Impact of Stroke in the United States
Recurrent Stroke Prevention: An Update on the Evidence and Opportunity in Ischemic Stroke or TIA Case-Based Review of Guidelines for Practitioners Who Care for Patients With Ischemic Stroke or TIA
y Of all CVDs, stroke is the third leading cause of death y Annual incidence – 780,000 strokes y 600,000 first attacks y 180,000 recurrent attacks
y 1 15% % off strokes k are h heralded ld d b by TIA y One-third of TIAs may be considered cerebral infarctions based on diffusion-weighted MRI results y 90-day risk of stroke after TIA: 3%–17% – Highest risk within the first 30 days CVD = cardiovascular disease; MRI = magnetic resonance imaging 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 the Cost of Stroke
Mean lifetime cost of ischemic stroke • $140,048
Average cost of ischemic stroke within 30 days • $13,019 (mild) • $20,346 (severe)
$65.5 billion* in 2008
Estimates of Long-term Risk of Stroke After Ischemic Stroke or TIA Percentage of Patients Experiencing Stroke After TIA1
After Stroke2
(%)
(%)
30 days
4–8 4 8
3–10 3 10
1 year
12–13
10–14
5 years
24–29
25–40
Time
*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
Putative Risk Factors for Stroke Recurrence
1. Feinberg WM et al. Stroke. 1994;25(6):1320 2. Sacco RL. Neurology. 1997;49(5 suppl 4):S39
Defining Stroke Subtype Is an Important Consideration in Recurrent Stroke Prevention
Early stroke recurrence y Stroke subtype
Other 5%
– High for large artery, extra- and intracranial occlusive disease
y Elevated blood glucose y HTN
Cryptogenic 30%
Late stroke k recurrence y y y y
Age HTN Heart disease (CHD, HF, AF) DM and hyperglycemia
Prior stroke or TIA AF = atrial fibrillation; CHD = coronary heart disease; DM = diabetes mellitus; HF = heart failure; HTN = hypertension Sacco RL et al. Neurology. 1999;53(7 suppl 4):S15
Cardiogenic embolism 20%
Ischemic stroke 88%
Hemorrhagic stroke 12%
Atherosclerotic cerebrovascular disease 20% Small vessel disease “lacunae” 25%
Albers GW et al. Chest. 2004;126(3 suppl):438S Thom T et al. Circulation. 2006;113(6):e85
1
Prevention of Recurrent Stroke y Evaluation for risk factors – HTN, DM, hyperlipidemia
y Evaluation for cause – Arterial diseases, heart diseases – Coagulopathies
Case Presentation
y Management of risk factors – Lifestyle and medications
y Antithrombotic therapy y Surgical or endovascular interventions Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman With 15-Year History of HTN y Chief complaint – Presented to the ED after a 30-minute spell of
transient right-sided face and arm weakness after exercising today
y Past medical history – HTN ×15 years
y Medications – HCTZ 25 mg once daily
65-Year-Old Woman With 15-Year History of HTN y 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))
y Laboratory examination – Total cholesterol = 230 mg/dL – LDL-C = 120 mg/dL – HDL-C = 39 mg/dL – Other laboratory tests unremarkable
ED = emergency department; HCTZ = hydrochlorothiazide
65-Year-Old Woman With 15-Year History of HTN
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
MRI Diffusion-Weighted Imaging (DWI)
y Diagnostic studies – EKG normal – Transthoracic echocardiography showed LVH – MRA of the head and neck was unremarkable – MRI of the head Right
Left
EKG = electrocardiogram LVH = left ventricular hypertrophy MRA = magnetic resonance angiography
2
65-Year-Old Woman With 15-Year History of HTN y Diagnostic studies – EKG is normal – Transthoracic echocardiography showed LVH – MRA of the head and neck was unremarkable
Guidelines for Management of TIA
– MRI of head shows DWI abnormality predominantly of left posterior limb of internal capsule consistent with ischemic injury
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 Johnston SC et al. Ann Neurol. 2006;60(3):301
Recent TIA: A Neurologic Emergency y Risk of stroke after TIA – 10.5% occurred within 90 days and half occurred within 2 days (Kaiser-Permanente HMO study)
y Risks may have been previously underestimated
Sacco RL et al. Stroke. 2006;37(2):577
Predicting Risk of Stroke After TIA: ABCD2 Score for 2- or 7-Day Risk of Stroke A Age
≥60 years
B Blood pressure
SBP >140 mm Hg or DBP ≥90 mm Hg
1 point
Unilateral weakness
2 points
C Clinical features
Speech disturbance without weakness k
1p point
Duration of D symptoms
≥60 minutes
2 points
10–59 minutes
1 point
D Diabetes
Diabetes
1 point
– 1%─2% 1% 2% at 7 days and 2% 2%─4% 4% at 30 days
y True risk – Up to 10% at 7 days and as high as 15% at 30 days
y Time window for prevention is brief
Maximum score
– 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
1 point
7 points
DBP = diastolic blood pressure; SBP = systolic blood pressure Johnston SC et al. Lancet. 2007;369(9558):283 Rothwell PM et al. Lancet. 2005;366(9479):29
3
ABCD2 Is Predictive of 2-Day Risk of Stroke in Patients With TIA
Traditional TIA Symptoms and Signs*: Carotid Territory (1974) Symptom
ABCD2 Score Level of Risk
2-Day Stroke Risk
Weakness, clumsiness, paralysis of 1 or both limbs on same side
2. Sensory
Numbness, loss of sensation, and paresthesias of 1 or both limbs on same side; without spread or march
3. Speech/language
Aphasia
4. Vision
Loss in 1 eye or part of 1 eye
(%)
6–7
High g
8.1
4–5
Moderate
4.1
0–3
Low
1.0
Sign
1. Motor dysfunction
5. Vision
Homonymous hemianopia
6. Multiple
Combination of above
*Symptoms/sign can last up to 24 hours Johnston SC et al. Lancet. 2007;369(9558):283
TIA: New Definition Is Proposed (2002) Definition y y y y
Brief episode of neurologic dysfunction caused by focal brain or retinal ischemia Clinical symptoms typically lasting less than 1 hour No evidence of cerebral infarction (using advanced neuroimaging techniques) q ) Urgent brain imaging is recommended
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
Albers GW et al. N Engl J Med. 2002;347(21):1713
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
Carotid imaging
pp ultrasound;; CTA and/or MRA for supra-aortic p Doppler vessels 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 count CEA = carotid endarterectomy TCD = transcranial Doppler TEE = transesophageal echocardiogram TTE = transthoracic echocardiogram Johnston SC et al. Ann Neurol. 2006;60(3):312
Heyman A et al. Stroke.1974;5:277
National Stroke Association (NSA) Guidelines for the Management of TIAs Factor
Comment
Hospitalization
• 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 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 Johnston SC et al. Ann Neurol. 2006;60(3):301
Medical and Surgical Management of TIAs y NSA and AHA/ASA guidelines for use of antithrombotic therapies, CEA, EC-IC bypass, and medical risk-factor modification for TIA patients are comparable y 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 EC-IC = extracranial-intracranial Johnston SC et al. Ann Neurol. 2006;60(3):301 Sacco RL et al. Stroke. 2006:37(2):577 Adams RJ et al. Stroke. 2008;39(5);1647
4
Does Rapid Assessment and Treatment of TIA/Minor Stroke Lead to Improved Outcomes? EXPRESS Study
Guidelines for Use of Antiplatelet Therapy in TIA or Ischemic Stroke Prevention
90-Day Risk of Recurrent S Stroke* (%)
y Urgent assessment and immediate clinical treatment in Oxford Vascular Study (OXVASC) of those at risk of stroke within 90 days y Phase 1 (4/1/02–9/30/04); Phase 2 (10/1/04–3/31/07) 12
10.3
10
Early treatment associated i t d with ith 80% reduction
8 6
Resting platelet
4 2
P=.0001
2.1
Activated platelets
(Scanning electron microscopy)
0 Phase 1
Phase 2
*When referred to study clinic EXPRESS study = Early Use of Existing Preventive Strategies for Stroke study Rothwell P et al. Lancet. 2007;370(9596):1432
65-Year-Old Woman With 15-Year History of HTN y 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 y 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)
y Other Oth recommendations d ti – –
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
“Variable Response” Preferred Term to “Aspirin Resistance”? y Variable response – Occurrence of breakthrough atherothrombotic events – Response to ASA differs among patients and may be attributed to various mechanisms
*New recommendation since 2006 guideline ASA = aspirin; bid = twice a day; ER = extended release; ESPRIT = European/Australasian Stroke Prevention in Reversible Ischaemia 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!20 85969891!181195628!8091!-1. Accessed July 16, 2008
5
Aspirin Resistance: More Than Just a Laboratory Curiosity?
PRoFESS Trial Study design
Multinational (more than 21 countries and 600 sites), randomized, double-blind, placebo-controlled, 2 x 2 factorial design
Study population
20,333 patients with recent stroke (within 90 days of study entry)
Cellular factors Genetic polymorphisms
Insufficient suppression of COX-1
Clinical factors
Overexpression of COX-2 mRNA
Noncompliance
COX-1 GP IIIa receptor
Failure to prescribe Nonabsorption
Collagen receptor
Erythrocyte-induced platelet activation
Interaction with ibuprofen
vWF receptor
Increased norepinephrine
Interaction with naproxen
Generation of 8-iso-PGF2α
Study drugs
ASA/ER dipyridamole vs clopidogrel and telmisartan vs placebo
Primary end point
Time to first recurrent stroke
Secondary end point
Stroke, MI, or vascular death; major bleeding; stroke or major hemorrhage
Anticipated data
2008
ASA resistance COX = cyclo-oxygenase; GP = glycoprotein; mRNA = messenger ribonucleic acid; PGF2α = prostaglandin F2 alpha; vWF = von Willebrand factor
MI = myocardial infarction; PRoFESS = Prevention Regimen For Effectively Avoiding Second Strokes
Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43(6):1127
Diener HC et al. Cerebrovasc Dis. 2007;23:368
PRoFESS Trial: Preliminary Results y Primary 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)
y Bleeding – 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)
Guidelines for Medical Risk Factor Management g in Patients With TIA or Ischemic Stroke
y 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 Boehringer Ingelheim. News Release. PRoFESS® results announced at XVII European Stroke Conference. http://www.boehringeringelheim.com/corporate/news/press_releases/detail.asp?ID=5534. Accessed August 12, 2008
65-Year-Old Woman With 15-Year History of HTN y Diagnosis – Patient was diagnosed with a lacunar or small artery territory infarction syndrome
y 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
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
– Her BP was initially not treated
y Within 48 hours of the neurologic symptoms, her neurologic examination was normal tPA = tissue plasminogen activator
6
Which one of the following statements best characterizes the use of statin therapy for recurrent stroke prevention?
Which one of the following statements best characterizes smoking as a risk factor for stroke?
A. There is no proof that statin therapy reduces stroke risk
A. Environmental (passive) smoke increases the risk of stroke
py reduces stroke risk,, but is not B. Statin therapy safe; fatal liver disease is common
g is a risk factor for ischemic,, but not B. Smoking hemorrhagic stroke
C. Statin therapy reduces stroke and major cardiovascular risks
C. Smoking increases the relative risk of stroke by 5 to 10 times
D. Statin therapy reduces stroke risk, but does not reduce major cardiovascular risks
D. Smoking cessation leads to reversal of stroke risk after 20 years
AHA/ASA 2008 Recurrent Stroke Prevention Guideline Update
AHA/ASA 2006 Recommendations for Lifestyle and Risk Factor Management in TIA or Ischemic Stroke Factor
y Statin therapy and lipid lowering – Based on the SPARCL results, statin therapy with intensive lipidlowering 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)* – Target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease
Recommendation 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 A Class IIa, LOE B
Smoking
Discontinue smoking Counseling, NRT, and oral smoking-cessation medications
Class I, LOE C Class IIa, LOE B
Alcohol use
Eliminate heavy drinking or reduce Men ≤2 drinks/day and non-pregnant women 1 drink/day
Class I, LOE A Class 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
y LDL-C level of <100 mg/dL or y LDL-C <70 mg/dL for very high-risk persons (those with multiple risk factors) *New recommendation since 2006 guideline SPARCL = 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=Lr9hG X0qz7ynry2TfJTs7r5sGmJbBVyq3ph0xMkhBn2p4T0rGs2Q!2085969891!1811956 28!8091!-1. Accessed July 16, 2008
LOE
HTN
ACEI = angiotensin-converting enzyme inhibitor; BMI = body mass index; NRT = nicotine replacement therapy; Rx = treatment Sacco RL et al. Stroke. 2006:37(2):577
Established Therapies Are Consistently Underused in all Patient Types Patients s Not Receiving Prove en Therapy (%)
Improving Patient Adherence
Lipid lowering
Antiplatelets
60 50
46
44 39
40
36 30
30 20
Statin
28
24 19
18
18
19
14
10 0 CAD (n=40,258)
CVD (n=18,843)
PAD (n=8273)
Multiple Risk Factors (n=12,389)
CAD = coronary artery disease; PAD = peripheral artery disease Bhatt DL et al. JAMA. 2006;295(2):180
7
65-Year-Old Woman With 15-Year History of HTN y Patient is now taking a diuretic, ACEI, statin, and ASA plus ER dipyridamole for recurrent stroke prevention
Steps to Consider to Enhance Adherence to TIA or Recurrent Stroke Prevention Regimen y Awareness or recognition of stroke risk and risk factors y Qualitative determination of recurrent stroke risk y Awareness of risk factor numbers ((eg, g BP, blood glucose, serum cholesterol)
What steps might be taken to assure adherence to the treatment regimen?
y Establish multimodality maintenance approach
American Stroke Association broadcast on Primary Stroke Prevention, October 2007
Recurrent Stroke Prevention Successful Maintenance of Treatment by Multimodality Approach y Motivation from family members y Reminders and encouragement from medical office staff y Pharmacy reminders to renew medications y Physician report cards: Is the patient meeting target numbers?
American Stroke Association broadcast on Primary Stroke Prevention, October 2007
What Can Stroke Teams Do? y In-hospital initiation of secondary prevention therapies to increase treatment utilization and adherence in the long term y 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
65-Year-Old Woman With 15-Year History of HTN y On physical examination, the patient’s pulse is noted to be irregularly irregular. A bedside EKG is ordered
Cardioembolic Stroke Management y Patient is diagnosed with cardioembolic stroke secondary to AF
8
Which one of the following therapies is recommended to prevent stroke recurrence for a high-risk patient with atrial fibrillation? A. Aspirin
Secondary Stroke Prevention: Cardioembolic Stroke y Cardioembolic stroke is responsible for ~20% of ischemic strokes y High risk of recurrence if not treated properly
B. Clopidogrel
y Underlying cardiac disease* – Nonvalvular AF (50%)
C. Ximelagatran
– LVT (33%)
D. Warfarin
– Valvular heart disease (25%) – Cardiomyopathy with low EF (25%) *Patients may have more than 1 underlying cardiac condition EF = ejection fraction; LVT = left ventricular thrombus Cerebral Embolism Task Force. Arch Neurol. 1989;46(7):727 Pujadas Capmany R et al. Int J Cardiol. 2004;95(2-3):129
Cardioembolic Stroke: AF y Persistent and paroxysmal AF are potent risk factors for recurrent stroke Risk factors for recurrent stroke in patients with AF
Age CHF HTN DM Prior thromboembolism (TIA or stroke)
Anticoagulation y Warfarin1 Outcome Stroke reduction (%)
Warfarin (INR goal of 2–3)
Antiplatelet agents
64 (95% CI 49-74%)
22 (95% CI 6-35%)
14
34
NNT for 1 year for secondary stroke prevention (n)
y 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 FDA = US Food and Drug Administration; INR = international normalized ratio; SPORTIF-V = Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation V
CHF = congestive heart failure
AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy in AF 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 II, LOE A) 2. For patients unable to take oral anticoagulants, ASA 325 mg/day is recommended (Class I, LOE A)
Sacco RL et al. Stroke. 2006;37(2):577
1. Hart RG et al. Ann Intern Med. 2007;146(12):857 2. Albers GW et al. JAMA. 2005;293(6);690
AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy in Acute MI With LVT 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 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)
Sacco RL et al. Stroke. 2006;37(2):577
9
65-Year-Old Woman With 15-Year History of HTN y On physical examination, a carotid bruit is heard on the left side
Guidelines for Symptomatic Extracranial Carotid Occlusive Disease Management
y CTA of the neck shows 70%–99% stenosis of the proximal portion of the left ICA
ICA = internal carotid artery
65-Year-Old Woman With 15-Year History of HTN
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
y Diagnosis: symptomatic left extracranial ICA stenosis
Secondary Stroke Prevention: Symptomatic Extracranial Carotid Occlusive Disease North American Symptomatic Carotid Endarterectomy Trial (NASCET)1
AHA/ASA 2006 Guideline Recommendations for CEA 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 patientspecific factors such as age, gender, comorbidities, and severity of initial 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)
• 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 (%)
Results
70–99
2-year risk of stroke was 9% with CEA and 26% with medical therapy
50–69
5-year 5 year risk of stroke was 15.7% 15 7% with CEA and 22.2% 22 2% with medical therapy Less 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):445 2. Rothwell PM et al. Lancet. 2004;363(9413):915
Sacco RL et al. Stroke. 2006; 37(2):577
10
AHA/ASA 2006 Guideline Recommendations for Carotid Angioplasty and Stenting 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 (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
Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman With 15-Year History of HTN
65-Year-Old Woman With 15-Year History of HTN
y Physical examination is unremarkable y Cerebral vascular diagnostic workup shows no cardiac source of embolism, and both carotid arteries are patent with no evidence of h hemodynamically d i ll significant i ifi t stenosis t i y Head MRA is ordered, which shows a proximal left MCA stenosis y Diagnosis: large artery intracranial occlusive disease (LAICOD) MCA = middle cerebral artery
Which one of the following is recommended as first-line treatment for large artery intracranial occlusive disease? A. Antiplatelet therapy
Secondary Stroke Prevention: Symptomatic Intracranial Carotid Occlusive Disease y Worldwide LAICOD is a common and well-defined stroke subtype y Certain population groups may be at higher risk for LAICOD
B. Anticoagulant therapy
Ethnic Group
Reported Frequency of LAICOD in Patients With Stroke (%)
C. Angioplasty and stenting
Chinese Korean South Asian Thai
35–50 56 54 47
D. Extracranial to intracranial bypass
y 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) Gorelick PB et al. Stroke. 2008;39(8):2396
11
AHA/ASA 2006 Guideline Recommendations for Treatment of LAICOD With Endovascular Therapy
LAICOD: Risk of Recurrent Cerebral Ischemic Stroke in Key Clinical Trials y
y
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 shown Warfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID)2 – 569 patients with symptomatic 50%–99% IC stenosis – INR goal of 2–3 – Mean follow up of 1.8 years
Outcomes in WASID
ASA (%)
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 (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.
Warfarin (%)
Ischemic stroke
20.4
17.0
Ischemic stroke in the territory of the stenotic vessel
15.0
12.1
Disabling or fatal ischemic stroke
8.9
6.2
1. Sacco et al. Stroke. 2006; 37(2):577 2. 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.
1. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):1191 2. Chimowitz MI et al. N Engl J Med. 2005;352(13):1305
Conclusions y TIA and ischemic stroke are important risk factors for recurrent cerebral ischemia y Recurrent stroke is preventable
Appendix I Additional Slides
y NSA 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
y
12 meta-analyses (106 studies, 210,926 patients)
y
Combination of – Diet – Exercise – ASA (ASA + dipyridamole) – Statin (high dose) – Antihypertensive A tih t i d drug (aggressive BP lowering)
y
Predicted 5-year major vascular event rate – RRR 80% (90%) – ARR 20% (22%) – NNT 5 (5) – Residual 5-year risk 5% (3%)
5-Yearr Major Vascular Event Rate (%)
Polytherapy for Recurrent Stroke Prevention: Opportunity for Reduction of Subsequent Stroke Risk 90 Untreated
80 70
Predicting Stroke Risk in AF: Who Benefits Most? Multivariate Analysis of Pooled Data
Treated
60 50
Clinical Risk Factors
40 30 20 10 0
Cartoid stenosis
AF
Diabetes
Smoking
RRR (%)
90
86
84
87
ARR (%)
41
67
27
25
NNT (n)
2
1
4
4
RR
Previous stroke or TIA
2.5 ×
History of HTN
1.6 ×
Diabetes
1.7 ×
Increasing age (per decade)
1.4 ×
Benefits of combination therapy in patients with CVD and specific subtypes or comorbidities
ARR = absolute risk reduction; NNT = number needed to treat; RRR = relative risk reduction
RR = relative risk
Adapted with permission from Hackam DG, Spence JD. Stroke. 2007;38(6):1881
Hughes M et al. Thromb Haemost. 2008;99(2):295
12
Initiation of Anticoagulation Therapy in AF Patient With Acute TIA or Stroke y Controversy exists regarding the timing of treatment
Cardioembolic Stroke: Acute MI and LVT y Acute MI and LVT
y Patients with TIA – May receive anticoagulation immediately if not contraindicated by CT, MRI brain, or otherwise
– Stroke and systemic embolism can occur in up to 12% of patients with LVT post MI – Risk of LVT is higher in anterior MI
y 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)
– 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
– Delaying anticoagulation may be reasonable in patients with uncontrolled HTN and large infarcts
Albers GW et al. Chest. 2004;126(3 suppl):483S Visser CA et al. Chest. 1984;86(4):532
Cardioembolic Stroke: Cardiomyopathy y Cardiomyopathy
AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy in Cardiomyopathy
– Significantly reduced LV systolic function causes relative stasis – Annual stroke rate in the Survival And Ventricular Enlargement (SAVE) study1 y 0.8% in patients with EF of 29%–35% y 1.7% in those with EF ≤28% – N No study t d h has d definitively fi iti l proven th the efficacy ffi off warfarin f i or ASA iin stroke prevention in patients with cardiomyopathy
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, IIb LOE C)
– 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
Sacco RL et al. Stroke. 2006;37(2):577
Cardioembolic Stroke: Valvular Disease
Cardioembolic Stroke: Valvular Disease Valvular Disorder
y PHV – Warfarin (INR, 1.8–2.5) versus antiplatelet agents1 Treatment Warfarin ASA-dipyridamole Pentoxifylline-ASA
Rheumatic valve disease
Thromboembolism (100 patient-years) (%) 2 9.8 7.9
•
– Warfarin (INR, 3.0–4.5) vs warfarin plus ASA (100 mg daily)2 Treatment Warfarin + placebo + ASA
Annual Rate of Embolic Events or Vascular Death (%)
9.8 7.9
1. Mok CK et al. Circulation. 1985;72(5):1059 2. Turpie AG et al. N Engl J Med. 1993;329(8):524
RR (%) (95% CI) 77 (44%–91%) P<.001
Bleeding (%) 22 35
Comments • •
Increase in Risk (%) (95% CI) 55 (8%–124%) P=.02
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
Treatment and LOE 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 prevention
Antiplatelet agent (Class IIa, LOE C)
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)
Sacco RL et al. Stroke. 2006;37(2):577
13
AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy in Valvular Disease y PFO 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 75–100 100 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)
Cardioembolic Stroke: PFO
– Prevalence in patients ≥45 years is ~26% – Atrial septal aneurysm affects ~2% – 4-year risk of stroke recurrence y 2.3% in patients with PFO y 15.2% 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 y 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 PFO Closure to Established Current Standard of Care Treatment (RESPECT) study and others are comparing percutaneous PFO closure versus medical treatment for recurrent stroke prevention
PHV = prosthetic heart valve Sacco RL et al. Stroke. 2006;37(2):577
Cruz-González I et al. Rev Esp Cardiol. 2008;61(7):738
AHA/ASA 2006 Guideline Recommendations for Recurrent Stroke Prevention for PFO 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) 3. Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and PFO
Guidelines for Carotid Dissection Stroke Management
4. PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical therapy (Class IIb, LOE C)
PFO = patent foramen ovale Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman With 15-Year History of HTN
65-Year-Old Woman With 15-Year History of HTN
y Patient complains of neck pain on the left side y On physical examination, there is a left partial Horner syndrome (ptosis and miosis) y Bedside carotid duplex p is p performed y Bedside carotid duplex shows a double lumen in the proximal left ICA (picture above) y Diagnosis: left extracranial ICA dissection How should subsequent cerebral ischemia be prevented in a patient with a symptomatic carotid artery dissection?
14
Arterial Dissections: Pathophysiology
Secondary Stroke Prevention: Arterial Dissections y Extracranial arterial dissections – Common with atherosclerotic disease
y
Tear in tunica media results in bleeding in arterial wall
y
Blood dissects longitudinally spreading distally and proximally
y
Tear of intima permits clots to enter lumen
y
Expansion of intramural hemorrhage narrows lumen causing stasis, activation of platelets, and the coagulation cascade
y
Main dissection plane can lie between the media and adventitia creating a pseudoaneurysm
y
Rupture through adventitia into the intracranial circulation causes subarachnoid hemorrhage
– 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 anchored y Anterior circulation: cervical portion of the ICA y Posterior circulation: segments of the vertebral arteries (V1 and V3)
Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34
Arterial Dissections: Treatment y 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
y Due to the pathophysiology (red thrombi) most experts recommend anticoagulants y Annual 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):CD000255 2. Touzé E et al. Neurology. 2003;61(10):1347
Adapted with permission from Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34
AHA/ASA 2006 Guideline Recommendations for Antithrombotic Therapy in Cerebral Artery Dissection 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, 2. months long-term 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)
Sacco RL et al. Stroke. 2006;37(2):577
Secondary Stroke Prevention: Aortic Arch Atheroma y Prevalence and severity of aortic arch atheroma (AAA) increases with age1 y 90% of the cases are stable and AAA progresses slowly over time
Stroke Management in Patients With Aortic Arch Atheroma
y Unclear if AAA is a source of emboli or a marker of an increased risk of atherosclerotic disease y Risk of stroke is higher in patients with complicated AAAs (ie, >5 mm in thickness, ulcerated plaque, and mobile)2 Type of AAA
Odds Ratio of Stroke
Simple
2.3
Complex
7.1
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
15
Carotid Angioplasty and Stenting: Summary of Key Studies I
AAA Treatment y
y New York University Atheroma Group1
y y
– Statin therapy was protective against embolic events
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
– No protective effect with warfarin or antiplatelet agents
y Antiplatelet therapy is usually used in patients with stroke or TIA
Hypotheses
y N No d definitive fi iti study t d h has d determined t i d if warfarin f i iis superior i to antiplatelet agents for treatment of AAA
Degree g of stenosis (%)
SAPPHIRE
EVA-3S
SPACE
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
334
527
1200
>50 symptomatic y p or >80 asymptomatic
60 99 symptomatic 60–99 t ti
≥50 symptomatic t ti
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
Patients (n)
y Aortic 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
Primary end point
Primary outcome (CEA vs CAS) (%) Early termination
20.1 vs 12.2*
3.9 vs 9.6
6.34 vs 6.84**
Slow recruitment
Safety and futility reasons
No further funding
*P=.004 for noninferiority; **P=.09 for noninferiority; CAS = carotid artery stenting 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
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
Treatment of LAICOD Based Upon Key Clinical Trials
Carotid Angioplasty and Stenting: Summary of Key Studies II Study Trial conclusion
High risk for CEA Symptomatic patients (%)
SAPPHIRE
EVA-3S
SPACE
CAS is not inferior to CEA for highrisk 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
Required
Not required
Not required
29
100
100
ASA Warfarin
22.1 21.8
EC-IC Bypass Study
Operator experience CAS
Required periprocedural risk <6%
39% done by operators in training
No prespecified experience in CAS
CEA
Required periprocedural risk <6%
≥25 CEAs performed in prior year before enrollment
≥25 CEAs performed
Stent type
2 stents (same manufacturer)
5 stents (different manufacturers)
3 stents (different manufacturers)
Mandatory (only 1 system)
Tried in 92% (any of 7 systems)
Used in 27% (any of 5 systems)
Protection device
Outcome (%)
WASID1 Ischemic stroke, brain hemorrhage, or death from vascular causes (primary outcome)*
Group2
Is an EC EC-IC IC anastomosis better than medical treatment for symptomatic LAICOD?** 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)
No
14 25
*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
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
1. Chimowitz MI et al. N Engl J Med. 2005;352(13):1305 2. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):1191 3. Zaidat OO et al. Neurology. 2008;70(17):1518
Secondary Stroke Prevention: Other Specific Conditions Condition
Recurrent Stroke Prevention in Other Cerebrovascular Conditions
Comments
Hyperhomocysteinemia
• 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?
Inherited thrombophilia
• 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 prevention have been done • Evaluate for alternative mechanism
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
Treatment and LOE
Daily vitamin B6, B12 and folate (Class IIa, LOE B)
Antiplatelet or anticoagulants (Class IIa, LOE C) Anticoagulants if recurrent thrombosis (Class IIb, LOE C) 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 Sacco RL et al. Stroke. 2006;37(2):577
16
Secondary Stroke Prevention: Other Specific Conditions Condition Cerebral venous sinus thrombosis
Comments
• 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 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
Postmenopausal hormone therapy
Treatment and LOE Anticoagulants (even in the presence of hemorrhagic infarction) (Class IIa, LOE B)
• Venous infarctions are frequently hemorrhagic • More frequent in patients with hypercoagulable states • Anticoagulant superior to placebo
• 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
Risk factor control and antiplatelet agents (Class IIa, LOE B) Blood transfusion to reduce HbS to <30%–50% of total Hb, hydroxyurea, and bypass surgery for advanced occlusive disease (Class IIb, LOE C)
Appendix II References
Postmenopausal hormone therapy is not recommended (Class III, LOE A)
HbS = sickle cell hemoglobin Sacco RL et al. Stroke. 2006;37(2):577
Adams RJ. Big strokes in small persons. Arch Neurol. 2007;64(11):1567-1574. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39(5);1647-1652.
Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-189. Caplan LR. Dissections of brain-supplying arteries. Nat Clin Pract Neurol. 2008;4(1):34-42.
Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system. Atherosclerosis. 2001;155(1):1-8.
Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol. 1989;46(7):727-743.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):483S-512S.
Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirtytwo genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61(11):1652-1661.
Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack—proposal for a new definition. N Engl J Med. 2002;347(21):1713-1716. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293(6):690-698. American Heart Association. Heart Disease and Stroke Statistics—2008 Update. Dallas, Texas: American Heart Association; 2008. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712. Assistance Publique-Hôpitaux de Paris; National Health and Medical Research Council, Australia; sanofi-aventis; Bristol-Myers Squibb. Aortic Arch Related Cerebral Hazard Trial (ARCH). http://clinicaltrials.gov/ct2/show/NCT00235248. Accessed July 22, 2008.
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316. Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E. Systemic embolism in mitral valve disease. Br Heart J. 1970;32(1):26 1970;32(1):26-34. 34. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecularweight heparin for cerebral sinus thrombosis. Stroke. 1999;30(3):484-488. De Silva DA, Woon FP, Pin LM, Chen CP, Chang HM, Wong MC. Intracranial large artery disease among OCSP subtypes in ethnic South Asian ischemic stroke patients. J Neurol Sci. 2007;260(1-2):147-149. The EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med. 1985;313(19):1191-1200. Engelter ST, Brandt T, Debette S, et al. Antiplatelets versus anticoagulation in cervical artery dissection. Stroke. 2007;38(9):2605-2611.
Bhatt DL. Aspirin resistance: more than just a laboratory curiosity. J Am Coll Cardiol. 2004;43(6):1127-1129.
Feinberg WM, Albers GW, Barnett HJ, et al. Guidelines for the management of transient ischemic attacks. From the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Circulation. 1994;89(6):2950-2965.
Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP; PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105(22):2625-2631.
Fulkerson PK, Beaver BM, Auseon JC, Graber HL. Calcification of the mitral annulus: etiology, clinical associations, complications and therapy. Am J Med. 1979;66(6):967-977.
Hughes M, Lip GY, Guideline Development Group, National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost. 2008;99(2):295-304.
Gorelick PB. Practice Perspective on the AHA/ASA 2008 Update for Recurrent Cerebral Ischemia Prevention. http://pt.wkhealth.com/pt/re/aha/editorial3_5_2008.htm;jsessionid=Lr9hGX0qz7ynry2TfJTs7r5sGmJbBVyq3 ph0xMkhBn2p4T0rGs2Q!2085969891!181195628!8091!-1. Accessed July 22, 2008.
Johnston SC, Nguyen-Huynh MN, Schwarz ME, et al. National Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol. 2006;60(3):301-313.
Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease. A large worldwide burden but a relatively neglected frontier. Stroke. 2008;39(8):2396-2399.
Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283-292.
Gurm HS HS, Yadav JS, JS Fayad P P, et al al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.
JJones EF EF, Kalman K l JM JM, Calafiore C l fi P, P Tonkin T ki AM, AM Donnan D GA. GA Proximal P i l aortic ti atheroma. th A An iindependent d d t risk i k factor for cerebral ischemia. Stroke. 1995;26(2):218-224.
Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38(6):1881-1885.
Levine SR, Brey RL, Tilley BC, et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA. 2004;291(5):576-584.
Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med. 2007;357(22):2262-2268.
Lyrer P, Engelter S. Antithrombotic drugs for carotid artery dissection. Cochrane Database Syst Rev. 2003;(3):CD000255.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.
Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345(24):1740-1746.
Holley KE, Bahn RC, McGoon DC, Mankin HT. Spontaneous calcific embolization associated with calcific aortic stenosis. Circulation. 1963;27:197-202.
Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355(16):1660-1671.
17
Medical University of South Carolina and US National Institutes of Health. Stenting vs Aggressive Medical Management for Prevention Recurrent Stroke in Intracranial Stenosis. http://clinicaltrials.gov/ct2/show/NCT00576693?term=stenting&rank=9. Accessed July 22, 2008. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke prevention: assessment of risk in a community. Mayo Clin Proc. 1999;74(9):862-869. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention of prosthetic heart valve thromboembolism: a prospective randomized clinical trial. Circulation. 1985;72(5):1059-1063. Molina CA, Santamarina E, Alvarez-Sabín J. Cryptogenic stroke, aortic arch atheroma and patent foramen ovale. Cerebrovasc Dis. 2007;24(suppl 1):84-88. North N th A American i S Symptomatic t ti C Carotid tid E Endarterectomy d t t T Trial i lC Collaborators. ll b t B Beneficial fi i l effect ff t off carotid tid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325(7): 445-453. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327(10):669-677. Pujadas Capmany R, Arboix A, Casañas-Muñoz R, Anguera-Ferrando N. Specific cardiac disorders in 402 consecutive patients with ischaemic cardioembolic stroke. Int J Cardiol. 2004;95(2-3):129-134. Pullicino P, Thompson JL, Barton B, et al. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail. 2006;12(1):39-46.
Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ; Carotid Endarterectomy Trialists Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004;363(9413):915-924. Rothwell PM, Giles MF, Flossmann E, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005;366(9479):29-36. Sacco RL. Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology. 1997;49(5 suppl 4):S39-S44. Sacco RL, Wolf PA, Gorelick PB. Risk factors and their management for stroke prevention: outlook for 1999 and beyond. Neurology. 1999;53(7 suppl 4):S15-S24. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577-617. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med. 2001;344(12):898-906. SPACE Collaborative Group, Ringleb PA, Allenberg J, et al. 30 day results from the SPACE trial of stentprotected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet. 2006;368(9543):1239-1247. [Published correction in Lancet. 2006;368(9543):1238] Steiner MM, Di Tullio MR, Rundek T, et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke. 1998;29(5): 944-948.
Rothwell PM. Does transient ischemic attack deserve emergency care? Nat Clin Pract Neurol. 2006;2(4):174-175.
Szekely P. Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J. 1964;1(5392):1209-1212.
White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation. 2005;111(10):1327-1331.
Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85-e151. [Published corrections in Circulation. 2006;113(14):e696; Circulation. 2006;114(23):e630]
Wong LKS. Global burden of intracranial atherosclerosis. Int J Stroke. 2006;1(3):158-159.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291(5):565-575.
Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med. 2004;351(15):1493-1501. Zaidat OO, Klucznik R, Alexander MJ, et al. The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis. Neurology. 2008;70(17):1518-1524.
Touzé E, Gauvrit JY, Moulin T, et al. Risk of stroke and recurrent dissection after a cervical artery dissection: a multicenter study. Neurology. 2003;61(10):1347-1351. Tunick PA, PA Nayar AC, AC Goodkin GM, GM et al. al Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol. 2002;90(12):1320-1325. Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med. 1993;329(8):524-529. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345(17):1243-1249. Visser CA, Kan G, Meltzer RS, Lie KI, Durrer D. Long-term follow-up of left ventricular thrombus after acute myocardial infarction. A two-dimensional echocardiographic study in 96 patients. Chest.1984;86(4): 532-536. Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease. Blood. 1999;94(9):3022-3026.
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