4/9/19 Disclosures • None to report Current Topics in Stroke Management Kenneth A. Fox, M.D. Chief – Department of Neurology Deputy Chair of Chiefs – Neurology, KP NCAL Medical Director – J.C.C. Primary Stroke Center Kaiser Permanente San Francisco Overview Example Case 69 RHF Obesity, HTN, DM, CAD - • Stroke Case Presentation BIBEMS 30 minutes after developing: • Acute Stroke Management at-a-glance • Slurred speech • Secondary Prevention • R facial droop • Guidelines for Women • R arm and leg weakness • Management of Carotid Disease • R visual field cut • Neurorehabilitation • R spatial neglect 1
4/9/19 Non-Contrast Head CT What’s the next best step for imaging? A) Non-contrast Head CT B) CT Angiogram C) MR Angiogram D) Catheter Angiography Large Vessel Occlusion 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
4/9/19 Time Is Brain !!! Currently Available Treatments Time of onset = last time seen normal • 0-4.5 Hours IV-tPA • 0-6; 6-24 Hours Mechanical Embolectomy • > 8 hours/subacute Anticoagulant/ Antiplatelet Extended Window EST Imaging – CTA/CT Perfusion • Last known well 6-24 hours • Good premorbid function, mRS ≤ 2 • NIH Stroke Scale score ≥ 6 • Infarct “core” volume <70 cc EST = Endovascular Stroke Treatment mRS = Modified Rankin (disability) Scale NEJM 2018 3
4/9/19 Expanding IV t-PA Window Intravenous Tissue Plasminogen Activator (IV t-PA) Pivotal IV t-PA NINDS trial I/II (0-3 hours) * ECASS III trial (3-4.5 hours) * • Day 1 – no significant cant outcome difference • Disability scale at 90 days • Day 90 – 30% more likely to have minimal • Favorable outcome in 52% vs 45%, deficit • Hemmorhage 2.4% vs 0.2%, • Hemorrhage 0.6 - 6.4% during 1 st 36 hrs, half • NO mortality difference were serious and/or fatal * NEJM 2008 * NEJM 1995 Telestroke! IV t-PA – Earlier Is Better Potential benefit of TPA 4
4/9/19 2017 DTN Times Example Stroke Case Kaiser San Francisco • Received IV t-PA within 1 hour • New onset atrial fibrillation • TTE showed L atrial enlargement • LDL 150, HDL 35, TG 108 • Fasting glucose 131, HgbA1c 7.2% • Carotid ultrasound showed bilateral ICA stenosis at origin - R 40%, L 55%. Secondary Stroke Prevention Imaging – MRI Diffusion Weighted • Should begin during acute hospitalization • Vascular/Atherosclerotic Risk Factor Reduction *HTN *Diabetes *Atrial Fibrillation *Lipids *Smoking *OSA? • Antithrombotic Therapy - Antiplatelet v. Anticoagulation • Carotid Disease Management 5
4/9/19 Hypertension Hyperlipidemia • #1 modifiable risk factor • SPARCL Trial 1 • Causes stenosis at arterial bifurcations - atorvastatin 80mg ↓ RR recurrent stroke 16% at 5yr • Maintaining BP < 120/80, ↓ recurrent stroke risk by • Retrospective - statins at discharge lowers the risk of 30-40% 1 10-year stroke recurrence and improves survival 3 • Optimal BP regimen has not been established and • Prospective – early post-stroke statin improves survival, and withdrawal, even for a brief period, is treatment is highly individualized associated with worsened survival. 4 • ACEI and ARBs may ↓ arterial dz progression 2 • Do statins ↑ risk of hemorrhagic stroke? • Lifestyle modifications (e.g. weight loss, exercise, - minimal, benefits outweigh risks 2 ↓ salt intake) 1 , 2 Stroke 2004 1 NEJM 2006, 2 Neurology 2007, 3 Neurology 2009, 4 Stroke 2012 Diabetes (DM) Insulin Resistance/Pioglitazone • IR = HAIC 5-7-6.4%, FGB 100-125 mg/dl • ~25% stroke patients have DM, 2-4x risk over non-DM patients • 2016 IRIS trial showed reduced recurrent • ↑ likelihood of recurrent ischemic stroke stroke/MI in patients with IR • ↑ morbidity and mortality after stroke • 2017 Meta-analysis consistent across studies • Current AHA/ASA guidelines recommend near • 2019 unpublished trial confirmed benefit normoglycemic levels (Hgaic <7%) for • Standard practice from now on? patients with recent ischemic stroke* • Optimal dose yet to be determined • Intensive statin therapy for all * Stroke 2011 NEJM 2016, Stroke 2016, JAMA 2019 6
4/9/19 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 promotion of atherosclerosis due to: - excessive daytime somnolence (EDS) 1) repeated hypoxemia → endothelial dysfunction • Characteristic Phenotypical Features and oxidative stress - obesity - short neck - low-set soft palate 2) promotion of hypercoaguability through - narrow oropharynx - retrognathia platelet activation and ↑ fibrinogen levels • Orofaciopharyngeal weakness secondary to stroke 3) chronic elaboration of inflammatory cytokines TX: Continuous Positive Airway Pressure (CPAP) Seminars in Neurology 2006 Stroke Guidelines For Women Antiplatelet Agents • Pre-eclampsia should be recognized as a risk factor well after pregnancy • Aspirin – Hx HTN before pregnancy, consider ASA + Calcium to reduce risk of pre-eclampsia • Aspirin/Dipyridimole (Aggrenox) – Hx pre-eclampsia 2x stroke and 4x HTN risk • Clopidogrel (Plavix) • HTN screening before taking OCPs because the combination raises stroke risk • Hx migraine/aura + smoking raises stroke risk • Atrial fibrillation screen for all women > 75 Stroke 2014 7
4/9/19 Clopidogrel (Plavix) Aspirin • ADP-GIIb/IIIa receptor binding antagonist • Cycloxygenase inhibitor • 1996 CAPRIE trial → 9% relative risk reduction compared to ASA, but no significant difference in • Effects on platelets detectable < 1hr patients with prior stroke 1 • 30-1300mg/day conveys significant secondary • 2004 MATCH trial → ASA + Clp v. Clp alone, combo ↑ hemorrhage risk w/o ↓ stroke 2 stroke prevention – optimal dose remains • 2006 CHARISMA trial → ASA + Clp v. ASA controversial (several positive trials) alone, combo ↑ hemorrhage risk w/o ↓ stroke 3 • Side effects: gastritis, PUD, GI bleed* • No neutropenia (rare TTP) and generally better tolerated than ASA *consider enteric coated to reduce risk 1 Lancet 1996, 2 Lancet 2004, 3 NEJM 2006 Aspirin/ER Dipyridamole (Aggrenox) 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 8
4/9/19 A Role For Dual Antiplatelets? Choosing Antiplatelet Therapy CHANCE/POINT Trials • Any of the following may be used to help prevent stroke recurrence - ASA 50-325mg QD (20x cheaper!) • ASA+Clopidogrel v ASA alone for first 21 days post- mild stroke or TIA (within 24 hours of symptom onset ≤ 24h) - ASA 50mg/ER Dypiridamole 200mg BID • Loading doses of Clopidogrel 300-600mg - Clopidogrel 75mg QD • Primary EP stroke incidence at 90 days • Clopidogrel 75mg QD if ASA intolerant – Combo confers lower stroke rate • ASA+Clopidogrel long-term is not more effective – Low hemorrhage rate in both groups, but higher when and may be dangerous patients treated beyond 21 days • No trials supporting antiplatelet switch following stroke NEJM 2013, 2018 * Stroke 2011 Antiplatelet Failure/ � Resistance � When should we anticoagulate? • Is the patient compliant? • Atrial Fibrillation • Diagnostic Failure (eg. PAF*, seizures, migraines, • Mechanical Heart Valve meds)? • Hypercoaguable State (e.g Factor V Mutation) • Are other risk factors being addressed adequately? • Severe Cardiomyopathy/EF Reduction* • Great Vessel Dissection* (eg. BP, Lipids, Hgbaic, Carotid Stenosis) • Acute Carotid Occlusion* • Drug interaction (eg. NSAIDs-ASA, PPI- • Aortic Arch Atheroma * Clopidogrel) ? • PFO with atrioseptal aneurysm* • Genetic predisposition to platelet aggregation? [* not clearly supported in the literature but employed on a case by case basis] • Is there any data to support switching anyway? *PAF – paroxysmal atrial fibrillation 9
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