Stroke prevention

1. Now What???
The Secondary Prevention of
Ischemic Stroke
Jon Zlabek, MD, FACP

2. Learning Objectives
• Review the evidence-based management
and guidelines for patients with transient
ischemic attack (TIA) and ischemic stroke
• Emphasize the urgency of TIAs

3. The Six “Big Boys”
• Hypertension
• Hypercholesterolemia
• Smoking
• Antiplatelet Therapy
• Cardioembolic TIA/Stroke
• Carotid Stenosis

4. 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

5. 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;357:572-9
www.strokeassociation.org

6. Very High Risk Groups
Increase in Risk of Stroke
Site of Initial Event vs. General Population
PAD 2-3 Times
MI 3-4 Times
Stroke 9 Times

7. BIG BUCK$
In 2010, for stroke-related
expenses, Americans will pay an estimated
73.7 BILLION
DOLLARS
www.strokeassociation.org

8. 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

9. 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

10. TIA vs. Stroke
• The distinction is becoming less important
– Share common pathological mechanisms
– Preventative approaches are similar
Stroke 2006;37:577-617

11. 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Dandapani B, unpublished data
www.strokeassociation.org

12. Transient Ischemic Attack
• 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.org
Stroke 2006;37:320-22
Arch Intern Med 2007;167(22)2417-22

13. Transient Ischemic Attack
• 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

14. Transient Ischemic Attack
• Isolated sensory or visual symptoms are
associated with lower risk of subsequent
stroke
JAMA 2000;284:2901-6
Lancet 2005;366:29-36

15. “ABCD” Score
• “ABCD” Score • 7-day risk of CVA
– Age > 60 (1 pt) – 6 = 31.4%
– SBP > 140 and/or DBP >90 – 5 = 12.1%
(1 pt) – 4 or less = 0.4%
– Clinical features
• Unilateral weakness (2 pts)
– All patients with a
• Speech problem (1 pt)
stroke within one
– Duration > 60 min (2 pts) week had scores 4
– Duration 10-59 min (1 pt)
Lancet 2005;366:29-36

16. 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

17. 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

18. 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

19. Phase 1 – Baseline Cohort
• 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

20. Phase 1 – Baseline Cohort
• 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

21. Phase 1 – Baseline Cohort
• 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

22. Phase 1 – Baseline Cohort
• No treatment/prescriptions were given to the
patient
• “Contact your primary care physician as
soon as possible”
Lancet 2007;370:1432-42

23. 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

24. 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

25. 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

26. Results of Express Care
• 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

27. Results of Express Care
• 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

28. Results of Express Care
• 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

29. Results of Express Care
• 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

30. Stat TIA and Stroke Clinic

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

32. First Things First
Do the best you can to determine the
mechanism of the ischemic event

33. Mechanisms of TIA/Stroke
• Large artery atherosclerotic
• Cardioembolic
• Small-vessel disease
• Hemorrhagic
• Undetermined cause
• Other:
– Dissections
– Hypercoagulable states
Stroke 2006;37:577-617

34. After you determine the mechanism,
THEN . . .

35. Target the “Big Boys”

36. Hypertension
THE MOST IMPORTANT RISK
FACTOR FOR STROKE
Stroke 2006;37:577-617

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

38. 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

39. 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

40. We Missed the News Flash!
• Stroke & heart disease death rises linearly
from 115/75 mmHg
JNC-7 NHLBI

41. We Missed the News Flash!

43. We Missed the News Flash!
• 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

44. 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 NHLBI
Stroke 2003;34:1056-83

45. 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

46. 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 NHLBI
Stroke 2003;34:1056-83

47. 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 NHLBI
Circulation 2007;115:2761-2788

49. 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;358:1033-41
Stroke 2005;36:1218-26

50. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 6105 patients with TIA or stroke within the
past 5 years
• Randomized to active treatment or placebo
•Perindopril 4 mg daily PLUS •Double placebo
Indapamide 2.5 mg daily (58%)
OR
OR
•Single placebo
•Perindopril 4 mg daily (42%)
Lancet 2001;358:1033-41

51. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 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

52. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Baseline blood pressures:
– Overall 147/86 mmHg
– Hypertensive group 159/94 mmHg
– Non-hypertensive group 136/79 mmHg
Lancet 2001;358:1033-41

53. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 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

54. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 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

55. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 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

56. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Combination therapy vs. perindopril only
– Perindopril + Indapamide better than placebo
– Perindopril alone not better than placebo
Lancet 2001;358:1033-41

57. Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 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

58. 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

59. 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

61. 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;35:1023
N Engl J Med 2005;352:1425
Ann Intern Med 1998;128:89
JAMA 1997;278:313

62. Hypercholesterolemia
• Statins were the most studied agents
• Niacin showed a reduction of
cerebrovascular events in the Coronary
Drug Project
Stroke 2006;37:577-617
JAMA 1975;231:360-81

63. Hypercholesterolemia
• 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

64. 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

65. 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

66. 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

67. Statins and Carotid Endarterectomy
• 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

68. Statin Withdrawal After Stroke
• 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

69. Statin Withdrawal After Stroke
• Measured:
– Death/dependency
– Early neurologic deterioration
– Infarct volume
Neurology 2007;69:904-10

70. Statin Withdrawal After Stroke
• 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

71. 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;35:1023
Stroke 2006;37:577-617

72. Smoking Is Bad
• 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
Stroke 2006;37:577-617

73. Antiplatelet Therapy

74. 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;54:1044-54
Gundersen Lutheran Medical Journal 2005;3:62-5

75. 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;338:1345-49
Gundersen Lutheran Medical Journal 2005;3:62-5

76. 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;1:1215-20
Gundersen Lutheran Medical Journal 2005;3:62-5

77. 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;321:501-7
Gundersen Lutheran Medical Journal 2005;3:62-5

78. 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

79. Lancet 1996;348:1329-39

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

81. Lancet 1996;348:1329-39

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

83. 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

84. Clopidogrel + Aspirin?
• 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

85. Clopidogrel + Aspirin?
• 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

86. 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 BID
2. ER-dipyridamole 200 mg BID
3. Combination of aspirin + ER-dipyridamole
(Aggrenox)
4. Placebo
J Neurol Sci 1996;143:1-13

87. European Stroke Prevention Study 2
(ESPS-2)
• 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

88. 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

89. 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

90. European Stroke Prevention Study 2
(ESPS-2)
• 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;143:1-13
Lancet 2006;367:1665-73

91. 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

92. 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)

93. 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)

94. PRoFESS
• Looked at:
– Recurrent stroke
– Modified Rankin scores (disability measure)
– Barthel index (disability measure)
– Mini-mental status examination
Lancet Neurology 2008;7(10)

95. PRoFESS
• No difference in recurrent stroke
• No difference in stroke disabilty
• No difference in MMSE
Lancet Neurology 2008;7(10)

97. Cost & Benefit Considerations for
Recurrent Stroke
Medication Cost per Benefit over aspirin
(Brand name) month* (NNT/year)
Aspirin ~Dirt -
Ticlopidine $101 90
(Ticlid)
Clopidogrel $152 No benefit
(Plavix)
ER-dipyridamole/aspirin $173 67
(Aggrenox)
*Price from www.drugstore.com; Accessed on March 10, 2009

98. 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

99. 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

100. Antiplatelet Take Home Points
• 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;37:577-617
Gundersen Lutheran Medical Journal 2005;3:62-5

101. Antiplatelet Take Home Points
• 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

102. Antiplatelet Take Home Points
• 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

104. 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;37:577-617
Ann Intern Med 2007;146:857-67

105. Cardiogenic TIA/Stroke
• 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

106. Cardiogenic TIA/Stroke
• 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;37:577-617
Lancet 2000;355:1205-10

108. 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

109. 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

110. North American Symptomatic Carotid
Endarterectomy Trial (NASCET)
• 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

111. North American Symptomatic Carotid
Endarterectomy Trial (NASCET)
• 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

112. 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

113. 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

114. 50-69% Stenosis after TIA/Stroke
• 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

115. 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

116. Carotid Evaluation
NNT 3.3 5.7 9 11
Lancet 2004;363:915-24

117. Carotid Take Home Points
• 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!

118. 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

119. Carotid Take Home Points
• When the ipsilateral stenosis is severe
(>70%), CEA is recommended
– (Class I, LOE A)
Stroke 2006;37:577-617

120. Carotid Take Home Points
• 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

121. Carotid Take Home Points
• 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

122. A Tidbit About Diabetes
• 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
Stroke 2007;38:865-73

123. A Tidbit About Diabetes
• 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

124. A Tidbit About Diabetes
• 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

125. Take Home Points
• TIA/stroke is common, deadly, costly, and
devastating
• First determine the mechanism, then target
the “Big Boys”

126. 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!

127. 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

128. Take Home Points
• Start a statin right away for patients with
TIA/stroke, regardless of baseline LDL
• Strongly emphasize smoking cessation

129. Take Home Points
• Start an antiplatelet agent after TIA/stroke
• Don’t combine clopidogrel + aspirin solely
for stroke prevention

130. Take Home Points
• Give warfarin to prevent another stroke if:
– Atrial fibrillation
– Acute MI with LV thrombus
– Rheumatic mitral valve disease
– Mechanical heart valve

131. 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

132. 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