UPDATE IN STROKE MANAGEMENT

David Lee Gordon, M.D., FAHA

Professor and Chairman Department of Neurology The University of Oklahoma Health Sciences Center

OU Neurology

DLG DISCLOSURES
FINANCIAL DISCLOSURE
I have no financial relationships or affiliations to disclose.

UNLABELED/UNAPPROVED USES DISCLOSURE

I will reference the following off-label or investigational use of drugs or products: intra-arterial t-PA in stroke patients

OU Neurology

STROKE IN THE UNITED STATES

Affects > 780,000 persons per year Major cause of death (#3) & long-term disability Oklahoma has 6th-highest stroke death rate Estimated U.S. cost for 2008 = $65.5 billion
Mostly hospital (esp. LOS) & poststroke costs Appropriate use of IV t-PA s long-term cost DRG 559 for AIS w/ thrombolysis ( hospital reimbursement from $5k to $11.5k)

OU Neurology

THREE STROKE TYPES

Focal Brain Dysfunction Ischemic Stroke Intracerebral Hemorrhage Subarachnoid Hemorrhage

85%

10%

5%

Clot occluding artery

Bleeding into brain

Bleeding around brain

Diffuse Brain Dysfunction

OU Neurology

ACUTE ISCHEMIC STROKE (AIS) & TIA

LOW BLOOD FLOW TO FOCAL AREA OF BRAIN Pathophysiology:
INFARCT

Usually thromboembolism (blood clot forms in vascular system, travels downstream, plugs cerebral artery)

Acute therapy:
Thrombolysis (or thrombectomy) Do NOT lower BP Avoid aspiration / IV glucose
CLOT

2 prevention:
Antithrombotic therapy Vascular risk factor therapy Possible carotid endarterectomy (CEA) or angioplasty (CAS)

Ischemic stroke = Infarction with sequelae Transient ischemic attack = No infarction and no sequelae

OU Neurology

TRANSIENT ISCHEMIC ATTACK (TIA) AND ACUTE NEUROVASCULAR SYNDROME

Transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without infarction Typically < 1 h, but time limit is no longer part of definition Risk of stroke = 5% w/in 2 d, 10% w/in 3 m Appropriate antithrombotic therapy based on cause Urgently evaluate for cause
MRI w/ DWI, intracranial MRA, carotid duplex, echo Can admit to observation status

Discover cause, determine therapy, decrease risk!

OU Neurology

ISCHEMIC STROKE PATHOPHYSIOLOGY The First Few Hours

TIME IS BRAIN: SAVE THE PENUMBRA Penumbra is zone of reversible ischemia around core of irreversible infarctionsalvageable in first few hours after ischemic stroke onset
Penumbra damaged by: Hypoperfusion Hyperglycemia Fever Seizure
Penumbra

Core

Clot in Artery

OU Neurology

Penumbra

ISCHEMIC PENUMBRA: PATHOPHYSIOLOGY OF THERAPEUTIC WINDOW

CEREBRAL BLOOD FLOW
(ml/100g/min)

Core

20 15 10 5

Normal function

PENUMBRA CORE
1 2 3

Neuronal dysfunction

CBF 8-18

Neuronal death

CBF <8

TIME (hours) Identification of penumbra through MRI perfusion-diffusion mismatch or perfusion CT may replace time as the major indication for emergency acute ischemic stroke therapies.

OU Neurology

ORGANIZED CARE OF STROKE PATIENTS:

PERFORMANCE IMPROVEMENT / UTILIZATION REVIEW

Acute stroke team

Stroke multidisciplinary team

Stroke unit Prewritten stroke orders

Supportive medical care Treatment of acute stroke Rehabilitation Outpatient planning Keep away future strokes Etiologic evaluation

Address each aspect of care each day

An organized approach enables emergency treatment, a thorough evaluation, and improved patient outcome at decreased cost. Stroke unit care results in decreased rate of aspiration pneumonia, decubiti, stroke progression or recurrence, and death.

OU Neurology

STROKE EMERGENCY BRAIN IMAGING: NONCONTRAST CT SCAN

Acute (4 hours) Infarction

Subacute (4 days) Infarction L R

Subtle blurring of graywhite junction & sulcal effacement

Obvious dark changes & mass effect (e.g., ventricle compression)

OU Neurology

STROKE EMERGENCY BRAIN IMAGING: NONCONTRAST CT SCAN

Intracerebral Hemorrhage Subarachnoid Hemorrhage

CT detects all ICHs immediately

CT detects 90% of SAHs; if SAH suspected & CT negative, must LP

OU Neurology

AIS EMERGENCY THERAPY: IV TISSUE PLASMINOGEN ACTIVATOR (T-PA)

Must give < 4.5 hearlier you give it, better the outcome Stroke onset = last time known to be normal Do NOT give if glucose < 50 Do NOT give if BP > 185/110 Disability risk 30% despite ~5% symptomatic ICH risk Lawsuits for not giving >>> lawsuits for giving
< 3.0 Hours No upper age limit No limit on stroke size Can give if taking warfarin & INR < 1.7 3.0-4.5 Hours Do NOT give if: Pt > 80 yo NIHSS > 25 DM w/ previous stroke Taking warfarin at all

OU Neurology

AIS ED STROKE CARE 24/7:

1-H EVALUATION, 1-H INFUSION

I. Triage10 min
Review t-PA criteria Page acute stroke team Draw pre t-PA labs*

III. CT & Labs45 min

Obtain lab results Read CT Return pt to ED

II. Medical Care25 min

Place O2 , 2 NS IVs Obtain BP, weight, NIHSS Obtain 12-lead ECG Send patient to CT

IV. Treatment60 min

Start IV t-PA Monitor for ICH sxs HTN, headache N/V, neuro status

*CBC, platelets, PT/INR, PTT, chem 7, cardiac panel

OU Neurology

OTHER AIS THERAPIES:

MAYBE IA, YES ASA, NO HIGH-DOSE HEPARIN
Intra-arterial t-PA
Only preliminary evidence to date, not FDA approved Theoretical window 6 hbut do NOT preclude IV t-PA w/in 4.5 h Studies ongoing, esp. combined w/ IV t-PA

MERCI or Penumbra device

Mechanical embolectomy devices Theoretical window 8 h Both FDA approved, but controlled trial results pending

Aspirin
Aspirin 325 mg per day begun within 48 h of stroke onset decreases morbidity & mortality (may begin 24 h after t-PA)

Heparin(s)
Insufficient evidence to recommend routine use of high-dose IV heparin, LMW heparin, or heparinoid as Rx for AIS per se

OU Neurology

THE AIS-BP RELATIONSHIP

In AIS, high BP is a response, not a causedont lower it! BP increase is due to arterial occlusion (i.e., an effort to perfuse penumbra) Failure to recanalize (w/ or w/o thrombolytic therapy) results in high BP and poor neuro outcomes Lowering BP starves penumbra, worsens outcomes
Clot in Artery

Penumbra

Core

OU Neurology

AIS IS NOT A HYPERTENSIVE EMERGENCY!

ASA/AHA AIS Guidelines tables no longer include recs for BP Rx in non t-PA patients Text of guidelines state Do not Rx unless BP > 220/120, but also state:
No data to suggest 220/120 is dangerous & requires Rx

Evidence that BP lowering worsens outcomes is concerning

Goal is to avoid overtreating pts until definitive data available

Only definite indications to BP emergently in AIS:

AMI, CHF, Ao dissection, ARF, or HTN encephalopathy Candidate for thrombolysis and BP > 185/110

OU Neurology

MAY LOWER BP SLIGHTLY PRE T-PA

MUST PICK AN UPPER LIMIT TO TREAT220/120 IS ONE OPTION

If all t-PA criteria met except sustained BP > 185/110:

Ensure 2 IVs (NS @ 75 cc/h, saline lock) Calm patient, empty bladder Recheck BP, lower slightly if necessary
SBP > 220 or DBP > 120 SBP > 185 and < 220 or DBP > 110 and < 120 No BP med, No t-PA Lower BP pre-t-PA

Avoid excessive lowering of BP just to give t-PA Dont kill the penumbra to save the penumbra

OU Neurology

LOWERING BP IN T-PA PATIENTS

Nicardipine 5 mg/h IV infusion
Increase 2.5 mg/h q5min to max 15 mg/h Easily titratable without an arterial line

Labetalol 10-20 mg IV
May repeat q 10-15 min Pre-t-PA: only use a 2nd dose only if necessary
Note Different Target BPs Pre & Post T-PA Pre t-PA: < 185/110 Post t-PA: < 180/105

OU Neurology

WORRYING ABOUT THE LUNGS: ASPIRATION, DYSPHAGIA, & OXYGEN

Weak oropharyngeal muscles common Neurogenic dysphagia: liquids worse than solids (purees best) Stroke pts on ventilator: 2/3 mortality, most survivors disabled Recommendations (science): Keep pt 100% NPO until evaluation Use NG feeding tube if necessary (& IV NS 75-125 cc/h) Evaluate with video fluoroscopy whenever possible Use continuous feed only if Dobhoff tip distal to pylorus Recommendations (art): Maintain HOB > 30 Maintain O2 sat > 92 or 95% w/ 2-4L O2

OU Neurology

HYPERGLYCEMIA & ACUTE STROKE / DIABETES & 2 STROKE PREVENTION

Acutely, peri-stroke hyperglycemia associated with worse clinical outcomes Inpatient goal BG < 150 Chronically, each 1% in Hgb A1C results in significant in risk of death, MI, vascular complications, including 12% in stroke risk Outpatient goal Hgb A1C < 7.0

OU Neurology

SECONDARY STROKE PREVENTION:

RISK-FACTOR MODIFICATION
Hypertension
Day 1 poststroke, start low-dose ACE-I or ARB Slowly (days to weeks) dose, add diuretic, watch K+ Anti-HTN meds benefit those w/ and w/o HTN history Evaluate for sleep apnea and treat w/ CPAP Outpatient goal < 120/80over weeks to months
*In stroke pts, ACE-Is & ARBs appear to decrease risk of stroke, MI, & vascular death beyond effect on BP alone. Based on theory and animal models, ARBs may be more effective than ACE-Is.

OU Neurology

SECONDARY STROKE PREVENTION: MECHANISMS OF ACE-I/ARB BENEFITS

ANGIOTENSIN CONVERTING ENZYME ACE-I ARB ANGIOTENSIN II
Vasodilatation Natriuresis Vascular proliferation Endothelial function Apoptosis No cholesterol effect

AT 1 The Bad

Vasoconstriction Na retention Vascular proliferation Endothelial function Inflammation LDL transport

ANGIOTENSIN I

Based on animal studies and pathophysiologic considerations, ARBs may be superior to ACE-Is for stroke prevention, but ONTARGET found no difference between telmisartan & ramipril in reducing vascular risk.

AT 2 The Good

OU Neurology

SECONDARY STROKE PREVENTION:

RISK-FACTOR MODIFICATION
Hypercholesterolemia
Do not discontinue statins on admission Obtain LDL w/in 48 of stroke onset If LDL > 100, use hi-dose statin shown to stroke/MI/death risk atorvastatin 20-80 mg/d pravastatin 40-80 mg/d simvastatin 40-80 mg/d rosuvastatin 10-40 mg/d If LDL < 100, use lower statin dose Outpatient goal LDL < 70 (but give statin to all pts)
OU Neurology

SUPPORTIVE MEDICAL CARE: PREVENT COMPLICATIONS

Aspiration (NPO until swallowing evaluation) Deep-vein thrombosis
Sequential compression devices (if stroke < 48 h) Heparin 5000 q8h or enoxaparin 40 mg/d

Urinary tract infection (avoid Foley catheters) Constipation (docusate sodium for all) Decubitus ulcers (move q2h, out of bed TID by day 2) UGI bleed (H2B, but not cimetidine) Fever (acetaminophen + antibiotics as indicated)

OU Neurology

REHAB & OUTPATIENT PLANNING:

BEGIN ON ADMISSION, DECREASE LENGTH OF STAY

SPswallowing evaluation before oral feedings PT, OTbedside first, out of bed ASAP Social workerplan based on level of care, pay source, caregiver support Communicate with primary-care clinician Educate pt, caregiver daily (not just on discharge)
Call 911 Follow-up after discharge Medications Risk Factors Stroke Symptoms OU Neurology

POSTSTROKE DEPRESSION
Suspect if sxs persist 1-2 wks after stroke Is an organic, not reactive depression Occurs in ~ 50% of stroke pts May affect rehab and recovery Often resolves w/in one year SSRIs equally effective, but if pt takes warfarin:
Escitalopram (Lexapro) 5-10 mg qAM Citalopram (Celexa) 10-20 mg qAM Sertraline (Zoloft) 25-50 mg qAM

OU Neurology

CAUSES (ETIOLOGIES) OF ISCHEMIC STROKE: SIX MAIN CATEGORIES

OLDER PATIENTS (> 55) YOUNGER PATIENTS (< 55)

Large-artery atherosclerosis Small-artery disease

Cardioembolism Hypotension

Hypercoagulable states

Nonatherosclerotic vasculopathies

Correct therapy depends on cause of stroke! Cause & risk factor are not synonymousmust Rx both!

OU Neurology

ETIOLOGIC EVALUATION:
IDENTIFY STROKE, FIND SOURCE OF CLOT
NONINVASIVE Day 1 ARTERIES MRI & intracranial MRA Carotid duplex (CD) ECG & monitor Cardiac biomarkers Transthoracic echo (TTE) *Hypercoagulable profile INVASIVE Day 2 *Catheter angiogram *TEE
*in select patients

HEART

BLOOD

OU Neurology

MRI BRAIN IN HYPERACUTE ISCHEMIC STROKE

DWI & ADC: Early infarction visible FLAIR: No signal changes; possible sulcal effacement in area of infarction
R L R L R L

DWI

ADC

FLAIR

OU Neurology

INTRACRANIAL MRA: AP VIEWS OF ANTERIOR CIRCULATION

Normal RACA LACA Paucity of R MCA Branches c/w Embolic Occlusions

RMCA

LMCA

RICA

LICA

RICA

LICA

OU Neurology

CAROTID DUPLEX
Evaluates carotid arteries in neck (operable area) Excellent screen in the right hands May not differentiate 99 vs. 100% stenosis Need contrast angiography for clinically relevant stenosis measurement ECA
CCA

Carotid duplex = Doppler (velocities) + B-mode ultrasound (echo picture)

ICA

Plaque

OU Neurology

ECHOCARDIOGRAPHY: TTE VS. TEE

TRANSTHORACIC ECHO TRANSESOPHAGEAL ECHO Left Atrium Thrombus Dilatation SEC/smoke Tumor PFO/IASA > 5 mm PFO Endocarditis Identifies source in Aortic Arch 30-40% Athero > 4 mm of pts with Thrombus unknown cause Tumor
LA

LV

SEC/EF 20% Identifies source in

Left Ventricle Thrombus Dilatation SEC/smoke Dyskinesis Aneurysm

37.2%
of pts in NSR

OU Neurology

HYPERCOAGULABLE PROFILE
PATIENTS < 55 YEARS OLD
CBC w/ diff & platelets PT/aPTT Fibrinogen Factor VIII Factor VII C-reactive protein Antithrombin III Protein C Protein S (total & free) Lipoprotein (a) Activated protein C resistance (APCR) (& Leiden factor V mutation if APCR -) Prothrombin G20210A mutation Antiphospholipid antibodies Lupus anticoagulant Anticardiolipin abs Anti--2-glycoprotein I abs Antiphosphatidylserine abs Methyltetrahydrofolatereductase (MTHFR) C677T & A1298C mutations Sickle cell screen

OU Neurology

CT / MRI APPEARANCE CANNOT DETERMINE ETIOLOGY OF SMALL CEREBRAL INFARCTS

small-art. occlusion = small-art. disease Dx of small-artery disease requires:
Lacunar syndrome
e.g., pure motor, pure sensory, pure sensorimotor

Medial, small (< 1.5 cm) infarct on CT or MRI History of longstanding HTN or DM Otherwise normal etiologic evaluation

Small L subcortical infarction in 40 yo woman w/ DMdue to embolus from aortic papilloma

Small-artery disease is a diagnosis of exclusion OU Neurology

SECONDARY STROKE PREVENTION: ANTITHROMBOTIC RX BASED ON CAUSE

High-flow states: platelets cause clots Platelets are like Velcro sticking to bumpy walls Low-flow & hypercoagulable states: clotting factors cause clots Clotting factors are like dissolved powdered gelatin that forms clumps of Jello when liquid is static cardioembolism hypercoagulable state

large-artery small-artery atherosclerosis disease

ANTIPLATELET AGENT aspirin 81-325/d clopidogrel 75/d aspirin + dipyridamole XR 25/200 twice/d

ANTICOAGULANT warfarin INR 2.0-3.0 or INR 2.5-3.5

OU Neurology

SECONDARY STROKE PREVENTION: ANTIPLATELET AGENTS FOR ARTERIAL DISEASE

Aspirin
Prevents MI & stroke Stroke rec 50-365 mg/d, but MI rec 75-162 mg/d Low dose with less side effects, > 1200 mg/d ineffective Enteric coating, NSAIDs may lessen efficacy

Clopidogrel 75 mg per day

Prevents MI and stroke Routine combination with aspirin not indicated in stroke pts, though not resolved for subset of pts with large-artery athero PPIs lessen efficacy

Aspirin / dipyridamole XR 25/200 twice daily

Data regarding MI prophylaxis lacking Headache common side effect of dipyridamole Not superior to clopidogrelwith more bleeding side effects

OU Neurology

SECONDARY STROKE PREVENTION: WARFARIN FOR CARDIOEMBOLISM

Underused for a. fib./flutter, esp. blacks, Hispanics, elderly Starting dose 5 mg qPM INR monitoring
Target 2.5, range 2.0-3.0 (mechanical HVR 2.5-3.5) Reflects dose 2-3 days ago, stabilizes in 10-14 days Vitamin K (greens, NG feedings, Ensure, Slimfast, MVI) Other meds, EtOH, cranberry juice Dose and formulation changes

Limit holding for procedures (e.g., dental, GI, surgery)

OU Neurology

SECONDARY STROKE PREVENTION: CAROTID STENOSIS PROCEDURES

Carotid Endarterectomy (CEA)
Clear benefit if 70-99% stenosis Some benefit if 50-69% stenosis Accept complication rate < 6%
External Carotid Artery Internal Carotid Artery

Carotid Angioplasty/Stenting (CAS)

Now, option only in high-risk pts
Restenosis after CEA Radiation-induced stenosis Increased medical risk for CEA Contralateral carotid occlusion stenosis in ICA bulb % stenosis = (D-N)/D by contrast angiography

Common Carotid Cerebral protection devices improving, Artery

trials continue

OU Neurology

SECONDARY STROKE PREVENTION:

RISK-FACTOR MODIFICATION
Cigarette smoking cessation
Bupropion (Wellbutrin SR or XL, Zyban)
Start 150 mg daily x 3 days Then 150 mg BID x 3 months

Nortriptyline (Pamelor)
Start 10-25 mg each night gradually to 75 mg each night

Nicotine patch/gum/inhaler
Concurrent with bupropion or nortriptyline

Varenicline (Chantix)
Start 0.5 mg daily x 3 days gradually to 1 mg BID x 11 wk

OU Neurology

SECONDARY STROKE PREVENTION:

RISK-FACTOR MODIFICATION
Lifestyle Alcohol: Diet: men < 2 oz / d, women < 1 oz / d Low saturated fat, low Na+, high K+, fruits > vegetables, Mediterranean diet Exercise: > 20 min aerobic exercise, > 3 x / wk Weight: maintain BMI 18.5-24.9 kg/m2

Drugs to Avoid Estrogen (oral contraceptives, HRT) Sympathomimetic agents (incl. decongestants, diet pills) NSAIDs (if taking aspirin) PPIs (if taking Plavix)

OU Neurology

ISCHEMIC STROKE / TIA 2 PREVENTION SUMMARY 1 OF 2

Prescribe:
Antithrombotic agent based on cause ARB or ACE-I regardless of BP Statin regardless of cholesterol

Maintain:
Hgb A1C < 7.0 BP < 120/80, including ARB or ACE-I LDL < 70, including statin Nutrition w/ fruits, Mediterranean diet Alcohol intake < 2 oz/d (men) or < 1 oz/d (women) BMI 18.5-24.9 kg/m2 Aerobic exercise > 20 min/d, > 3 d/wk
OU Neurology

ISCHEMIC STROKE / TIA 2 PREVENTION SUMMARY 2 OF 2 Discontinue:

Cigarette smoking Sympathomimetic agents (incl. decongestants) Estrogens

Treat:
Carotid stenosis 50/70-99% (CEA or CAS) Sleep apnea (CPAP) Sickle cell disease (monitor TCD, Hgb S < 30%)

OU Neurology

THE END

OU Neurology