Transcript Evaluation for Cause and Prevention of Stroke Recurrence

Prevention of Stroke or
Recurrent Stroke, Including
Management of Risk Factors
Evaluation for Cause and
Prevention of Stroke
Recurrence
Recurrent Stroke
• An important outcome for diagnosis and
prevention
• Approximately 25% of the estimated 750,000
strokes each year in the US are recurrences
• Must be distinguished from worsening or
evolving stroke and medical complications of
stroke (e.g., infection, electrolyte imbalance)
Risk of Stroke Recurrence
(percentage experiencing
stroke)
30 days
1 Year
After TIA
4-8%
12-13%
After Stroke
3-10%
10-14%
5 Years
24-29%
25-40%
Source: Sacco RL, Wolf PA, Gorelick PB.
Neurology 1999; 53 (supp 4): S15-S24.
High Risk of Early Stroke
Recurrence After TIA
• Study of 1707 TIA patients who were
evaluated in the ED of a large health care
plan
• 180 patients or 10.5% developed stroke
within 90 days
• 91 patients did so within 2 days
• Predictors of stroke: >60 yrs, diabetes
mellitus, focal symptoms of weakness or
speech impairment, TIA lasting >/= 10
minutes
• Importance of rapid diagnosis and treatment
of TIA
Recurrence Rate by Stroke
Subtype
Athero Cardiac Emb
30 day 18.5%
5.3%
Lacune Etiol?
1.4%
3.3%
90 day 21.4%
8.6%
1.4%
4.8%
1 year
24.4%
13.7%
7.1%
13.2%
5 year
40.2%
31.7%
24.8% 33.2%
Source: Petty et al. Stroke 2000; 31: 1062-1068
Early Stroke Worsening:
Recurrence or Evolving
Stroke?
US NINDS National Stroke Data Bank
1. Approximately 75% of cases with early
worsening of stroke deficit have
deterioration due to the incident stroke
2. Common within the first 3-4 days after
stroke onset and with larger artery
atherosclerotic disease
3. Lacunes more likely to improve within the
first 7-10 days after stroke onset
Source: Unpublished (cited in Sacco RL et al.
Neurology 1999; 53 (Supp 4): S15-S24
Putative Predictors of Early
Stroke Recurrence
• Hypertension
• Elevated blood glucose
Source: Sacco RL, Shi T, Zamanillow MC,
Kargman D. Neurology 1994; 25: 958962 and Lai Min S, Alter S, Friday G,
Sobel E. Stroke 1994; 25: 958-962
Putative Predictors of Late
Stroke Recurrence
•
•
•
•
•
Age
Hypertension
Heart Disease
Atrial Fibrillation
Heavy Alcohol Use
•
•
•
•
CHF
Diabetes Mellitus
Hyperglycemia
Prior stroke/TIA
Stroke Recurrence and
Mortality After Ischemic Stroke
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
30 days
1 year
5 years
At 30 days: 8%
At 1 year: 22%
At 5 years: 45%
Immediate cause of death
is vascular disease in
about 60%
For hemorrhagic stroke at
30 days: </= 50%
Source: Sacco RL et al.
Neurology 1994; 44:
626-634
Stroke Recurrence and
Subsequent Stroke Subtype
• May be difficult to determine stroke subtype
as a comprehensive battery of diagnostic
tests are not performed
• Ischemic stroke begets ischemic stroke
recurrence
• Primary intracerebral hemorrhage (PICH)
may give rise to recurrent hemorrhage in the
same location or in the mirror image location,
or an ischemic stroke
• Annual recurrence rates after PICH: PICH
(2.4%) vs. ischemia (3.0%)
Source: Hill MD, Silver FL, Austin PC, Tu JV. Stroke 2000; 31: 123-
Diagnostic Evaluation for
Cause of Stroke Recurrence:
Pertinent Questions
• Early stroke recurrence?
• Worsening of incident stroke (e.g.,
cerebral edema/mass effect,
hemorrhagic infarction)?
• Medical complication of stroke (e.g.,
infection, or electrolyte, fluid, glucose or
other metabolic imbalance)?
Diagnostic Evaluation for
Cause of Stroke Recurrence:
Pertinent Questions
(continued)
• Was the prior stroke diagnostic work-up
complete or were key diagnostic studies
omitted?
• Am I providing the appropriate stroke
treatment and preventatives based on the
stroke mechanism?
• Based on the extent of the prior stroke
diagnostic work-up, the patient’s overall
clinical condition and severity of illness, and
Diagnostic Evaluation for
Cause of Recurrent Stroke-1
• CT or MRI to distinguish hemorrhagic stroke
from ischemic stroke and extension of the
incident stroke
• Diffusion-weighted MRI to diagnose new
brain infarction
• Clues from general medical history and
examination to establish possible medical
complications and appropriate diagnostic
studies
Diagnostic Evaluation for
Cause of Recurrent Stroke-2
•
Follow principles in other sections of
this course:
1. Section 1: Clinical Diagnosis of Stroke
2. Section 2: Neuroimaging Evaluation
Pharmacologic Therapy for
Recurrent Stroke Prevention:
Antithrombotic Agents
Antiplatelet Therapy
• In the US, 4 approved antiplatelet
agents for use in recurrent stroke
prevention:
*Aspirin 50-325 mg/day
*Ticlopidine 250 mg twice daily
*Clopidogrel 75 mg/day
*Aspirin (25 mg) plus extended-release
dipyridamole (200 mg) twice a day
Mechanism of Antiplatelet
Agents
Agent
Aspirin
Mechanism
Irreversible loss of cyclooxygenase activity
Ticlopidine/ Inhibition of ADP binding to
Clopidogrel
platelet glycoprotein IIb/IIIa
receptor
ExtendedInhibition of platelet phosphdiest.
Release
(increases c-AMP) potentiates
Dipyridamole prostacyclin, release of prostacyclin,
and inhibits uptake and metabolism
of adenosine (platelet inhibitor and
vasodilating agent)
US FDA Ruling on Aspirin Dose
for Patients with Symptomatic
Cerebrovascular Disease
• Based on individual studies of efficacy of lower
doses of aspirin for recurrent cerebral ischemia
prevention and more favorable side effect
profile with lower doses of aspirin
• Meta-analyses show no difference between
high, medium and low doses of aspirin for
prevention of major vascular events
• FDA recommendation: 50-325 mg/day
• Antiplatelet Trialists’ Collaboration: for
stroke/TIA patients a 40/1000 reduction of
major vascular events (stroke, MI, vascular
death) over 3 years
Aspirin As Acute Stroke
Therapy: IST and CAST
• Aspirin dose: 300 mg or 160 mg/day
• Results: Modest Benefits
1. Reduction of recurrent ischemic stroke:
7/1000
2. Reduction of death w/o further stroke:
4/1000
3. Reduction of stroke/death in hospital:
9/1000
4. Hemorrhagic stroke or hemorrhagic stroke
transformation: 2/1000
IST= International Stroke Trial
Explanations for Aspirin
“Failure” in Clinical Practice
• Non-compliance
• Inadequate aspirin dose
• Resistance to aspirin (tachyphylaxis)
• Irrelevance of biological effect
• Other mechanisms
*Correlative studies of platelet function and
clinical outcome are needed
Source: Helagason CM, Hoff JA, Kondos G,
Brace LD. Stroke 1993; 24: 1458-1461
Aspirin vs. Placebo for
Prevention of Major Vascular
Events
• 15% relative risk reduction in favor of aspirin
for stroke prevention
• 13% relative risk reduction in favor of aspirin
for stroke, MI and vascular death prevention
Source: Johnston ES, et al. Arch Intern Med
1999; 159: 1248-1253 and Algra A and Avan
Gijn J. J Neurol Neurosurg Psychia 1996; 60:
197-199
Risk of Hemorrhagic Stroke in
Persons Taking Aspirin:
Collaborative Trials
•
Hemorrhagic stroke risk appears to be
low:
1. Increase in hemorrhagic stroke:
12/10,000
2. Reduction in myocardial infarction:
137/10,000
3. Reduction in ischemic stroke:
39/10,000
Source: He J, Whelton PK, Vu B, Klag
MJ. JAMA 1998; 280: 1930-1935
Aspirin, ACE-I and NSAIDs:
Antagonistic Interactions?
• At aspirin doses of >/= 300mg, aspirin’s
effect of inhibiting prostaglandin
synthesis may undo a beneficial effect
of ACE-I (ACE-I increases bradykinin
which promotes synthesis of
vasodilating prostaglandins)
• Ibuprofen may competitively inhibit COX
site and prevent aspirin effect
Efficacy of Ticlopidine,
Clopidogrel, and Aspirin plus
Extended-Release
Dipyridamole vs. Aspirin Alone:
Indirect Comparisons
Can We Achieve Better
Outcomes for Stroke with NonAspirin Antiplatelet Agents?
• Agent ARR over Aspirin NNT p-value
Ticlopidine
2.5%
40
.02
Clopidogrel
0.8%
125
.28
Aspirin plus
3.0%
33
.006
Extended-release
Dipyridamole
ARR= absolute risk reduction NNT=number
needed to treat Source: Albers G et al.
Chest 2001; 119:300S-320S
Pitfalls of Indirect Antiplatelet
Comparisons
• Lack of head-to-head comparison of
agents
• Different study epochs
• Different types of patients
• Different doses of aspirin
*A rigorous study with head-to-head direct
comparisons is needed
Common and Key Side Effects
and Cost of Antiplatelet
Agents-1
• Aspirin: dyspepsia and GI bleeding,
inexpensive
• Ticlopidine: diarrhea, GI symptoms, rash,
neutropenia, TTP; cost-effective over aspirin
• Clopidogrel: more favorable side effect
profile than ticlopidine and about as safe as
aspirin; rash, diarrhea, GI symptoms, ?TTP;
may be cost-effective over aspirin
• Aspirin plus Extended-Release
Dipyridamole: headache, GI symptoms,
dizziness; cost-effective over aspirin
American College of Chest
Physicians’Recommendation
for Initial Antiplatelet Therapy
• Any one of the following agents:
Aspirin
Aspirin plus extended-release
dipyridamole
Clopidogrel
Source: Albers GW, Amarenco P, Easton
JD, et al. Chest 2001; 119: 300S-320S
Combination Antiplatelet
Therapy for Recurrent Stroke
Prevention
• Aspirin plus extended-release
dipyridamole is the only combination
antiplatelet agent that is approved for
prevention of stroke by the FDA
• Aspirin plus clopidogrel vs. clopidogrel
is being tested in high risk stroke
patients (MATCH study)
Oral Anticoagulation for
Recurrent Stroke Prevention
Warfarin
• The primary indication is for stroke prevention
in non-valvular atrial fibrillation (NVAF)
• Adjusted-dose warfarin reduces risk of stroke
in AF by about 60% (vs. 20% for aspirin)
• Recommended INR range: 2.0-3.0, target=
2.5
• Other indications: other cardiac sources of
embolism (e.g., acute MI with thrombus,
cardiomyopathy with low ejection
fraction[undergoing further testing in Warfarin
vs. Aspirin in Reduced Cardiac Ejection
Fraction study])
Selection of Antithrombotic
Therapy in AF by Risk Strata
Risk
High
Risk Factors
Treatment
Prior stroke/TIA or
Warfarin
systemic emb, HTN,
poor LV function,
+75yrs, rheumatic
mitral valve disease
Medium 65-75yrs, DM and
1 factor:
warfarin
CAD w preserved LV or aspirin*; >
1
systolic function
factor:
warfarin
Warfarin: A Double-Edged
Sword
• High risk reductions in NVAF
• Narrow therapeutic index drug
• Patient selection: compliant, reliable, and
willing to undergo frequent INR monitoring
• Elderly stand to benefit most on warfarin but
may have complicating conditions that make
administration of warfarin problematic: prone
to falls, cognitive impairment, visual
difficulties, social isolation, etc
Warfarin Aspirin Recurrent
Stroke Study (WARSS)
•
Multicenter, double-blind, randomized trial of
warfarin (INR 1.4-2.8) vs. aspirin 325
mg/day in non-cardioembolic stroke patients
• Primary outcome: stroke or death within 2
years
• Results:
1. No major difference in the 2 treatment
groups for the primary outcome endpoint
(17.8% warfarin vs. 16.0% aspirin) or major
hemorrhage (2.22/100 pt-yrs warfarin vs.
1.49/100 pt-yrs for aspirin
Source: Mohr JP, Thompson JLP, Lazar RM, et
Recently Completed or
Ongoing Recurrent Stroke
Prevention Studies in Adults
• Women’s Estrogen for Stroke Trial
(WEST):Estradiol does not reduce mortality
or stroke recurrence in postmenopausal
women with cerebrovascular disease (higher
risk of fatal stroke and worse neurologic and
functional deficits)*
• African American Antiplatelet Stroke
Prevention Study (AAASPS): Ticlopidine vs.
aspirin
• Warfarin-Aspirin Symptomatic Intracranial
Disease Study (WASID): Warfarin vs. aspirin
*Viscoli CM, Brass LM, Kernan W, et al. N Engl
Recurrent Stroke Prevention
Through Risk Factor Control
• Paucity of information regarding efficacy and
safety of most risk factor therapies in
recurrent stroke prevention
• Well-established methods to control risk
factors for a first stroke are utilized to control
risk factors to prevent a recurrent stroke
Source: Gorelick PB, Sacco RL, Smith DB, et
al. JAMA 1999; 281: 1112-1120 and Goldstein
LB, Adams R, Becker K, et al Stroke 2001;
32: 280-299
Stroke Risk Factor Reduction
Recommendations
Risk Factor Goal
Recommendation
Hypertension <140/90* JNC VI guidelines
Smoking
Cessation Counseling,
nicotine, bupropion
Diabetes
HbA1c
ADA guidelines
<7%
Alcohol
</= 2 drinks Counseling
*<130/80-85 if diabetic
Stroke Risk Factor Reduction
Recommendations (cont.)
Risk Factor
Goal
Recommendation
Physical
30-60 min. Moderate
exercise
Inactivity
most days
Weight
</= 120% of Diet, exercise
ideal body wght
Lipids*
LDL <100mg/dl NCEP III
guidelines
*if symptomatic atherosclerotic carotid artery
disease
Effect of Blood Pressure
Reduction on Risk of Recurrent
Stroke
• Overview analysis shows a 19% recurrent
stroke reduction; suggestive of benefit but
inconclusive as small numbers of study
subjects
• Perindopril Protection Against Recurrent
Stroke Study (PROGRESS): Does perindopril
(ACE-I) +/- indapamide (diuretic) reduce
recurrent stroke risk among ischemic and
hemorrhagic stroke patients who do or do not
have hypertension and are treated for 4
years?
PROGRESS Results
• Perindopril-based therapy was well tolerated
• Overall BP reduction in the active treatment
group was about 9/4 mm Hg
• Stroke risk reduction was 28% (95% CI 17,
38)
• Major vascular event risk reduction was 26%
(95% CI 16, 34)
• Subgroups that benefited the most: dual
therapy group, Asians, hypertensives,
hemorrhagic stroke reduction
• Source: PROGRESS Collaborative Group.
Implications of PROGRESS
• Development of new guidelines for blood
pressure control in recurrent stroke
prevention (hypertensives and nonhypertensives benefited)
• Blood pressure and stroke: a continuum of
risk
• Important implications for physicians who
treat stroke patients
• Findings are complementary to HOPE study
results
Carotid Endarterectomy (CEA)
Indications for CEA
Condition % Stenosis Indicated? NNT
Symptomatic 70-99%
yes
8
Symptomatic 50-69%
yes*
20
Symptomatic <50
no
67
Asymptomatic 60-99% yes**
83
*indicated in high risk patients
** indication subject to controversy
Source: Gorelick PB. Stroke 1999; 30: 17451750
Aspirin Dose After CEA
• Aspirin Carotid Endarterectomy (ACE) Trial
• Trend for reduction of stroke or death at 3
months with lower dose aspirin (81 or 325
mg) vs. higher dose aspirin (650 or 1300 mg)
(p=.12)
• Statistically significant trend for reduction of
stroke/MI/death at 3 months with lower dose
aspirin vs. higher dose aspirin (p=.03)
• Source: Taylor and Thorpe. Lancet
Conference 1998 (Montreal, Quebec,
Canada)
Endovascular Interventions:
Angioplasty/Stenting and Coil
Embolism
• These procedures are considered
experimental until more clinical
evidence becomes available
• Randomized, controlled clinical trials will
determine the efficacy and safety of
these procedures vs. standard
treatment
National Institute of Neurologic
Disorders and Stroke Ongoing
Clinical Trials
• Carotid Revascularization Endarterectomy vs. Stent
Trial (CREST)
A trial to compare carotid endarterectomy vs.
carotid
stenting in symptomatic carotid occlusive
disease
• Carotid Occlusion Surgery Study (COSS)
A trial to compare STA-MCA anastomosis to best
medical therapy in patients with symptomatic
internal
carotid artery occlusion and hemodynamic
failure
based on increased oxygen extraction
fraction by PET study
Angioplasty vs. Carotid
Endarterectomy (CEA) in
CAVATAS
Outcome
Angioplasty
CEA
RRR (95% CI)
1. Nondisabling
Stroke at 30d
3.6%
4.0%
9% (-114,62)
2. Death or
Disabling Stroke
at 30d
6.4%
5.9%
8% (-45,110)
3. Death or
Disabling Stroke
at 3y
14.3%
14.2%
0.8% (-34,54)
(source: ACP Journal Club: Nov/Dec 2001, pg 91)
Management
Controversies
• PFO
• Antiphospholipid Antibodies
Atrial Septal Abnormalities and
4-Year Recurrence Risk on Aspirin
Patients ages 18-55 years with cryptogenic stroke
• No PFO or atrial
septal aneurysm
• Patent foramen
ovale (PFO)
alone
• PFO and atrial
septal aneurysm
4.2%
2.3%
15.2%
Source: Mas et al. N Engl J Med 2001, 345:1740-6.
PICSS Substudy: Warfarin vs. Aspirin
WARFARIN
ASPIRIN
RR (95% CI)
16.5%
(N=97)
13.2%
(N=106)
1.29 (0.63-2.64) 0.5
No PFO
13.4%
(N=195)
(N=398)
CRYPTOGENIC
COHORT
17.4%
(N=203)
0.80 (0.49-1.33) 0.4
With PFO
(N=98)
9.5%
(N=42)
17.9%
(N=56)
0.52 (0.16-1.67) 0.3
No PFO
(N=152)
8.3%
(N=72)
16.3%
(N=80)
0.50 (0.19-1.31) 0.2
ENTIRE PICSS
COHORT
With PFO
(N=203)
Preliminary data courtesy of Shunichi Homma, NY, NY
P value
Management of Stroke with
Antiphospholipid Antibodies
• Recent NEJM review article* suggests high
dose warfarin is preferred treatment based
on several small nonrandomized
retrospective case series
• WARSS randomized substudy on
antiphospholipid antibodies
(720 patients with aPL)
shows no significant difference and trend
in
favorLevine
of aspirin
*Source:
et al. N Engl J Med 2002;346:752-63.
WARSS/APASS: WARFARIN & ASPIRIN*
Proportion with event at 2 Years
RR = 0.99
p = 0.94
RR = 0.95
p = 0.71
40%
35%
30%
aPL+
26.2% 26.2%
25%
22.2% 21.8%
aPL-
20%
15%
10%
5%
0%
Warfarin
(N=361 aPL+, 520 aPL-)
Aspirin
(N=359 aPL+, 530 aPL-)
Interaction (Treatment*aPL) p=0.91
*Relative risk, p-values reflect analyses adjusted for History of Cardiac Disease, History
of Stroke, Exercise Status and Age