Stroke, Part I -An Evidence-Based Review

of Risk Factors and Prevention

Laurence J. Kinsella, M.D., F.A.A.N.

Stroke: Incidence and Cost in the United States

795,000 new or recurrent cases yearly

1 stroke every 40 seconds #3 cause of death $73 billion annual health cost 4,400,000 stroke survivors at

high risk for recurrence

75 yo M with multiple Large artery territory infarctions, typical of cardiogenic embolus

AHA Heart and Stroke Statistics Update 2009. Available at http://www.americanheart.org/downloadable/heart/1240250946756LS-1982%20Heart%20and

%20Stroke%20Update.042009.pdf

Cost of Stroke

20% institutionalized after 3 months

15-30% permanently disabled

$73 billion in direct and indirect costs

Average lifetime cost of stroke in the U.S. estimated to be $140,000.

Stroke 2011;42:517-583.

Causes of Stroke

85%Infarction

30-60%Cerebrovascularatherosclerosis

20%Penetrating

arterydisease (lacunes)

15-30%Cardiogenic

Embolism(higher < 50, > 80)

5%Other,

unusualcauses

Hemorrhage - Intracerebral - Subarachnoid

15%

Well-Documented and Modifiable Risk Factors

Hypertension exposure to cigarette

smoke diabetes atrial fibrillation and

certain other cardiac

conditions dyslipidemia

Carotid artery stenosis

Sickle cell disease Postmenopausal

hormone therapy Poor diet physical inactivity Obesity body fat distribution

Stroke 2011;42:517-584

Less well-documented or potentially modifiable

Risk Factors Metabolic syndrome Excessive alcohol

consumption Drug abuse Sleep-disordered

breathing Migraine

Hyperhomocysteinemia Elevated lipoprotein(a) Use of oral

contraceptives Hypercoagulability Inflammation Infection

Stroke 2011;42:517-584

Stroke risk varies by clinical setting

Risk Factor Annual RiskAFIB, Low Risk 1%Amaurosis Fugax 2-3%Asx carotid > 60% 2-3%TIA 5-6%AFIB, High Risk 8%Prior Stroke 6-10%Sx carotid > 70% 16%

Gorelick P. Arch Neurol 1995;52:347-354

Causes of Stroke: Cerebrovascular Atherosclerosis

85%Infarction

30-60%Cerebrovascularatherosclerosis

20%Penetrating arterydisease (lacunes)

15-30%Cardiogenic embolism

5%Other,

unusualcauses

Hemorrhage - Intracerebral - Subarachnoid

15%

Vascular Territories of the Cerebral Hemisphere

Circle of Willis:Key Collateral Circulation

Antero-posterior Axial

Carotid Ultrasound

Internal carotidartery

Common carotidartery

Critical Internal Carotid artery stenosis

Most frequent cause of recurrent or crescendo TIAs

Mechanism is stenosis with flow reduction

Ulcerated plaque with artery to artery embolism

Causes of Stroke:Penetrating Artery Disease

(Lacunes)85%

Infarction

60%Cerebrovascularatherosclerosis

20%Penetrating

arterydisease (lacunes)

15%Cardiogenic embolism

5%Other,

unusualcauses

Hemorrhage - Intracerebral - Subarachnoid

15%

Lacunar Stroke

Thalamic Lacune Subcortical White matter lacunes

Lacunar Infarction Vessels undergo lipohyalinosis 4 most common locations

Internal capsule Thalamus Pons Cerebellum

Lacunar Infarcts(Small Subcortical Strokes):

Summary

Diagnosis: Clinical syndrome (e.g., pure motor or pure sensory) plus CT/MRI confirmation

Risk factor management: Hypertension, diabetes Carotid stenosis: Present in only 10% Rate of re-occurrence: High (10%/yr) Antiplatelet agents probably effective

Causes of Stroke: Cardiogenic Embolism

85%Infarction

60%Cerebrovascularatherosclerosis

20%Penetrating arterydisease (lacunes)

15%Cardiogenic embolism*

5%Other,

unusualcauses

Hemorrhage - Intracerebral - Subarachnoid

15%

Cardiogenic Embolism

Nonvalvular atrialfibrillation

(45%)

Acute MI(15%)

Other,lesscommon sources

(10%)Prosthetic

cardiac valves(10%)

Rheumatic heartdisease(10%)

Ventricularaneurysm

(10%)

Atrial Fibrillation (AF) Predisposes to Stroke

Mean Onset Age 64, > 2 Million People

35% Have Stroke During Lifetime

5% /Yr Stroke Rate, 12% after TIA

> 75,000 Strokes/Yr in U.S. 30% of all strokes > 80 years old

Gorelick P. Arch Neurol 1995;52:347-354.

Stroke: Other, Unusual Causes

*Dissection, migraine, oral contraceptive use in smokers, meningovascular syphilis, cocaine and amphetamine use, associated with prothrombotic states (e.g., sickle cell anemia)

5%Other,

unusualcauses

85%Infarction

60%Cerebrovascularatherosclerosis

20%Penetrating arterydisease (lacunes)

15%Cardiogenic embolism

Hemorrhage - Intracerebral - Subarachnoid

15%

Hemorrhagic Stroke

85%Infarction

60%Cerebrovascularatherosclerosis

20%Penetrating arterydisease (lacunes)

15%Cardiogenic

embolism

5%Other,

unusualcauses

Hemorrhage - Intracerebral - Subarachnoid

15%

Subdural hematoma Not considered a stroke, but may have focal signs from mass

effect

Obvious right SDH with mass effect Subtle SDH in 75 yo M with confusion, myoclonus after falling at home s/p trimalleolar fracture repair

Hypertensive Intracerebral Hemorrhage

Same locations as lacunes Thalamus, basal ganglia,

pons, cerebellum Lipohyalinosis, microaneurysms Amyloid angiopathy may have

similar appearance Prognosis dependent on volume

of blood and Glasgow Coma Scale

Intraventricular blood - poor prognostic sign

Ritter MA, Droste DW, et al. Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients.

Neurology. 2005;64:1233–7.Clarke JL. Neurocrit Care. 2004;1:53-60.

Lobar Hemorrhages Present in frontal, parietal, temporal lobes Rarely due to HTN Consider -

hemorrhagic embolic infarction tumor AVM amyloid septic embolus

57 yo Hunter with sudden onset headache, minimal left hand weakness.

Qureshi AI, Tuhrim S, et al. Spontaneous intracerebral hemorrhage. N Engl J Med.2001;344:1450–60

Subarachnoid Hemorrhage

30,000 per year 80% due to aneurysm 20% non-aneurysmal

(venous rupture?) 1% of all ED

headaches

 Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.

 http://stroke.ahajournals.org/cgi/content/full/40/3/994. Stroke. 2009;40:994-1025.

Risk Factor Modification is critical

>77% of all strokes are first time events without a warning TIA

Risk factor control for hypertension, diabetes, smoking, hyperlipidemia, etc.

Antiplatelet agents for cerebrovascular disease. Anticoagulation for atrial fibrillation and other

selected heart diseases. Endarterectomy vs stenting for high-grade

symptomatic carotid stenosis

Reduction in Stroke in SHEP

36% reduction in stroke (p = 0.003)

0 12 24 36 48 60

Placebo

Active Treatment

months

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JAMA. 1991 Jun 26;265(24):3255-64

Therapeutic Goals for Antihypertensive Rx

Condition Pre-Hypertension Uncomplicated Diabetic or Kidney Dz African-American

Goal BP

120/80-129/89

140/90

130/80

135/85

JNC VII, Hypertension 2003

Stroke reduction published inthe large statin trials

Trial % reduction GREACE 47 4S 37 CARE 31 ASCOT-LLA 27 HPS 25 LIPID 19 ALHAT-LLA 9

Guidelines for Cholesterol

With CHD or symptomatic athero, target goal is LDL < 100 mg/dl, < 70 for high risk patients (DM, smoking)

Patients with TIA or stroke with normal cholesterol levels will benefit from statin therapy

Low HDL may be treated with gemfibrozil or niacin

Sacco RL, et al. Guidelines for prevention of stroke. Stroke 2006;37:577-617.

Statins and ACEI in Secondary Stroke Prevention

SPARCL trial 80 mg atorvastatin in 4731 pts after TIA or stroke LDL 73 mg/dl in Tx, 129 mg/dl in placebo 11.2 vs. 13.1% had fatal/non-fatal stroke (p < .03) 20% RRR for all major cardiac events Increased hemorrhages in those with prior ICH

Dagenais Metanalysis of 3 clinical trials of ACE inhibitors (ACEI) 29,805 patients Reduced all cause mortality 7.8 vs 8.9% placebo

Amerenco P. SPARCL: high dose atorvastatin after stroke or transient ischemic attack. NEJM 2006;355:613-615.

Dagenais GR, et al. ACE inhibitors in stable vascular disease without LV dysfunction or CHF. Lancet 2006;368:581-588.

Vitamins and Stroke - Does Homocysteine Suppression work?

Homocysteine lowering with folic acid, pyridoxine (B6), and cobalamin (B12)

Reduced average by 2.5 µmol/liter

No difference in vascular events despite significant lowering of homocysteine

Same results as VISP 2004 trial - no effect

The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. N Engl J Med 2006; 354:1567-77.

Aspirin - what dose and when?

30 - 1200 mg qd has shown statistical benefit. (25% RRR)

Not as effective after TIA (13% RRR) 325 mg paralyzes all platelets immediately when

chewed and swallowed, therefore this is ideal in acute settings (TIA and Stroke)

81 mg is appropriate as “maintenance therapy” - may reduce bleeding risk

8th ACCP Guidelines. Chest 2008http://chestjournal.chestpubs.org/content/133/6_suppl

Combination ASA and Clopidogrel

MATCH trial shows increased risk of hemorrhage with combination.

ASA-clopidogrel arm dropped from the ProFESS trial

Combination not recommended for the secondary prevention of stroke due to hemorrhage risk

J Am Coll Cardiol 2011 Feb 22; 57:1002.

Diener et al, Lancet 2004.

Combination of ASA and Clopidogrel in AFIB

Low dose ASA 75-160 mg daily vs ASA plus clopidogrel 75 mg daily No reduction seen in vascular outcomes Stroke, MI, vascular death rates unaffected Found to be more effective at stroke reduction than ASA alone

for AFIB in patients who are poor candidates for anticoagulation

Bhatt DL, et al. N Engl J Med 2006;354. ACTIVE-A,NEJM 2009;360:2066-2078

Problems with Clopidogrel? Requires P450 2C19 metabolism 2-3% are deficient in the enzyme, therefore no

antiplatelet effect 2C19 Inhibited by proton pump inhibitors

(omeprazole, etc), reducing efficacy of clopidogrel

 Frere C et al, Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol

2008; 101:1088-93

Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA

(Omeprazole Clopidogrel Aspirin) Study. J Am Coll Cardiol 2008: 51:256-60.

Dipyridamole and ASA 2

ESPRIT 1363 pts randomized to ASA 30-325 mg alone,

1376 ASA with dipyridamole 200 mg bid w/in 6 mos of TIA or stroke

Primary outcome - death, stroke, MI or bleeding at 3.5 yrs

ARR 1% per year NNT 100 pts to prevent outcome per year,

20 @ 5 yrs

ESPRIT study group. Lancet 2006;367:1665-73

ASA-dipyridamole vs Clopidogrel

PROFESS trial Combination pill no better than clopidogrel

in preventing recurrent stroke. No neuroprotective effect seen for

dipyridamole (Persantine®) or telmisartan (Micardis®)

Sacco RL, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-51.

Antiplatelets and AFIB

Warfarin reduces stroke by 64% and ASA 26% 50% of patients with Afib are not treated with

warfarin- risk of bleeding, fall risk, etc. ASA + Clopidogrel demonstrated additional 28%

reduction in stroke and MI, but increased hemorrhages over ASA alone (2%/yr)

ASA + Clopidogrel is an option for warfarin intolerant patients with afib, with risks

Active-A. Effect of clopidogrel added to aspirin in patients with atrial fibrillation.N Engl J Med. 2009 May 14;360(20):2066-78

When to use Coumadin in Afib CHADS2 score

CHF - any history HTN - prior history Age > 75 Diabetes Secondary prevention after

systemic embolization

1 1 1 1 2

Go AS, et al. JAMA 2003;290:2685Gage BF, et al. JAMA 2001;285:2864.

When to use Warfarin in afibCHADS2 score

Event rate/yr

Warfarin

Event rate/yr

No warfarin

NNT

0 0.25 0.49 417

1 0.72 1.52 125*

2 1.27 2.50 81*

3 2.20 5.27 33*

4 2.35 6.02 27*

5-6 4.60 6.88 44*

Go AS, et al. JAMA 2003;290:2685Gage BF, et al. JAMA 2001;285:2864.*consider warfarin therapy

Dabigatran

Direct thrombin inhibitor 110mg equally effective than warfarin at stroke

prevention with fewer hemorrhages 150mg superior to warfarin, similar hemorrhages No drug interactions No monitoring expensive relative to warfarin

RELY Trial NEJM 2010www.nejm.org/doi/full/10.1056/NEJMoa0905561

Stroke Prevention in AFIB 2011Risk Recommendation

sAlternatives

lone AF < 65 yr ASA 325 mg/d ---

low risk 65-75 yr ASA 325 mg/d -Warfarin INR 2-3-ASA 81mg plus clopidogrel 75mg-Dabigatran 110mg

high risk or > 75 yr Warfarin INR 2-3Or Dabigatran 110mg

-ASA plus clopidogrel if warfarin isContraindicated-Dabigatran 110mg

Active A Trial. NEJM 2009;360:2066-2078www.nejm.org/doi/full/10.1056

Carotid Endarterectomy: Symptomatic vs. Asymptomatic Carotid Stenosis

0

2

4

6

8

10

12

14

Str

oke

Rat

e (%

/yr)

SymptomaticCarotid Stenosis

( > 70% )

AsymptomaticCarotid Stenosis

( > 60% )

Medical Rx

Carotid Endarterectomy

SymptomaticCarotid Stenosis

( 50-69% )Circulation. 2006;113:e409-e449.

Lancet. 2004 May 8;363(9420):1491-502.

Carotid Endarterectomy -How soon after stroke/TIA?

NASCET Data analysis For > 50% symptomatic stenosis NNT to prevent one ipsilateral stroke in 5 yrs: 5 for those within 2 weeks of last ischemic event 125 if randomized after 12 weeks. 9 for men vs 36 for women 5 for > 75 years 18 for < 65 years

Rothwell PM. Lancet. 2004;363:915-24.

Steps to reduce Morbidity and Mortality in Stroke

Control fever and glucose IV tPA within 4.5 hours of

onset - 30% increased chance of little or no deficit at 3 months.

Aspirin 325 mg within 48 hrs - 10/1000 reduction in deaths at 6 months

Admission to Stroke Unit - 40% reduction in death

Don’t withdraw statins Use an ACE inhibitor

NPO and Swallowing eval within 24 hrs - prevents pneumonia, fever, prolonged LOS, ?deaths

DVT prophylaxis - calf SCDs, Subq Heparin

No BP Rx for < 200/120 for 48 hours (<185/110 w tPA)

80 mg Atorvastatin acutely after TIA and Stroke, not hemorrhage

Acute Stroke Treatment 2010 emedicine.medscape.com/article/1159752-treatment#Table4

Adams H et al. Stroke. 2007;38:1655-1711Blanco M et al. Neurology. 2007 Aug 28;69(9):904-10

2011 Guidelines Risk Factor Modification

BP <140/90 or BP <130/80 with DM,

renal disease EtOH </=1 F, </=2 M Statin use to maintain

LDL < 100 in low risk, <100 in high risk pts

Warfarin for Afib or ASA +/- clopidogrel

for poor risk Afib

Population screening for carotid dz not recommended.

Consider CEA for highly select pts with Asx carotid stenosis

Stenting for Asx dz not established

Stroke 2011;42:517–584. 

Questions from the Audience?

References1. Guideline on the management of patients with extracranial carotid and

vertebral artery disease. J Am Coll Cardiol 2011 Feb 22; 57:1002.2. Sacco RL, etal. Guidelines for prevention of stroke. Stroke 2006;37:577-

617.3. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and

thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):483S-512S.

4. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet. 2004 May 8;363(9420):1491-502.

5. NASCET: beneficial effect of carotid endarterectomy in symptomatic patients with high grade stenosis. N Engl J Med 1991;325:445-453.

6. ACAS Study group: Endarterectomy for asymptomatic carotid stenosis. JAMA 1995;273:1421-1428.

6. Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.  http://stroke.ahajournals.org/cgi/content/full/40/3/994. Stroke. 2009;40:994-1025.

7. Diener H-C, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial Lancet 2004;364:331-337.