recurrent stroke prevention: y an update on the. aspirin plus extended-release dipyridamole c....

1

Recurrent Stroke Prevention: An Update on the

Evidence and Opportunity in Ischemic Stroke or TIAIschemic Stroke or TIA

Case-Based Review of Guidelines forPractitioners Who Care for Patients With

Ischemic Stroke or TIA

Impact of Stroke in the United StatesOf all CVDs, stroke is the third leading cause of death Annual incidence– 780,000 strokes

600,000 first attacks180,000 recurrent attacks

1 % f k h ld d b TIA15% of strokes are heralded by TIAOne-third of TIAs may be considered cerebral infarctions based on diffusion-weighted MRI results90-day risk of stroke after TIA: 3%–17% – Highest risk within the first 30 days

American Heart Association. Heart Disease and Stroke Statistics–2008 Update. Dallas, Texas: American Heart Association; 2008 Rosamond W et al. Circulation. 2008;117(4);e25

CVD = cardiovascular disease; MRI = magnetic resonance imaging

Estimates of the Cost of Stroke

Average cost of ischemic stroke within 30 days

• $13,019 (mild)• $20,346 (severe)

Mean lifetime costof ischemic stroke

• $140,048

$65.5 billion* in 2008*Estimated direct and indirect costs American Heart Association. Heart Disease and Stroke Statistics–2008 Update. Dallas, Texas: American Heart Association; 2008; Rosamond W et al. Circulation. 2008;117(4);e25

Estimates of Long-term Risk of Stroke After Ischemic Stroke or TIA

Percentage of Patients Experiencing Stroke

TimeAfter TIA1

(%)After Stroke2

(%)

30 days 4–8 3–10

1. Feinberg WM et al. Stroke. 1994;25(6):13202. Sacco RL. Neurology. 1997;49(5 suppl 4):S39

30 days 4 8 3 10

1 year 12–13 10–14

5 years 24–29 25–40

Putative Risk Factors for Stroke RecurrenceEarly stroke recurrence

Stroke subtype– High for large artery, extra- and intracranial occlusive disease

Elevated blood glucoseHTN

kLate stroke recurrence Age HTNHeart disease (CHD, HF, AF) DM and hyperglycemia

Prior stroke or TIA

Sacco RL et al. Neurology. 1999;53(7 suppl 4):S15

AF = atrial fibrillation; CHD = coronary heart disease; DM = diabetes mellitus; HF = heart failure; HTN = hypertension

Defining Stroke Subtype Is an Important Consideration in Recurrent Stroke Prevention

Hemorrhagic stroke12%Other

5%

Cryptogenic30% Atherosclerotic

cerebrovascular

Ischemic stroke88%

Cardiogenicembolism

20%

Small vesseldisease

“lacunae”25%

cerebrovasculardisease

20%

Albers GW et al. Chest. 2004;126(3 suppl):438S Thom T et al. Circulation. 2006;113(6):e85

2

Prevention of Recurrent Stroke

Evaluation for risk factors– HTN, DM, hyperlipidemia

Evaluation for cause– Arterial diseases, heart diseases– Coagulopathies

Management of risk factors– Lifestyle and medications

Antithrombotic therapySurgical or endovascular interventions

Sacco RL et al. Stroke. 2006;37(2):577

Case PresentationCase Presentation

65-Year-Old Woman With 15-Year History of HTN

Chief complaint– Presented to the ED after a 30-minute spell of

transient right-sided face and arm weakness after exercising today

Past medical history– HTN ×15 years

Medications – HCTZ 25 mg once daily

ED = emergency department; HCTZ = hydrochlorothiazide


Physical exam – BP 149/95 mm Hg; HR 80 BPM and regular– Neurologic examination normal except for slight

weakness of the right arm and leg (NIH Stroke Scale score = 2)( )

Laboratory examination– Total cholesterol = 230 mg/dL– LDL-C = 120 mg/dL– HDL-C = 39 mg/dL – Other laboratory tests unremarkable

BP = blood pressure; BPM = beats/minute; HDL-C = high-density lipoprotein cholesterol; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; NIH = National Institutes of Health


Diagnostic studies– EKG normal– Transthoracic echocardiography showed LVH– MRA of the head and neck was unremarkable– MRI of the head

EKG = electrocardiogram LVH = left ventricular hypertrophy MRA = magnetic resonance angiography

MRI Diffusion-Weighted Imaging (DWI)

LeftRight

3


Diagnostic studies– EKG is normal– Transthoracic echocardiography showed LVH– MRA of the head and neck was unremarkable– MRI of head shows DWI abnormality

predominantly of left posterior limb of internal capsule consistent with ischemic injury

Guidelines for Management of TIAGuidelines for Management of TIA

Johnston SC et al. Ann Neurol. 2006;60(3):301

Definitions of Classes and Levels of Evidence: AHA/ASA 2006 Stroke Prevention Guidelines

Class I Evidence or general agreement that procedure or treatment is useful and effective

Class II Conflicting evidence or divergence of opinion of usefulness/efficacy

Class IIa Weight of evidence or opinion is in favor

Class IIb Usefulness/efficacy is less well established by evidence or opinion

Class III Evidence and/or general opinion that usefulness/effectiveness does not exist and may be harmful

LOE A Derived from multiple RCTs

LOE B Derived from a single RCT or nonrandomized studies

LOE C Expert opinion or case series


AHA/ASA = American Heart Association/American Stroke Association RCT = randomized clinical trial LOE = level of evidence

Recent TIA: A Neurologic Emergency

Risk of stroke after TIA – 10.5% occurred within 90 days and half occurred within

2 days (Kaiser-Permanente HMO study)

Risks may have been previously underestimated1% 2% at 7 days and 2% 4% at 30 days– 1%─2% at 7 days and 2%─4% at 30 days

True risk– Up to 10% at 7 days and as high as 15% at 30 days

Time window for prevention is brief– 17% of TIAs occur on the day of stroke– 43% during the 7 days prior to stroke

Rothwell PM. Nat Clin Pract Neurol. 2006;2(4):174

Predicting Risk of Stroke After TIA:ABCD2 Score for 2- or 7-Day Risk of Stroke

A Age ≥60 years 1 point

B Blood pressure SBP >140 mm Hg or DBP ≥90 mm Hg 1 point

C Clinical featuresUnilateral weakness 2 pointsSpeech disturbance without

k 1 point

Johnston SC et al. Lancet. 2007;369(9558):283 Rothwell PM et al. Lancet. 2005;366(9479):29

weakness p

D Duration of symptoms

≥60 minutes 2 points10–59 minutes 1 point

D Diabetes Diabetes 1 point

Maximum score 7 points

DBP = diastolic blood pressure; SBP = systolic blood pressure

4

ABCD2 Is Predictive of 2-Day Risk of Stroke in Patients With TIA

ABCD2 Score Level of Risk2-Day Stroke Risk

(%)

6–7 High 8.1

Johnston SC et al. Lancet. 2007;369(9558):283

g

4–5 Moderate 4.1

0–3 Low 1.0

Traditional TIA Symptoms and Signs*: Carotid Territory (1974)

Symptom Sign

1. Motor dysfunction Weakness, clumsiness, paralysis of 1 or both limbs on same side

2. SensoryNumbness, loss of sensation, and paresthesias of 1 or both limbs on same side; without spread or marchside; without spread or march

3. Speech/language Aphasia4. Vision Loss in 1 eye or part of 1 eye5. Vision Homonymous hemianopia6. Multiple Combination of above

Heyman A et al. Stroke.1974;5:277

*Symptoms/sign can last up to 24 hours

TIA: New Definition Is Proposed (2002)Definition

Brief episode of neurologic dysfunction caused by focal brain or retinal ischemiaClinical symptoms typically lasting less than 1 hourNo evidence of cerebral infarction (using advanced neuroimaging techniques)q )Urgent brain imaging is recommended

Albers GW et al. N Engl J Med. 2002;347(21):1713

Rationale• Traditional definition is out of date and no longer consistent with current

concepts of brain ischemia• Most TIAs are short lived, and advanced imaging techniques may show

cerebral ischemic injury

National Stroke Association (NSA) Guidelines for the Management of TIAs

Factor CommentHospitalization • Consider within 24–48 hours of first TIA

• Timely hospital referral of recent (within 1 week) TIA and hospital admission is generally recommended in the case of crescendo TIAs, symptoms longer than 1 hour, symptomatic carotid stenosis >50%, known cardiac-source embolism, hypercoagulable state, or appropriate California or ABCD score

• Hospitals/practitioners should have local admission policy and referral policy for specialists’ assessments

• Local written protocols for diagnostic testingLocal written protocols for diagnostic testing

Clinical evaluation • Specialized clinic for rapid assessment and evaluation within 24–48 hours

Timing of initial assessment

• For recent TIA, need same-day access to imaging such as CT/CTA, MRI/A, and/or CUS

• If not admitted to hospital, rapid (within 12 hours) access to urgent assessment and investigation

• If TIA occurred in past 2 weeks and the patient was not hospitalized, prompt (24–48 hour) investigations (CUS, blood work, EKG, echocardiogram) needed


CT/CTA = computed tomography/computed tomographic angiography CUS = carotid ultrasound

NSA Guidelines for the Management of TIAs: Evaluation

Factor Comment

General EKG, CBC, serum electrolytes, creatinine, fasting blood glucose, lipids

Brain imaging CT/CTA or MRI/A; TCD is complementary

Doppler ultrasound; CTA and/or MRA for supra-aortic

Carotid imaging

pp ; pvessels if Doppler not reliable or CEA considered; conventional angiogram if Doppler and MRA/CTA discordant or not feasible

Cardiac evaluation

TTE or TEE in patients younger than 45 years when neck, brain, and hematology studies negative for cause


CBC = complete blood countCEA = carotid endarterectomyTCD = transcranial Doppler TEE = transesophageal echocardiogramTTE = transthoracic echocardiogram

Medical and Surgical Management of TIAs

NSA and AHA/ASA guidelines for use of antithrombotic therapies, CEA, EC-IC bypass, and medical risk-factor modification for TIA patients are comparable

These prevention strategies in TIA and ischemic stroke patients plus angioplasty and stenting are reviewed in subsequent sections of this activity according to 2006 and 2008 AHA/ASA guidelines

Johnston SC et al. Ann Neurol. 2006;60(3):301Sacco RL et al. Stroke. 2006:37(2):577 Adams RJ et al. Stroke. 2008;39(5);1647

EC-IC = extracranial-intracranial

5

Does Rapid Assessment and Treatment of TIA/Minor Stroke Lead to Improved Outcomes?

EXPRESS StudyUrgent assessment and immediate clinical treatment in Oxford Vascular Study (OXVASC) of those at risk of stroke within 90 daysPhase 1 (4/1/02–9/30/04); Phase 2 (10/1/04–3/31/07)

10

12

Stro

ke* (

%)

10.3Early treatment

i t d ith

Rothwell P et al. Lancet. 2007;370(9596):1432

0

2

4

6

8

Phase 1 Phase 290-D

ay R

isk

of R

ecur

rent

S

2.1P=.0001

*When referred to study clinic EXPRESS study = Early Use of Existing Preventive Strategies for Stroke study

associated with 80% reduction

Guidelines for Use of Antiplatelet Therapy in TIA or Ischemic Stroke Prevention

Resting platelet Activated platelets

(Scanning electron microscopy)


Case impression– No evidence of cardiac source of embolism or

high-grade carotid stenosis

Which one of the following antiplatelet agents are acceptable for prevention of recurrent cerebral

ischemia according to current guidelines?

A. Aspirin

B. Aspirin plus extended-release dipyridamole

C. Clopidogrel

D. Aspirin, aspirin plus extended-release dipyridamole, or clopidogrel

AHA/ASA 2008 Recurrent Stroke Prevention Guideline Update

Acceptable antiplatelet options for initial recurrent stroke prevention (Class I, LOE A)– ASA (50–325 mg/day) – ASA plus ER dipyridamole (25 mg/200 mg bid)– Clopidogrel (75 mg/day)

Oth d tiOther recommendations– ASA plus ER dipyridamole favored over ASA alone

(Class 1, LOE B; upgraded based on ESPRIT study result)* – ASA added to clopidogrel is not recommended for routine use

Adams RJ et al. Stroke. 2008;39(5);1647; Gorelick PB. AHA Communities Learning Library. http://pt.wkhealth.com/pt/re/aha/editorial3_5_2008.htm; jsessionid=Lr9hGX0qz7ynry2TfJTs7r5sGmJbBVyq3ph0xMkhBn2p4T0rGs2Q!2085969891!181195628!8091!-1. Accessed July 16, 2008

*New recommendation since 2006 guidelineASA = aspirin; bid = twice a day; ER = extended release; ESPRIT = European/Australasian Stroke Prevention in Reversible Ischaemia Trial

“Variable Response”Preferred Term to “Aspirin Resistance”?

Variable response– Occurrence of breakthrough atherothrombotic

events– Response to ASA differs among patients and

may be attributed to various mechanisms

6

Cellular factorsInsufficient suppression

of COX-1Overexpression of COX-2 mRNA

Erythrocyte-induced platelet activation

Genetic polymorphisms

COX-1GP IIIa receptor

Collagen receptor

Clinical factorsFailure to prescribe

NoncomplianceNonabsorption

Interaction with ibuprofen

Aspirin Resistance: More Than Just a Laboratory Curiosity?

ASA resistance

platelet activationIncreased norepinephrineGeneration of 8-iso-PGF2α

Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43(6):1127

Collagen receptorvWF receptor

Interaction with ibuprofenInteraction with naproxen

COX = cyclo-oxygenase; GP = glycoprotein; mRNA = messenger ribonucleic acid; PGF2α = prostaglandin F2 alpha; vWF = von Willebrand factor

Study population 20,333 patients with recent stroke (within 90 days of study entry)

Study drugs ASA/ER dipyridamole vs clopidogrel and telmisartan vs placebo

Study design Multinational (more than 21 countries and 600 sites), randomized, double-blind, placebo-controlled, 2 x 2 factorial design

PRoFESS Trial

telmisartan vs placeboPrimary end point Time to first recurrent stroke

Anticipated data 2008

Secondary end point Stroke, MI, or vascular death; major bleeding; stroke or major hemorrhage

Diener HC et al. Cerebrovasc Dis. 2007;23:368

MI = myocardial infarction; PRoFESS = Prevention Regimen For Effectively Avoiding Second Strokes

PRoFESS Trial: Preliminary ResultsPrimary end point– Across an average observation time of 2.5 years, rates of first

recurrent stroke were similar (9.0% ASA + ER dipyridamole vs 8.8% clopidogrel; HR 1.01, 95% CI 0.92−1.11)

Bleeding – More frequent in ASA + ER dipyridamole group

Boehringer Ingelheim. News Release. PRoFESS® results announced at XVII European Stroke Conference. http://www.boehringer-ingelheim.com/corporate/news/press_releases/detail.asp?ID=5534. Accessed August 12, 2008

More frequent in ASA ER dipyridamole group (major hemorrhagic events: 4.1% vs 3.6%; HR 1.15, 95% CI 1.00−1.32, P=.06)

Benefit-risk ratio– Similar between groups (11.7% ASA + ER dipyridamole vs

11.4% clopidogrel; HR 1.03, 95% CI 0.95−1.11, P=.50)

CI = confidence interval; HR = hazard ratio

Guidelines for Medical Risk Factor Management in Patients With g

TIA or Ischemic Stroke


Diagnosis– Patient was diagnosed with a lacunar or small artery

territory infarction syndrome

Treatment– She did not receive intravenous tPA therapy since she had

only a very minor neurologic impairment– After the MRI head study was reviewed in the ED, she was

treated with ASA 81 mg/day– Her BP was initially not treated

Within 48 hours of the neurologic symptoms, her neurologic examination was normal

tPA = tissue plasminogen activator

When it is deemed safe to lower BP following the initial phase of acute ischemic stroke, what is

the long-term target BP?

A. <140/90 mm Hg

B. <130/80 mm Hg

C. <120/70 mm Hg

D. <110/75 mm Hg

7

Which one of the following statements best characterizes the use of statin therapy for

recurrent stroke prevention?

A. There is no proof that statin therapy reduces stroke risk

B. Statin therapy reduces stroke risk, but is not py ,safe; fatal liver disease is common

C. Statin therapy reduces stroke and major cardiovascular risks

D. Statin therapy reduces stroke risk, but does not reduce major cardiovascular risks

Which one of the following statements best characterizes smoking as a

risk factor for stroke?

A. Environmental (passive) smoke increases the risk of stroke

B. Smoking is a risk factor for ischemic, but not g ,hemorrhagic stroke

C. Smoking increases the relative risk of stroke by 5 to 10 times

D. Smoking cessation leads to reversal of stroke risk after 20 years

Statin therapy and lipid lowering– Based on the SPARCL results, statin therapy with intensive lipid-

lowering effects is indicated for patients with LDL-C in the 100–190 mg/dL range, atherosclerotic ischemic stroke or TIA, and no known CHD to reduce occurrence of stroke and vascular events (Class I, LOE B)*

AHA/ASA 2008 Recurrent Stroke Prevention Guideline Update

– Target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease

LDL-C level of <100 mg/dL or LDL-C <70 mg/dL for very high-risk persons (those with multiple risk factors)

*New recommendation since 2006 guidelineSPARCL = Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial

Adams RJ et al. Stroke. 2008;39(5);1647; Gorelick PB. AHA Communities Learning Library. http://pt.wkhealth.com/pt/re/aha/editorial3_5_2008.htm;jsessionid=Lr9hGX0qz7ynry2TfJTs7r5sGmJbBVyq3ph0xMkhBn2p4T0rGs2Q!2085969891!181195628!8091!-1. Accessed July 16, 2008

AHA/ASA 2006 Recommendations for Lifestyle and Risk Factor Management in TIA or Ischemic Stroke

Factor Recommendation LOE

HTN Initiate Rx when safe; individualize Rx; consider BP reduction of 10/5 mm Hg with a diuretic and ACEI Class I, LOE A

DM Rigorous control of BP and lipids; aim for hemoglobin A1c ≤7%

Class I, LOE AClass IIa, LOE B

SmokingDiscontinue smokingCounseling, NRT, and oral smoking-cessation medications

Class I, LOE CClass IIa, LOE Bmedications

Alcohol useEliminate heavy drinking or reduceMen ≤2 drinks/day and non-pregnant women 1 drink/day

Class I, LOE AClass IIb, LOE C

Obesity Goal BMI 18.5 to 24.9 kg/m2 and waist circumference women (<35 inches) and men (<40 inches) Class IIb, LOE C

Physical activity If capable, at least 30 minutes of moderate-intensity exercise daily Class IIb, LOE C

ACEI = angiotensin-converting enzyme inhibitor; BMI = body mass index; NRT = nicotine replacement therapy; Rx = treatment

Sacco RL et al. Stroke. 2006:37(2):577

Improving Patient AdherenceImproving Patient Adherence

Established Therapies Are Consistently Underused in all Patient Types

46

39

3024

44

36

2830

40

50

60

s N

ot R

ecei

ving

en

The

rapy

(%)

Antiplatelets Lipid lowering Statin

Bhatt DL et al. JAMA. 2006;295(2):180

1418 1819 19

0

10

20

CAD (n=40,258)

CVD(n=18,843)

PAD (n=8273)

Multiple Risk Factors (n=12,389)

Patie

nts

Prov

e

CAD = coronary artery disease; PAD = peripheral artery disease

8


Patient is now taking a diuretic, ACEI, statin, and ASA plus ER dipyridamole for recurrent stroke prevention

What steps might be taken to assure adherence to the treatment regimen?

Steps to Consider to Enhance Adherence to TIA or Recurrent Stroke Prevention Regimen

Awareness or recognition of stroke risk and risk factorsQualitative determination of recurrent stroke riskAwareness of risk factor numbers (eg, BP, blood ( gglucose, serum cholesterol)Establish multimodality maintenance approach

American Stroke Association broadcast on Primary Stroke Prevention, October 2007

Recurrent Stroke PreventionSuccessful Maintenance of Treatment by

Multimodality Approach

Motivation from family members Reminders and encouragement from medical office staff Pharmacy reminders to renew medicationsPharmacy reminders to renew medicationsPhysician report cards: Is the patient meeting target numbers?

American Stroke Association broadcast on Primary Stroke Prevention, October 2007

What Can Stroke Teams Do?

In-hospital initiation of secondary prevention therapies to increase treatment utilization and adherence in the long term Adopt a systematic management approach in coordination with primary care physicians to help optimize post-stroke care

Ovbiagele B et al. Neurology. 2004;63(7):1217; Ovbiagele B et al. Stroke. 2004;35(12):2879; Ovbiagele B et al. Stroke. 2008;39(6):1850

Cardioembolic Stroke ManagementCardioembolic Stroke Management


On physical examination, the patient’s pulse is noted to be irregularly irregular. A bedside EKG is ordered

Patient is diagnosed with cardioembolic stroke secondary to AF

9

Which one of the following therapies is recommended to prevent stroke recurrence for

a high-risk patient with atrial fibrillation?

A. Aspirin

B. Clopidogrel

C. Ximelagatran

D. Warfarin

Secondary Stroke Prevention:Cardioembolic Stroke

Cardioembolic stroke is responsible for ~20% of ischemic strokesHigh risk of recurrence if not treated properlyUnderlying cardiac disease*– Nonvalvular AF (50%)– LVT (33%)– Valvular heart disease (25%)– Cardiomyopathy with low EF (25%)

Cerebral Embolism Task Force. Arch Neurol. 1989;46(7):727Pujadas Capmany R et al. Int J Cardiol. 2004;95(2-3):129

*Patients may have more than 1 underlying cardiac conditionEF = ejection fraction; LVT = left ventricular thrombus

Risk factors for recurrent stroke in patients with AF

Age

Cardioembolic Stroke: AF

Persistent and paroxysmal AF are potent risk factors for recurrent stroke

CHFHTNDM

Prior thromboembolism (TIA or stroke)

CHF = congestive heart failure

Outcome Warfarin (INR goal of 2–3) Antiplatelet agents

Stroke reduction (%) 64 (95% CI 49-74%) 22 (95% CI 6-35%)NNT for 1 year for secondary stroke prevention (n) 14 34

Warfarin1

Anticoagulation

Ximelagatran (investigational)Ximelagatran (investigational)– Oral direct thrombin inhibitor that does not require coagulation

monitoring – SPORTIF-V: 36 mg twice daily was not inferior to warfarin (INR,

2–3) for stroke prevention in AF2

– Potential risk of hepatotoxicity– Not approved by FDA for use

1. Hart RG et al. Ann Intern Med. 2007;146(12):8572. Albers GW et al. JAMA. 2005;293(6);690

FDA = US Food and Drug Administration; INR = international normalized ratio; SPORTIF-V = Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation V

1. For patients with ischemic stroke or TIA with persistent or paroxysmal (intermittent) AF, anticoagulation with adjusted-dose warfarin (target INR, 2.5; range, 2–3) is recommended (Class I LOE A)

AHA/ASA 2006 Guideline Recommendationsfor Antithrombotic Therapy in AF

(Class I, LOE A)

2. For patients unable to take oral anticoagulants, ASA 325 mg/day is recommended (Class I, LOE A)


1. For patients with an ischemic stroke or TIA caused by an acute MI in whom LVT is identified by echocardiography or another form of cardiac imaging, oral anticoagulation is reasonable, aiming for an INR of 2–3 for at least

AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy

in Acute MI With LVT

3 months and up to 1 year (Class IIa, LOE B)

2. ASA should be used concurrently for ischemic CAD during oral anticoagulant therapy in doses up to 162 mg/day (Class IIa, LOE A)


10

Guidelines for Symptomatic Extracranial Carotid Occlusive

Disease Management


On physical examination, a carotid bruit is heard on the left side CTA of the neck shows 70%–99% stenosis of the proximal portion of the left ICA

ICA = internal carotid artery


Diagnosis: symptomatic left extracranial ICA stenosis

Which of the following is recommended as first-line treatment of high-grade, symptomatic,

extracranial carotid artery stenosis?

A. Extracranial to intracranial bypass

B. Warfarin

C. Carotid endarterectomy

D. Aspirin plus extended-release dipyridamole

North American Symptomatic Carotid Endarterectomy Trial (NASCET)1

• 659 patients with symptomatic stenosis randomized to CEA or medical management• Only patients with ≥5-years life expectancy were included• Perioperative stroke/death rate 5.8%

Stenosis (%) Results70–99 2-year risk of stroke was 9% with CEA and 26% with medical therapy

5 year risk of stroke was 15 7% with CEA and 22 2% with medical

Secondary Stroke Prevention: Symptomatic Extracranial Carotid Occlusive Disease

50–695-year risk of stroke was 15.7% with CEA and 22.2% with medical therapyLess benefit for women and patients with retinal stroke/TIA

<50 No significant benefit of CEA

Carotid Endarterectomy Trialist Collaboration2

• Pooled data from European Carotid Surgery Trial and NASCET• In the CEA arm, benefits were greatest among patients randomized within

2 weeks of symptoms

1. North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med. 1991;325(7):4452. Rothwell PM et al. Lancet. 2004;363(9413):915

1. For patients with recent TIA or ischemic stroke within the last 6 months and ipsilateral severe (70%–99%) carotid artery stenosis, CEA by a surgeon with a perioperative morbidity and mortality rate of <6% is recommended (Class I, LOE A)

2. For patients with recent TIA or ischemic stroke and ipsilateral moderate (50%–69%) carotid stenosis, CEA is recommended depending on patient-specific factors such as age, gender, comorbidities, and severity of initial

AHA/ASA 2006 Guideline Recommendations for CEA

symptoms (Class I, LOE A)

3. When the degree of stenosis is <50%, CEA is not routinely indicated (Class III, LOE A)

4. When CEA is indicated for patients with TIA or stroke, surgery within 2 weeks is suggested rather than delaying surgery (Class IIa, LOE B)

Sacco RL et al. Stroke. 2006; 37(2):577

11

Among patients with symptomatic severe stenosis (>70%) in whom the stenosis is difficult to access surgically, medical conditions are present that greatly increase the risk for surgery, or other specific circumstances exist such as radiation-induced stenosis or restenosis after CEA, CAS is not inferior to endarterectomy and may be considered (Class IIb, LOE B). CAS is reasonable when performed by operators with established periprocedural morbidity and mortality rates of 4% to 6%, similar to that observed in trials of CEA and CAS

AHA/ASA 2006 Guideline Recommendations for Carotid Angioplasty and Stenting

mortality rates of 4% to 6%, similar to that observed in trials of CEA and CAS (Class IIa, LOE B)

Special Note:The results of the EVA-3S and SPACE studies were published after the 2006 AHA/ASA guidelines became available. EVA-3S and SPACE have added data which support clinical equipoise in relation to CAS. We await the results of Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) to clarify the role of CAS in the management of patients with extracranial occlusive disease.


Guidelines for Symptomatic Intracranial Carotid Occlusive

Disease Management


Physical examination is unremarkableCerebral vascular diagnostic workup shows no cardiac source of embolism, and both carotid arteries are patent with no evidence of h d i ll i ifi t t ihemodynamically significant stenosisHead MRA is ordered, which shows a proximal left MCA stenosis

MCA = middle cerebral artery


Diagnosis: large artery intracranial occlusive disease (LAICOD)

Which one of the following is recommended as first-line treatment for large artery intracranial

occlusive disease?

A. Antiplatelet therapy

B. Anticoagulant therapy

C. Angioplasty and stenting

D. Extracranial to intracranial bypass

Ethnic Group Reported Frequency of LAICOD in Patients With Stroke (%)

Secondary Stroke Prevention:Symptomatic Intracranial

Carotid Occlusive DiseaseWorldwide LAICOD is a common and well-defined stroke subtypeCertain population groups may be at higher risk for LAICOD

Relative risk of intracranial atherosclerotic stroke in the United States– Hispanics vs whites: 5.00 (95% CI 1.69 to 14.76)– African Americans vs whites: 5.85 (95% CI 1.82 to 18.73)

ChineseKorean

South AsianThai

35–50565447

Gorelick PB et al. Stroke. 2008;39(8):2396

12

LAICOD: Risk of Recurrent CerebralIschemic Stroke in Key Clinical Trials

EC-IC Bypass Study1

– 1377 patients with symptomatic ICA or MCA stenosis randomized to either surgery or medical management

– Patients with symptomatic carotid siphon or MCA stenosis had an annual stroke rate of 8%–10%

– No significant benefit for EC-IC was shownWarfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID)2

Outcomes in WASID ASA (%) Warfarin (%)

Ischemic stroke 20.4 17.0Ischemic stroke in the territory of the stenotic vessel 15.0 12.1

Disabling or fatal ischemic stroke 8.9 6.2

– 569 patients with symptomatic 50%–99% IC stenosis– INR goal of 2–3– Mean follow up of 1.8 years

1. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):11912. Chimowitz MI et al. N Engl J Med. 2005;352(13):1305

For patients with hemodynamically significant intracranial stenosis who have symptoms despite medical therapies (antithrombotics, statins, and other treatments for risk factors), the usefulness of endovascular therapy (angioplasty and/or stent placement) is uncertain and is considered investigational

AHA/ASA 2006 Guideline Recommendations for Treatment of LAICOD

With Endovascular Therapy

(Class IIb, LOE C)1

Special Note:The results of the NIH registry on use of Wingspan stent for symptomatic 70%–99% intracranial arterial stenosis were published after the 2006 AHA/ASA guidelines. Based on these results, NIH has funded a study called Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)2 to study the possible benefit of stenting for symptomatic intracranial artery stenosis.

1. Sacco et al. Stroke. 2006; 37(2):5772. Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis. http://clinicaltrials.gov/ct2/show/NCT00576693?term=SAMMPRIS&rank=1. Accessed August 21, 2008.

Conclusions

TIA and ischemic stroke are important risk factors for recurrent cerebral ischemia

Recurrent stroke is preventable

NSA guidelines for the management of patientsNSA guidelines for the management of patients with TIA and AHA/ASA guidelines for recurrent stroke prevention are useful clinical tools to reduce the risk of recurrent cerebral ischemia

Appendix I Additional Slides

Polytherapy for Recurrent Stroke Prevention: Opportunity for Reduction of Subsequent Stroke Risk

20

30

40

50

60

70

80

90Untreated

Treated

r Maj

or V

ascu

lar E

vent

Rat

e (%

)

12 meta-analyses (106 studies, 210,926 patients)Combination of

– Diet– Exercise– ASA (ASA + dipyridamole)– Statin (high dose)

A tih t i d

Adapted with permission from Hackam DG, Spence JD. Stroke. 2007;38(6):1881

0

10

Cartoid stenosis

AF Diabetes Smoking

5-Ye

ar

RRR (%) 90 86 84 87ARR (%) 41 67 27 25NNT (n) 2 1 4 4

Benefits of combination therapy in patients with CVD and specific subtypes or comorbidities

– Antihypertensive drug (aggressive BP lowering)

Predicted 5-year major vascular event rate

– RRR 80% (90%)– ARR 20% (22%)– NNT 5 (5) – Residual 5-year risk 5% (3%)

ARR = absolute risk reduction; NNT = number needed to treat; RRR = relative risk reduction

Predicting Stroke Risk in AF: Who Benefits Most?

Multivariate Analysis of Pooled Data

Clinical Risk Factors RRPrevious stroke or TIA 2.5 ×History of HTN 1.6 ×Diabetes 1.7 ×Increasing age (per decade) 1.4 ×

Hughes M et al. Thromb Haemost. 2008;99(2):295

RR = relative risk

13

Initiation of Anticoagulation Therapy in AF Patient With Acute TIA or Stroke

Controversy exists regarding the timing of treatmentPatients with TIA– May receive anticoagulation immediately if not contraindicated by

CT, MRI brain, or otherwise

Patients with ischemic stroke– Initiate anticoagulation within 2 weeks of ischemic stroke or

sooner depending on CT or MRI brain findings, neurologic examination findings (size and severity of infarct to be considered), and urgency of anticoagulation (eg, mechanical heart valve)

– Delaying anticoagulation may be reasonable in patients with uncontrolled HTN and large infarcts

Cardioembolic Stroke: Acute MI and LVT

Acute MI and LVT – Stroke and systemic embolism can occur in up to

12% of patients with LVT post MI– Risk of LVT is higher in anterior MI– Risk of stroke is higher during the first 3 months– In one-third of patients, LVT may remain

echcardiographically apparent for 1 year after MI

Albers GW et al. Chest. 2004;126(3 suppl):483SVisser CA et al. Chest. 1984;86(4):532

Cardioembolic Stroke: CardiomyopathyCardiomyopathy– Significantly reduced LV systolic function causes relative stasis– Annual stroke rate in the Survival And Ventricular Enlargement

(SAVE) study1

0.8% in patients with EF of 29%–35%1.7% in those with EF ≤28%

N t d h d fi iti l th ffi f f i ASA i– No study has definitively proven the efficacy of warfarin or ASA in stroke prevention in patients with cardiomyopathy

– In practice, patients with thromboembolism suspected of cardioembolic origin with EF below 30% are usually managed with warfarin (INR, 2–3)

– WARCEF (Warfarin versus Aspirin for Reduced Cardiac Ejection Fraction) study is in progress2

1. Pfeffer MA et al. N Engl J Med. 1992;327(10):669 2. Pullicino P et al. J Card Fail. 2006;12(1):39

For patients with ischemic stroke or TIA who have dilated cardiomyopathy, either warfarin (INR, 2–3) or antiplatelet therapy may be considered for prevention of recurrent events (Class IIb LOE C)


in Cardiomyopathy

of recurrent events (Class IIb, LOE C)


Cardioembolic Stroke:Valvular Disease

PHV– Warfarin (INR, 1.8–2.5) versus antiplatelet agents1

Treatment Thromboembolism (100 patient-years) (%)

Warfarin 2ASA-dipyridamole 9.8Pentoxifylline-ASA 7.9

– Warfarin (INR, 3.0–4.5) vs warfarin plus ASA (100 mg daily)2

1. Mok CK et al. Circulation. 1985;72(5):10592. Turpie AG et al. N Engl J Med. 1993;329(8):524

Treatment Annual Rate of Embolic Events or Vascular Death (%)

RR(%) (95% CI)

Bleeding(%)

Increase in Risk(%) (95% CI)

Warfarin+ placebo 9.8 77 (44%–91%)

P<.00122 55 (8%–124%)

P=.02+ ASA 7.9 35

Valvular Disorder Comments Treatment and LOE

Rheumatic valve disease

• Recurrent stroke occurs in 30%–65% of patients• Valvulplasty does not eliminate the risk of recurrent

thromboembolism• Observational studies show that long-term anticoagulation

significantly reduces the risk of recurrent stroke

Warfarin (INR, 2–3)(Class IIa, LOE C)

Consider adding ASA (81 mg/day) if recurrent embolism

while on warfarin (Class IIa, LOE C)

Mitral valve prolapse

• Most common form of valve disease, usually innocuous• No large-scale, randomized trials have addressed the

efficacy of major antithrombotics for secondary preventionAntiplatelet agent(Class IIa, LOE C)

Cardioembolic Stroke: Valvular Disease

Aortic valve disease

• Associated with small and often clinically silent microthrombi or calcific embolism

Antiplatelet agent(Class IIb, LOE C)

Mitral annular calcification (MAC)

• Considered a form of atherosclerosis• Associated with mitral regurgitation or stenosis• Endocarditis, arrhythmia, and embolic phenomenon may

occur (thromboembolism vs fibro-calcified material)

Antiplatelet agent(Class IIb, LOE C)

Antiplatelet agent or warfarin may be considered in patients with mitral

regurgitation caused by MAC(Class IIb, LOE C)


14

1. For patients with ischemic stroke or TIA who have modern mechanical PHVs, oral anticoagulants are recommended, with an INR target of 3.0 (range, 2.5–3.5) (Class I, LOE B)

2. For patients with mechanical PHV who have an ischemic stroke or systemic embolism despite adequate therapy with oral anticoagulants, ASA 75–100 mg/day in addition to oral,

AHA/ASA 2006 Guideline Recommendationsfor Antithrombotic Therapy in Valvular Disease

anticoagulants, ASA 75 100 mg/day in addition to oral, anticoagulants and maintenance of the INR at a target of 3.0 (range 2.5–3.5) are reasonable (Class IIa, LOE B)

3. For patients with ischemic stroke or TIA who have bioprosthetic heart valves with no other source of thromboembolism, anticoagulation with warfarin (INR, 2–3) may be considered (Class IIb, LOE C)


PHV = prosthetic heart valve

Cardioembolic Stroke:PFO

PFO– Prevalence in patients ≥45 years is ~26%– Atrial septal aneurysm affects ~2%– 4-year risk of stroke recurrence

2.3% in patients with PFO15.2% in patients with PFO and atrial septal aneurysm

– Increased risk of stroke in patients with large right-to-left shunt– Higher prevalence of PFO in patients with cryptogenic stroke– PFO in Cryptogenic Stroke Study

No statistically significant difference in the rate of recurrent stroke in patients with or without PFO or among those treated with ASA or warfarin

– Randomized Evaluation of Recurrent Stroke Comparing PFOClosure to Established Current Standard of Care Treatment (RESPECT) study and others are comparing percutaneous PFO closure versus medical treatment for recurrent stroke prevention

Cruz-González I et al. Rev Esp Cardiol. 2008;61(7):738

1. Antiplatelet therapy is reasonable to prevent a recurrent event (Class IIa, LOE B)

2. Warfarin is reasonable for high-risk patients who have other indications for oral anticoagulation (Class IIa, LOE C)

AHA/ASA 2006 Guideline Recommendations for Recurrent Stroke Prevention for PFO

3. Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and PFO

4. PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical therapy (Class IIb, LOE C)


PFO = patent foramen ovale

Guidelines for Carotid Dissection Stroke Management


Patient complains of neck pain on the left sideOn physical examination, there is a left partial Horner syndrome (ptosis and miosis)Bedside carotid duplex is performedp p


Bedside carotid duplex shows a double lumen in the proximal left ICA (picture above)Diagnosis: left extracranial ICA dissection

How should subsequent cerebral ischemia be prevented in a patient with a symptomatic carotid artery dissection?

15

Secondary Stroke Prevention: Arterial Dissections

Extracranial arterial dissections– Common with atherosclerotic disease– Frequent in young patients– May be spontaneous or traumatic (neck manipulation,

hyperextension, lifting) – More commonly detected in extracranial arteries– Location includes mostly regions where the arteries are

mobile and not anchoredAnterior circulation: cervical portion of the ICAPosterior circulation: segments of the vertebral arteries (V1 and V3)

Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34

Arterial Dissections: Pathophysiology

Tear in tunica media results in bleeding in arterial wallBlood dissects longitudinally spreading distally and proximallyTear of intima permits clots to enter lumenExpansion of intramural hemorrhageExpansion of intramural hemorrhage narrows lumen causing stasis, activation of platelets, and the coagulation cascadeMain dissection plane can lie between the media and adventitia creating a pseudoaneurysmRupture through adventitia into the intracranial circulation causes subarachnoid hemorrhage

Adapted with permission from Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34

2003 Cochrane Database review1

– Poor quality studies comparing ASA to warfarin– ASA is likely to be effective and safer than warfarin– Further studies are needed

Arterial Dissections:Treatment

Due to the pathophysiology (red thrombi) most experts recommend anticoagulantsAnnual risk of stroke recurrence in carotid dissection is low (0.3% per year)2

1. Lyrer P, Engelter S. Cochrane Database Syst Rev. 2003;(3):CD0002552. Touzé E et al. Neurology. 2003;61(10):1347

1. For patients with extracranial arterial dissection, use of warfarin for 3 to 6 months or use of antiplatelet agents is reasonable (Class IIa, LOE B)

2 Beyond 3 to 6 months long-term antiplatelet therapy


in Cerebral Artery Dissection

2. Beyond 3 to 6 months, long term antiplatelet therapy is reasonable. Anticoagulant therapy beyond 3 to 6 months may be considered among patients with recurrent ischemic events (Class IIb, LOE C)


Stroke Management in Patients With Aortic Arch Atheroma

Secondary Stroke Prevention:Aortic Arch Atheroma

Prevalence and severity of aortic arch atheroma (AAA) increases with age1

90% of the cases are stable and AAA progresses slowly over timeUnclear if AAA is a source of emboli or a marker of an increased risk of

Type of AAA Odds Ratio of StrokeSimple 2.3

Complex 7.1

atherosclerotic diseaseRisk of stroke is higher in patients with complicated AAAs (ie, >5 mm in thickness, ulcerated plaque, and mobile)2

1. Molina CA et al. Cerbrovasc Dis. 2007;24(suppl 1):84 2. Adapted with permission from Jones EF et al. Stroke. 1995;26(2):218

16

AAA TreatmentNew York University Atheroma Group1

– Statin therapy was protective against embolic events

– No protective effect with warfarin or antiplatelet agents

Antiplatelet therapy is usually used in patients with stroke or TIAN d fi iti t d h d t i d if f i i iNo definitive study has determined if warfarin is superior to antiplatelet agents for treatment of AAAAortic Arch Related Cerebral Hazard Trial (ARCH) is comparing clopidogrel + ASA vs oral anticoagulation in preventing brain infarction, brain hemorrhage, MI, peripheral embolism, and vascular death2

1. Tunick PA et al. Am J Cardiol. 2002;90(12):1320 2. Aortic Arch Related Cerebral Hazard Trial (ARCH). http://clinicaltrials.gov/ct2/show/NCT00235248. Accessed July 16, 2008

SAPPHIRE EVA-3S SPACE

Hypotheses CAS is not inferior to CEA for high-risk patients

CAS is not inferior to CEA for symptomatic carotid stenosis

CAS is not inferior to CEA for symptomatic carotid stenosis

Patients (n) 334 527 1200

Degree of stenosis (%) >50 symptomatic or 60 99 t ti ≥50 t ti

Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators (SAPPHIRE)1,2

Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S)3

Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy (SPACE)4

Carotid Angioplasty and Stenting: Summary of Key Studies I

*P=.004 for noninferiority; **P=.09 for noninferiority; CAS = carotid artery stenting

g (%) y p>80 asymptomatic 60–99 symptomatic ≥50 symptomatic

Primary end point Death, stroke, or MI within 30 days after procedure or

death/ipsilateral stroke between 30 days and 1 year

Composite of stroke or death within 30 days posttreatment

Ipsilateral stroke (ischemic or hemorrhagic) or death within

30 days postprocedure

Primary outcome (CEA vs CAS) (%) 20.1 vs 12.2* 3.9 vs 9.6 6.34 vs 6.84**

Early termination Slow recruitment Safety and futility reasons No further funding

1. Yadav JS et al. N Engl J Med. 2004;351(15):1493; 2. Gurm HS et al. N Engl J Med. 2008;358(15):1572; 3. Mas JL et al. N Engl J Med. 2006;355(16):1660; 4. SPACE Collaborative Group. Lancet. 2006;368(9543):1239

SAPPHIRE EVA-3S SPACE

Trial conclusion CAS is not inferior to CEA for high-risk patients at 6 months, 1 year,

and 3 years

Rates of stroke or death at 1 month and 6 months are

lower in CEA

Trial failed to prove noninferiority of CAS vs CEA

High risk for CEA Required Not required Not required

Symptomatic patients (%) 29 100 100

Operator experienceCAS Required periprocedural risk <6% 39% done by operators in No prespecified experience in

Carotid Angioplasty and Stenting: Summary of Key Studies II

CAS

CEA

Required periprocedural risk <6%

Required periprocedural risk <6%

39% done by operators in training

≥25 CEAs performed in prior year before enrollment

No prespecified experience in CAS

≥25 CEAs performed

Stent type 2 stents (same manufacturer)

5 stents (different manufacturers)

3 stents (different manufacturers)

Protection device Mandatory (only 1 system)

Tried in 92% (any of 7 systems)

Used in 27% (any of 5 systems)

1.Yadav JS et al. N Engl J Med. 2004;351(15):1493; Gurm HS et al. N Engl J Med. 2008;358(15):1572; Mas JL et al. N Engl J Med. 2006;355(16):1660; 4. SPACE Collaborative Group. Lancet. 2006;368(9543):1239

Study Outcome (%)WASID1

Ischemic stroke, brain hemorrhage, or death from vascular causes (primary outcome)*

ASAWarfarin

22.121.8

EC-IC Bypass Study Group2

Is an EC-IC anastomosis better than medical treatment for symptomatic No

Treatment of LAICOD Based Upon Key Clinical Trials

Is an EC IC anastomosis better than medical treatment for symptomatic LAICOD?**

No

NIH registry on use of WingspanTM stent for 70%–99% intracranial stenosis3

Stroke or death within 30 days or stroke in the territory (1–6 months)Restenosis (50% or more)

1425

1. Chimowitz MI et al. N Engl J Med. 2005;352(13):13052. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):11913. Zaidat OO et al. Neurology. 2008;70(17):1518

*Major hemorrhage occurred more frequently in warfarin vs ASA group (8.3% vs 3.2%; HR 0.40; 95% CI 0.18-0.84; P=.01)**Carotid Occlusion Surgery Study (COSS) is ongoing and retesting the hypothesis of benefit for EC-IC bypass

Recurrent Stroke Prevention in Other Cerebrovascular Conditions

Condition Comments Treatment and LOE

Hyper-homocysteinemia

• Hyperhomocysteinemia is associated with a 2x risk of stroke• Vitamin Intervention for Stroke Prevention (VISP) study, reduction

of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes

• Are there subgroups who might receive benefit from multivitamin therapy?

Daily vitamin B6, B12 and folate(Class IIa, LOE B)

Inherited

• Weak association between FVL, PTGM, MTHFR, APCR, and stroke in adults; more clear in younger age groups

• No studies comparing antiplatelets to warfarin for secondary

Antiplatelet or anticoagulants(Class IIa, LOE C)

Anticoagulants if recurrent

Secondary Stroke Prevention:Other Specific Conditions

thrombophilia • No studies comparing antiplatelets to warfarin for secondary prevention have been done

• Evaluate for alternative mechanism

Anticoagulants if recurrent thrombosis

(Class IIb, LOE C)

Antiphospholipid (APL) antibodies

• Associated with venous and arterial occlusive disease• In Warfarin vs Aspirin Recurrent Stroke Study/Antiphospholipid

Antibodies and Stroke Study (WARSS/APASS) collaboration, the risk of vascular occlusive events in patients with ischemic stroke and APL was not different in patients treated with ASA or warfarin

Antiplatelet(Class IIa, LOE B)

Anticoagulants if APL syndrome with occlusive disease in multiple organs, miscarriages, and livedo reticularis

(Class IIa, LOE B)

APCR = activated protein C resistance; FVL = factor V Leiden; MTHFR =methylenetetrahydrofolate reductase C677T mutation; PTGM = prothrombin G20210A mutation


17

Condition Comments Treatment and LOE

Cerebral venous sinus thrombosis

• Venous infarctions are frequently hemorrhagic • More frequent in patients with hypercoagulable states• Anticoagulant superior to placebo

Anticoagulants (even in the presence of hemorrhagic

infarction)(Class IIa, LOE B)

Sickle cell disease

• In Stroke Prevention Trial in Sickle Cell Anemia (STOP), children with mean flow velocity ≥200 cm/sec at MCA (measured noninvasively by TCD) were randomized to exchange transfusion (goal: HbS <30%) or placebo

• Annual stroke rate was 1% in children undergoing

Risk factor control and antiplatelet agents

(Class IIa, LOE B)Blood transfusion to reduce HbS

Secondary Stroke Prevention:Other Specific Conditions

Sickle cell disease • Annual stroke rate was 1% in children undergoing transfusion and 10% in those not receiving transfusion

• Small studies suggested that hydroxyurea reduces the risk of stroke recurrence

• High risk of moyamoya disease

Blood transfusion to reduce HbS to <30%–50% of total Hb,

hydroxyurea, and bypass surgery for advanced occlusive disease

(Class IIb, LOE C)

Postmenopausal hormone therapy

• In Women's Estrogen for Stroke Trial (WEST) and Women’s Health Initiative (WHI) studies, women assigned to hormonal replacement had a higher risk of stroke compared with placebo

Postmenopausal hormone therapy is not recommended

(Class III, LOE A)


HbS = sickle cell hemoglobin

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18

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recurrent stroke prevention: y an update on the. aspirin plus extended-release dipyridamole c....

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