The Secondary Prevention Of Stroke For Linked In

The Secondary Prevention of Ischemic Stroke

Jon Zlabek, MD, FACP

Now What???

Learning Objectives

• Review the evidence-based management and guidelines for patients with transient ischemic attack (TIA) and ischemic stroke

• Emphasize the urgency of TIAs

The Six “Big Boys”

• Hypertension • Hypercholesterolemia• Smoking• Antiplatelet Therapy• Cardioembolic TIA/Stroke• Carotid Stenosis

The Scope of the Problem

• 795,000 people in the United States have a stroke each year– One every 40 seconds

• 150,000 people in the United States die from a stroke each year– One every 4 minutes– Third leading cause of death

www.strokeassociation.org

The Scope of the Problem

• Good News! From 1994-2004 the stroke rate FELL by 24.2% and the number of stroke deaths FELL by 6.8%

• Bad News! Thirty-day case fatality for ischemic stroke is 10-17%

• 185,000 people have a recurrent stroke every year

NEJM 2007;357:572-9www.strokeassociation.org

Very High Risk Groups

9 Times

2-3 Times

3-4 Times

MI

PAD

Stroke

Site of Initial Event

Increase in Risk of Stroke vs. General

Population

In 2010, for stroke-related expenses, Americans will pay an estimated

73.7 BILLION DOLLARS

www.strokeassociation.org

BIG BUCK$

Transient Ischemic Attack

A brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia with clinical symptoms typically lasting less than 1 hour, and without evidence of infarction.

Stroke 2006;37:577-617

Stroke

An episode of neurological dysfunction caused by a focal disturbance of brain ischemia with clinical symptoms lasting > 24 hours, OR imaging of an acute clinically relevant brain lesion with rapidly vanishing symptoms.

Stroke 2006;37:577-617

TIA vs. Stroke

• The distinction is becoming less important– Share common pathological mechanisms– Preventative approaches are similar

Stroke 2006;37:577-617

TIA vs. Stroke

• However, patients with TIA receive less aggressive diagnostic testing and treatment than stroke patients, despite a 5-year stroke risk over 30%

• 200,000-500,000 patients have a TIA each year

Dandapani B, unpublished datawww.strokeassociation.org


• About 15% of strokes are preceded by a TIA

• The risk of a stroke after a TIA is very high, and most of the risk is very early– 9.9% at 2 days– 13.4% at 30 days– 17.3% at 90 days

www.strokeassociation.orgStroke 2006;37:320-22Arch Intern Med 2007;167(22)2417-22


• Patients with TIA are very heterogenous in terms of symptoms, risk factors, and underlying pathology

• However, you can predict who is headed for big trouble . . .

Stroke 2006;37:320-22


• Isolated sensory or visual symptoms are associated with lower risk of subsequent stroke

JAMA 2000;284:2901-6Lancet 2005;366:29-36

“ABCD” Score

• “ABCD” Score– Age > 60 (1 pt)– SBP > 140 and/or DBP

>90 (1 pt)

– Clinical features• Unilateral weakness (2

pts)• Speech problem (1 pt)

– Duration > 60 min (2 pts)

– Duration 10-59 min (1 pt)

• 7-day risk of CVA– 6 = 31.4%– 5 = 12.1%– 4 or less = 0.4%

– All patients with a stroke within one week had scores 4

Lancet 2005;366:29-36

Express TIA Care Works!

• EXPRESS study• Very thought-provoking study of patients with

TIA or minor stroke

• Several treatments are effective for secondary stroke prevention; assuming the effects are independent, appropriate use of these interventions should reduce the long term risk of recurrent stroke by 80-90%

Lancet 2007;370:1432-42

Express TIA Care Works!

• 91,000 patients in 9 primary care practices in Oxfordshire, UK

• Lifelong medical records are kept (closed system)

Lancet 2007;370:1432-42

Phase 1 – Baseline Cohort

• Created an Express “TIA and Minor Stroke Clinic”• Physicians were asked to refer all patients with

suspected TIA and minor stroke that didn’t need hospital admission

• Kept the usual UK practice of:– Appointment-based (delays in referrals/contacting patients)– Didn’t start treatment; just made recommendations to the

primary care provider

Lancet 2007;370:1432-42


• Primary physician faxed an appointment request after they saw an appropriate patient

• The clinic contacted the patient at home by telephone

• Made appointment for the next available weekday slot

Lancet 2007;370:1432-42


• Performed usual studies:– CT– EKG– Carotid Ultrasound– Transthoracic ECHO (when clinically indicated)

• All studies were arranged during the following week

Lancet 2007;370:1432-42


• Recommendations faxed to primary care physician within 24 hours:– Aspirin 75 mg/day or Clopidogrel 75 mg/day

(if aspirin contraindicated)• If “high early risk”, combined both for 30 days

– Simvastatin 40 mg/day– Perindopril 4 mg/day +/- Indapamide 1.25 mg/day

if SBP > 130 mmHg– Anticoagulation if indicated

Lancet 2007;370:1432-42


• No treatment/prescriptions were given to the patient

• “Contact your primary care physician as soon as possible”

Lancet 2007;370:1432-42

Phase 2 – Intervention Cohort

• No appointments necessary

• Physicians instructed to send all patients to the clinic the weekday afternoon after they first presented

• Treatment initiated immediately– Both a time effect and a “get it done” effect

Lancet 2007;370:1432-42

Phase 2 – Intervention Cohort

• All patients given 300 mg of aspirin in clinic or a 300 mg loading dose of clopidogrel

• Given a 30-day prescription for other medications:– Simvastatin– Perindopril +/- Indapamide– Warfarin if indicated– Clopidogrel if indicated

Lancet 2007;370:1432-42

Results of Express Care

• Phase 1 = 634 patients• Phase 2 = 644 patients

• 95% of all referrals went to the Express Clinic

Lancet 2007;370:1432-42


• Delay to assessment in Express Clinic:– Phase 1 = 3 days– Phase 2 = less than 1 day (p<0.0001)– 1.7% vs 29.0% were seen in ≤ 6 hours (p<0.0001)

• Delay to first prescription of treatment:– Phase 1 = 20 days (8-53 days)– Phase 2 = 1 day (0-3 days) (p<0.0001)

Lancet 2007;370:1432-42


• Statin used:– Phase 1 = 65%– Phase 2 = 84% (p<0.0001)

• Aspirin + 30 days of clopidogrel:– Phase 1 = 10%– Phase 2 = 49% (p<0.0001)

Lancet 2007;370:1432-42


• On one or more blood pressure medications:– Phase 1 = 62%– Phase 2 = 83% (p<0.0001)

• Carotid surgery within 7 days:– Phase 1 = 0% (n=17)– Phase 2 = 40% (n=15) (p=0.006)

Lancet 2007;370:1432-42


• 90-day risk of recurrent stroke–Phase 1 = 10.3%–Phase 2 = 2.1% (p=0.0001)–80% reduction in risk

• Those patients not referred to Express Care did not have any reduction of stroke

• Early treatment did not increase risk of intracerebral or other bleeding

Lancet 2007;370:1432-42

Stat TIA and Stroke Clinic

Now What???

• What can be done to combat this disease?– Very common– Deadly– Extremely costly– Devastating to patients and family

First Things First

Do the best you can to determine the mechanism of the ischemic event

Mechanisms of TIA/Stroke

• Large artery atherosclerotic• Cardioembolic• Small-vessel disease• Hemorrhagic• Undetermined cause• Other:

– Dissections– Hypercoagulable states

Stroke 2006;37:577-617

After you determine the mechanism,

THEN . . .

Target the “Big Boys”

Hypertension

THE MOST IMPORTANT RISK FACTOR FOR STROKE

Stroke 2006;37:577-617

Hypertension

• Affects 31% of U.S. adults (~50 million)• Control is poor:

– 31% of patients with HTN are controlled– 53% of patients with HTN on therapy

• Control in clinical trials is much better:– 66-70%

Hypertension 2006;47:345-51Stroke 2006;37:577-617

Hypertension

• Stroke risk rises linearly from 115/75 mmHg

• For every SBP elevation of 20 mmHg or DBP elevation of 10 mmHg, there is a doubling of stroke mortality

JNC-7 NHLBI

Hypertension

• About 60% of all strokes are attributable to hypertension– That’s 468,000 strokes per year in USA

• Blood pressure control decreases initial stroke rate by 35-40%

JNC-7 NHLBI

We Missed the News Flash!

• Stroke & heart disease death rises linearly from 115/75 mmHg

JNC-7 NHLBI


• Stroke & heart disease death rises linearly from 115/75 mmHg

• 141/88 should take on a new meaning with this tidbit– Get them off the bubble and into the “safe zone”

JNC-7 NHLBI

Hypertension

• During and immediately after a stroke, blood pressure may transiently elevate in a compensatory fashion

• Acute reductions in blood pressure during the first 24 hours may be deleterious

JNC-7 NHLBIStroke 2003;34:1056-83

Hypertension

• Blood pressure can fall by as much as 20/10 mmHg over the 10 days after stroke

• Antihypertensive therapy can lead to an exaggerated reduction in cerebral blood flow acutely due to impaired autoregulation

Hypertension

• Recommended only to acutely lower blood pressure if: – SBP >220 mmHg, or– DBP >120-140 mmHg

• Use labetolol +/- nitroprusside to lower blood pressure by 10-15%

JNC-7 NHLBIStroke 2003;34:1056-83

Hypertension

• After the acute event has passed, tight blood pressure control is essential– <130/80 mmHg if:

• Diabetes or Chronic kidney disease• CAD or CAD equivalent (carotid disease, PAD, AAA, or

10 year risk ≥ 10%)

– <120/80 if left ventricular dysfunction– <140/90 mmHg for the few others remaining

JNC-7 NHLBICirculation 2007;115:2761-2788

HTN Treatment after TIA/Stroke

• PROGRESS: Perindopril Protection against Recurrent Stroke Study

– Currently is the best data available in this group of patients

– Another recent study (MOSES) had poor design and is fraught with controversy

Lancet 2001;358:1033-41Stroke 2005;36:1218-26

Perindopril Protection Against Recurrent Stroke Study (PROGRESS)

• 6105 patients with TIA or stroke within the past 5 years

• Randomized to active treatment or placebo

Lancet 2001;358:1033-41

• Perindopril 4 mg daily PLUS Indapamide 2.5 mg daily (58%)

OR

• Perindopril 4 mg daily (42%)

• Double placebo

OR

• Single placebo

• Primary outcome was fatal or non-fatal stroke

• Duration of follow up 3.9 years• Prespecified subgroups of hypertensive and

non-hypertensive patients at study entry– HTN defined as either SBP >160 mmHg

or DBP >90 mmHg

Lancet 2001;358:1033-41


• Baseline blood pressures:– Overall 147/86 mmHg– Hypertensive group 159/94 mmHg– Non-hypertensive group 136/79 mmHg

Lancet 2001;358:1033-41


• Reduction in blood pressure vs. placebo – Active treatment group = 9.0/4.0 mmHg

• Perindopril + Indapamide = 12.3/5.0 mmHg• Perindopril only = 4.9/2.8 mmHg

– Hypertensive group = 9.5/3.9 mmHg– Non-hypertensive group = 8.8/4.2 mmHg

Lancet 2001;358:1033-41


• Patients with primary endpoint of stroke: – Active treatment group = 10.1%– Placebo group = 13.8%

• Absolute risk reduction 3.7% over 3.9 years• Number needed to treat = 27

Lancet 2001;358:1033-41


• In the active treatment group:– Fewer major vascular events– Fewer non-fatal vascular events– Fewer major coronary events– Fewer hospitalizations and if hospitalized, a

shorter stay of 2.5 days

Lancet 2001;358:1033-41


• Combination therapy vs. perindopril only– Perindopril + Indapamide better than placebo– Perindopril alone not better than placebo

Lancet 2001;358:1033-41


• Hypertensive vs. Non-hypertensive groups– Reduction of stroke was the same– Reduction of major vascular events was the same

• Patients without hypertension benefited as much as those with hypertension!!!– Similar to HOPE study (ramipril)

Lancet 2001;358:1033-41


Hypertension Take Home Points

• Don’t acutely lower blood pressure after stroke

• Tight blood pressure control after the acute period is essential– Class I, LOE A

Hypertension Take Home Points

• Start thiazide plus ACE-I after stroke– Class I, LOE A

• Start blood pressure therapy regardless of presence of baseline hypertension– Class IIa, LOE B

• After the acute event passes 115/75 mmHg is optimal

Hypercholesterolemia

• Cholesterol studies to date mainly looked at patients from a cardiac point of view

• Relative risk reduction for ischemic stroke in these studies ~ 20-30%

Stroke 2002;35:1023N Engl J Med 2005;352:1425Ann Intern Med 1998;128:89JAMA 1997;278:313


• Statins were the most studied agents

• Niacin showed a reduction of cerebrovascular events in the Coronary Drug Project

Stroke 2006;37:577-617JAMA 1975;231:360-81


• SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels – 4731 patients with TIA/stroke within 1-6 months– No known coronary disease– LDL 100-190 mg/dl (mean 133 mg/dl)– Atorvastatin 80 mg/day vs placebo– Primary endpoint of fatal or non-fatal stroke

NEJM 2006;355:549-59

SPARCL

• Followed for 4.9 years• LDL levels at end of study

– Atorvastatin group: 73 mg/dl– Placebo group: 129 mg/dl

• Absolute risk reduction of stroke: 2.2%– P = 0.03 adjusted and 0.05 unadjusted

NEJM 2006;355:549-59

SPARCL

• Absolute risk reduction of major cardiovascular events: 3.5%– P = 0.002

• Small increase in hemorrhagic stroke in atorvastatin group

• Overall mortality was the same in both groups

NEJM 2006;355:549-59

Statins and Carotid Endarterectomy

• Retrospective study looking at the association of statin use before CEA and outcomes– 1566 patients– Indication was for symptomatic disease in 42%– 42% received statin > 1 week before CEA

J Vasc Surg 2005;42:829-36

• Statin use was associated with:– Perioperative stroke rate 1.2% vs. 4.5%– Perioperative TIA rate 1.5% vs. 3.6%– All-cause mortality 0.3% vs. 2.1%– Length of stay 2 days vs. 3 days

J Vasc Surg 2005;42:829-36

Statins and Carotid Endarterectomy

• Eighty-nine patients taking a statin who suffered an ischemic stroke

• Randomized to atorvastatin 20 mg/day by mouth or NG tube vs. placebo for 3 days

• On day 4, all patients were given atorvastatin 20 mg/day for 3 months

Neurology 2007;69:904-10

Statin Withdrawal After Stroke

• Measured:– Death/dependency– Early neurologic deterioration – Infarct volume

Neurology 2007;69:904-10


• Statin withdrawal associated with:– 4.66-fold increased risk of death/dependency– 8.67-fold increased risk of early neurologic

deterioration– 37.63 mL increase in mean infarct volume

Neurology 2007;69:904-10


Hypercholesterolemia Take Home Point

• Statin therapy should be started during hospitalization for patients with TIA/stroke, regardless of baseline LDL– Class I, LOE A if known atherosclerotic disease

or elevated cholesterol levels– Class IIa, LOE B if no evidence of

atherosclerosis and normal cholesterol levels

Stroke 2002;35:1023Stroke 2006;37:577-617

• Major independent risk factor for ischemic stroke– Doubling of risk compared with nonsmokers

• Risk of recurrent stroke decreases after quitting, and disappears after 5 years– Reduction in stroke-related hospitalizations

Smoking Is Bad

Stroke 2006;37:577-617

Antiplatelet Therapy

Aspirin is Beneficial

• United Kingdom TIA Trial– 2435 patients with TIA or minor stroke – Given 300 or 600 mg of aspirin or placebo– Duration of 4 years; endpoint of stroke– Both aspirin groups showed similar benefits– ARR = 2.2%; NNT = 45– NNT/year = 180

J Neurol Neurosurg Psychiatry 1991;54:1044-54Gundersen Lutheran Medical Journal 2005;3:62-5

Aspirin is Beneficial

• Swedish Aspirin Low-Dose Trial– 1360 patients with ischemic stroke – Given 75 mg of aspirin or placebo– Duration of 32 months; endpoint of stroke– ARR = 2.6%; NNT = 38– NNT/year = 101

Lancet 1991;338:1345-49Gundersen Lutheran Medical Journal 2005;3:62-5

What about Ticlopidine?

• Two major studies showed good results in TIA/stroke patients to prevent recurrence

• CATS (ticlopidine vs. placebo)– Two years in duration– ARR = 6.6%; NNT = 15– NNT/year = 30

Lancet 1989;1:1215-20Gundersen Lutheran Medical Journal 2005;3:62-5

What about Ticlopidine?

• TASS (1300 mg aspirin vs. ticlopidine)– 2.3 years in duration– ARR = 2.6%; NNT = 39– NNT/year = 90

• Not used much due to adverse effects– Severe neutropenia in 0.8%– CBC every 2 weeks x 3 months

NEJM 1989;321:501-7Gundersen Lutheran Medical Journal 2005;3:62-5

Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE)

• 19,185 patients with recent myocardial infarction, stroke, or symptomatic PAD

• Randomized to clopidogrel (Plavix) 75 mg/day or aspirin 325 mg/day for 3 years

• Combined endpoint of fatal or nonfatal CVA, fatal or nonfatal MI, or vascular death

Lancet 1996;348:1329-39

Lancet 1996;348:1329-39


• Endpoint reached with aspirin 5.83%• Endpoint reached with clopidogrel 5.32%• ARR = 0.51% per year• NNT/year = 196

Lancet 1996;348:1329-39

Lancet 1996;348:1329-39


• In the stroke subgroup (n=12,033 pt-yrs); to prevent another stroke:– ARR/year = 0.45%– Not significantly better than aspirin 325 mg– NNT is not applicable

• No statistical significance

Lancet 1996;348:1329-39

Clopidogrel + Aspirin?

• MATCH: Management of Athero-Thrombosis with Clopidogrel in High-Risk Patients with Transient Ischemic

Attack or Ischemic Stroke

Lancet 2004;364:331-7


• 7599 high risk patients with recent TIA or ischemic stroke– Clopidogrel + aspirin 75 mg vs.– Clopidogrel alone

• 18 month follow-up for stroke, MI, vascular death, or rehospitalization for ischemia

Lancet 2004;364:331-7


• No difference in vascular events• Increased life-threatening bleeding in the

clopidogrel + aspirin group– No difference in mortality however

• No rationale for using this combination in this patient population

Lancet 2004;364:331-7

European Stroke Prevention Study 2 (ESPS-2)

• 6602 patients with TIA or stroke within the prior 3 months

• Randomized to one of four arms:1. Aspirin 25 mg BID2. ER-dipyridamole 200 mg BID3. Combination of aspirin + ER-dipyridamole

(Aggrenox) 4. Placebo

J Neurol Sci 1996;143:1-13


• Primary endpoints were stroke, death, or both

• Secondary endpoints were TIA and vascular events

• Followed for two years

J Neurol Sci 1996;143:1-13

Benefit vs. Placebo for Endpoint of Stroke

• Aspirin 25 mg BID– ARR = 2.7%; NNT = 37– NNT/year = 74

• ER-dipyridamole 200 mg BID– ARR = 2.4%; NNT = 42; – NNT/year = 84

• Combination of these– ARR = 5.6%; NNT = 17.7– NNT/year = 35

J Neurol Sci 1996;143:1-13

Benefit vs. Aspirin for Endpoint of Stroke

• Combination aspirin + ER-dipyridamole– ARR = 3.0%; NNT = 33.6– NNT/year = 67

• No significant effect on death rate alone• Less TIAs and vascular events in

combination therapy group

J Neurol Sci 1996;143:1-13


• Headache and gastrointestinal disturbances prompting stopping medication were more common in the combination group– 8.1% vs. 2.3% for headache– 7.0% vs. 3.6% for GI troubles

• ESPRIT trial confirmed the superiority of aspirin + dipyridamole over aspirin alone

J Neurol Sci 1996;143:1-13Lancet 2006;367:1665-73

PRoFESS

Effects of aspirin plus extended release dipyridamole versus clopidogrel and

telmisartan on disability and cognitive function after recurrent stroke in patients

with ischemic stroke in the Prevention Regimen for Effectively Avoiding Second

Strokes trial

PRoFESS

• Patients ≥ 50 years old with an ischemic stroke in the last 90 days

• Patients 50-54 years old, or who presented 90-120 days after stroke if they had two of:– Diabetes– Hypertension– Smoker– Obesity– Prior vascular disease– High cholesterol– End organ vascular damage (retinopathy, LVH,

microalbuminuria)Lancet Neurology 2008;7(10)

PRoFESS

• Randomized to:– Aggrenox plus placebo– Plavix plus placebo– Aggrenox plus Telmisartan 80 mg daily– Plavix plus Telmisartan 80 mg daily

Lancet Neurology 2008;7(10)

PRoFESS

• Looked at:– Recurrent stroke– Modified Rankin scores (disability measure)– Barthel index (disability measure)– Mini-mental status examination


PRoFESS

• No difference in recurrent stroke

• No difference in stroke disabilty

• No difference in MMSE


Cost & Benefit Considerations for Recurrent Stroke

Medication(Brand name)

Cost per month*

Benefit over aspirin (NNT/year)

Aspirin ~Dirt -

Ticlopidine(Ticlid)

$101 90

Clopidogrel(Plavix)

$152 No benefit

ER-dipyridamole/aspirin

(Aggrenox)$173 67

*Price from www.drugstore.com; Accessed on March 10, 2009

Warfarin vs. Antiplatelets for Non-cardioembolic TIA/Stroke

• No evidence of warfarin superiority over antiplatelets for non-cardioembolic stroke– SPIRIT– WARSS– WASID

Stroke 2006;37:577-617

Antiplatelet Take Home Points

• In patients with non-cardioembolic ischemic TIA/stroke, antiplatelet agents are recommended to reduce recurrent events– Class I, LOE A

• Aspirin, aspirin + ER-dipyridamole, and clopidogrel are all acceptable initial options– Class IIa, LOE A

Stroke 2006;37:577-617


• Aspirin + ER-dipyridamole is more effective than aspirin alone– Class IIa, LOE B

• Clopidogrel is not superior to aspirin in stroke patients, but is reasonable if aspirin allergic– Class IIa, LOE B

Stroke 2006;37:577-617Gundersen Lutheran Medical Journal 2005;3:62-5


• Addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely recommended for TIA/stroke patients– Class III, LOE A – (Class III means don’t do it!)

Stroke 2006;37:577-617


• For patients that have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose is beneficial

• No drug has been studied exclusively in patients who have had an event while taking aspirin

Stroke 2006;37:577-617

Cardiogenic TIA/Stroke

• Warfarin should be given for those with TIA or stroke if:– Persistent or paroxysmal atrial fibrillation

• Risk of stroke is 5X higher• Class I, LOE A (Reduces stroke by ~ 60%)• If unable to take warfarin, give aspirin 325 mg/day

– Class I, LOE A (Reduces stroke by ~ 20%)

– Acute MI with left ventricular thrombus• Class IIa, LOE B

Stroke 2006;37:577-617Ann Intern Med 2007;146:857-67


• Warfarin should be given for those with TIA or stroke if:– Rheumatic mitral valve disease

• Add aspirin 81 mg daily if recurrent embolism• Class IIa, LOE C for both

– Mechanical heart valves• Class I, LOE B• Add aspirin 81 mg daily if recurrent embolism

– Class IIa, LOE B

Stroke 2006;37:577-617


• No solid data available on timing of anticoagulation after cardioembolic TIA or stroke– Aspirin 160 mg vs. full anticoagulation with

LMWH for the first 14 days are equivalent– Initiate anticoagulation within 2 weeks, unless

large infarct or uncontrolled hypertension

Stroke 2006;37:577-617Lancet 2000;355:1205-10

Carotid Stenosis

• NASCET: North American Symptomatic Carotid Endarterectomy Trial

• Enrolled 659 patients with TIA or nondisabling stroke with ipsilateral carotid stenosis 70-99% to CEA vs. standard treatment

N Engl J Med 1991;325:445-53

North American Symptomatic Carotid Endarterectomy Trial (NASCET)

• All patients were less than age 80• All patients underwent cerebral angiogram• All patients received:

– Up to 1300 mg daily of aspirin– Hypertension, cholesterol and/or diabetic

therapy as indicated

N Engl J Med 1991;325:445-53


• Stopped early due to great benefits of CEA:– 9% vs. 26% 2 year risk of ipsilateral stroke

• ARR = 17%; NNT = 6

– 2.5% vs. 13.1% major or fatal ipsilateral stroke• ARR = 10.6%; NNT = 9

N Engl J Med 1991;325:445-53


• Absolute risk reduction greater with increasing levels of stenosis:– 90-99% = 26% NNT = 4– 80-89% = 18% NNT = 6– 70-79% = 12% NNT = 8

N Engl J Med 1991;325:445-53

Lesser Levels of Stenosis after TIA/Stroke

• NASCET also looked at carotid stenoses <50% and 50-69% followed for 5 years:

• <50% stenosis (n=1368)– No benefit

N Engl J Med 1998;339:1415-25

50-69% Stenosis after TIA/Stroke

• 50-69% Stenoses (n=858) CEA vs. Medical– 15.7% vs. 22.2% of ipsilateral stroke

• ARR = 6.5%; NNT = 15

– 33.2% vs. 43.3 % of stroke or death from any cause• ARR = 10.1%; NNT = 10

N Engl J Med 1998;339:1415-25

• Surgery for all 50-69% symptomatic patients? – Women didn’t benefit as much with CEA

• Due to low overall stroke rate in women• NNT for ipsilateral stroke was 67• NNT for disabling stroke was 125

– TIA as entry symptom didn’t benefit as much• NNT for ipsilateral stroke was 27• NNT for disabling stroke was 59

N Engl J Med 1998;339:1415-25

50-69% Stenosis after TIA/Stroke

NASCET + ECST Pooled Data

• Greater benefit for CEA if done earlier

• Time from last event to randomization to surgery was studied, looking at ipsilateral stroke and stroke/death

Lancet 2004;363:915-24

Carotid Evaluation

Lancet 2004;363:915-24

93.3 5.7 11NNT

• In the right patient, at the right time, the benefit is excellent!– Single-digit number needed to treat

• Surgeons must have excellent outcomes data, as benefit quickly drops otherwise– Ours do!

Carotid Take Home Points

• Better outcomes for CEA are seen with:– Higher (>70%) vs. lower (50-69%) degrees of

stenosis– Men vs. Women– Stroke vs. TIA– CEA within 2 weeks of event vs. waiting – Surgeons with low rates of complications


• When the ipsilateral stenosis is severe (>70%), CEA is recommended – (Class I, LOE A)


Stroke 2006;37:577-617

• When the ipsilateral stenosis is moderate (50-69%), CEA is recommended depending on patient-specific factors:– Age– Gender– Comorbidities– Severity of initial symptoms

• (Class I, LOE A)


Stroke 2006;37:577-617


• Order early carotid ultrasound in patients with stroke or TIA

• If the ultrasound shows greater than 50% stenosis, order a confirmatory CT Angiogram or MRA

• PROactive: Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke

• Prospective, double blind; 34.5 months• 5238 patients with history of macrovascular

disease and diabetes• 984 patients with, and 4254 patients without

prior stroke

A Tidbit About Diabetes

Stroke 2007;38:865-73

• In those with prior stroke, pioglitazone reduced fatal or nonfatal stroke– 5.6% vs 10.2%– ARR = 4.6% – NNT = 22


Stroke 2007;38:865-73

• HbA1C was 0.6 lower in the treatment group (P<0.0001)

• HDL and Triglycerides were also significantly better in the treatment group (P<0.0001)

• No benefit seen in those without a prior stroke– Risk of first stroke is lower than recurrent stroke


Stroke 2007;38:865-73

• TIA/stroke is common, deadly, costly, and devastating

• First determine the mechanism, then target the “Big Boys”

Take Home Points

• The early risk of a significant stroke after a TIA or minor stroke is very high

• Don’t blow off TIAs! Consider it a medical emergency!

Take Home Points

• Don’t acutely lower blood pressure after stroke

• Start thiazide plus ACE-I after stroke regardless of baseline hypertension

• After the acute event passes 115/75 mmHg is optimal

Take Home Points

• Start a statin right away for patients with TIA/stroke, regardless of baseline LDL

• Strongly emphasize smoking cessation

Take Home Points

• Start an antiplatelet agent after TIA/stroke

• Don’t combine clopidogrel + aspirin solely for stroke prevention

Take Home Points

• Give warfarin to prevent another stroke if:

– Atrial fibrillation

– Acute MI with LV thrombus

– Rheumatic mitral valve disease

– Mechanical heart valve

Take Home Points

• Order an early carotid ultrasound

• Order a CTA or MRA if stenosis is greater than 50% on ultrasound

• Great benefit for CEA for stenoses >70%and in select patients with stenoses 50-69%– Best done within 2 weeks of event

Take Home Points

• Consult the Vascular Institute for all TIA and Stroke patients

• We are modeled after the Express Care Study– Showed 80% decrease in 90 day recurrent

events vs no benefit for usual care– We will see them within 3 days

Take Home Points

The Secondary Prevention Of Stroke For Linked In

Business

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