UPDATE IN STROKE MANAGEMENT

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UPDATE IN STROKE MANAGEMENT

• David Lee Gordon, M.D., FAHA
• Professor and Chairman
• Department of Neurology
• The University of Oklahoma Health Sciences Center

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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

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STROKE IN THE UNITED STATES

• Affects gt 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)

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THREE STROKE TYPES
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ACUTE ISCHEMIC STROKE (AIS) TIALOW BLOOD FLOW
TO FOCAL AREA OF BRAIN

• Pathophysiology
• 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
• 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
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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 lt 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!

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ISCHEMIC STROKE PATHOPHYSIOLOGYThe 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

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ISCHEMIC PENUMBRA PATHOPHYSIOLOGYOF THERAPEUTIC
WINDOW
Identification of penumbra through MRI
perfusion-diffusion mismatch or perfusion CT may
replace time as the major indication for
emergency acute ischemic stroke therapies.
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ORGANIZED CARE OF STROKE PATIENTSPERFORMANCE
IMPROVEMENT / UTILIZATION REVIEW

• Acute stroke team
• Stroke multidisciplinary team
• Stroke unit
• Prewritten stroke orders
• Address each aspect of care each day

Supportive medical care Treatment of acute
stroke Rehabilitation Outpatient planning Keep
away future strokes Etiologic evaluation
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.
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STROKE EMERGENCY BRAIN IMAGINGNONCONTRAST CT
SCAN
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STROKE EMERGENCY BRAIN IMAGINGNONCONTRAST CT
SCAN
Intracerebral Hemorrhage
Subarachnoid Hemorrhage
CT detects 90 of SAHs if SAH suspected CT
negative, must LP
CT detects all ICHs immediately
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AIS EMERGENCY THERAPY IV TISSUE PLASMINOGEN
ACTIVATOR (T-PA)

• Must give lt 4.5 hearlier you give it, better
  the outcome
• Stroke onset last time known to be normal
• Do NOT give if glucose lt 50
• Do NOT give if BP gt 185/110
• Disability risk ? 30 despite 5 symptomatic
  ICH risk
• Lawsuits for not giving gtgtgt lawsuits for giving

• lt 3.0 Hours
• No upper age limit
• No limit on stroke size
• Can give if taking warfarin INR lt 1.7

• 3.0-4.5 Hours
• Do NOT give if
• Pt gt 80 yo
• NIHSS gt 25
• DM w/ previous stroke
• Taking warfarin at all

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AIS ED STROKE CARE 24/71-H EVALUATION, 1-H
INFUSION

• I. Triage10 min
• Review t-PA criteria
• Page acute stroke team
• Draw pre t-PA labs
• II. Medical Care25 min
• Place O2 , 2 NS IVs
• Obtain BP, weight, NIHSS
• Obtain 12-lead ECG
• Send patient to CT

• III. CT Labs45 min
• Obtain lab results
• Read CT
• Return pt to ED
• 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
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OTHER AIS THERAPIESMAYBE 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

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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

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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 gt
  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 gt 185/110

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MAY LOWER BP SLIGHTLY PRE T-PAMUST PICK AN UPPER
LIMIT TO TREAT220/120 IS ONE OPTION

• If all t-PA criteria met except sustained BP gt
  185/110
• Ensure 2 IVs (NS _at_ 75 cc/h, saline lock)
• Calm patient, empty bladder
• Recheck BP, lower slightly if necessary
• SBP gt 220 or
• DBP gt 120
• SBP gt 185 and lt 220 or
• DBP gt 110 and lt 120

Avoid excessive lowering of BP just to give
t-PA Dont kill the penumbra to save the
penumbra
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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 lt 185/110
• Post t-PA lt 180/105

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WORRYING ABOUT THE LUNGSASPIRATION, 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 gt 30
• Maintain O2 sat gt 92 or 95 w/ 2-4L O2

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HYPERGLYCEMIA ACUTE STROKE /DIABETES 2?
STROKE PREVENTION

• Acutely, peri-stroke hyperglycemia associated
  with worse clinical outcomes
• Inpatient goal BG lt 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 lt 7.0

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SECONDARY STROKE PREVENTIONRISK-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 lt 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.

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SECONDARY STROKE PREVENTIONMECHANISMS OF
ACE-I/ARB BENEFITS
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.
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SECONDARY STROKE PREVENTIONRISK-FACTOR
MODIFICATION

• Hypercholesterolemia
• Do not discontinue statins on admission
• Obtain LDL w/in 48 of stroke onset
• If LDL gt 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 lt 100, use lower statin dose
• Outpatient goal LDL lt 70 (but give statin to all
  pts)

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SUPPORTIVE MEDICAL CAREPREVENT COMPLICATIONS

• Aspiration (NPO until swallowing evaluation)
• Deep-vein thrombosis
• Sequential compression devices (if stroke lt 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)

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REHAB OUTPATIENT PLANNINGBEGIN 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

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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

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CAUSES (ETIOLOGIES) OF ISCHEMIC STROKESIX MAIN
CATEGORIES
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ETIOLOGIC EVALUATIONIDENTIFY STROKE, FIND
SOURCE OF CLOT
INVASIVE Day 2
NONINVASIVE Day 1
Catheter angiogram
ARTERIES
MRI intracranial MRA Carotid duplex (CD)
TEE
HEART
ECG monitor Cardiac biomarkers Transthoracic
echo (TTE)
BLOOD
Hypercoagulable profile
in select patients
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MRI BRAIN IN HYPERACUTE ISCHEMIC STROKE

• DWI ADC Early infarction visible
• FLAIR No signal changes possible sulcal
  effacement in area of infarction

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INTRACRANIAL MRAAP VIEWS OF ANTERIOR CIRCULATION
Normal
Paucity of R MCA Branches c/w Embolic Occlusions
RACA
LACA
RMCA
LMCA
RICA
RICA
LICA
LICA
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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
• Carotid duplex
• Doppler (velocities)
• B-mode ultrasound
• (echo picture)

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ECHOCARDIOGRAPHYTTE VS. TEE
TRANSTHORACIC ECHO
TRANSESOPHAGEAL ECHO

• Left Atrium
• Thrombus
• Dilatation
• SEC/smoke
• Tumor
• PFO/IASA gt 5 mm
• Endocarditis
• Aortic Arch
• Athero gt 4 mm
• Thrombus
• Tumor

• Left Ventricle
• Thrombus
• Dilatation
• SEC/smoke
• Dyskinesis
• Aneurysm

LA
LV
SEC/EF 20
PFO
Identifies source in 37.2 of pts in NSR
Identifies source in 30-40 of pts with unknown
cause
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HYPERCOAGULABLE PROFILEPATIENTS lt 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-ß-2-glycoprotein I abs
• Antiphosphatidylserine abs
• Methyltetrahydrofolatereductase (MTHFR) C677T
  A1298C mutations
• Sickle cell screen

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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 (lt 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
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SECONDARY STROKE PREVENTIONANTITHROMBOTIC 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
large-artery atherosclerosis
small-artery disease
cardioembolism
hypercoagulable state
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
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SECONDARY STROKE PREVENTIONANTIPLATELET 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, gt 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

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SECONDARY STROKE PREVENTIONWARFARIN 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)

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SECONDARY STROKE PREVENTIONCAROTID STENOSIS
PROCEDURES

• Carotid Endarterectomy (CEA)
• Clear benefit if 70-99 stenosis
• Some benefit if 50-69 stenosis
• Accept complication rate lt 6
• 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
• Cerebral protection devices improving, trials
  continue

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SECONDARY STROKE PREVENTIONRISK-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

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SECONDARY STROKE PREVENTIONRISK-FACTOR
MODIFICATION

• Lifestyle
• Alcohol men lt 2 oz / d, women lt 1 oz / d
• Diet Low saturated fat, low Na, high K,
• fruits gt vegetables, Mediterranean diet
• Exercise gt 20 min aerobic exercise, gt 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)

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ISCHEMIC STROKE / TIA2? 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 lt 7.0
• BP lt 120/80, including ARB or ACE-I
• LDL lt 70, including statin
• Nutrition w/ fruits, Mediterranean diet
• Alcohol intake lt 2 oz/d (men) or lt 1 oz/d (women)
• BMI 18.5-24.9 kg/m2
• Aerobic exercise gt 20 min/d, gt 3 d/wk

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ISCHEMIC STROKE / TIA2? 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 lt 30)

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THE END