Sixth Annual Intensive Update in Neurology 9/15-16/2016. W Tom Kushner DO Swedish Stroke Clinic Neurohospitalist

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Giles Manning
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1 W Tom Kushner DO Swedish Stroke Clinic Neurohospitalist 1

2 One Strategy for cryptogenic stroke: ESUS Positively defined criteria FDA allows clinical trials NOACs have lower risk profile Another strategy Focus on undetected Atrial fibrillation which is a common cause of cryptogenic stroke VIENNA The concept of cr yptogenic str oke is outdated and should be r eplaced by the r elatively new clinical constr uct of embolic str oke of undeter mined sour ce, or ESUS, Dr. Hans Chr istoph Diener said at the annual European Stroke Conference. 2

3 Embolic strokes of undetermined source: the case for a new clinical construct RG Hart, HC Diener, et all - The Lancet Neurology, ; Reassessment Cryptogenic Stroke (of unknown cause) Ischemic stroke about 25% cryptogenic 3

4 Re assessment of cryptogenic stroke Rationale EXCLUDES LACUNAR STROKE LARGE VESSEL STENOSIS/DISSECTION ATRIAL FIBRILLATION OBVIOUS KNOWN CAUSES -TUMOR, VALVE, MI, ARTERITIS Thromboemolism is likely in cryptogenic stroke Anticoagulation better than antiplatelet for emboli ESUS is a therapeutically relevant and allows randomized trials 4

5 Etiologies most likely in this group Atrial fibrillation PFO CHF Aortic plaque Non stenotic plaque of carotid/ verterbral / intracranial arteries 5

6 ESUS as a subcategory of cryptogenic stoke Paroxysmal Atrial fibrillation newer technologies for detection PFO update closure controversy/ RoPE SCORE Case Studies 6

7 Cryptogenic stroke is defined as "a brain infarct not attributed to a definite source of large-vessel atherosclerosis, cardioembolism, or small vessel disease; it can be in the presence of an extensive work-up, incomplete evaluation, or more than one cause, 7

8 A cryptogenic stroke, or stroke of undetermined etiology, as defined by the Trial of Org in Acute Stroke Treatment criteria, is a brain infarct not attributed to a definite source of large-vessel atherosclerosis, cardioembolism, small-vessel disease, in the presence of (1) extensive cardiac, vascular, hematologic, and serologic evaluation; (2) incomplete evaluation; or (3) evidence of more than one competing cause. 4 Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org in Acute Stroke Treatment.Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd Stroke Jan; 24(1):35-41.Pub med [Ref list] 8

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10 Regional newspaper : Rookie cop s quick action likely saved woman s life Officer arrived : patient was leaning against her vehicle. replied Yep, even when it wasn t a yes or no question. No smell alcohol or signs of drug use..the woman s right arm drooped. Her right leg couldn t support her. The right side of her face sagged. She lacked balance. Instead of bringing out handcuffs, he called for a medic. 10

11 CTA left M1 occlusion CT Perfusion Large left mismatch tpa Cerebral Angio persistent MI occlusion Thrombectomy TICI 3 recanalization one pass. =work above by DR Hensley and Dr Loh. 11

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13 Work up hypercoag normal No extracranial stenosis. Post thrombectomy no intracranial stenosis Telemetry and 14 day monitor neg for AFIB PFO 5+/5 DVT discharged on warfarin RoPE score 6. 62% probability stroke attributed to PFO But with DVT etiology is likely. Kent et al Neurology 2013; 81:619 13

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15 Randomized double blind Evaluation secondary prevention of ischemic stroke Efficacy and safety thrombin inhibitor Dabigatran vs Aspirin Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source (RE-SPECT ESUS) This study is currently recruiting Verified September 2016 Sponsor: ClinicalTrials.gov Identifier: NCT Inclusion Age 18 to 59 stroke plus another risk factor Age 60 or older ESUS in the last 3-6 months Non lacunar cortical or subcortical if> 1.5 cm on CT or 2 cm on MRI Absence of >or = 50% stenosis of artery supplying area of ischemia No cardio embolic cause of stroke 24 holter/ echo No dissection vasculitis substance abuse 15

16 Approval for life threatening bleeding or need for emergency surgery. Monoclonal antibody to reverse dabigatran Study Three randomized, placebo-controlled studies 224 received at least one dose 30 subjects were aged 65 years or older (median age=36 years) Idarucizumab Mechanism of Action specifically binds to dabigatran and its acylglucuronide metabolites and reverses their anticoagulant effect immediately after administration. 2.5 g vials x 2 unbound dabigatran levels : undetectable levels immediately following administration. Coagulation parameters returned to baseline e thrombin time (dtt), ecarin clotting time (ECT), thrombin time (TT), activated partial thromboplastin time (aptt), and activated clotting time (ACT) 16

17 Standard work up ECG / Telemetry /24 to 48 hour Holter monitor VS 2 to 4 weeks ambulatory monitors 17

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19 Open label RCT Mean age 72.5 yo 572 patients Detection 30 seconds or more Atrial fibrillation Primary outcome Intervention group: 45/280 patients 16.1% had Afib Control: 9/277 patients or 3.2% had Afib Gladstone NEJM ,

20 Primary Outcome :Detection of atrial fibrillation with duration 30 sec within 90 days: 16.1% vs. 3.2% (number needed to screen 8; 95% CI ; P<0.001) Secondary Outcome: Detection of atrial fibrillation with duration 2.5 min 9.9% vs. 2.5% (number needed to screen 14; 95% CI ; P<0.001) Detection of atrial fibrillation of any duration 19.7% vs. 4.7% (number needed to screen 7; 95% CI ; P<0.001) Anticoagulant therapy at 90 days 52/280 (18.6%) vs. 31/279 (11.1), Absolute difference 7.5% (95% CI: 1.6 to 13.3), P=0.01 Antiplatelet therapy only at 90 days 223/280 (79.6%) vs. 246/279 (88.2%), Absolute difference 8.6% (95% CI: 14.6 to 2.5), P=0.006 Therapy at randomization changed by 90 days from antiplatelet therapy to anticoagulant therapy 38/280 (13.6%) vs. 13/279 (4.7%), Absolute difference 8.9%, (95% CI: 4.2 to 13.6), P <0.001 Therapy at randomization changed by 90 days from anticoagulant therapy to antiplatelet therapy 3/280 (1.1%) vs. 2/279 (0.7%), Absolute difference 0.4%, (95% CI: 1.2 to 1.9), P=

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22 Cryptogenic Stroke and Underlying Atrial Fibrillation patients 221 to ICM and 220 control -all had MRI, CTA, TEE, ECG, 24 hour telemetry, -thrombophilia < 55 yo and CUS was accepted for greater > age 55 yo -Atrial fibrillation defined as irregular HR lasting greater than 30 seconds with absence of p waves. Tommaso Sanna et al N Engl J Med 2014; 370: June 26,

23 Implanted monitor vs control 6 months P value % vs 1.4 % 12 months 12.4% vs 2.0 % P value years 30.0% vs 3.0% P value

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25 Cost Varies.implanted monitor in Crystal AF vs other $5,295, which is $1,500 more than competing device $1,700 less Overall reimbursement rates for this procedure, including the explant, are currently at about $7,400. From MD Buyline Wayne Adams 25

26 Implanted monitor 30 day ambulatory monitor 2 week patch adhesive Wide range thousands or greater $ to $$$ Reports around $30,000 for most expensive. Variability in coverage Individual insurance Medicare Medicaid 26

27 Advantages -Cost -Ease of use and compliance -Apply in clinic -Mail in 2 weeks Cardiology review Disadvantages -2 weeks maximum -Rare rash and adhesion problems 27

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29 RoPE score helps identify patient where the PFO was the likely cause for stroke. PFO attributable stroke RoPE score is not a tool for identifying closure patients PFO recurrent stroke risk is low and anticoagulation risk is greater than benefit ASA is the best option Neurology Messe ; Kernan 29

30 10 POINT THRESHOLD 7 POINTS -No Hypertension (1) -No Diabetes (1) -No history of stroke or TIA (1) -Non smoker (1) -Cortical infarct on imaging (1) Age y -18 to 29 (5) (4) -40 to 49 (3) 50 to 59 (2) (1) 30

31 FDA Panel Asked these questions Re Amplatzer closure Is it safe? Is it effective? Are risks greater than benefits? Heartwire from Medscape FDA Panel Gives Tepid Nod to PFO-Closure Device for Cryptogenic Stroke Busko; May 25,

32 Safety vote 15 yes/ 1 no atrial Efficacy vote 9 yes / 7 no Benefit vs risk 11 yes/ 5 no -moderate modest or uncertain RESPECT TRIAL Prolonged enrollment and event rate was low Superiority was not proven RRR 0.53 CI ; P= % DEVICE VS 1.9% had Afib -but procedures may trigger Afib 18 Device VS 3 had DVT or PE 32

33 Level A PFO is common 25% Effectiveness of closure is uncertain Closure has uncommon but serious risks Level C Rarely closure may be considered in patients with recurrent stroke on medical therapy with Amplatzer Occluder Level R Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting. Enroll patients in research trials. 33

34 41yo F in exercise class had speech and R side weakness. Resolved in ED. No tpa. MRI L infarct TEE no appendage clot ; Tox cannabis+ Telemetry neg CTA no stenosis ; old cerebrellar infarct Advanced Hypercoag neg Emboli monitoring neg 14 day Heart monitor neg 34

35 TEE negative Echo right to left shunt TCD PFO grade 2 /5 with strain. Old cerebellar stroke likely due to chiropractor visit with dissection years previously RoPE score assessment of probability stroke is associated with PFO. Score 7/10 or 72% chance that stroke may be attributed to PFO 1point for no HTN, DM, tobacco or prior stroke. 1 for cortical location (4) and for age group (3)=7 Kent et al Neurology 2013,81:619 35

36 Atrial fibrillation The longer you look the more you find. -consider cost -insurance coverage -use CHADS2 VASC score CHF HTN Age Diabetes Prior stroke Age Vascular disease PFO in young patients Use RoPE score Transcranial Doppler PFO study with Valsalva strain -can grade 1 to 5 -find PFO missed by TEE or TTE -cost effective and non invasive except IV Thank you Thank you 36

PFO Management update

PFO Management update May 12, 2017 Peter Casterella, MD Swedish Heart and Vascular 1 PFO Update 2017: Objectives Review recently released late outcomes of RESPECT trial and subsequent FDA approval of PFO