1. Management of TIA/Stroke:
Preventing a Second Event
Robert D. Brown, Jr., MD, MPH
Department of Neurology
Mayo Clinic, Rochester
November, 2010
American College of Physicians Meeting
Minneapolis, MN
3. Case: Transient
Weakness and Speech Dysfunction
68 year old woman with 20 minutes of right
upper extremity weakness and “difficulty
finding the correct word”
One day earlier, 5 minute episode of
darkness and blurring in the left eye
Prior history
– Mild hypertension
– Mild hyperlipidemia
– On no medications
Exam: systolic bruit over left neck
– BP 160/88
4. Stroke Prevention:
Secondary Prevention Strategies
Mechanism evaluation
Intervention
– Carotid endarterectomy
– Carotid angioplasty with stent placement
Selection of antithrombotic agent
Risk factor control
5. Management Decisions After TIA/CI
Step-Wise Approach to Optimize Stroke Prevention
1) Are the symptoms caused by a TIA or
ischemic stroke?
2) Localize the symptoms: anterior or posterior
circulation
3) What is the mechanism?
4) Initiate the best medical, surgical or
endovascular means of stroke prevention
6. Management Decisions After TIA/CI
Step-Wise Approach to Optimize Stroke Prevention
1) Are the symptoms caused by a TIA or ischemic
stroke?
2) Localize the symptoms: anterior or posterior
circulation
3) What is the mechanism?
4) Initiate the best medical, surgical or
endovascular means of stroke prevention
7. Management Decisions After TIA/CI
Step-Wise Approach to Optimize Stroke Prevention
1) TIA/CI versus other cause of symptoms:
Are the symptoms caused by a TIA or ischemic
stroke? Seizure
2) Localize the symptoms: anterior or posterior
Migraine
circulation
Hemorrhage (SDH, EDH, intracerebral)
3) What is the mechanism?
Metabolic (hypoglycemia, other)
4) Initiate the best medical, surgical or
Transient global amnesia
endovascular means of stroke prevention
Other non-vascular cause:
MS, tumor, infection
8. Management Decisions After TIA/CI
1) Are the symptoms caused by a TIA or
ischemic stroke?
2) Localize the symptoms: anterior or posterior
circulation
3) What is the mechanism?
4) Initiate the best medical, surgical or
endovascular means of stroke prevention
10. Functional Anatomy
Posterior Circulation:
Vertebrobasilar system
In isolation or in combination
diplopia
dysarthria
ataxic gait or limbs
unilateral or bilateral visual
facial sensation change or weakness
vertigo
unilateral or bilateral motor / sensory
changes
11. Management Decisions After TIA/CI
Step-Wise Approach to Optimize Stroke Prevention
1) Are the symptoms caused by a TIA or Stroke?
2) Localize the symptoms: anterior or posterior
circulation
3) What is the mechanism?
4) Initiate the best medical, surgical or
endovascular means of stroke prevention
12. Defining the Mechanism of a TIA or
Cerebral Infarction:
Four Major Categories
1. Cardiac: ~30%
– Arrhythmia
– Dilated cardiomyopathy, recent MI,
other structural disorders
– Cardiac mass lesions
– Valve disease 2
– Venous source with right-to-left shunt
2. Large vessel disease: 15-20%
– Atherosclerosis 1
– Dissection, fibromuscular dysplasia
13. Defining the Mechanism of a TIA or
Cerebral Infarction:
Four Major Categories
3. Small vessel disease: 15-20%
– Atherosclerosis, hypertension, smoking,
diabetes 4
– Infectious 3
– Non-infectious arteritis
4. Hematologic: <5%
– Polycythemia, thrombocytosis,
sickle cell disease
– Lupus anticoagulant positivity,
anticardiolipin antibodies
14. Anterior Circulation TIA or Ischemic Stroke
Step 1: Evaluate for Large Artery Stenosis
Carotid ultrasound, MRA or CTA
Step 2: Consider Cardiac Source of embolus
Transesophageal Echocardiography
Step 3: Consider intracranial stenosis
Brain MRA or CTA
Step 4: Baseline eval is negative.
The carotid ultrasound, TEE, and MRA are negative.
15. Anterior Circulation TIA or Ischemic Stroke
Step 1: Evaluate for Large Artery Stenosis
Carotid ultrasound, MRA or CTA
Step 2: Consider Cardiac Source of embolus
Transesophageal Echocardiography
Step 3: Consider intracranial stenosis
Brain MRA or CTA
Step 4: Baseline eval is negative.
The carotid ultrasound, TEE, and MRA are negative.
16. Symptomatic Carotid Artery
Occlusive Disease: CEA Guidelines
♦ Carotid stenosis, >70%
♦ NASCET data: stroke risk ipsilateral to carotid stenosis
♦ Surgical outcome: 9% over 2 years
♦ Medical management: 26% over 2 years
♦ Absolute risk reduction: 8.5% per year. NNT: 12
♦ Carotid stenosis, 50-69%
♦ NASCET data: stroke risk ipsilateral to carotid stenosis
♦ Surgical outcome: 16% over 5 years
♦ Medical management: 22% over 5 years
♦ Absolute risk reduction: 1.2% per year. NNT: 83
♦ Carotid stenosis <50%
♦ No benefit
17. What is the Role of
Carotid Angioplasty/Stenting?
Carotid Revascularization
Endarterectomy
vs. Stent Trial (CREST)
New England Journal of Medicine,
May, 2010
18. CREST
Primary and Secondary Endpoints
Primary endpoint
– Peri-procedural a composite of:
• Any clinical stroke
• Myocardial infarction
• Death
– Post-procedural
• Ipsilateral stroke up to 4 years
Secondary endpoint
– Differential efficacy based on symptomatic status,
gender and age
19. CREST
Results
Primary endpoint
– Carotid angioplasty/stenting: 7.2% / 4 years
– Carotid Endarterectomy: 6.8% / 4 years
– P value 0.51
Peri-procedural stroke
– CAS 4.1 % CEA 2.3% HR 1.79, p=0.01
Peri-procedural MI
– CAS 1.1% CEA 2.3% HR 0.50, p=0.03
20. CREST
Conclusions
Similar Primary Endpoint driven by differences in
peri-operative stroke and MI
– More MIs after CEA
– More strokes after CAS
CEA and CAS have similar net outcomes though the
individual risks vary, lower stroke with CEA and
lower MI with CAS
Younger patients may have improved efficacy with
CAS and older patients have improved efficacy with
CEA
21. Symptomatic Carotid Disease:
Carotid Angioplasty/Stenting
Medicare/Coverage Issues
Medicare coverage for carotid artery stenting
is restricted to:
– Patients who would be at high risk of
complications from CEA, and
– Have symptomatic narrowing of the carotid
artery of 70 percent or more
22. Cerebrovascular Update
Secondary Prevention
Aspirin? Warfarin? Clopidogrel? Dipyridamole?
– Selecting the best anti-thrombotic therapy after
TIA or ischemic stroke
23. Selecting an Anti-Platelet Agent for
Secondary Prevention: Conclusions
Decision based on mechanism identified, co-morbid conditions, cost,
potential side effects, & other medical illnesses
♦ Aspirin, clopidogrel and aspirin/ER dipyridamole are appropriate
initial therapies in non-cardioembolic CI, when no clear indication
for warfarin
♦ Aspirin intolerance or aspirin allergy: clopidogrel indicated
♦ Aspirin/ER dipyridamole may be more effective than aspirin alone
♦ Clopidogrel may be more effective than aspirin
♦ No clear difference between ASA/DP and clopidogrel
♦ Aspirin in combination with clopidogrel only indicated for selected
acute coronary syndromes, and after angioplasty/stenting
24. Selecting an Anti-Thrombotic Agent
for Secondary Prevention:
Antiplatelet Agent Summary
Decision based on mechanism identified, co-morbid conditions, cost,
Combination ASA, Clopidogrel? NO
potential side effects, & other medical illnesses
MATCH, Lancet 2004
CHARISMA, NEJM 2006
♦ Aspirin, clopidogrel and aspirin/ER dipyridamole are appropriate
initial therapies in non-cardioembolic CI, when no clear indication
Combination ASA, Dipyridamole? YES
for warfarin
ESPS-2, J Neurol Sci 1997
♦ Aspirin intolerance or aspirin allergy: clopidogrel indicated
ESPRIT, Lancet 2006
♦ Aspirin/ER dipyridamole may be more effective than aspirin alone
♦ Combination ASA, Clopidogrel:
Clopidogrel may be more effective than aspirin
Which is better? NEITHER
♦ Aspirin in combination with clopidogrel only indicated for
PROFESS, NEJM 2008
selected acute coronary syndromes, and after
angioplasty/stenting
25. Selecting an Anti-Platelet Agent for
Secondary Prevention: Conclusions
Decision based on mechanism identified, co-morbid conditions, cost,
potential side effects, & other medical illnesses
♦ In general, warfarin not indicated for non-cardioembolic ischemic
stroke unless very specific indications present
26. Clopidogrel:
FDA Black Box Warning, Background
Effectiveness of clopidogrel is dependent on its activation
to an active metabolite by the cytochrome P450 (CYP)
system, mainly CYP2C19
– Enzyme effectiveness dependent on the genotype of that
enzyme
• 2 normal metabolism alleles should have fully
functional metabolism
• 2 loss-of-function alleles will have poor metabolizer
status
• The overall clinical relevance of these loss-of-
function alleles continues to be evaluated
27. Clopidogrel:
FDA Black Box Warning, Recommendations
For urgent indications: use standard clopidogrel
loading and dosing.
– Administration should not be delayed pending
genetic testing
For longer term use:
– For those patients who are already on clopidogrel
and doing well, continue clopidogrel and genetic
testing is not indicated
28. Clopidogrel:
FDA Black Box Warning, Recommendations
If an antithrombotic medication other than clopidogrel
would be indicated, it would be reasonable to use an
alternative to clopidogrel
If clopidogrel is indicated for long-term use: consider
(not mandatory) CYP2C19 genetic testing. If testing is
performed:
– If 2 non-metabolizer alleles are present, use an
alternative to clopidogrel if possible*
– If 1 non-metabolizer allele is present, consider use
of an alternative to clopidogrel*
*The efficacy of higher dose clopidogrel use is unclear in this situation,
and is not recommended.
29. Selecting an Anti-Thrombotic Agent
for Secondary Prevention:
When is Warfarin Indicated?
Probable cardiac source of embolus
– Use depends on specific cardiac findings
Aortic arch: thrombus or mobile debris
Hypercoagulable states
Extracranial dissection with TIA or CI
Recurrent events on aspirin?
– Typically use alternative anti-platelet agent and not a/c,
although this has not been proven
Intracranial stenosis? WASID data, NEJM 2005
Not beneficial in “non-cardioembolic” ischemic stroke in
aggregate: Publication: WARSS, NEJM 2001
30. Cardiac issues: secondary prevention
♦AF: warfarin proven in multipleof TIA/Ischemic Stroke
Step 2: Consider Cardiac Source studies, INR 2-3
Transesophageal Echocardiography
♦No indication for combination therapy
♦Aspirin 325 mg if unable to take warfarin
♦Recent MI: if LV thrombus noted, NORMAL: 2-3
ABNORMAL: warfarin INR
Cardiac or Aortic Source No cardiac source
♦Use aspirin as well for ischemic CAD
♦Cardiomyopathy: warfarin or aspirin acceptable
Warfarin,
♦Rheumatic mitral valve disease: warfarin INR 2-3
surgery
Continue evaluation
♦Mitral valve prolapse: anti-platelet therapy
♦Prosthetic valve, recurrence on A/C: add aspirin
Risk Factor
~81 Control
mg per day to warfarin, INR 2.5 - 3.5
31. Case: Transient
Weakness and Speech Dysfunction
68 year old woman with 20 minutes of right
upper extremity weakness and “difficulty
finding the correct word”
One day earlier, 5 minute episode of
darkness and blurring in the left eye
Prior history
– Mild hypertension
– Mild hyperlipidemia
– On no medications
Exam: systolic bruit over left neck
– BP 160/88
32. Management Decisions After TIA/CI
Step-Wise Approach to Optimize Stroke Prevention
1) Are the symptoms caused by a TIA or Stroke? yes
2) Localize the symptoms: anterior or posterior
circulation Anterior/carotid
3) What is the mechanism? Carotid u/s: high-grade stenosis
4) Initiate the best medical, surgical Carotid endarterectomy
or endovascular means of stroke Aspirin, 325 mg per day
prevention
Can we do anything more?
33. Modifiable Risk Factors To Be
Assessed Simultaneously With Mechanism
Defining the
mechanism alone is
NOT enough:
Risk Factor Control
35. Strategies in Secondary
Prevention After Stroke or TIA
Robert D. Brown, Jr., MD, MPH
Department of Neurology
Mayo Clinic, Rochester
November, 2010
American College of Physicians Meeting
Minneapolis, MN
