Transcript New Developments in Antiplatelet Therapy for Stroke Prevention

Medical Prevention of Stroke
November 17, 2000
Ash Singhal
University of Toronto
Objectives

Prevention
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What are the most effective stroke prevention
strategies?
Management of Symptomatic Patients
endarterectomy
 warfarin
 antiplatelet drugs

How common is stroke?
Important Stroke Stats to
Remember
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A stroke occurs every
minute
Leading cause of adult
neurological disability
4th leading cause of death
Longest length of hospital
stay
Leading cause of transfer
to long-term care
Stroke Prevention
The Modifiable Risk Factors
The Asymptomatic Patient
Encourage Risk Factor
Modification
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Hypertension (increases stroke risk 4x)
Smoking (increases stroke risk 1.5x)
Diabetes
Physical inactivity, obesity
Serum cholesterol
?Homocysteine
Hypertension
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Strongest link as a risk factor
42% risk reduction
benefit seen within 12 months
optimal SBP/DBP unknown
recommendation: <140/85
Smoking
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50% increase in stroke risk
rates normalize after only 2-4 years
this is regardless of age/pack years
Diabetes
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Progression of risk by severity
stroke risk stratified by HgA1C
goal is normoglycemia
Alcohol
I’ll have a double rye n’ coke...
Physical Activity
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Lesser impact risk factor
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Even modest activity beneficial
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20 minutes 3 times/week
Graded benefit with more activity
Little/no effect for women
Cholesterol
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Well documented factor for M.I.
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Less clear in stroke
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Statins reduce risk up to 20%
Homocysteine
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Circulating amino acid
1997: JAMA, NEJ articles
under 60, top quintile
adjusted OR 1.2
folic acid, B6, B12 reduce serum levels
VISP trial
The Symptomatic Patient
TIA or completed stroke
Etiology Determines Treatment
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Need to search for underlying cause(s)
Carotid Endarterectomy for high-grade
symptomatic stenosis
Anticoagulation for cardioembolic events
Antiplatelet therapy for large and small vessel
arteriosclerosis
Symptomatic Carotid Stenosis
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70-99% - surgery
50-69% - ?
<50% - no surgery
Carotid Endarterectomy is
Extremely Effective
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NASCET Study
2-year stroke risk: 26% with medical Rx vs.
9% with carotid surgery
RRR 65%
NNT = 6 to prevent one stroke in 2 years
Carotid Angioplasty and Stenting:
An Emerging Treatment
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2 RCTs to begin this year:
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CREST (n=2400)
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SAPHIRE (n=600, only high risk pts)
Cardioembolic Events
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Atrial fibrillation most important factor
others include:
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recent anterior MI
artificial heart valves
severe dyskinetic sections (on Echocardiography)
PFO
Atrial Fibrillation
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Most important cardiac factor
6 large clinical trials
3-16%/year risk of stroke
best estimate: 5%/year
stratification important
Rat Poison
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SPAF SPAF SPAF
70% RR for Warfarin (INR=2-3)
20% RR for ASA
1%/year risk major bleeding
increases by 1%/INR point
Antiplatelet Therapy
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ASA
Ticlopidine (Ticlid)
Clopidogrel (Plavix)
Dipyridamole
Dipyridamole + ASA (Aggrenox)
Other combinations?
 MATCH trial: ASA 75mg +
Plavix 75mg vs.Plavix 75mg
New Recommendations
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American College of Chest Physicians 2001:
 ASA or Plavix or Aggrenox can be first line
agents for secondary stroke prevention
Antiplatelet Trialists’ Collaboration
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Meta-analysis of 145 trials
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70,000 high-risk patients
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Antiplatelet drugs reduced risk of composite outcome
of ischemic stroke, MI, or vascular death by 27% in
high-risk patients
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Relative odds reduction was consistent:
– Over a wide range of clinical manifestations
(CAD, CVD, PVD)
– Across subsets of patients at varying risks within
specific clinical disorders
Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106
Patients with stroke, MI, or
vascular death (%)
Antiplatelet Trialists’ Collaboration
25
Antiplatelet therapy
Control
22% odds reduction
20
29% odds
reduction
25% odds
reduction
15
27% odds
reduction
32% odds
reduction
10
5
0
Prior
Acute MI
stroke/TIA
Prior MI
Other
high risk
All
high risk
Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106
Aspirin
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rapid onset of action
30 mg sufficient for antiplatelet effect in lab
Optimal dose controversial
Low dose (50-325 mg) now recommended for
stroke prevention by FDA
ACE Trial
Prevention of Vascular Events Following Carotid Endarterectomy
10
9
p=0.120
p=0.030
8.4%
Event rate (%)
8
7
6
Low-dose (N=1,395)
(81 or 325 mg)
7.1%
5.7%
6.2%
High-dose (N=1,409)
(650 or 1,300 mg)
5
4
3
2
1
0
Stroke or death
at 3 months
Stroke, MI, or death at
3 months
Taylor DW, et al. Lancet 1999;353:2179-2184
Advantages and
Disadvantages of ASA
Advantages
 Proven efficacy in patients having suffered a TIA or minor stroke
(when compared with placebo)
 Cost of daily treatment
 Generally well tolerated
 Efficacy can be increased if combined with other antiplatelet drugs
Disadvantages
 Gastrointestinal discomfort
 Bleeding
 Low relative risk reduction
Unanswered questions
 Does the beneficial effect of aspirin persist after longer follow-up and
should aspirin be prescribed for life?
Advantages and
Disadvantages of Ticlopidine
Advantages
 Modest superiority over ASA
 No GI ulceration
Disadvantages
 Onset of action 48 hrs, max 8–11 days
 1% risk of neutropenia, small risk TTP
 Requires monitoring for the first 3 months
 10% incidence of diarrhea, rash, dyspepsia
Dose
 250 mg bid with meals
Clopidogrel in the Secondary
Prevention of Stroke
Clopidogrel versus Aspirin in
Patients at Risk of Ischaemic Events (CAPRIE)
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Clopidogrel 75 mg/day versus ASA 325 mg/day
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>19,000 patients divided equally into three groups
according to qualifying condition
– Ischemic stroke
– MI
– Peripheral arterial disease
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1–3 year follow-up
CAPRIE Steering Committee. Lancet 1996;348:1329-1339
Clopidogrel: Primary Analysis
RRR 8.7% (p=0.043) intent-to-treat analysis
RRR 9.4% on-treatment analysis
Stroke
MI
Treatment
group
Nonfatal
Other
Total
vascular
first
Nondeath
events
Fatal fatal Fatal
Event
rate/
year
Clopidogrel
405
33
226
49
226
939
5.32%
ASA
430
32
270
63
226
1,021
5.83%
CAPRIE Steering Committee. Lancet 1996;348:1329-1339
Clopidogrel: RRR by
Qualifying Condition*
8.7
All events
7.3
Stroke
- 3.7
MI
23.8
PAD
- 40
- 30
- 20
- 10
ASA better
0
10
20
30
40
Clopidogrel better
Relative-risk reduction (%)
* Qualifying condition at entry
PAD = peripheral arterial disease
CAPRIE Steering Committee. Lancet 1996;348:1329-1339
Clopidogrel: Clinically Important*
Adverse Events
ASA
=
Rash
Clopidogrel
Diarrhea
Indigestion/nausea/
vomiting
Any bleeding disorder
Intracranial
hemorrhage
* Severe
Gastrointestinal
hemorrhage
= Statistically significant
(p<0.05)
=
0
0.2
Clopidogrel 75 mg/day (n=9,599)
ASA 325 mg/day (n=9,586)
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Incidence (%)
Adapted from CAPRIE Steering Committee. Lancet 1996;348:1329-1339
Advantages and Disadvantages
of Clopidogrel
Advantages

Proven efficacy “modest” compared with ASA in patients with
stroke, MI or PAD
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Well tolerated
Disadvantages
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Cost of daily treatment
Unanswered questions
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Is the combination of clopidogrel plus ASA superior to ASA alone?
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Is clopidogrel more efficacious than ASA in stroke and myocardial
infarction subgroups?
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Is clopidogrel associated with thrombocytopenic purpura?