Strokes and the Importance of Anticoagulant Therapy for Prevention

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1/31/2014
ANTIPLATELET SELECTION IN SECONDARY
STROKE PROPHYLAXIS
Presented By: Andres G. Morales, D.O.
Texoma Neurology Associates
DISCUSSION OBJECTIVES
At the completion of the discussion,
participants should be able to:
 1. Discuss the demographics of stroke and it’s
impact in the U.S and worldwide.
 2. Identify the classification / types of stroke
based on the initial clinical presentation.
 3. Discuss the various mechanisms of ischemic
stroke.

DISCUSSION OBJECTIVES
4. Identify modifiable and non-modifiable risk
factors for ischemic stroke.
 5. Be familiar with the available antiplatelet
regimens for secondary prevention of ischemic
stroke.

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PRE TEST QUESTIONS
1.Stroke ranks worldwide as the second leading
cause of death.
A. True
B. False
PRE TEST QUESTIONS
2. Stroke ranks as the leading cause of long-term
disability in the United States.
A. True
A
T
B. False
PRE TEST QUESTIONS
3. Which of the following are considered strokes?
a. Ischemic
b. Hemorrhagic
c. Subarachnoid hemorrhage
d. Venous occlusion / thrombosis
e. all of the above
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PRE TEST QUESTIONS
4. Which of the following are acceptable
medications for secondary stroke prophylaxis in
the U.S.:
a. Aspirin
b Clopidogrel
b.
c. Aspirin plus sustained release
dipyridamole
d. Ticlopidine
e. all of the above
EPIDEMIOLOGY OF STROKE
Stroke (“Brain Attack”) is the sudden cessation
of blood flow to the brain leading to cerebral
infarction.
 The most common neurologic emergency
 Third leading cause of death in the U.S. and 2nd
worldwide.
 Leading cause of adult disability in the U.S.

EPIDEMIOLOGY OF STROKE
Stroke affects people of all ages
 Incidence doubles every 5 years after the age
of 55
 Women and men affected equally
 Blacks and Hispanics are at greater risk than
non-Hispanic whites.

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EPIDEMIOLOGY OF STROKE
Mortality varies from 10-15% during the initial
hospitalization and >30% after 1 year.
 Age is significant predictor for poor outcome.
 Approximately
residual
A
i t l 2/3 off patients
ti t have
h
id l
symptoms at 1 year.
 50% return to functional independence and
work with approximately 1/3 requiring
permanent institutionalization.

STROKE TYPES



There are two main types of stroke: ischemic and
hemorrhagic.
Ischemic stroke is caused by three main mechanisms:
occlusion through thrombosis (arterial or venous),
embolism, or systemic hypoperfusion. Account for 85%
of all strokes
Hemorrhagic stroke is caused by two non-traumatic
mechanisms: intracerebral hemorrhage or subarachnoid
hemorrhage. Account for 15% of all strokes.
NON-MODIFIABLE RISK FACTORS
Age- strongest determinant of stroke
Sex
 Family history
 Race/ethnicity


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ISCHEMIC STROKE SUBTYPES
Thrombosis: primary pathology is thrombosis of
local arteries with resultant reduced flow or
embolization (80%)
 Embolism: originate in distal vessels rather
than local thrombosis.
 Global hypoperfusion: from cardiovascular
collapse with either global or regional infarction

MODIFIABLE RISK FACTORS
Hypertension
Diabetes
 Hypercholesterolemia
 Heart disease
 Atrial fibrillation
 Smoking
 Carotid occlusive disease
 Sedentary life style


ARTERIAL VASCULAR ANATOMY
1. Extracranial Circulation
a.
b.
c.
Aorta
Extracranial Carotid System
Extracranial Vertebral System
2. Intracranial Circulation
a.
b.
Intracranial Carotid System
Vertebrobasilar System
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EXTRACRANIAL VASCULAR ANATOMY
EXTRACRANIAL VASCULAR ANATOMY
INTRACRANIAL VASCULATURE (CIRCLE OF
WILLIS)
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CIRCLE OF WILLIS
MECHANISM OF THROMBOTIC STROKES
Local thrombosis with subsequent reduction in
cerebral blood flow.
 Local thrombosis with subsequent embolization
of thrombotic debris downstream (intra-arterial
(intra arterial
embolization).
 Venous thrombosis with backward pressure
and edema leading to reduced arterial
perfusion.

ATHEROSCLEROTIC THROMBOSIS
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THROMBOTIC STROKE SUBTYPES
Large vessel disease: both extracranial and
intracranial carotid and vertebral system and
Circle of Willis.
 Small vessel disease: penetrating branches of
the intracranial circulation (lacunar disease).

LACUNAR INFARCTS
MCA ISCHEMIC INFARCTION
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MCA INFARCTION WITH VISIBLE THROMBUS
MCA THROMBUS
ACA ISCHEMIC INFARCT
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PCA INFARCT
CEREBELLAR INFARCT
BASILAR ARTERY INFARCT
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HYPOPERFUSION –WATERSHED INFARCT
HYPOPERFUSION-WATERSHED INFARCTS
LACUNAR INFARCTS
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CARDIOEMBOLIC INFARCTION
VENOUS SINUS THROMBOSIS
VENOUS INFARCTION
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CURRENTLY AVAILABLE APPROVED
ANTIPLATELET AGENTS
Aspirin
 Ticlopidine
 Clopidogrel
 Dipyridamole
 ASA/ER dipyridamole

ACUTE POST STROKE THERAPY: ANTIPLATELET VS
ANTICOAGULATION
Aspirin vs Heparin
A. International Stroke Trial
1. Randomized open trial comparing Aspirin vs heparin, vs
both vs no medication.
2. Treatment initiated within 48 hours up to 14 days.
3. Aspirin 300 mg daily group had significant reduction in
recurrent stroke during the 14 days and fewer combined
non-fatal stroke and death vs heparin or nothing at all.
4. Aspirin had no increased hemorrhage occurrence.
5. Heparin had no benefit
6. Benefits persisted at 6 months
ACUTE POST–STROKE THERAPY
B. Chinese Acute Stroke Trial (CAST)
1. Randomized placebo controlled trial comparing
aspirin 160 mg daily vs placebo.
2. Treatment onset within 48 hours
p
death anyy cause or death or dependence
p
3. Endpoints
at 4 weeks.
4. 14% reduction in death within 4 weeks vs placebo
C. Evidence suggests early anticoagulation with heparin or
low molecular weight heparin has worse outcomes and
higher mortality.
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ACUTE POST-STROKE THERAPY
Aspirin Plus Clopidogrel
1. CHANCE Trial
a. Randomized double blind placebo controlled trial
comparing clopidogrel plus aspirin vs placebo plus
aspirin in high risk patients with TIA or stroke.
g within 24 hours of symptom onset.
b. Treatment begun
c. Clopidogrel plus aspirin found superior at 90 days in
preventing stroke with no increased adverse events.
2. MATCH Trial
a. Randomized double-blind placebo controlled trail
comparing aspirin plus clopidogrel vs aspirin alone.
b. Combination therapy offered no benefit and greatly
increased risk of bleeding complications.
3. FASTER Trial
Aspirin plus clopidogrel demonstrated no benefit vs aspirin alone
ACUTE POST-STROKE THERAPY
Aspirin plus Dipyridamole
EARLY Trial
1. Randomized controlled trail which was open label.
p
25 mgg and
2. Patients randomized to either aspirin
extended release dipyridamole 200 mg BID vs aspirin
100 mg Daily.
3. Enrollment within 24 hours of symptoms and at 7
days all patients received aspirin and extended
release dipyridamole combine. No difference in 90
day outcome.
ACUTE POST-STROKE TREATMENT
Heparin in Acute Thrombotic Stroke
TOAST Trial and other studies
1. No benefit of heparin in stuttering TIA or
“stroke
stroke in evolution
evolution”.
2. More adverse events vs benefit.
3. DVT prophylaxis with heparin or LMW appear to be
safe and not contraindicated.
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SECONDARY STROKE PREVENTION
Aspirin
1. Meta-analysis of numerous placebo controlled trials
have clearly established the benefit of aspirin in
reducing occurrence of ischemic stroke
2.
15%
2 Relative risk reduction is 1
% ffor all strokes, ischemic or
hemorrhagic, 22% for ischemic.
3. Dose varies from 50-1500 mg per day. American College
of Chest Physicians recommends 75-100 mg/day
4. Adverse events increase with dose.
5. Inexpensive
SECONDARY STROKE PREVENTION
Clopidogrel
1. Inhibits platelet aggregation by induced adenosine
diphosphate.
2. CAPRIE Trial: randomized blinded trial clopidogrel vs
aspirin in patients at risk for ischaemic events.
3 Patients randomized to either clopidogrel 75 mg daily or
3.
aspirin 325 mg daily and compared compound outcome
of ischemic stroke, MI vascular death. Patients had
either CVA, MI or symptomatic PAD for enrollment
criteria.
4. Clopidogrel group had a annual risk of 5.32% vs aspirin at
5.83%. Relative risk reduction was 8.7%.
5. MATCH,FASTER, CHARISMA
SECONDARY STROKE PREVENTION
Aspirin/ER Dipyridamole
1. Inhibits adenosine deaminase and phosphodiesterase.
2. ESPS -2: randomized placebo controlled double blind
trial comparing aspirin alone vs ER dipyridamole alone,
ASA
S plus ER dipyridamole, vs placebo. Primary end
points stroke, death or both.
3. Stroke risk reduced 18% in ASA, 16% dipyridamole, 37%
in combined group vs placebo. Stroke and death
reduced 13% in ASA, 15% dipyridamole and 24%
combined group.
4. Relative risk reduction 36% in combined group vs placebo.
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1/31/2014
SECONDARY STROKE PREVENTION
Ticlopidine
1. Adenosine diphosphate inhibitor
2. Canadian American Ticlopidine Study (CATS)
3.
3 Ticlopidine Aspirin Stroke Study (TASS)
4. African American Stroke Prevention Trial
5. Similar GI affects as aspirin, also rash and diarrhea
common. TTP and Neutropenia.
FINAL COMMENTS
POST TEST QUESTIONS
1. Aspirin at any dose is an acceptable choice for
the pharmacologic secondary prevention for any
ischemic stroke?
A. True
B. False
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POST TEST QUESTIONS
2. Combination therapy with Clopidogrel and
Aspirin is an approved intervention for secondary
ischemic stroke prophylaxis.
A. True
B. False
POST TEST QUESTIONS
3. The use of parenteral heparin either
fractionated or unfractionated is an appropriate
first line intervention in the acute ischemic stroke
setting.
A. True
B. False
POST TEST QUESTIONS
4 Which of the following risk factors is the
strongest determinant for stroke?
A. Hypertension
B. Sex
C. Diabetes
D. Age
E. Hyperlipidemia
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1/31/2014
POST TEST QUESTIONS
5. Which of the following statements is true?
1. Clinical trials suggest that switching antiplatelet
agents after a patient has suffered a first time or
second stroke may be beneficial.
2. Risk of GI hemorrhage is higher in aspirin or
aspirin/dipyridamole combination therapy vs
clopidogrel.
3. Long term anticoagulation with warfarin or other
anticoagulants is an acceptable alternative to
antiplatelet therapy in select patients.
4. Subdural hemorrhage is a type of stroke.
BIBLIOGRAPHY

Caplan LR. Basic pathology, anatomy and pathophysiology of stroke. In: Caplan’s Stroke: A Clinical Approach, 4th ed. Saunders Elsevier, Philadelphia 2009. P.22.

Biller J. Practical Neurology, 4th ed. Lippincott, Williams & Wilkins, Philadelphia 2012.

Kasner SE Gorelick PB Prevention and treatment of ischemic stroke Blue
Kasner, SE, Gorelick PB. Prevention and treatment of ischemic stroke, Blue books of practical neurology, 29th ed. Elsevier 2004.

Rowland LP, Pedley TA. Merritt’s Neurology 12th ed. Lippincott, Williams & Wilkins, Philadelphia 2010.

Petty GW. Khandeheria BK, Meissner I, et al. Population‐based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006: 81:609.
BIBLIOGRAPHY

Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med:1474 331

Go As, Mozaffaria D, Roger VL, et al. Heart disease and stroke statistics‐2013 update: a report from the American Heart Association. Circulation 2013: 127:e6

Feigin VL Global and regional burden of strike during 1990 2010: findings
Feigin VL, Global and regional burden of strike during 1990‐2010: findings from the Global Burden of Diseased Study 2010. Lancet 2013.

SPS3 Investigators Benavente OR, Hart RG, et al. Effects of Clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012: 367‐817.

Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011: 365‐993.
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BIBLIOGRAPHY

Leonardi‐Bee J, Bath PM, Bousser MG, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta‐analysis of individual patient data from randomized controlled trials. Stroke 2005: 36‐162.

ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebra ischaemia of arterial origin (ESPRIT): a randomized controlled trial. Lancet 2006: 367‐1665.

Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular effects of stroke or TIA: a meta‐analysis. Stroke 2008: 39‐1358.

Gent M, Blakely JA, Easton Je, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lance 1989: 1‐1215.

Hass WK, Eason JD, Adams HP, et al. A randomized trial comparing Ticlopidine hydrochloride with aspirin for the prevention of stroke in high‐risk patients. Ticlopidine Aspirin Stroke Study Group N Engl J Med 1989: 321‐501.
BIBLIOGRAPHY

Wong KS, Wang Y, Leng X, et al. Early dual versus mono antiplatelet therapy for acute non‐ cardioembolic ischemic stroke for transient ischemic attack: an updated systematic review and meta‐analysis. Circulation 2013: 128‐1656.

Lansberg MG, O’Donnell MJ, Kharti P, et al. Antithrombic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Practice Guidelines. Chest 2012: 141:e601S.
141:e601S

Berge I, Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database Syst Rev 2002: CD003242.

Wong KS, Chen C, Ng PW, et al. Low‐molecular‐weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomized study. Lancet Neurology 2007; 6:407.

Roden‐Jullig A, Britton M. Effectiveness of heparin treatment for progressing ischaemic stroke: before and after study. J Intern Med 2000: 248:287.
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