemorrhagic stroke? - minimal, benefits outweigh risks 2 • Tighter target LDL control goals (<70mg/dL) * Stroke 1/2011 1 NEJM 2006, 2 Neurology 2007, 3 Neurology 2009, 4 Stroke 2012 Obstructive Sleep Apnea & Stroke: Identifying OSA A Reciprocal Relationship • Historical Features • Share common risk factors (e.g. smoking, HTN) - snoring - fragmented sleep - observed apneas • OSA may be an independent stroke risk factor via - excessive daytime somnolence (EDS) promotion of atherosclerosis due to: • Characteristic Phenotypical Features - repeated hypoxemia → endothelial dysfunction - obesity - short neck - low-set soft palate and oxidative stress - narrow oropharynx - retrognathia - promotion of hypercoaguability through • Orofaciopharyngeal weakness secondary to stroke platelet activation and ↑ fibrinogen levels - chronic elaboration of inflammatory cytokines TX: Continuous Positive Airway Pressure (CPAP) • > 50% of stroke patients may exhibit OSA within the first 24 hours after stroke Seminars in Neurology 2006 6
3/22/2017 STRESS?! Antiplatelet Agents • 6 year longitudinal analysis of Chicago Health and Aging Project CHAP* pop • Aspirin • 4190 eligible (>65 yo) took inventory to determine presence of psychosocial distress (perceived stress, • Aspirin/Dipyridimole (Aggrenox) depression, neuroticism, life satis.) • Overall 13% incidence of stroke • Ticlopidine (Ticlid) • Higher distress scores: – 31% increased incidence of stroke (mainly ICH) • Clopidogrel (Plavix) – 2 fold increase in stroke mortality • Responsible physiological mechanisms unknown * Stroke 2012 Aspirin Clopidogrel (Plavix) • Cycloxygenase inhibitor through acetylation • ADP-GIIb/IIIa receptor binding antagonist • 1996 CAPRIE trial → 9% relative risk reduction • Effects on platelets detectable < 1hr, and may compared to ASA, but no significant difference in have additional fibrinolytic properties patients with prior stroke 1 • 30-1300mg/day conveys significant secondary • 2004 MATCH trial → ASA + Clp v. Clp alone, combo confers ↑ hemorrhage risk w/o ↓ stroke 2 stroke prevention – optimal dose remains • 2006 CHARISMA trial → ASA + Clp v. ASA controversial (several positive trials) alone, combo confers ↑ hemorrhage risk w/o ↓ stroke 3 • Side effects: gastritis, peptic ulcer disease, and • No neutropenia (rare TTP) and generally better gastrointestinal bleeding (lower doses and tolerated than ASA enteric coated preps help reduce incidence) 1 Lancet 1996, 2 Lancet 2004, 3 NEJM 2006 7
3/22/2017 Aspirin/ER Dipyridamole (Aggrenox) 2008 PRoFESS TRIAL • Dipyridamole is a phosphodiesterase inhibitor • Randomized, double-blind trial of ASA/Dipyridimole in platelets → indirectly blocks activation versus Clopidogrel in > 20k pts with ischemic stroke • ESPS-2 * and ESPIRIT ** trials compared • No significance difference event recurrence rates aggregate to ASA alone for stroke prevention, between the two medications over 2.5 yrs convincingly in favor of aggregrate – Composite rates of stroke, MI, CV death: both 13.1% – Major hemorrhagic events higher in ASA/Dyp group • In both trials, risk of bleeding from dual (Clp 3.6%, ASA/Dyp 4.1%; P=.06) therapy was not greater than that of ASA alone – More drop-outs in ASA/Dyp group owing to headache • Side effects: headache (Clp 0.9%, ASA/Dyp 5.9%) NEJM 2008 * J Neur Sci 1996 ** Lancet 2006 Choosing Antiplatelet Therapy 2013 CHANCE TRIAL • Any of the following may be used to help prevent • RCT, multicentered, >5k pts in China stroke recurrence • ASA+Clopidogrel v ASA for first 21 days post- mild stroke or - ASA 50-325mg QD (20x cheaper!) TIA (time of onset ≤ 24h) - ASA 50mg/ER Dypiridamole 200mg BID • Primary EP stroke incidence at 90 days - Clopidogrel 75mg QD – Combo 8.2%, ASA alone 11.7% – Hemorrhagic stroke rate 0.3% in both groups • Clopidogrel 75mg QD if ASA intolerant • Limitations: China differs from West in epidemiology and • ASA+Clopidogrel is not more effective and may be overall access to/compliance with CV-specific treatments dangerous • Analagous US study (POINT) – completed, awaiting pub. • No trials supporting antiplatelet switch following stroke NEJM 2013 * Stroke 2011 8
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