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Stroke prevention; new findings

Sunarya Soerianata
National Cardiovascular Center Harapan Kita
Jakarta
The worldwide burden of stroke and ischemic heart disease

 Stroke and ischemic heart disease were the


top two causes of death in 1990.

 Stroke = 4.4 million deaths (1 in 12).


 Projected to remain leading causes of death
and disability worldwide through 2020.

Murray CJL, Lopez AD. Lancet. 1997;349:1269-1276, 1498-1504.


Chronic disability: Major burden of stroke

 Most strokes are not fatal.


 Aftermath or stroke includes:
– Neurologic disability
– Dementia
– Depression
– Epilepsy
– Falls/fractures
 Up to 30% of survivors are permanently disabled.

Rothwell PM. Lancet 2001;357:1612-16.


American Heart Association. 2002 Heart and Stroke Statistical Update.
The association between severity of CAD and ischemic stroke

 Ischemic stroke and coronary artery disease (CAD)


share risk factors and pathogenic process =
atherosclerosis and thrombosis.
 Development of carotid atherosclerosis closely parallels
coronary atherosclerosis .
 Carotid artery stiffness, intima-media thickness, and
early plaque formation are potentially useful predictors of
the risk of both ischemic stroke and CAD.

Tanne D, et al. Stroke 2002; 33: 245-50.


Strategies for preventing stroke and reducing stroke related disability

Blood Pressure
Smoking Stroke
Lipids
Mortality
Acute treatment

Mass strategy in
population
First-ever Secondary Secondary
High-risk strategy stroke prevention stroke

In individual

Hypertension Rehabilitation Stroke-related


TIA
AFIB Disability
Other vascular disease
Primary prevention of ischemic stroke

Risk of stroke

Nonmodifiable Modifiable
Nonmodifiable risk factors
Factors Incidence Relative Risk

Age Doubling of stroke rate


each 10 years after age
65
Race Blacks 233/100,000
Hispanics 196/100,000
Whites 93/100,000
Sex Men 174/100,000
Women 122/100,000

Family history of Paternal 2.4


stroke/ TIA Maternal 1.4
Major modifiable risk factors (WHO)

 Hypertension
 Hyperlipidemia
 Atrial fibrillation
 Smoking
 Carotid artery disease
 Diabetes
Hypertension (by age group)

4.5
4
4
3.5
3
Relative Risk

3
2.5
2
2
1.4
1.5
1
1
0.5
0
50 60 70 80 90
Age
Importance of controlling hypertension to prevent stroke.

-34%

-35%

-36%
-36%
-37%

-38%

-39%

-40%
-40%
-41%
Syst-Eur SHEP
Nitrendipine, possibly enalapril Chlorthalidone or atenolol
or HCT

Staessen JA, et al. Lancet 1997; 265: 757-64


SHEP Cooperative Research Group. JAMA 1991; 265: 3255-64
Hyperlipidemia

3
2.6
2.5
Relative Risk

2 1.8

1.5

0.5

0
240-279 > 280
TC level
Reduction of stroke risk with elevated cholesterol level

0%

-10%
-11%
-20%
TIA
-30%
-32% -32% Stroke
-40% -35%

-50%
-51%
-60%

4S WOSCOPS CARE

Simvastatin Pravastatin Pravastatin

Scandinavian Simvastatin Survival Study. Lancet 1994; 344: 1383-9


Sheperd J, et al. N Engl J Med 1995; 333: 1301-7
Plehn JF, et al. Circulation 1999; 99: 216-23
Atrial fibrillation (nonvalvular) by age group

5
4.5
4.5
4
4
3.5 3.3
Relative Risk

3 2.6
2.5
2
1.5
1
0.5
0
50-59 60-69 70-79 80-89
Age
Cigarette smoking
 Facts (Cohort studies)
 independent risk factor for ischemic stroke in men
and women
 6-fold risk compared to non-smokers

 50% risk reduction by stop of smoking


Asymptomatic carotid artery stenosis

3.50%
3.20%

3.00%

2.50%
Relative Risk

2.00%
1.70%

1.50%

1.00%

0.50%

0.00%
Asymtomatic Cervical Bruit NASCET

TIA, stroke stroke


Chambers BR, Norris JW. N Engl J Med 1986; 1: 888-90
Barnett HJ, et al. JAMA 2000; 283: 1429-36
The benefit of carotid endarterectomy

0%

-10%

-20%
Risk Reduction

-30%

-40% -38%

-50%
-53%
-60%
Trials Veteran Affairs Cooperative ACAS
Endpoints TIA, blindness, stroke Stroke
p < 0.001 < 0.004
Hobson RWI , et al. N Engl J Med 1993; 328:221-7
Executive committee for the ACAS study. JAMA 1995; 273: 1421-8
Diabetes mellitus
 independent risk factor for ischemic stroke (RR
1.8-6).
 strict control of blood glucose not established for
stroke prevention
 elevated blood glucose at stroke onset worsens
mortality and functional outcome
 The combination of hyperglycemia and
hypertension has long believed to increase the
frequency of diabetic complication, including
stroke.
 Reduction of stroke risk in hypertensive diabetics
with blood pressure control.
Effects of ramipril on cardiovascular and microvascular
outcomes in DM

0%
Combined Stroke
-10% -10%
-12%

-20%
-25%
RR

-30%
-33%
-36%
-40%

-50% -50%

-60%
Heart Outcomes Prevention Evaluation Study Investigators.
Lancet 2000; 355: 253-9
HOPE: Risk reduction by stroke type

Nonfatal Fatal Ischemic Hemorraghic


All stroke stroke stroke stroke stroke
0
Beyond baseline
10
therapy with:
20 24*  Aspirin
26*
 Other antiplatelet
30 32*
Relative 36* agent
risk 40  Ca++ channel
reduction blockers
(%) 50
 Statins
61*
60  b-blockers
 Diuretics
70

80

*Statistically significant difference compared with placebo Bosch J, et al. BMJ. 2002;324:699-702.
HOPE: Risk reduction by stroke type

Nonfatal Fatal Ischemic Hemorraghic


All stroke stroke stroke stroke stroke
0
Beyond baseline
10
therapy with:
20 24*  Aspirin
26*
 Other antiplatelet
30 32*
Relative 36* agent
risk 40  Ca++ channel
reduction blockers
(%) 50
 Statins
61*
60  b-blockers
 Diuretics
70

80

*Statistically significant difference compared with placebo Bosch J, et al. BMJ. 2002;324:699-702.
HOPE: Reduced risk of cognitive and motor changes

Ocular or Face or
Conscious- visual limb Sensory Dysarthria/
Cognition ness symptoms weakness symptoms dysphagia Dysphagia
12
10

Relative 10
risk
reduction 20
(%)
30
30 32
33
40 38
41
43
50

Bosch J, et al. BMJ. 2002;324:699-702.


ACE inhibition in CVD

Laboratory and experimental evidence that ACE


inhibitors may have multiple mechanisms (of benefit)
in CVD:
- Antihypertensive effect
- Antiproliferative actions
- Hormonal/vascular effects
- Anti-atherogenic action

Lonn E et al. Circulation 1994;90:2056-69.


ACE INHIBITORS

Platelet
Angiotensin I Bradykinin
aggregation + AcH
Inactive
Angiotensin II peptide

ACE B2 M
Endothelial cell
NO EDHF
Angiotensin I

Angiotensin II NO
-
EDHF

Smooth muscle cell AT


ACE Platelet
aggregation
 cGMP Hyperpolarization
Angiotensin II
Relaxation growth inhibition
MICRO-HOPE - rationale

 Diabetes is a strong risk factor for renal and CVD.


 ACE inhibitors may delay or prevent overt nephropathy
and other microvascular outcomes in diabetic patients.
 ACE inhibitors may also delay or prevent CV outcomes
in some subgroups of diabetic patients Post-MI,
hypertension, low EF or HF
 Role for ACE inhibitors in a wider range of diabetic
patients at high risk of CV events?

HOPE Study Investigators. Lancet 2000;355:253-9


SECURE (ramipril) - secondary outcomes

 Single maximum IMT regression slope in


the ramipril 10 mg group significantly lower
than in the placebo group (p = 0.055).
 Trend towards fewer CV events
(composite endpoint of MI/stroke/CV
death) in ramipril group.

Lonn E ACC 49th Session, Anaheim, USA, March 2000


SECURE (ramipril) - primary outcome

p = 0.028
Increase in mean maximum IMT (mm/year) 0.025

0.02

0.015

0.01

0.005

0
Placebo Ramipril 2.5 Ramipril 10
mg/day mg/day

Lonn E ACC 49th Session, Anaheim, USA, March 2000