Tremendous Progress in Age Adjusted Analyses • Epidemiology Outline • Acute treatment » Supportive care » IV fibrinolysis » Endovascular mechanical thrombectomy • Preventive medical therapy » For cardioembolic stroke » For atherothromboembolic Stroke • From ttetrad to pentad » 1 – Diet and lifestyle » 2 - BP lowering » 3 – Antithrombotics » 4 – Statins for cholesterol lowering » 5 – PCSK9 Inhibitors for cholesterol --Age adjusted stroke mortality rates 75%, lowering 1960UCLA - 2010 Stroke Center--Towfighi + Saver, Stroke 2011 R ttkitil tl 50%

Stroke Subtypes in Large US Registries

Worldwide Impact of Stroke Ischemic Stroke (83%) Hemorrhagic Stroke (17%) Large Artery Atherothrombotic Cardioembolic (30%) Intracerebral • The leading cause of serious disability (30%) Hemorrhage (70%) » Over 16 million strokes / year, including over 10 million nonfatal strokes / year • Second leading cause of dementia • Second leading cause of death » Over 6 million deaths / year » 10% of all deaths worldwide Lacunar (25%) Subarachnoid Hemorrhage (30%) • 85% of the disease burden of stroke (small vessel disease) borne by low-income and middle- Other (10%) income countries Cryptogenic (5%) --Johnston et al, Global variation in stroke burden and UCLA Strokemortality, Center Lancet Neurology 2009 Strategies in Acute Ischemic Stroke Early Supportive Acute Stroke Care Therapy 5-15% Increase in Good Outcomes in Acute Stroke Unit Controlled Trials • Proven • Treat hypoxemia » Continuous pulse oximetry, supplemental oxygen as needed » Recanalization • Maintain normothermia » Early antipyretics/antibiotics » Supportive Care • Avoid hyperglycemia Prevent Clot Propagation » Avoid glucose infusions/use SSI/maintain glucose < 200 mg/dl » • Early parental fluid to support collaterals » Maintenance normotonic IV fluids (IV NS 75-100 cc/h) • Experimental • Permissive hypertension to support collaterals » Neuroprotection » Treat only if >220/120 (lower if tPA) • DVT prophylaxis » Collateral Enhancement » Compression boots/hep/LMWH » Early mobilization • Early swallow assessment to guide oral feeding

UCLA Stroke Center UCLA Stroke Center

In a typical acute ischemic The Ischemic Penumbra stroke, every minute the brain loses Irreversible Core Infarct • 1.9 million neurons

• 14 billion synapses Ischemic Penumbra zone of salvageable • 7.5 miles myelinated fibers tissue surrounding core infarct -- Saver, Stroke 2006 Two Major Strategies in Acute Ischemic Onset to Treatment Time for IV TPA and Odds of Stroke Treatment Excellent Outcome Reperfusion Neuroprotection • Pooled, patient level analysis • 8 trials » NINDS 1 and 2 » ATLANTIS A and B » ECASS 1, 2, and 3 » EPITHET • 3670 patients UCLA Stroke Center UCLA Stroke Center --Lees et al, Lancet 2010

TPA Treatment Time and Benefit Magnitude 58,353 Patients from 1395 GWTG-Stroke Hospitals Improvement Over Time in GWTG-Stroke in --Saver et al, JAMA 2013 the Use of IV rt-PA in Eligible Patients

Among 1000 patients, for every 15 100% Baseline YR1 YR2 YR3 YR4 YR5 min acceleration of tPA treatment • 18 more will have improved ambulation at discharge 80% 72.65% 72.84% 69.10% – Including 8 more who will 65.00% ambulate fully independently 60% • 13 more will be discharged to a 53.46% more independent environment 42.09% – Including 7 more discharged to 40% home • 4 fewer patients will die prior to discharge 20%

0% IV rt PA 2 Hour Substantial Opportunity to Improve Timeliness of IV rt-PA in Ischemic Stroke Door-to-IV rt-PA within 60 minutes 2005 2006 2007 2008 2009 100%

80%

60%

40% 25.80% 27.40% 24.10% 22.30% 24.70% 20%

0% DTN within 60 min

Target: Stroke Best Practice Strategies Target: Stroke The Time is Now 1. *EMS Pre-Notification 7. *POC Laboratory Testing Door-to-IV rt-PA within 60 minutes 2. Stroke Toolkit 8. *Premix TPA 100% 3. Rapid Triage and Stroke 9. *Rapid TPA Access - 80% Team Notification store TPA in ED/radiology,

60% start in imaging suite 50.0% 4. *Single Call Activation System 10.Team approach 40% 27.4% 5. *Transfer Directly to CT 11.*Prompt data feedback 20% 6. Rapid Brain Imaging

0% •2009 •Goal DTN within 60 min 0.6 IV TPA Under 3 Hours – Patient Education Target:0.5 Stroke Impact and Success in US: Fonarow et al, JAMA 2014 • Joint AHA-AAN-ACEP text tool to educate 0.4 patients and families • UCLA icon array tool 0.3 based on AHA-AAN- ACEP 0.2 % DTN Time ≤60 Minutes ≤60 Time DTN % 0.1 Target: Stroke Initiation --Gadhia et al, Stroke 2010

(P<0.0001 for comparison of the two slopes) 0 UCLA Stroke Center 3Q2 3Q3 3Q4 4Q1 4Q2 4Q3 4Q4 5Q1 5Q2 5Q3 5Q4 6Q1 6Q2 6Q3 6Q4 7Q1 7Q2 7Q3 7Q4 8Q1 8Q2 8Q3 8Q4 9Q1 9Q2 9Q3 9Q4 0Q1 0Q2 0Q3 0Q4 1Q1 1Q2 1Q3 1Q4 2Q1 2Q2 2Q3 2Q4 3Q1 3Q2 3Q3

Target: Stroke Phase 2 Time Trend in the Proportion of Patients with DTN Times within 45 Minutes Pre-Target: Stroke and During Target: Stroke Phase I and II • Target: Stroke Elite » DTN ≤ 60m in 75% Time Period Estimate P‐ » DTN ≤ 45m in 50% (per year) (95% CI) value <.0001 Pre‐Target: 0.12 (‐0.20, 0.4741 Stroke 0.43) Target: Stroke 2.87 (2.49, <.0001 Phase I 3.25) Target: Stroke 10.20 (5.92, 0.0018 Phase II 14.48)

UCLA Stroke Center Door to Needle Times with “Direct to CT” or “ED Pitstop” in Best Practice Hospitals

Stroke Center Median Door to Needle Times

Helsinki, Finland 20 mins Mobile Stroke Units for Prehospital Thrombolysis Erlangen, Germany 25 mins Wash U, St. Louis 39 mins

--Meretojoa et al, Neurology 2012 --Korhmann et al, Int J Stroke 2011 --Ford et al, Stroke 2012 UCLA Stroke Center

TPA Frequency and Speed CT p CT p Control Ambulan value Ambulan value Weeks ce ce Weeks Patients N 1804 3213 2969 Pct of AIS 32.6% <0.00 28.9% <0.00 21.1% --JAMA, April 2014 1 1 DTN Hosp (min) 42 Alarm to Hosp 85 <0.00 67 <0.00 35 (min) 1 1 Alarm to 38 <0.00 44 <0.00 52

Imaging 1 1 *Primary Endpoint UCLA Stroke Center ImaUCLAgin Strokeg to CenterTPA 14 <0.00 17 <0.00 24 No difference in efficac or safet o tcomes MSU CT Dispatcher impression: Stroke

Provider impression: Stroke

NIHSS : 7 LAMS: 3

Clinical scenario: 76 year old woman with history of prior TIA (lip numbness & dysarthria 5 month prior), presenting with witnessed acute onset left face/arm weakness, difficulty with ambulation

Acute NIHSS 7: left face/arm weakness, numbness, ataxia, dysarthria, sensory

LKWT-to-Tx time: 45 min MSU admission-to-CT time: 5 min MSU admission-to-needle time: 19 min

24 hr NIHSS 1: mild sensory deficit in left arm Hospital MRI

BEnefits of Stroke Treatment Delivered Using a Mobile Stroke Unit (BEST-MSU) Trial

• Cluster-control RCT » 5 EMS Regions USA » 1 week on, 1 week off » Patients • ~9000 assessed • ~2000 enrolled » ~1000 fully tPA eligible • Key entry criteria » LKW within 4.5h prior to ambulance evaluation » tPA eligible prior to CT/labs • Outcome: Utility-weighted mRS at 90d • Timeline: 2014-2021 Growing Worldwide Use of Catheter-Based Reperfusion Therapies Mobile Stroke Units

UCLA Stroke Center --Fassbender, Grotta,Walter, Grunwald, Ragoschke-Schumm, Saver, Lancet Neurol 2017

Acute Mechanical Recanalization Strategy Historical Development of Endovascular Depends on Target Occlusion Composition Technologies for Acute Recanalization Embolus In Situ Atherothrombosis Technology First Human Studies • Relatively normal • Substantial local IA microcatheter lysis 1988 (1999) recipient artery atherosclerotic plaque IA angioplasty 1994 • Strategy: remove the • Strategy: Crack the IA aspiration thrombectomy 2001 (2009) thrombus plaque IA ultrasound sonothrombolysis 2003 IA implanted stents 2003 •Retrievers • Angioplasty IA laser clot destruction 2004 • Aspirators • Stents IA Archimedes screw 2004 •+/- Lytics •+/- Lytics IA coil retrievers 2004 (2004) IA basket/brush retrievers 2006 IAUCLA stent Stroke retrievers Center 2010 (2010) UCLA Stroke Center Mechanical Thrombectomy Devices Mechanical Thrombectomy Devices

Covered Covered Coil Basket Brush Aspiration Stent Coil Basket Brush Aspiration Stent Stent Stent Retriever Retriever Retriever Catheter Retriever Retriever Retriever Retriever Catheter Retriever Retriever Retriever

UCLA Stroke Center UCLA Stroke Center

UCLA – MCA Occlusion 30-Year-Old Female – Baseline NIHSS 24 Symptom Onset to Final Angiogram – 5:37

NIHSS 24 hours 1 mRS 5 days post 0 30 days post 0 90 day post 0 UCLA Stroke Center

de ce o e e Independence (mRS≤2) at 3 Months

Trial ERT+Med MedRx OR P value Rx MR CLEAN 32.6% 19.1% 2.05 0.0007 ESCAPE 53.0% 29.3% 2.73 0.00003 EXTEND-IA 71.4% 40.0% 3.75 0.009 SWIFT PRIME 60.2% 35.5% 2.75 0.0008 REVASCAT 43.7% 28.2% 1.98 0.021 All (weighted 46.1% 26.4% 2.39 <0.0000000 avg) 1 Odds that SR ERT is beneficial are more than 100,000,000 UCLA Stroke Center to 1 NNTs for Cerebral and Cardiac Ischemia Binary Outcomes Thrombectomy for AIS (vs Lysis) (4) Independence

Endovascular therapy if patients meet all the following criteria IV Lytics • Prestroke mRS score 0-1 for AIS (vs ASA) (10) • Received IV tPA (Ia) or tPA-ineligible (IIa) Nondisability • ICA or M1 MCA occlusion • Age ≥ 18 yo • NIHSS ≥ 6 PCI • ASPECTS ≥ 6 for STEMI (vs Lysis) (29) • Treatment start (puncture) within 6h of onset Mortality UCLA Stroke Center UCLA Stroke Center

Time to Puncture Time to Puncture and Thrombectomy Outcome and Thrombectomy Outcome HERMES HERMES 2.3 Collaboration Collaboration 2.5 2.9 •NNTs 3.4 4.2 5.5 8.6 7.3 hrs 7.3 hrs

--Saver et al, JAMA 2016 --Saver et al, JAMA 2016 Minutes Matter • IV TPA Progressors: Fast / Slow / Variable » Every 8 minute delay causes 1 fewer of 100 treated patients to benefit in improved ambulation • IA Neurothrombectomy » Every 4 minute delay causes 1 fewer of 100 reperfused patients to benefit in reduced final disability

--Saver, Stroke 2013; Saver et al, DEFUSE 2 UCLA Series UCLA Stroke Center JAMA 2013; Sheth et al, Ann Neurol 2015; Saver et al, JAMA 2016 --Wheeler et al, Int J Stroke 2015 --Liebeskind, 2016

Pathophysiology of Variation in Speed of Strategies to Identify LVO Patients with Stroke Progression Salvageable Ischemic Penumbra • Perfusion pressure » Ejection fraction < 6 Hrs > 6 Hrs • Blood oxygenation » Hemoglobin Imaging required to assess » Respiratory compromise pathophysiology • Collaterals » Circle of Willis = 100 » Leptomeningeal 75 » Deep 50 • Tissue ischemic tolerance » White vs gray matter 25 » Excitatory vs inhibitory 0 Hyperacute therapy when nearly 0 3 6 9 12 15 18 24

» Ischemic pre-conditioning Penumbra with Patients % all patients have penumbra --Leemans, Neuro Bureau 2015 Time From Onset (Hours) Tissue Status Perfusion Status Vessel Status Era of Highly Effective Imaging Selection CBV CT PCT CTA for Reperfusion Therapy

Multimodal CT

DWI PWI MRA

Multimodal MRI

Bioenergetic Hemodynamic Occlusions or CiCompromise Stenoses

Case-Control Study in 22 Countries --O’Donnell, Lancet 2009

Risk Factor Population Attributable Risk HTN 52% Prevention Physical Activity 29% Abdominal obesity 27% Hyperlipidemia 25% Smoking 19% Diet 19% Cardiac 7% Stress-depression 5% UCLA Stroke Center Diabetes 5% 71,683 randomized patients RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF

Primary Efficacy: Stroke or Systemic Embolization

Dabigatran Rivaroxaban Apixaban Edoxaban Combined (random) Apixaban

Heterogeneity: I2=47%; p=0.13

71,683 randomized patients RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF

Primary Efficacy: Primary Safety: Stroke or Systemic Embolization Major Bleeding

Dabigatran Rivaroxaban Apixaban Edoxaban Combined (random) Apixaban

Heterogeneity: I2=47%; p=0.13 Heterogeneity: I2=83%; p=0001 Stroke Risk Stratification in AF Stroke Risk Stratification in AF CHADS2 CHA2DS2-VASc CHADS2 CHA2DS2-VASc Risk Factor Score Risk Factor Score Risk Factor Score Risk Factor Score Cardiac failure 1 Cardiac failure 1 Cardiac failure 1 Cardiac failure 1 HTN 1 HTN 1 HTN 1 HTN 1 Age ≥75 y 1 Age ≥75 y 2 Age ≥75 y 1 Age ≥75 y 2 Diabetes 1 Diabetes 1 Diabetes 1 Diabetes 1 Stroke 2 Stroke 2 Stroke 2 Stroke 2 Vasc dz (MI, PAD, aortic ath) 1 Vasc dz (MI, PAD, aortic ath) 1 Age 65-74 y 1 Age 65-74 y 1 Sex category (female) 1 Sex category (female) 1 20 20 15.2 15.2 15 15 9.8 9.6 Relationship between 9.8 9.6 Relationship between 10 10 6.7 6.7 CHA2DS2-VASc score and 6.7 6.7 CHA2DS2-VASc score and 4.0 annual risk of stroke 4.0 annual risk of stroke 5 2.2 3.2 5 2.2 3.2 1.3 1.3

Stroke Rate, % Rate, Stroke 0 % Rate, Stroke 0 0 0 CHADS-VASc Therapy 012 34 5 6789 0123456789 0 No Rx (or AP) CHA2DS2-VASc Score CHA2DS2-VASc Score 1 NOAC or AP or No RX

Ambulatory Cardiac Monitoring Technology Occult Very-Low Burden pAF in Cryptogenic Stroke • 1940s » 75 lb backpack (Evident Only After Prolonged Monitoring) • 1980-2010 » Miniaturized, 24h standard • 2010 – 2017 » Mobile cardiac outpatient telemetry • Meta-analysis of low burden systems pAF detection • Monitor or patch, 2-4 wks » Loop recorders » 20 studies, 1723 patients • External, event monitors, 2-4 wks » MOCT – 15.3% • Implantable SQ, 1-3 yrs » External loop – 16.2% • 2015 – 2017 » Smartphones, AliveCor iOS app » Impantable loop – 16.9% • Sens 100%, spec 97%, vs standard » Total – 16.9% • Lifelong “The more you look, the more • 2017 – 2019 • » Smartwatches, smartbands you find” » FDA clearance AliveCor EKG for iWatch • But causal relation and Rx Nov 2017 benefit not yet establishsed • 2020 – 2030 » Smart clothes - Lifelong UCLA Stroke Center UCLA Stroke Center Provisional Management Algorithm for Cryptogenic Stroke and Occult AF (based on “Atrial Cardiopathy”) • Stroke cryptogenic after standard evaluation » Discharge on mobile outpatient cardiac telemetry x 30 days  Aortic arch » If multiple risk factors* for occult AF, discharge on DOAC  Origin of great vessels » If no risk factors for occult AF, discharge on antiplatelet therapy  Common carotid artery • Initial 30 day monitoring results  Vertebral artery » No evidence pAF  Cervical • If multiple risk factors for occult AF ◦ Internal carotid artery bulb » Subcutaneous loop recorder monitoring x 1-3 years ◦ Distal vertebral artery » Continue DOAC for first year, then reconsider  Intracranial If no risk factors for occult AF, continue antiplatelet therapy • ◦ Internal carotid artery siphon » Low burden pAF (between 5 - 15 mins in a single 24h period) ◦ Middle cerebral artery • If multiple risk factors for occult AF, continue DOAC ◦ Basilar artery • If no risk factors for occult AF  » Subcutaneous loop recorder monitoring x 1-3 years Penetrating arteries » Switch to DOAC for first year, then reconsider ◦ Intracranial branch » Higher burden AF (>15 mins in a single 24h period) atherosclerosis  • If multiple risk factors for occult AF, continue DOAC (Generally not lipohyalinosis)

UCLA Stroke Center• If no risk factors for occult AF, switch to DOAC © UCLA Stroke Center

Frequency of Atherosclerosis as Cause of Ischemic Stroke Atherosclerotic Origin – 70% Non-Atherosclerotic Origin- 30% Large Artery Athero - 30% • Nonatherosclerotic arteriopathies – 5% • » Dissection » Cervical – 15% » FMD Intracranial – 10% » CADASIL » » Vasculitis » Aorto-thoracic – 5% » Moyamoya, etc • Cardiac not related to CAD – 10% » Endocarditis 1. Diet and Lifestyle • Small Artery Athero – 20% » Mechanical valve » Viral cardiomyopathy » Microatherosclerosis – 15% » A fib/SSS due to conduction aging » Ostial parent artery athero – 5% » Myxoma, etc • Vasospasm – 2% » RCVS • Cardiac related to CAD – 20% » Eclampsia, etc • Hypercoagulable arterial state – 2% » A fib – 12% • Transcardiac – PFO. Pulm shunt, etci – 3% » Post-MI / ↓LVEF – 8% • Cryptogenic – 8%

UCLA Stroke Center UCLA Stroke Center AHA’s “Life’s Simple 7” AHA’s “Life’s Simple 7” Tobacco Tobacco • • Cardiovascular Risk per Life’s Simple 7 and None/ quit ≥ 12 mos None/ quit ≥ 12 mos » » New Stroke in African-Americans • Physical activity • Physical activity » 150 mins/wk moderate, or » 150 mins/wk moderate, or » 75 mins/wk vigorous » 75 mins/wk vigorous • Healthy weight • Healthy weight » < 25 kg/m2 » < 25 kg/m2 • Healthy Diet • Healthy Diet » 4-5 of 5 components* » 4-5 of 5 components* • Blood pressure • Blood pressure » <120/80 » <120/80 • Cholesterol • Cholesterol » Tchol < 170 mg/dl » Tchol < 170 mg/dl • Blood glucose • Blood glucose » Fasting < 100 mg/dl » Fasting < 100 mg/dl *Fruits and vegetables: ≥4.5 cups/d UCLA Stroke Center Fish: ≥ two 3.5-oz servings/wk (preferably oily fish) UCLA Stroke Center Whole grains: ≥three 1-oz servings/d --Foraker et al, Am Heart J 2016

1 - Diet and Lifestyle Change Stroke Prevention Tobacco Diet • Cardiovascular Risk per Life’s Simple 7 and • None/ quit ≥ 12 mos Food-based » New Stroke in African-Americans » • Mediterranean - 1 positive long-term • Physical activity RCT » 150 mins/wk moderate, or » Nutrient-based » 75 mins/wk vigorous • Low fat – 1 negative long-term RCT • Healthy weight • Low carb – no long-term RCT » < 25 kg/m2 • Healthy Diet • Behavior change Specific, proximal, shared goals » 4-5 of 5 components* » » Self-monitoring • Blood pressure » Scheduled follow-up » <120/80 » Regular feedback • Cholesterol » Self-efficacy (belief one can » Tchol < 170 mg/dl succeed) • Blood glucose » Motivational interviewing » Fasting < 100 mg/dl » Family and peer support » Multicomponent approaches UCLA Stroke Center --Foraker et al, Am Heart J 2016 UCLA Stroke Center 2 – Blood Pressure Lowering JNC 7

Definition of HTN ≥ 140

Start of Antihypertensive Medication General Population ≥ 140 2. Blood Pressure Lowering Diabetes or CKD ≥ 130 Age ≥ 65 or High CV Risk --

Treatment Goal with Medication General Population - SBP < 140/90 Diabetes or CKD < 130/80 UCLA Stroke Center UCLA Stroke Center

g Stroke Secondary Prevention New ACC/AHA Guidelines ACC/AHA BP Guidelines 2017 JNC 7 2017 ACC/AHA Definition of HTN ≥ 140 ≥ 130

Start of Antihypertensive Medication General Population ≥ 140 ≥ 140 Diabetes or CKD ≥ 130 ≥ 130 Age ≥ 65 or High CV Risk -- ≥ 130

Treatment Goal with Medication General Population - SBP < 140/90 < 130/80

UCLADiabetes Stroke Center or CKD < 130/80 < 130/80 UCLA Stroke Center The Two Processes of Thrombus Formation: White Clots and Red Clots • “White clots” » Platelet rich with some fibrin strands » Form in settings of high speed, dyslaminar flow, shear stress » Driving force: platelet activation and aggregation » Rx: Antiplatelet 3. Antithrombotics • “Red clots” » RBC rich with dense fibrin strands » Form in settings of stasis (venous, A fib, very slow arterial flow) » Driving force: clotting protein cascade » Rx: Anticoagulant UCLA Stroke Center UCLA Stroke Center

The Two Processes of Thrombus Formation: The Two Processes of Thrombus Formation: White Clots and Red Clots White Clots and Red Clots • “White clots” • “White clots” » Platelet rich with some » Platelet rich with some fibrin strands fibrin strands » Form in settings of high » Form in settings of high speed, dyslaminar flow, speed, dyslaminar flow, shear stress shear stress » Driving force: platelet » Driving force: platelet activation and activation and aggregation aggregation » Rx: Antiplatelet » Rx: Antiplatelet • “Red clots” • “Red clots” » RBC rich with dense » RBC rich with dense fibrin strands fibrin strands » Form in settings of stasis » Form in settings of stasis (venous, A fib, very slow (venous, A fib, very slow arterial flow) arterial flow) » Driving force: clotting » Driving force: clotting protein cascade protein cascade » Rx: Anticoagulant » Rx: Anticoagulant UCLA Stroke Center --Gsib et al, J Molec Biol Biotech 2017; Bhatt et al, Circ Res 2014 UCLA Stroke Center --Gsib et al, J Molec Biol Biotech 2017; Bhatt et al, Circ Res 2014 The Two Processes of Thrombus Formation: Antiplatelet vs NOAC vs Both White Clots and Red Clots • “White clots” » Platelet rich with some COMPASS Trial fibrin strands • 27,395 patients with cor or periph athero » Form in settings of high » Cerebral athero NOT qualifying speed, dyslaminar flow, » Certain prior strokes excluded shear stress • Any recent » Driving force: platelet • Lacunar ever activation and • Hemorrhagic ever aggregation • Treatments » Rx: Antiplatelet » Aspirin 100 mg / d • “Red clots” » Rivoroxaban 5 mg 2x / d » RBC rich with dense » Combined ASA 100 + Rivor 2.5 mg 2x / d fibrin strands • Mean f/up 23 months » Form in settings of stasis (venous, A fib, very slow • Outcomes: A+R vs A (vs R) arterial flow) » Primary (MI, stroke, CV death): 4.1% vs 5.4% (vs 4.9%), HR 0.76 (0.66 to 0.86), p<0.001 » Driving force: clotting --Eikelboom et al, NEJM 2017 protein cascade » Major bleeding: 3.1% vs 1.9% (vs 2.8%), HR 1.70 (1.40 to 2.05) » Rx: Anticoagulant • ICH: 0.3% vs 0.3% (vs 0.5%), HR 1.16 (0.67-2.00) UCLA Stroke Center --Gsib et al, J Molec Biol Biotech 2017; Bhatt et al, Circ Res 2014 » Mortality: 3.4% vs 4.1% (vs 4.0%), HR 0.82 (0.71 UCLA Stroke Center to 0.96)

Meta-Analysis of Statins for Prevention of Recurrent Stroke

4. Statins

--Amarenco + Labreuche, Lancet Neurol 2009 UCLA Stroke Center UCLA Stroke Center Statins for Secondary Prevention of Recurrent Stroke AHA/ASA 2° Prevention Guideline 2014

“Statin therapy with intensive lipid-lowering effects is 5. PCSK9 Inhibitors recommended to reduce risk of stroke and cardiovascular events among patients with ischemic stroke or TIA presumed to be of atherosclerotic origin…

UCLA Stroke Center UCLA Stroke Center

PCSK9 Inhibitors PCSK9 Inhibitors

• Proprotein • Monoclonal antibody agents convertase subtilisin/kexin » Evolocumab (Repatha) type 9 (PCSK9) » Alirocumab (Praluent) » Serine protease • Initially trials in familial » Binds to low density hypercholesterolemia lipoprotein receptor (LDL-R) » FDA approved 2015 on surface of hepatocytes » Pricing ~$14,000/yr » Leads to degradation of the • For ASCVD LDL-R and higher plasma » FOURIER trial 2017 LDL-cholesterol » FDA approved (evo) 2018 • Inhibitors lead to higher » Pricing – evolving UCLA Stroke Center LDL-R and lower plasma UCLA Stroke Center • Express scripts May 2018: $4,500 LDL cholesterol to $8,00/yr Further Cardiovascular Outcomes Research with PCSK9 Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial --Sabatine et al, NEJM 2017 Inhibition in Subjects with Elevated Risk (FOURIER) Trial --Sabatine et al, NEJM 2017

• 27,564 patients 27,564 patients Key 2º Endpoint » 1242 sites, 49 countries • » 1242 sites, 49 countries CV Death, MI, Stroke Entry criteria • • Entry criteria » Symptomatic ASVD » Symptomatic ASVD • MI, Ischemic stroke of athero origin (19.4%, • MI, Ischemic stroke of athero origin (19.4%, 5337), OR 5337), OR Peripheral arterial disease Peripheral arterial disease » Additional risk factors » Additional risk factors • At least 1 of 6 major RFs, or • At least 1 of 6 major RFs, or • At least 2 of 6 minor RFs • At least 2 of 6 minor RFs » LDL ≥ 70 or HDL ≥ 200 on statin » LDL ≥ 70 or HDL ≥ 200 on statin • Mean LDL 92 • Mean LDL 92 • SQ PCSK9 or placebo 1x per month • SQ PCSK9 or placebo 1x per month » LDL during trial » LDL during trial • 30 (IQR 19-46) [vs 90] • 30 (IQR 19-46) [vs 90] • ≤ 25 in 42% [vs 0.1%] • ≤ 25 in 42% [vs 0.1%]

UCLA Stroke Center --FOURIER, NEJM 2017 UCLA Stroke Center --Pedersen et al FOURIER: Focus on Cerebrovascular Disease NNT to prevent 1 event over 3 years: 50

FOURIER and Stroke FOURIER and Stroke as Qualifying Event as Outcome Event

--Primary Endpoint: CV Death, MI, Stroke, Unstable Angina, Coronary Revascularization --Key Secondary Endpoint: CV Death, MI, Stroke

UCLA Stroke Center UCLA Stroke Center When to Use PCSK9 Inhibitors (Provisional) Stroke (IS+ICH), MI CVD Over 3 Years 30 • “Statin Failure” 26.6 Cumulative impact of broad medical » Ischemic stroke or highly probable TIA 25 therapies of ischemic stroke/TIA of 22.1 of atherosclerotic origin while on moderate-high dose statin, OR atherosclerotic origin 20 17.1 • Statin Naïve but High Risk Treatment Rx Control RR NNT 15 » Ischemic stroke or highly probable TIA

Antiplatelet 26.6 22.1 0.83 22 Percent of atherosclerotic origin while on no or BP Lowering 18.7 17.1 0.91 63 10 9.0 low dose statin, and 1 of: 7.3 • Severe 70-99% vertebrobasilar LAAD Statins 11.2 9.0 0.81 46 5 • Severe 70-99% anterior intracranial LAAD PCSK9 Inhibs 8.9 7.3 0.83 62 • Severe ascending/transverse aortic LAAD All 26.6 7.3 0.27 5 0 • Familial dyslipidemia Natural Hx AntiplateletsBP Lowering High Dose PCSK9 Statins Inhibitors UCLA Stroke Center UCLA Stroke Center

CS C CS C CS C