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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 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. TrueB. False

PRE TEST QUESTIONS

2. Stroke ranks as the leading cause of long-term disability in the United States.

A T A. True B. False

PRE TEST QUESTIONS

3. Which of the following are considered strokes?a. Ischemicb. Hemorrhagicc. Subarachnoid hemorrhaged. Venous occlusion / thrombosise. all of the above

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PRE TEST QUESTIONS4. Which of the following are acceptable medications for secondary stroke prophylaxis in the U.S.:

a. Aspirinb Clopidogrelb. Clopidogrelc. Aspirin plus sustained release

dipyridamoled. Ticlopidinee. 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 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 55Women and men affected equally 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.A i t l 2/3 f ti t h id l Approximately 2/3 of patients have residual 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 strokesof 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 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 Heart disease Atrial fibrillation Smoking Carotid occlusive disease Sedentary life style

ARTERIAL VASCULAR ANATOMY

1. Extracranial Circulationa. Aortab. Extracranial Carotid Systemc. Extracranial Vertebral System

2. Intracranial Circulationa. Intracranial Carotid Systemb. 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 of thrombotic debris downstream (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 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 HeparinA. 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 benefit6. 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 3. Endpoints death any cause or death or dependencep y p

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 Clopidogrel1. 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.

b. Treatment begun within 24 hours of symptom onset.gc. 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 TrialAspirin plus clopidogrel demonstrated no benefit vs aspirin alone

ACUTE POST-STROKE THERAPY

Aspirin plus DipyridamoleEARLY Trial

1. Randomized controlled trail which was open label.

2. Patients randomized to either aspirin 25 mg and p gextended 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 StrokeTOAST Trial and other studies

1. No benefit of heparin in stuttering TIA or “stroke in evolution”stroke in 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

Aspirin1. Meta-analysis of numerous placebo controlled trials

have clearly established the benefit of aspirin in reducing occurrence of ischemic stroke

2 1 % f2. Relative risk reduction is 15% for 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. Patients randomized to either clopidogrel 75 mg daily or

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 Dipyridamole1. Inhibits adenosine deaminase and phosphodiesterase.

2. ESPS -2: randomized placebo controlled double blind trial comparing aspirin alone vs ER dipyridamole alone, SASA 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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SECONDARY STROKE PREVENTION

Ticlopidine1. Adenosine diphosphate inhibitor

2. Canadian American Ticlopidine Study (CATS)3 Ticlopidine Aspirin Stroke Study (TASS)3. Ticlopidine Aspirin Stroke Study (TASS)4. African American Stroke Prevention Trial5. 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. TrueB. 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.setting.

A. True B. False

POST TEST QUESTIONS

4 Which of the following risk factors is the strongest determinant for stroke?

A. HypertensionA. HypertensionB. SexC. DiabetesD. AgeE. Hyperlipidemia

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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.

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