Prevention of

recurrent stroke in primary care

Prof.Dr. dr. Kiking Ritarwan, SpS (K), MKT

Departemen Ilmu Penyakit Saraf
The Indonesian Medical Association
Branch of Medan
16/10/2021
CURICULUM VITAE
 NAMA : Prof .Dr. dr.KIKING RITARWAN,SpS(K). MKT
 Tempat/ tgl lahir: Medan/ 17 November 1968
 Riwayat Pendidikan:
- DOKTER UMUM FK-USU – 1991
- Sp Saraf (Sp1) FK-USU – 2003
- Magister Kedokteran Tropis (S2)- 2007
- Konsultan Neurologi/ Consorsium Neurologi -2010
- Program Pendidikan Doktor (S3) USU -2014
- GURU BESAR Neurologi FK USU 17/12/2020
 Riwayat Pekerjaan:
- Staf Pengajar Dept Neurologi FK-USU/RSUP HAM
- Ketua Program Studi Neurologi FK USU 2017-2021
- Asesor LamPTKes (2018-sekarang)
- Research Reviewer Komite Akreditasi Nasional-
RISTEKDIKTI (2017-sekarang)
- Auditor Audit Mutu Internal USU siklus 14 (2021-sekarang)
Stroke

 The third leading cause of death and the

leading cause of adult disability in the USA.
 The second leading cause of death worldwide
 Until recently the only treatment available for
stroke was prevention.
 Stroke is the second most important cause of
dementia
 Major clinical manifestations of atherothrombosis:
Ischaemic stroke. Transient ischemic attack.
Myocardial infarction. Angina
OUTCOMES AFTER ISCHEMIC
STROKE
___________________________________
Stroke recurrence  Functional Disability
30 day 3 % - 10 % 24 – 53 % of stroke
1 year 5 % - 14 % survivor with complete or
5 year 25 % - 40 % partial dependences
 Quality of life decrease in
Mortality 27 %
30 day 8 – 20 %  Dementia or cognitive
decline 34 % at 52 week
1 year 15 – 25 %
post stroke
5 year 40 – 60 %
Sacco RL . Neuroloy 1997;49:S19-S44
 Cerebrovascular Disease:
Stroke Subtype

Hemorrhagic stroke Ischemic stroke

Lacunar small vessel
disease (25%)
Intracerebral
hemorrhage (59%)

Atherothrombotic
disease (20%)

SAH (41%)
Embolism (20%)

Albers GW et al. Chest. 1998;114:683S-698S. Cryptogenic (30%)

Rosamond WD et al. Stroke. 1999;30:736-743.
Efforts to Prevent the Secondary Vascular Event ?

Continued efforts are needed to improve secondary

prevention and clinical outcomes1:
• Initiatives to improve adherence to evidence-based guidelines
and care are an important tool in this respect

• The strong association of asymptomatic and symptomatic multiple

locations of atherothrombosis with event rates suggests that
atherothrombosis should be addressed as a global arterial disease in
patients

1. Steg PG et al, on behalf of the REACH Registry Investigators. JAMA

2007;297(11): 1197-1206.
7
 5 STROKE SUBTYPES
 LARGE ARTERY ATHEROSCL
 Moderate to severe stenosis of a major vessel to the brain associated with cortical
signs ( aphasia,neglect, cerebellar signs)

 CARDIOEMBOLISM
 Directly referrable to the heart ( due to AF or mechanical heart valve)

 SMALL VESSEL OCCLUSION

 Usually with no clinical sign of cortical involvement ( usually occuring in px with DM or
HT or both )

 STROKE DUE TO NON ATHEROSCL CONDITIONS

 Arterial dissection or hypercoagulable state

 STROKE W/ NO IDENTIFIABLE CAUSE

Incidence of Ischemic vs Hemorrhagic
Stroke and Rates of Death
The majority of strokes are ischemic

Ischemic stroke Hemorrhagic stroke

40 36%-37%

30-day mortality (%)

12% 30

88% 20

8%-12%
10

Incidence Mortality

American Heart Association Heart Disease and Stroke Statistics—2005 Update.

Interventions for secondary stroke
prevention1
 Lifestyle changes
 Management of risk factors
 Antithrombotic drugs
 Anticoagulants
 Carotid Arterial Stenting
 Surgery
• Carotid endarterectomy
• Angioplasty

1. Straus SE, et al. JAMA 2002;288:1388-95 10

The Effect of Antiplatelet in Stroke Patient
with high risk (ATC)

Category % Odds reduction

 Acute MI

 Acute stroke
* TIA = transient ischemic attack;
** CAD, PAD, high risk of embolism
 Prior MI and other
high-risk conditions (including hemodialysis,
DM, carotid disease)
 Prior stroke/TIA*

 Other high risk**

 All trials 25% ±3 (P<0.0001)

0.0 0.5 1.0 1.5 2.0

Antiplatelet better Control better

Adapted from: Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

11
Therapeutic Options

Four main classes of antiplatelet drug:

Cyclooxygenase inhibitors (e.g. aspirin)
Thienopyridine derivatives (e.g. clopidogrel

and ticlopidine)
Phosphodiesterase inhibitors (e.g. cilostazol, dipyridamole)

Glycoprotein IIb/IIIa receptor blockers

(e.g. abciximab)

12
Antithrombotic Trialists’ Collaboration: evidence
supports low dose aspirin (75–150mg)

ASA dose % odds reduction

500–1500 mg daily
160–325 mg daily ASA < 75 mg less
75–150 mg daily effective
< 75 mg daily

Any ASA dose 23% ±2

(p < 0.0001)

0.0 0.5 1.0 1.5 2.0

ASA better Control better

Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. 13

Dyslipidemia & Stroke
Risk Factors—Overview

Unmodifiable Risk Factors

 Age

 Male sex

 Race

 Family history of stroke/coronary heart disease

Modifiable Risk Factors

 Smoking

 Diet

 Sedentary lifestyle

 Alcohol/Drug abuse

 Obesity

 Carotid artery disease

 Atrial fibrillation

 Hypertension

 Diabetes

 Dyslipidemia

Treatment Options
 Carotid endarterectomy
 Antiplatelet therapy

Anticoagulation therapy
 Antihypertensive therapy
 Antidiabetic therapy
 Lipid-lowering therapies

Goldstein LB et al. Stroke. 2001;32:280-299.

 Risk factor CHD Stroke
Relatively fixed Age, sex, race, family Age, sex, race, family
history, history,
sosioeconomic status, sosioeconomic status,
geography geography

Major, established, HYPERTENSION HYPERTENSION

potentially HYPERCHOLESTEROL CHD
modifiable,with high ATRIAL FIBRILLATION
Elevated LDL chol
prevalence
HYPERCHOLESTEROL
Low HDL chol

+/- Elevated TG CICARETTE SMOKING

CIGARETTE SMOKING DM
DM PHYSICAL INACTIVITY
PHYSICAL INACTIVITY HIGH SALT /LOW FRUIT
AND VEGETABLE DIET
ATHEROSCLEROTIC/

HIGH SALT DIET

PAUL. K. Whelton . Highlight Report ESC Congress 2003

 VASCULAR DISEASE


 CAD STROKE


HYPERTENSION

HYPERCHOLESTEROLEMIA

HYPERCHOLESTEROLEMIA


 Stroke 1997;28:2315-2320
 Risk of a second vascular event
Increased risk vs general population (%)
 Original event Myocardial infarction
 Stroke


Myocardial infarction 5–7 x greater risk1 3–4 x greater risk2

(includes death) (includes TIA)

 Stroke 2–3 x greater risk2 9 x greater risk3

(includes angina and

sudden death*)
Peripheral arterial 4 x greater risk4 2–3 x greater risk3
disease (includes only fatal MI (includes TIA)

and other CHD death†)

 *Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD)
† Includes only fatal MI and other CHD death; does not include non-fatal MI
1. Adult Treatment Panel II. Circulation 1994; 89:1333–63. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–9.
3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 857–63. 4. Criqui MH et al. N Engl J Med 1992; 326: 381–6.
 Association Dyslipidemia and CHD is well established

Dyslipidemia

 Atherosclerosis

 Coronary Heart Disease

 Is there association between


dyslipidemia and stroke ?

Dyslipidemia
 Stroke ?
Is Cholesterol a Risk Factor for Stroke?

 Yes, atherosclerosis is the most common cause of

CAD, PVD and stroke worldwide. Atherogenesis is a
multi- factorial process involving cholesterol…

 No, easy no, but the counterquery is, why bother?

Controversies in Neurology
Arch Neurol/Vol 56.Dec 1999.
 Stroke – cholesterol
 Reasons for the weak or absent relationship

Virtually all CHD can be ascribed to coronary atheroma,

whereas less than half strokes is due to carotid or
cerebral artery atheroma . Remainder : non
atheromatous causes eg. Cardiac arrythmia and small
cerebral vessel disease
Cholesterol Levels Linked To Increased Risk of
Cardio-Cerebro Vascular Disease (CCVD)

180 180
170 170
160 160

Age-adjusted CVD rate/

Age-adjusted CVD rate/

10,000 person-years
10,000 person-years

150 141 150 142

140 140
130 123 130
117 118
120 120 115

110 103 104 110 104

100 100 97
90 90
80 80
70 70
Quintile of total cholesterol Quintile of LDL-C

Adapted with permission from Koren-Morag N et al. Arch Intern Med. 2002;162:993-999.
 Total Cholesterol, LDL-C,
and Risk of Ischemic Stroke

180 180

170 170

Rate/10,000 Person-Years
Rate/10,000 Person-Years

160 (n=11,177) 160

150 150
141 142
140 140

130 123 130

117 115 118
120 120

110 103 104 110 104

100 100 97
90 90

80 80

70 70

Quintile of Total Cholesterol Quintile of LDL-C

LDL-C = low-density lipoprotein cholesterol.

Adapted from Koren-Morag N et al. Arch Intern Med. 2002;162:993-999.
Statins in Primary Stroke Prevention
(With & Without CHD)
Statin & Stroke : 1st Paradox

 Intervention trials “Non statin lipid lowering drugs “

(fibrates – cholestyramine etc)  failed to show stroke
incidence 
 Conversely : MRFIT : 351.000 middle age men /6 yr
very high chol  death from IS 
 Eastern Stroke & Coronary Heart dis Collaborative
Research group (1998) : 70.000 px showed risk of non
hemorrhagic  with Lower Chol levels.
 Low chol  hemorrhagic stroke ( esp.HT ) (MRFIT
cutoff : chol < 160  Hemorrh strk ↑ )

Endres M. Statins and stroke.J of Cerebral Blood Flow & Metabolism 2005;25:1093
Statin & Stroke : 2nd Paradox
 Large placebo controlled trial :

4S CARE LIPID WOSCOPS HPS MIRACL

ASCOT PROSPER PPP AFCAPS

Statin Treatment : Stroke ↓ - RRR 25%-30%

“Statin Stroke paradox”

 Statin & Stroke : 2nd Paradox
 Secondary prevention :
• Stroke protective effects : Cerebrovasc disease + CHD or other vasc
disease
• HPS subgroup : in Cerebrovasc px – no reduction stroke rate

Role of statin in recurrent stroke prevention is not yet defined

 Primary prevention : statin  stroke in HT (ASCOT )

 AHA Stroke Council (2004) :
• Majority of patients with history IS or TIA could benefit from statin
• The effects apparently independent of cholesterol level
• Initiation of statin R/ during hospitalization for 1 st IS of atheroscl origin
is probably justified
 MEVALONATE PATHWAY

Acethyl CoA

HMG CoA

HMG CoA Reductase

Mevalonate
(6 carbons)

Mevalonate pyrophosphate

Isopentyl pyrophosphate
(5 carbons)
Geranyl pyrophosphate
(10 carbons)
Geranylgeranylation
Farnesylation
(20 carbons) of Farnesyl pyrophosphate
of proteins
Proteins –p21 RhoB; (15 carbons)
(Ras); p21 ras
Rab small GTP
Squalene (30 carbons)

Cholesterol (27 carbons)

 Cholesterol Synthesis and Atherogenesis: more than LDL?
Statins
Acetyl-CoA HMG-CoA Mevalonate Isopentenyl-PP
HMG-CoA Reductase

Dolichol, Farnesylated
Protein (ie, Ras)
Farnesyl-PP
+Isopentenyl-PP

Squalene Geranylgeranyl-PP

CHOLESTEROL eNOS, t-PA RhoA Rac1 Cdc42

PAI-1, ET-1
LDL Proliferation,
NAD(P)H oxidase Actin
cytoskeleton
Oxidative stress
Atherosclerosi constriction, migration

s
eNOS=endothelial nitric oxide synthase.
Takemoto et al. Arterioscler Thromb Vasc Biol.
Biol. 2001;21:1712-1719.
Stroke Reduction in TNT (CHD Patients)

0.04
HR = 0.75 (95% CI 0.59, 0.96)
Proportion of Patients With Event

P=.02

0.03 Atorvastatin 10 mg (n=5006)

Atorvastatin 80 mg (n=4995)
RRR 25%
0.02

0.01

0 1 2 3 4 5 6
Time (years)
TNT = Treating to New Targets; RRR = relative risk reduction.
Atorvastatin is not indicated for secondary prevention of CVD.
Adapted from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
Prevention of Stroke in Patients
With ACS

20 P=NS
9
10
Relative Risk Reduction

(n=4162) (n=3086) (n=4497)

0
for Stroke (%)

PROVE-IT MIRACL A to Z
–10

–20
–21
–30
P=.36
–40

–50
–50
–60 P<.05*
* 95% CI for RR = 0.26–0.99.

MIRACL=Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering.

Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Schwartz GG et al. JAMA. 2001;285:1711-1718;
de Lemos JA et al. JAMA. 2004;292:1307-1316.
Statin Therapy for Stroke Prevention
in ACS: MIRACL

2
Cumulative Incidence (%)

Placebo (n=1548)
1.5

1
Atorvastatin (n=1538)

0.5
Relative risk = 0.49
P=.04
95% CI 0.24–0.98
0
0 4 8 12 16
Time Since Randomization (weeks)

Adapted from Waters DD et al. Circulation. 2002;106:1690-1695.

Statins in Secondary Stroke
Prevention ?
Possible Neuroprotective Effects
of Statins
STATIN
Pleiotropic effects

LDL-C Reduction Plaque Stabilization

35-80% of benefit  Macrophages

 Smooth muscle cells

 Immunologic response

 Lipid core

 Oxidized LDL

 Improved endothelial function

 Reduced hemorheologic stress
 Reduced platelet aggregation
 Reduced thrombotic and
 enhanced fibrinolytic state
 Blood pressure reduction
 Decreased incidence of MI and of
left ventricular mural thrombus
Neuroprotective Actions of
Statins Cerebral Blood Vessel

Platelet
ANTITHROMBOTIC RBC
Anti-thrombotic
Vasodilation
Anti-inflammatory

NO NO
Macrophage ENDOTHELIAL PROTECTION

Adhesion Molecules
eNOS

iNOS
Neutrophil ANTI-INFLAMMATORY
NO + O2– ONOO–

Cytokines
Brain Parenchyma nNOS
II-1
TNF- ANTIOXIDANT
IL-6
Neuron

Apoptosis DNA/RNA damage

Lipid peroxidation
Protein oxidation
iNOS NO NO iNOS

Astrocyte Microglia
BRAIN – STATIN- PLEOTROPIC EFFECT

Upgrade endothelial nitric oxide synthase eNOS

Inhibit inducible NOS
Attenuate inflammatory cytokine respons that
accompany cerebral ischemia
Antioxidant properties that ameliorate ischemic
oxidative stress of the brain
Upstream effect of statin

Improving Cerebral Blood Flow

to ischemic brain & more resistant to
ischemia

Reduced infarct size

Improved neurological deficit

Stroke 2002;33:862-875
Statin – Brain Ischemia - CBF
 SPARCL — The Stroke Prevention by Aggressive
Reduction of Cholesterol Levels Study

RATIONAL:

 Analyses of data from a number of clinical

trials suggest that statin therapy may
reduce the incidence of stroke (1-3)
 SPARCL is the first trial primarily designed
to evaluate prospectively the effect of
statin treatment on secondary stroke
prevention in patients with a history of
cerebrovascular disease and no history of
cardiovascular disease
-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J
Med.
1998;339:1349-1357. 2. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 3. HPS
Study Group. Lancet. 2002;360:7-22.
SPARCL: Study Design

Patient
Patient Population
Population Double-blind period

 ~200 sites worldwide Atorvastatin 80 mg/d

 Documented stroke or
TIA within previous 6 4732
months Patients


No history of CHD Placebo
 LDL-C levels ≥100
mg/dL and
≤190 mg/dL 540 primary end points

Primary
Primary End
End Point
Point
Time
Time to
to the
the first
first occurrence
occurrence of
of aa fatal
fatal or
or nonfatal
nonfatal stroke
stroke
TIA = transient ischemic attack; CHD = coronary heart disease; LDL-C = low-density
lipoprotein cholesterol.
The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389–395.
Placebo

Atorvastatin
What is the Guidelines tell us?
AHA/ASA Recommendation 2008;39:000
AHA/ASA Recommendation 2008;39:000
Lipid Treatment ISSUES in
Neurologist Aspect
Are the use of statin can increase
incidence of Hemorrhagic Stroke?
 Stroke Risk Reduces With Reduction
in LDL-C
Each 10% low-density lipoprotein cholesterol (LDL-C) reduction was
estimated to reduce the risk of stroke by 15.6%
1.2
Post-CABG
1.1 GISSI PROSPER
Odds ratios, non–log-scale

1.0
WOSCOPS
0.9 ALLHAT-LLT AFCAPS/TexCAPS
0.8 LIPID
ASCOTT-LLA
0.7 HPS 4S
CARE
0.6
0.5 GREACE
MIRACL
0.4
0.3 Small Trials

0.2
-10 -15 -20 -25 -30 -35 -40 -45 -50 -55
Between group difference in LDL-C reduction (%)
Adapted with permission from Amarenco P et al. Stroke. 2004;35:2902-2909.
Meta-Analysis of Stroke Reduction in
Statin Trials
Across 26 trials, statins reduced stroke by 21% (P<.0001), with no
evidence of heterogeneity between trials (P=.35)
Trials Odds Ratios (95% CI)

ASCOT-LLA
ALLHAT-LLT
PROSPER
HPS
GREACE
MIRACL
GISSI
LIPID
AFCAPS/TexCAPS
Post-CABG
CARE
WOSCOPS
4S
SMALL TRIALS

OVERALL (95% confidence interval) 0.79 (0.73-0.85)

0.2 0.4 0.6 0.8 1.0 1.2 1.4
Statin better Control better

Adapted with permission from Amarenco P et al. Stroke. 2004;35:2902-2909.

Statin Therapy Is Not Associated With
Increased Risk for Hemorrhagic Stroke
A recent meta-analysis demonstrated that statin therapy does not
increase risk of hemorrhagic stroke vs control

Trials Odds Ratios (95% Cl)

HPS
GREACE*
MIRACL
KLIS*
LIPID
CARE
4S
AFCAPS
OVERALL (95% Cl) HR 0.90 (0.65-1.22)
Heterogeneity P=.15

0.05 0.2 0.5 1.0 3.0 10.0

*Statin vs usual care. Favors statin Favors control

Adapted with permission from Amarenco P et al. Stroke. 2004;35:2902-2909.

LDL < 66 mg/dl
 SUMMARY

 Stroke is common and accounts for about 10% of all

deaths worldwide
 Hypertension, Hypercholesterolemia, DM, and smoking
are the principal risk factor for ischemic stroke
 Reductions in cholesterol are associated with reductions
in ischemic stroke
 Multiple clinical trials have documented the effectiveness
of statin in reducing stroke
 SPARCL is the 1st trial that demonstrated the benefit of
statin in reducing risk of recurrent stroke
 AHA/ASA guideline recommends the use of statin in
stroke patients to prevent CV diseases and recurrent
stroke.
Summary(2)

 Hypercholesterolemia and hyperlipidemia are

not as well established as risk factors for first
or recurrent stroke in contrast to what is seen
in cardiac disease. Overall, prior observational
cohort studies have shown only a weekly
positive association for cholesterol level and risk
of ischemic stroke or no clear relationship
between plasma cholesterol and total stroke.
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