Guidelines for Prevention of

Stroke in Patients with

Ischemic Stroke or Transient
Ischemic Attack From the
Stroke Council of the AHA
Ralph L. Sacco, Chair; Robert Adams, Vice-Chair
Greg Albers, Mark J. Alberts, Oscar Benavente, Karen Furie, Larry B.
Goldstein, Philip Gorelick, Jonathan Halperin, Robert Harbaugh, S.
Claiborne Johnston, Irene Katzan, Margaret Kelly-Hayes, Edgar J.
Kenton, Michael Marks, Lee H. Schwamm, Thomas Tomsick

Stroke 2006;37:577-617
Presentation Compiled by the
AHA/ASA Professional
Education Committee
Susan C. Fagan, Chair
Deborah Bergman
Glenn D. Graham
S. Claiborne Johnston
Karen Johnston
Edgar J. Kenton
Dawn Kleindorfer
Creed Pettigrew
Kathryn Taubert, Staff Scientist
Karen Modesitt, Staff
Introduction
This slide set was adapted from the AHA/ASA
Guidelines for Prevention of Stroke in Patients with
Ischemic Stroke or Transient Ischemic Attack.

From the American Heart Association/American

Stroke Association Council on Stroke

Co-Sponsored by the Council on Cardiovascular

Radiology and Intervention

Affirmed by the American Academy of Neurology

The full-text guidelines are available on the Web site

of the AHA (www.americanheart.org)
Introduction

Since the 1999 AHA Stroke Council guidelines

for the secondary prevention of stroke, important
evidence from clinical trials has emerged that
further supports and broadens the options for
aggressive risk reduction therapies.

The secondary prevention patient population to

be addressed includes those with prior stroke or
transient ischemic attack, regardless of etiology.
 Changes from 1999 Guidelines
• 1999 guidelines* DID NOT include levels of
evidence

• BP targets have been lowered to 120/80

• For diabetes, HbA1c <7%, rather than glucose

<126 mg/dL is now targeted.

• LDL <70 mg/dL now recommended for very-high-

risk persons with multiple risk factors
• Physical activity recommendations have been
increased.
* Wolf PA et al. Stroke 1999;30:1991-94
 Changes from 1999 Guidelines

• Antiplatelet agents now the sole antithrombotic

recommended for noncardioembolic stroke
• Aspirin no longer solely recommended as first line
• Ticlopidine no longer recommended as an option
• New guidelines much more comprehensive

Wolf PA et al. Stroke 1999;30:1991-94

Secondary Prevention Definition

Therapy to reduce recurrent stroke and other

cardiovascular events and decrease cardiovascular
mortality in patients with previous stroke or TIA.
Although prevention of stroke is of primary
interest, many grades of recommendations were
chosen to reflect the existing evidence on the
reduction of all cardiovascular outcomes.
Transient Ischemic Attacks

• Guidelines now recognize TIA as an important

harbinger of stroke.
- >10% 90-day risk of stroke after TIA

• Prevention recommendations for patients with

ischemic stroke are now broadly applied to
those with TIA.
- Recognizes common etiologies and urgent
need for treatment
AHA Classes and Levels of Evidence
• Class I Agreement the treatment is useful and effective

• Class II Conflicting evidence and/or a divergence of opinion about

the usefulness/efficacy of a treatment.
- Class IIa Weight of evidence is in favor of the treatment.
- Class IIb Usefulness/efficacy is less well established by evidence

• Class III Evidence and/or general agreement that the treatment is

not useful/effective and in some cases may be harmful.

Levels of Evidence
• A: Data derived from multiple randomized trials.
• B: Data derived from a single randomized trial or nonrandomized
studies.
• C: Consensus opinion of experts.
Components of Secondary
Prevention
Blood pressure control
Diabetes management
Lipid management
Smoking cessation
Alcohol moderation
Weight reduction / physical activity

Carotid artery Interventions

Antiplatelet agents / anticoagulants

Statins
Diuretics +/- ACE inhibitors
Challenges of Dissemination
The committee acknowledges that strategies for
implementation of the guidelines need to be
developed and disparities in health care delivery
addressed.
 Blood Pressure Control
ASA 2006 Secondary Stroke Recs
• Antihypertensives are recommended beyond the
hyperacute period (Class I, Evidence A).
- Benefit for those with & w/o HTN (Class IIa,
Evidence B)
- Target BP level and reduction are uncertain, but
normal BP levels are <120/80 by JNC-7* (Class IIa,
Evidence B).

• Lifestyle modifications have been associated with BP

reductions and should be included (Class IIb, Evidence C).

• Optimal drug regimen uncertain; data support diuretics

and the combination of diuretics and an ACEI (Class I,
Evidence A).
*Chobanian AV et al. JAMA 2003;289:2560-71.
 PROGRESS Trial Results
Combination versus Monotherapy
Events Favors Favors Risk
Reduction
active placebo active placebo
(95%CI)

• Stroke

• Combination 150/1770 255/1774 43% (30 to 54)

• Single Drug 157/1281 165/1280 5% (-19 to 23)

• Total Stroke 307/3051 420/3054 28% (17 to 38)

0.4 1.0 2.0

Hazard Ratio
PROGRESS Collaborative Group. Lancet 2001;358:1033-41
 PROGRESS Trial Results
Hypertensive versus Normotensive Patients
Events/patients Favors Favors Risk reduction
Active Placebo active placebo (95%CI)
• Stroke
Hypertensive 163/1464 235/1452 32% (17 to 44)
Non-hypertensive 144/1587 185/1602 27% (8 to 42)

Total stroke 307/3051 420/3054 28% (17 to 38)

• Major vascular events

Hypertensive 240/1464 331/1452 29% (16 to 40)
Non-hypertensive 218/1587 273/1602 24% (9 to 37)

Total events 458/3051 604/3054 26% (16 to 34)

0.5 1.0 2.0

Hazard ratio
PROGRESS Collaborative Group. Lancet 2001;358:1033-41
Diabetes
ASA 2006 Secondary Stroke Recs
• More rigorous control of HTN and dyslipidemia
should be considered in patients with DM.
- BP targets of 130/80 mm Hg (Class IIa,
Evidence B). ACEIs and ARBs are recommended as
first-choice medications for patients with DM (Class
I, Evidence A).
• Glucose control is recommended to near
normoglycemic levels to reduce microvascular
complications (Class I, Evidence A) and possibly
macrovascular complications (Class IIb, Evidence B).
• Hemoglobin A1c goal <7% (Class IIa, Evidence B).
 Cholesterol Control
ASA 2006 Secondary Stroke Recs
• Those with elevated chol, CHD, or evidence of an
atherosclerotic origin should be managed according
to NCEP III* (Class I, Evidence A).
• Statins are recommended with target LDL-C of
<100 mg/dL and <70 mg/dL for the very high–risk
(Class I, Evidence A).
• Those with no pre-existing indications for statins
(nl chol levels, no CHD, or no atherosclerosis), are
reasonable to consider for statins to reduce the risk
of vascular events (Class IIa, Evidence B).
*JAMA. 2001;285:2486-97
 Cholesterol Control
ASA 2006 Secondary Stroke Recs
Baseline SIMVASTATIN PLACEBO Rate ratio & 95% CI
feature (10269) (10267) STATIN better PLACEBO better
Prior coronary disease
Yes 1459 (21.8%) 1841 (27.5%)
No 574 (16.1%) 744 (20.8%)
Prior cerebrovascular disease
Yes 406 (24.7%) 488 (29.8%)
No 1627 (18.9%) 2097 (24.3%)
Prior diabetes
Yes 601 (20.2%) 748 (25.1%)
No 1432 (19.6%) 1837 (25.2%)
24% SE 3
ALL PATIENTS 2033 (19.8%) 2585 (25.2%) reduction
(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Heart Protection Study Collaborative Group. Lancet 2002;360:7-22

 HPS: Conclusions for people with
cerebrovascular disease
• Lowering LDL cholesterol by 1 mmol/L (40 mg/dL)
reduces the 5-year risk of ischemic stroke by about one
quarter, with no apparent adverse effect on cerebral
hemorrhage.

• Similar proportional reductions in stroke risk are seen

with statin therapy irrespective of age, sex, lipid levels,
blood pressure, or use of other medications (including
aspirin).

• Statin therapy clearly reduces the risk of major vascular

events among people with pre-existing cerebrovascular
disease, irrespective of the presence of coronary disease.
Heart Protection Study Collaborative Group. Lancet 2002;360:7-22
 Recommendations for Modifiable
Behavioral Risk Factors
• Smoking: All ischemic stroke or TIA patients who
smoked in the past should be encouraged not to smoke
(Class I, Level C).
• Alcohol: Patients with prior ischemic stroke or TIA who
are heavy drinkers should eliminate or reduce their
consumption of alcohol (Class I, Level A).
• Obesity: Weight reduction may be considered for all
overweight ischemic stroke or TIA patients to maintain the
goal BMI (Class IIb, Level C).
• Physical activity: Substantial evidence exists that physical
activity exerts a beneficial effect on multiple cardiovascular
risk factors including those for stroke (Class IIB, Level C).
Symptomatic Carotid
Endarterectomy ASA 2006
Secondary Stroke Recs
• Ipsilateral severe (70% to 99%) carotid stenosis,
CEA is recommended (Class I, Evidence A).
• Ipsilateral moderate (50% to 69%) carotid
stenosis, CEA is recommended depending on age,
gender, comorbidities, and the severity of symptoms
(Class I, Evidence A).
• Stenosis <50%, there is no indication for CEA
(Class III, Evidence A).
 Urgent Endarterectomy

Surgery within 2 weeks is suggested rather than delaying surgery

(Class IIa, Evidence B).
Rothwell PM. Lancet 2004;363(9413):915-24
Carotid Angioplasty and Stenting
ASA 2006 Secondary Stroke Recs
• CAS may be considered (Class IIb, Evidence B).
- Stenosis (>70%) difficult to access surgically
- Medical conditions that greatly increase the
risk for surgery, or
- When other circumstances exist such as
radiation-induced stenosis or restenosis after
CEA.
• CAS is reasonable when performed by operators
with morbidity and mortality rates of 4% to
6% (Class IIa, Evidence B).
Atrial Fibrillation
ASA 2006 Recommendations
• For patients with ischemic stroke or TIA with
persistent or paroxysmal (intermittent) AF,
anticoagulation with adjusted-dose warfarin (target
INR 2.5, range 2.0 to 3.0) is recommended (Class I,
Evidence A).
• For patients unable to take oral anticoagulants,
aspirin 325 mg per day is recommended (Class I,
Evidence A).
Stroke Prevention:
Non-cardioembolic
ASA 2006 Recommendations
For patients with noncardioembolic ischemic
stroke or TIA, antiplatelet agents are
recommended rather than oral anticoagulation
to reduce the risk of recurrent stroke and other
cardiovascular events (Class I, Evidence A).
 Warfarin-Aspirin for Recurrent
Stroke Study (WARSS)
30

1.13
Probability of Event (%)

Hazard Ratio
20 Warfarin P=0.25

The primary
outcome occurred
10 Aspirin in 17.8% of
patients in the
warfarin group and
16.0% in the ASA
group.
0
0 90 180 270 360 450 540 630 720
No. at Risk Days After Randomization
Warfarin 1103 1047 1013 998 972 956 939 924 885
Aspirin 1103 1057 1032 1004 984 974 951 932 900
Mohr JP et al. N Engl J Med 2001;345:1444-51
Stroke Prevention: Non-cardioembolic

ASA 2006 Recommendations

• Acceptable options for initial therapy
(Class IIa, Evidence A).
- aspirin (50-325 mg qd)
- the combination of aspirin and extended-
release dipyridamole (25/200 mg bid)
- clopidogrel (75 mg qd)
Antiplatelet Therapy
ASA 2006 Recommendations
• Compared to aspirin alone, both the
combination of aspirin and extended-release
dipyridamole and clopidogrel are safe.

• The combination of aspirin and extended-release

dipyridamole is suggested instead of aspirin alone
(Class IIa, Level A).

• Clopidogrel is suggested instead of aspirin alone

based on direct comparison trials
(Class IIb, Level B).
 ESPS 2: Effects on Stroke—Relative
Risk Reduction (Pair-wise Comparisons)
37.0%
40.0% P < 0.001
35.0%
30.0% ASA/ER-DP vs. Placebo
23.1%
25.0% P = 0.006
18.1% ER-DP vs. Placebo
16.3%
20.0% P = 0.013
P = 0.039
ASA vs. Placebo
15.0%
10.0% ASA/ER-DP vs. ASA
5.0%
0.0%
RRR ER-DP = Extended-Release
Dipyridamole
ASA = Acetylsalicylic Acid
RRR = Relative Risk Reduction

ESPS 2 Group. J Neurol Sci 1997;151(suppl):S1-S77

CAPRIE Study

Efficacy of Clopidogrel vs Aspirin in MI,

Ischemic Stroke, or Vascular Death (n=19,185)
Event Rate per Year 8.7%*
Aspirin
16 Overall
Relative Risk
Cumulative Event Rate (%)

Reduction
12 Aspirin Clopidogrel
5.83%

8 5.32%
Clopidogrel
4

0
3 6 9 12 15 18 21 24 27 30 33 36
Months of Follow-up

*ITT analysis.
CAPRIE Steering Committee. Lancet 1996;348:1329-39
Secondary Stroke Prevention
ASA 2006 Recommendations

• Insufficient data are available to make evidence-

based recommendations regarding choices between
antiplatelet options other than aspirin. Selection of
an antiplatelet agent should be individualized based
on patient risk factor profiles, tolerance, and other
clinical characteristics.
Secondary Stroke Prevention
ASA 2006 Recommendations

• The addition of aspirin to clopidogrel increases

the risk of hemorrhage and is not routinely
recommended for stroke or TIA patients (Class
III, Evidence A).
• For patients allergic to aspirin, clopidogrel is
recommended (Class IIa, Evidence B).
 MATCH Trial Primary End Point:
MI, IS, Vascular Death, or Rehospitalization for an Acute
Ischemic Event
0.20 N=7,599 6.4%*
Overall
0.16 Relative Risk
Clopidogrel Reduction
Cumulative Event Rate

+ Placebo
0.12 P = 0.244
Clopidogrel
+ ASA *ITT Analysis
0.08

0.04

0.00
0 3 6 9 12 15 18
Months of Follow Up

Diener H-C et al. Lancet 2004;364:331-7

 MATCH: Safety Outcomes
• Excess life-threatening bleeding events with
combination versus clopidogrel monotherapy:
96 (2.6%) vs. 49 (1.3%); p<0.0001

• Excess minor bleeds with combination therapy

versus clopidogrel alone:
120 (3.2%) vs. 39 (1.0%); p<0.0001

Diener H-C et al. Lancet 2004;364:331-7

Secondary Stroke Prevention
ASA 2006 Recommendations
• For patients who have an ischemic
cerebrovascular event while taking aspirin,
there is no reliable evidence that increasing the
dose of aspirin provides additional benefit.
Although alternative antiplatelet agents are
often considered for these patients, no single
agent or combination has been specifically
evaluated in patients who have had an event
while receiving aspirin.
Stroke and Pregnancy
ASA 2006 Secondary Stroke Recs
• High-risk thromboembolic conditions consider:
- adjusted-dose UFH throughout pregnancy,
- adjusted-dose LMWH with Factor Xa
monitoring
- UFH or LMWH until week 13, followed by
warfarin until mid-3rd trimester, then UFH or
LMWH in last trimester (Class IIb,
Evidence C).
• Lower risk conditions
- UFH or LMWH in the first trimester followed
by - low-dose aspirin for the remainder of the
pregnancy (Class IIb, Evidence C).
 Adjusted Relative Risk of Stroke
According to a Woman’s Status With
Respect to Pregnancy*
RR of RR of RR
of Cerebral Intracerebral Either
Type Infarction Hemorrhage of
Stroke‡
Risk Period†
(95% CI)
During pregnancy or 6 weeks
(95% CI) (95%
1.6 (1.0-2.7) 5.6
CI)
(3.0-10.5) 2.4 (1.6-3.6)
After pregnancy
During pregnancy 0.7 (0.3-1.6) 2.5 (1.0-6.4) 1.1
(0.6-2.0)
During 6 weeks after pregnancy 5.4 (2.9-10.0)18.2
(8.7-38.1)
* Relative risks have been 7.9 (5.0-12.7)
adjusted for age and race; † The 6-
weekAfter delivery
period after pregnancy 8.7was
(4.6-16.7)28.3
defined as the (13.0-61.4)
6 weeks after a
12.7 (7.8-20.7)
spontaneous or induced abortion, stillbirth, or live birth; ‡
Subarachnoid
After abortion hemorrhages (SAHs)
1.1 have been
(0.2-7.9) excluded. 1.8
4.5 (0.6-33.1)
Kittner SJ et al. (1996), N Engl J Med 335(11):768-774
 Postmenopausal Hormones
ASA 2006 Secondary Stroke Recs

For women with ischemic stroke or TIA,

postmenopausal hormone therapy (with estrogen
with or without a progestin) is not recommended
(Class III, Evidence A).
 Women’s Health Initiative
• 16,608 postmenopausal women, 50-79 years,
with an intact uterus at baseline were recruited
by 40 U.S. clinical centers for the period 1993-
1998.
• Received conjugated equine estrogens, 0.625
mg/d, plus medroxyprogesterone acetate, 2.5
mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
• After a mean of 5.2 years of follow-up, the trial
was stopped because of high rates of invasive
breast cancer and the global index statistic
supported risks exceeding benefits.
Rossouw et al. JAMA 2002;288(3):321-33
 Estimates of Cumulative Hazards for
Strokes in Women’s Health Initiative
0.030
Study
Estrogen +
Cumulative Hazard

0.025
Progestin
0.020
Placebo
0.015
0.010

0.005

0
0 1 2 3 4 5 6 7
Time (Years)

Rossouw et al. JAMA 2002;288(3):321-33

Other Circumstances
ASA 2006 Secondary Stroke Recs
• Dissections
• PFO and hyperhomocysteinemia
• Hypercoagulable states
• Sickle cell disease
• Cerebral venous thrombosis
• Anticoagulation after cerebral hemorrhage
Level A Recommendations
• Antihypertensive treatment
• Glucose control to reduce microvascular
complications of diabetes
• Statins to reduce LDL to <100 or <70 for high-risk
patients (sympt CHD or athero)
• CEA for sympt 50-99%
• NO CEA for <50% sympt stenosis
• Warfarin at INR 2.5 for Afib. (ASA if unable)
• Antiplatelet for noncardioembolic
• NO combination clopidogrel and ASA
Summary
• These guidelines provide comprehensive and
timely evidence-based recommendations.
• There is an intent to fully update the guidelines
every 3 years, with updates encouraged when
pivotal studies are published.