1. STROKE PREVENTION- A REALITY
IN THIS MILLENNIUM
Prof. A.V. SRINIVASAN,
MD, DM, Ph.D, F.A.A.N, F.I.A.N.
Emeritus Professor
The Tamilnadu Dr. M.G.R. Medical University
Former Head
Institute of Neurology, Madras Medical College
21-08-10

2. Cerebrovascular
Prevention
Is survival a mere stroke of Luck?
“My Opinions are founded on knowledge but modified by experience”

3. INTRODUCTION
 Perceptual Sense(Observation)
 Word Sense (Recording)
 Common Sense (Thinking)
 Will lead you to get - Clinical Sense
“ He who cannot forgive others destroys the bridge over
which he himself must pass” - Annoy

4. Cerebrovascular disease –
Mind boggling facts
 World wide incidence: 2/1000 population/annum 1
 Incidence in people aged 45 – 84 years: about 4/1000 1
 Incidence in India: was 36/100,000 for the year 1998-1999 3 in a
study in Calcutta
 Incidence of mortality due to stroke (India: WHO study):
73/100,000 per year2
CVD is the most disabling of all neurologic diseases.
50% of survivors have a residual neurologic deficit.
Greater than 25% require chronic care.
1.A practical approach to management of stroke patients; 1996; 360-384
2. Epidemology of cerebrovascular disorders in India; 1999; 4-19
3. Neuroepidemiology 2001;20:201-207
If you think you can or you can’t You are always right

5. Annual risk CVD, MI, vascular death
following TIA, minor CVD
• CVD 6.7 %
• MI 2.5 %
• Death 7.2 %
• CVD, MI, Vascular death 8.6 %
• CVD, MI, Death 10.3 %
Experience can be defined as yesterday’s answer to
today’s problems

6. Common Stroke Mimics
 Hypoglycemia
 Post ictal state
 Drug overdose
 Concussion with neck injury
 Migrainous accompaniment
 Encephalopathies with focal signs
 Hyponatremia
 Subdural hematoma, Empyema
 Focal Encephalitis: Herpes
Being ignorant is not so much a shame as being unwilling to learn

7. Drugs used for stroke
prevention…
ACE inhibitors
Lipid lowering agent
Anti-platelets

8. Prevention of
Cerebrovascular Events
with Perindopril:
New Evidence

9. Why ACE inhibitors in stroke
prevention ?
 Blood pressure lowering effect
 Prevention of endothelial dysfunction
 Prevention of progression of
atherosclerosis
 Favourable alteration of the fibrinolytic
balance
 Prevention of cardiac remodelling
Clinical evidence…

10. Objective of PROGRESS
Whether in patients with…
Stroke OR TIA
Perindopril + Indapamide
Risk of stroke & vascular events
WHO – ISH initiated the study
PROGRESS collaborative group. Lancet 2001;358:1033-41.

11. Patient selection criteria
Evidence of
Stroke / TIA
> 2 weeks and < 5 years of event
…but without a definite indication /
contraindication to treatment with an ACE inhibitor
PROGRESS collaborative group. Lancet 2001;358:1033-41.

12. Patient selection criteria
Young
Diabetic Non-diabetic
Included
Hypertensive Normotensive
Old
PROGRESS collaborative group. Lancet 2001;358:1033-41.

13. Baseline characteristics
Characteristic Perindopril + indapamide Placebo
N = 3051 N = 3054
Mean age (yrs) 64 64
Females (%) 30 30
Stroke history
 Ischaemic stroke (%) 71 71
 Haemorrhagic stroke (%) 11 11
 TIA (%) 22 22
 Duration since event (months) 8 8
Diabetes (%) 13 12
CAD (%) 16 16
Mean BP (mmHg) 147/86 147/86
Hypertension (%) 48 48
Antihypertensive therapy (%) 50 51
PROGRESS collaborative group. Lancet 2001;358:1033-41.

14. Total stroke
28%
28%
Placebo group
risk
risk
reduction
Risk reduction (%)
reduction
38%
Active group
0 1 2 3 4 Years
PROGRESS collaborative group. Lancet 2001;358:1033-41.

15. Stroke subtype (1)
Fatal / Non fatal /
disabling stroke disabling stroke
24
33
Risk reduction (%)
PROGRESS collaborative group. Lancet 2001;358:1033-41.

16. Stroke subtype (2)
Ischaemic Haemorrhagic
stroke
stroke
24
50
Risk reduction (%)
PROGRESS collaborative group. Lancet 2001;358:1033-41.

17. Hypertensives / normotensives
Stroke
Hypertensives Normotensives
27
32
Risk reduction (%)
PROGRESS collaborative group. Lancet 2001;358:1033-41.

18. Treatment acceptability
Active group
Causes of withdrawal (%)
Placebo
23
21
8 8
2 2 0.9
0.4
All causes Voluntary Cough Hypotension
PROGRESS collaborative group. Lancet 2001;358:1033-41.

19. PROGRESS results showed…
 Perindopril+ indapamide substantially
reduced risk of secondary stroke and
other vascular events
Irrespective of

Age
 Blood pressure level
 Other diseases

Background medication
PROGRESS collaborative group. Lancet 2001;358:1033-41.

20. Summarise…
 ACE inhibitors are beneficial in the
prevention of stroke
 All stroke patients, hypertensive as well as
normotensives should receive an ACE
inhibitor
 All CAD patients, diabetic patients, who
are at-risk of developing stroke should
receive an ACE inhibitor
Which ACE inhibitor ?

21. Which ACE inhibitor ?
Treatment Number-needed-to-treat
Perindopril- 23 to prevent
based therapy 1 stroke in 5 years
Ramipril-based 67 to prevent
therapy 1 stroke in 5 years
JNC – 7 reference only to perindopril
Stroke 2002;33:862-875. JNC-7, JAMA May 2003 – Vol.289; No.19: 2560-2571.

22. Statins: Stroke
Prevention and
Survival Benefits

23. Primary Prevention of Ischemic Stroke
A Guideline From the American Heart
Association/American Stroke
Association Stroke Council
 It is recommended that patients with
known CAD and high-risk hypertensive
patients even with normal LDL cholesterol
levels be treated with lifestyle measures
and a statin (Class I, Level of Evidence A).
Stroke 2006;37;1583-1633

24. JUPITER & STROKE
 JUPITER is the first large-scale, prospective
study to examine the role of statin therapy in
individuals with low to normal LDL-C levels, but
with increased cardiovascular risk identified by
elevated CRP
 Nearly half of all cardiovascular events occur in
patients who are apparently healthy and who
have low or normal levels of LDL-C
 hsCRP predicts cardiovascular disease
independent of LDL-C levels

25. JUPITER JUPITER
Trial Design
Multi-National Randomized Double Blind Placebo Controlled
Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL 4-week Placebo (N=8901)
hsCRP >2 mg/L run-in
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker et al, Circulation 2003;108:2292-2297.

26. JUPITER: Results
No. of patients with any stroke
70 64
60
48%
50 Reduction
40 33 *
30
20
10
0
Rosuvastatin Placebo
n=8901 n=8901
Circulation 2010;121:143-150
* p< 0.002 vs. placebo

27. JUPITER: Results
No. of patients with non-fatal stroke
60 58
50 48%
40 Reduction
30 *
30
20
10
0
Rosuvastatin Placebo
n=8901 n=8901
Circulation 2010;121:143-150
* p< 0.003 vs. placebo

28. JUPITER: Results
No. of patients with fatal stroke
6 6
50%
5
Reduction
4
3
3
2
1
0
Rosuvastatin Placebo
n=8901 n=8901
Circulation 2010;121:143-150

29. JUPITER: Results
No. of patients with ischemic stroke
50 47
45
51%
48%
40
35 Reduction
30 *
23
25
20
15
10
5
0
Rosuvastatin Placebo
n=8901 n=8901
Circulation 2010;121:143-150
* p< 0.004 vs. placebo

30. Primary Prevention of
Stroke:
What do the previous
statins trials suggest?

31. WOSCOPS STUDY:
Statin: Pravastatin 40 mg AFCAPS/TexCAPS STUDY:
n=6595 Statin: Lovastatin 10-40 mg
Results: Stroke 11% n=6605
Results: Stroke 18%
MEGA STUDY:
JUPITER STUDY:
Statin: Pravastatin 10-20 mg
Statin: Rosuvastatin 20 mg
n=7730
n=17802
Results: Stroke 17%
Results: Stroke 48%
Circulation 2010;121:143-150

32. A meta-analysis of WOSCOPS+AFCAPS/TexCAPS+MEGA
•Stroke reduction by 14% (statistically non-
significant)
A meta-analysis of these 3 trials along with JUPITER
•Stroke reduction by 25% (statistically
significant)
Analysis of JUPITER only:
Stroke reduction by 48% (statistically non-significant)

33. Summary
 Stroke is one of the leading cause of
death worldwide.
 Guidelines recommends the use of statins
for primary as well as secondary
prevention of stroke.
 JUPITER trial has established that
rosuvastatin is the most effective statin in
preventing stroke in high risk population.

34. Symptomatic Carotid
Endarterectomy ASA 2006
Secondary Stroke Recs
• Ipsilateral severe (70% to 99%) carotid stenosis,
CEA is recommended (Class I, Evidence A).
• Ipsilateral moderate (50% to 69%) carotid stenosis,
CEA is recommended depending on age, gender,
comorbidities, and the severity of symptoms (Class I,
Evidence A).
• Stenosis <50%, there is no indication for CEA (Class
III, Evidence A).

35. Urgent Endarterectomy
Surgery within 2 weeks is suggested rather than delaying surgery
(Class IIa, Evidence B).
Rothwell PM. Lancet 2004;363(9413):915-24

36. Carotid Angioplasty and Stenting
ASA 2006 Secondary Stroke
Recs
• CAS may be considered (Class IIb, Evidence B).
- Stenosis (>70%) difficult to access surgically
- Medical conditions that greatly increase the
risk for surgery, or
- When other circumstances exist such as
radiation-induced stenosis or restenosis after
CEA.
• CAS is reasonable when performed by operators
with morbidity and mortality rates of 4% to
6% (Class IIa, Evidence B).

37. Atrial Fibrillation
ASA 2006 Recommendations
• For patients with ischemic stroke or TIA with
persistent or paroxysmal (intermittent) AF,
anticoagulation with adjusted-dose warfarin (target INR
2.5, range 2.0 to 3.0) is recommended (Class I,
Evidence A).
• For patients unable to take oral anticoagulants,
aspirin 325 mg per day is recommended (Class I,
Evidence A).

38. Stroke Prevention:
Non-cardioembolic
ASA 2006 Recommendations
For patients with noncardioembolic ischemic
stroke or TIA, antiplatelet agents are
recommended rather than oral anticoagulation to
reduce the risk of recurrent stroke and other
cardiovascular events (Class I, Evidence A).

39. Stroke Prevention: Non-
cardioembolic
ASA 2006 Recommendations
• Acceptable options for initial therapy
(Class IIa, Evidence A).
- aspirin (50-325 mg qd)
- the combination of aspirin and extended-
release dipyridamole (25/200 mg bid)
- clopidogrel (75 mg qd)

40. Antiplatelet Therapy
ASA 2006 Recommendations
• Compared to aspirin alone, both the combination of
aspirin and extended-release dipyridamole and
clopidogrel are safe.
• The combination of aspirin and extended-release
dipyridamole is suggested instead of aspirin alone
(Class IIa, Level A).
• Clopidogrel is suggested instead of aspirin alone
based on direct comparison trials
(Class IIb, Level B).

41. Secondary Stroke Prevention
ASA 2006 Recommendations
• Insufficient data are available to make evidence-
based recommendations regarding choices between
antiplatelet options other than aspirin. Selection of an
antiplatelet agent should be individualized based on
patient risk factor profiles, tolerance, and other clinical
characteristics.

42. Secondary Stroke Prevention
ASA 2006 Recommendations
• The addition of aspirin to clopidogrel increases
the risk of hemorrhage and is not routinely
recommended for stroke or TIA patients (Class
III, Evidence A).
• For patients allergic to aspirin, clopidogrel is
recommended (Class IIa, Evidence B).

43. MATCH: Safety Outcomes
• Excess life-threatening bleeding events with
combination versus clopidogrel monotherapy:
96 (2.6%) vs. 49 (1.3%); p<0.0001
• Excess minor bleeds with combination therapy
versus clopidogrel alone:
120 (3.2%) vs. 39 (1.0%); p<0.0001
Diener H-C et al. Lancet 2004;364:331-7

44. Secondary Stroke Prevention
ASA 2006 Recommendations
• For patients who have an ischemic
cerebrovascular event while taking aspirin,
there is no reliable evidence that increasing the
dose of aspirin provides additional benefit.
Although alternative antiplatelet agents are
often considered for these patients, no single
agent or combination has been specifically
evaluated in patients who have had an event
while receiving aspirin.

45. Stroke and Pregnancy
ASA 2006 Secondary Stroke Recs
• High-risk thromboembolic conditions consider:
- adjusted-dose UFH throughout pregnancy,
- adjusted-dose LMWH with Factor Xa monitoring
- UFH or LMWH until week 13, followed by
warfarin until mid-3rd trimester, then UFH or
LMWH in last trimester (Class IIb, Evidence
C).
• Lower risk conditions
- UFH or LMWH in the first trimester followed
by - low-dose aspirin for the remainder of the
pregnancy (Class IIb, Evidence C).

46. Postmenopausal Hormones
ASA 2006 Secondary Stroke Recs
For women with ischemic stroke or TIA,
postmenopausal hormone therapy (with estrogen
with or without a progestin) is not recommended
(Class III, Evidence A).

47. Women’s Health Initiative
• 16,608 postmenopausal women, 50-79 years,
with an intact uterus at baseline were recruited
by 40 U.S. clinical centers for the period 1993-
1998.
• Received conjugated equine estrogens, 0.625
mg/d, plus medroxyprogesterone acetate, 2.5
mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
• After a mean of 5.2 years of follow-up, the trial
was stopped because of high rates of invasive
breast cancer and the global index statistic
supported risks exceeding benefits.
Rossouw et al. JAMA 2002;288(3):321-33

48. Other Circumstances
ASA 2006 Secondary Stroke Recs
• Dissections
• PFO and hyperhomocysteinemia
• Hypercoagulable states
• Sickle cell disease
• Cerebral venous thrombosis
• Anticoagulation after cerebral hemorrhage

49. Level A Recommendations
• Antihypertensive treatment
• Glucose control to reduce microvascular
complications of diabetes
• Statins to reduce LDL to <100 or <70 for high-risk
patients (sympt CHD or athero)
• CEA for sympt 50-99%
• NO CEA for <50% sympt stenosis
• Warfarin at INR 2.5 for Afib. (ASA if unable)
• Antiplatelet for noncardioembolic
• NO combination clopidogrel and ASA

50. Carotid Angioplasty and Stenting
ASA 2006 Secondary Stroke Recs
• CAS may be considered (Class IIb, Evidence B).
- Stenosis (>70%) difficult to access surgically
- Medical conditions that greatly increase the
risk for surgery, or
- When other circumstances exist such as
radiation-induced stenosis or restenosis after
CEA.
• CAS is reasonable when performed by operators
with morbidity and mortality rates of 4% to
6% (Class IIa, Evidence B).

51. Other Circumstances
ASA 2006 Secondary Stroke Recs
• Dissections
• PFO and hyperhomocysteinemia
• Hypercoagulable states
• Sickle cell disease
• Cerebral venous thrombosis
• Anticoagulation after cerebral hemorrhage

52. Level A Recommendations
• Antihypertensive treatment
• Glucose control to reduce microvascular
complications of diabetes
• Statins to reduce LDL to <100 or <70 for high-risk
patients (sympt CHD or athero)
• CEA for sympt 50-99%
• NO CEA for <50% sympt stenosis
• Warfarin at INR 2.5 for Afib. (ASA if unable)
• Antiplatelet for noncardioembolic
• NO combination clopidogrel and ASA

53. PROGNOSTIC PEARLS
 Flaccid Paralysis for more than 96 hrs
 When tendon reflexes recover without return of voluntary
movement – prognosis poor
 Recovery of sensory less in usual to a degree. Postion
sense recovers but not pain and temperature
 Recovery from Dysphasia is never complete
 Dysarthria usual improves and Dysphagia never improves
 Diplopia due to brain stem is usually permanent
 Conjugate gaze – recovers
 Vertigo improves but hearing loss is permanent
 Pseudobulbar palsy permanent
“ByNature All Men/W en are alike but
om
byEducation widelydifferent”

54. CVD – Prevention or Cure?
While number of curative methods are
available, preventive therapy is
undoubtedly the main strategy in the
management of CVD
Lijec Vjesn. 2003 Nov-Dec;125(11-12):322-8
The sign wasn’t placed there
By the Big Printer in the sky

56. Dedicated to my family for
making everything worthwhile

57. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU
My sincere thanks to Serdia pharmaceuticals