Lipid Management in Stroke :
Statin and Other Lipid Modifying
Agents
Professor Pierre Amarenco
INSERM U-698 and Paris-Diderot University
Department of Neurology and Stroke Centre
Bichat-Claude Bernard Hospital, Paris, France
INTERSTROKE: Population-attributable risk for
common risk factors
Risk factor
Population-attributable
risk, % (99% CI)
Hypertension
Smoking
Waist-to-hip ratio (tertile 2 vs tertile 1)
Dietary risk score (tertile 2 vs tertile 1)
Regular physical activity
Diabetes
Alcohol intake
Cardiac causes
Ratio of apolipoprotein B to A1
(tertile 2 vs tertile 1)
Psychological factors
•Stress
•Depression
34.6 (30.4–39.1)
18.9 (15.3–23.1)
26.5 (18.8–36.0)
18.8 (11.2–29.7)
28.5 (14.5–48.5)
5.0 (2.6–9.5)
3.8 (0.9–14.4)
6.7 (4.8–9.1)
24.9 (15.7–37.1)
4.6 (2.1–9.6)
5.2 (2.7–9.8)
*For the protective factor of physical activity, the population-attributable risks are provided
for individuals who do not participate in regular physical activity.
O'Donnell MJ et al. Lancet 2010; available at: http://www.thelancet.com.
Meta-analysis : Statin and Stroke
N total=165 732
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Meta-Analysis Stroke Death
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Meta-analysis Hemorrhagic stroke
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Stroke Risk and LDL Lowering
Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95%
CI 6.3 to 33.5%, p<0.001)
Total n=165,732
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
N=17,802
LDL-c<130 mg/dL
hsCRP >2 mg/dL
F/U 1.9 yrs
Event
JUPITER
Rosuva *
Placebo *
Men >50 yrs
Women >60 yrs
Hazard Ratio
Risk Reduction (CI)
Primary endpoint
142 (1.6%) 251 (2.8%)
44% (31-54)
p=0.000001
Any MI
31 (0.35%) 68 (0.76%)
54% (30-70)
Stroke
33 (0.37%) 64 (0.72%)
48% (21-66)
p=0.002
Revascularisation or
Unstable angina
76 (0.85%) 143 (1.6%)
47% (30-60)
MI, Stroke, CVdeath
83 (0.93%) 157 (1.8%)
47% (30-61)
.2 .4 .6 .8
* N (% randomised)
Favours Rosuvastatin
1 1.2
Favours Placebo
Secondary End Point: Fatal
and Nonfatal Stroke
Cumulative Incidence (%)
3
Atorvastatin 10 mg
Number of events
89 (1.7%)
Placebo
Number of events
121 (2.4%)
27%
reduction
2
1
HR = 0.73 (0.56-0.96)
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
Years
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
3,5
p=0.0236
CARDS:
Cumulative Hazard for Stroke
Cumulative Hazard (%)
4
Atorvastatin10 mg
Placebo
48%
Risk
Reduction
In Stroke
Placebo n=39
[31% of all first
CVD events]
3
(P=0.016)
2
1
Atorvastatin n=21
[25% of all first CVD
events]
0
0
1
2
3
Years from Randomization
Hitman GA, et al. EASD Diabetologia. 2005; Abstract 120
Data on file, Pfizer Inc.
4
4.75
Pleiotropic Effects
Studied Parameter Within the
Plaque
Control
Group n=13
Pravastatin
Group n=11
P Value
23.9%
8.2%
<0.001
22%
13.3%
<0.001
Macrophage contain
25.3%
15.3%
<0.05
T-Cell count
23.4%
11.2%
<0.05
SMC
16.9%
24.3%
<0.05
32%
17.7%
<0.05
Lipid contain (Oil Red O)
Ox-LDL (NA59)
Apoptotic Cells (TUNEL)
Crisby et al. Circulation 2001
Between-Group LDL Reduction and CarotidIMT Reduction Per Year
r=0.70 , p=0.0013
For Each 10% LDL-cholesterol
IMT reduction per year = 0.76% (95%CI, 0.34-1.18)
Amarenco et al. Stroke 2004;35:2902-9
Lacunar B.I.C.H.A.T. Study Design
Lacunar Brain Infarction, Cerebral
Hyperreactivity, and Atorvastatin Trial
Atorvastatin 80 mg
Patient population


Lacunar stroke 3
months prior rando
2-month Run-in
period prior rando:

BP treatment to target
guidelines

Blood glucose control
if diabetic
94
patients
Double-blind placebo
CVMR
3 months
CVMR
Randomization with stratification on
hypertensive and diabetic status
Primary end point:
 Cerebral vasoreactivity
Secondary end point:
 Brachial artery vasoreactivity
Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009
Primary and Secondary Endpoints
Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009
PRIMARY ENDPOINT
SECONDARY
ENDPOINT
PRIMARY ENDPOINT
SECONDARY
ENDPOINT
TREATMENT WORSE
TREATMENT BETTER
Stroke:
Potential Mechanisms of Benefit
Statin
LDL Reduction
35 to 80% of the benefit
Plaque stabilization:
macrophages
smooth muscle cells
immunologic response
lipid core
oxidized LDL
Improved endothelial function
Reduced hemorheologic stress
Reduced platelet aggregation
Blood pressure reduction
Neuroprotection
. Up-regulation NO
. Improves CBF
. Reduces infarct size
Reduced thrombotic and
Enhanced fibrinolytic state
Decrease incidence of MI
and of left ventricular mural
thrombus
Patient with Event (5)
HPS: No Reduction in Risk of
Recurrent Stroke in Patients With Prior
Cerebrovascular Disease
n=406
n=488
Major Vascular Events
*29% RR, P=.001
Heart Protection Study Collaborative Group. Lancet. 2004;363:757–767.
n=169
Stroke
n=170
SPARCL: Study Design
Double-Blind Period
Patient Population
 205 sites worldwide
Atorvastatin 80 mg/day
 Previously documented
stroke or TIA within
6 months
4,731
Patients
 No history of CHD
Placebo
 LDL-C levels ≥100
mg/dL and ≤190 mg/dL
540 Primary Endpoints
Primary End Point
Time to the First Occurrence of a Fatal or Nonfatal Stroke
Source: The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389–395
LCL-C During Follow-up
Baseline LDL-C: 133 mg/dL
140
+1%
-7%
120
Mean (mg/dL)
100
-38%
80
60
-53%
40
Mean on-treatment LDL-C:
Placebo = 129 mg/dL
Atorvastatin = 73 mg/dL
20
0
Baseline Month 1 Month 3 Month 6 Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Timepoint
Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59
Last
Primary Endpoint:
Time to Fatal or Non-Fatal Stroke
Fatal or Non-Fatal Stroke (%)
16%
16%
RR
Placebo
Atorvastatin
12%
8%
4%
Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03
0%
0
1
2
3
4
5
Years Since Randomization
* Treatment effect from Cox proportional hazards models with pre-specified adjustment
for geographical region, entry event, time since entry event, gender, and baseline age.
Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59
6
Secondary Endpoint:
Time to Major Coronary Event
Major Coronary Event (%)
8%
35%
RR
6%
4%
Placebo
Atorvastatin
2%
Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003
0%
0
1
2
3
4
5
Years Since Randomization
* Treatment effect from Cox proportional hazards models with pre-specified adjustment
for geographical region, entry event, time since entry event, gender, and baseline age.
Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59
6
Gender: Stroke Outcomes
Gender X Treatment
Interaction p-value
All Stroke
Women
0.99
Men
Non-fatal Stroke
Women
0.77
Men
Fatal Stroke
Women
0.23
Men
0.0
0.5
Treatment Better
1.0
1.5
Placebo Better
Adjusted Hazard Ratio
Pre-specified adjustment for region, entry event, time since entry event and age
Goldstein LB, Amarenco P, Callahan A III, al.. Stroke. 2008;39:2444-48
SPARCL Elderly vs Young
YOUNG
ELDERLY
STROKE
CV events
Chaturvedi S et al. Neurology. 2008 ;E-pub
SPARCL Elderly vs Young
Chaturvedi S et al. Neurology. 2008 ;E-pub
Ischemic and Hemorrhagic Stroke
Post hoc analysis
Fatal and Non-fatal Stroke
Is c hem i c or H em orrhagi c S trok e (% )
16
Placebo: Ischemic
Atorvastatin: Ischemic
Placebo: Hemorrhagic
Atorvastatin: Hemorrhagic
12
Ischemic: HR (95% CI) = 0.79 (0.66, 0.95)
8
4
Hemorrhagic: HR (95% CI) = 1.68 (1.09, 2.59)
0
0
1
2
3
4
5
6
Years Since Randomization
Unadjusted HR
Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70
Multivariable Cox Regression Model
Baseline Characteristics & Time Varying Blood Pressure
Risk of hemorrhage
OR (95% CI)
p
Atorvastatin treatment
1.69 (1.10, 2.60)
0.02
Hemorrhage as entry event
5.81 (2.91, 11.60)
<0.001
Male sex
1.77 (1.11, 2.81)
0.02
Age (10 yr increments)
1.37 (1.12, 1.69)
0.003
3.18 (0.76, 13.34)
3.49 (0.83, 14.61)
6.19 (1.47, 26.11)
0.01
0.11
0.09
0.01
Blood Pressure
Pre-hypertension
Stage 1 hypertension
Stage 2 hypertension
Treatment X entry event interaction, p=0.20
Treatment X hypertension interaction, p=0.25
Pre-HTN: SBP 120-139 or DBP 80-89
Stage 1: SBP 140-159 or DBP 90-99
Stage 2: SBP>160 or DBP>100
Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70
Impact of Atorvastatin on
Hemorrhagic stroke by Entry Event
Goldstein LB, Amarenco P et al. Neurology. 2008;70:2864-70
Entry Event
HR (95% CI)
P-value
Large Vessel
1.23 (0.44, 3.39)
0.6934
TIA
0.97 (0.44, 2.17)
0.9473
Hemorrhagic
4.67 (0.96, 22.6)
0.0556
Small Vessel
5.07 (1.73, 14.9)
0.0031
Unknown
0.80 (0.30, 2.13)
0.6494
-2
*Adjusted for time since
entry event, gender, and age
0
2
4
Hazard ratio*
Atorvastatin better
Placebo better
6
8
Impact of Atorvastatin on Stroke Risk
HR (95% CI)
Stroke
p-value
Large Vessel
0.70 (0.49, 1.02)
0.0604
TIA
0.81 (0.57, 1.17)
0.2639
Hemorrhagic
3.24 (1.01, 10.4)
0.0482
Small Vessel
0.85 (0.64, 1.12)
0.2491
Unknown
0.87 (0.61, 1.24)
0.4422
P for heterogeneity = 0.421
0
1
2
Hazard Ratio
Amarenco et al. Stroke. 2009
3
4
Impact of Atorvastatin
on Coronary Risk and Death
HR (95% CI)
Major
Coronary
Event
Large Vessel
TIA
Hemorrhagic
Small Vessel
Unknown
0.60 (0.29, 1.25)
0.70 (0.40, 1.25)
1.09 (0.15, 7.93)
0.80 (0.50, 1.27)
0.43 (0.24, 0.80)
p-value
0.1690
0.2317
0.9324
0.3407
0.0071
P for heterogeneity = 0.360
Death
Large Vessel
TIA
Hemorrhagic
Small Vessel
Unknown
0.77 (0.48, 1.22)
0.99 (0.68, 1.45)
2.24 (0.67, 7.55)
1.20 (0.86, 1.68)
0.84 (0.56, 1.27)
0.2657
0.9615
0.1918
0.2799
0.4035
0
1
2
Hazard Ratio
Amarenco et al. Stroke. 2009
3
4
Benefit/Risk
P=0.002
P=0.03
Incidence (%)
17.2%
13.1%
Major Coronary
Event
14.1%
Ischemic
Stroke
11.2%
Hemorrhagic
Stroke
Unclassified
Stroke
Atorvastatin
n = 2365
Placebo
n = 2366
Stroke
Atorvastatin
n = 2365
Placebo
n = 2366
Stroke and Major
Coronary Events
Amarenco P, et al. Exp Op Pharmacotherapy. 2007
Ischemic Stroke Severity: Last
Dose 1 Month Before Stroke
Goldstein LG, Amarenco P et al. Stroke. 2009
Placebo
(n=222)
Atorvastatin
(n=175)
Mild
Moderate
Severe
42.8
42.8
32.4
11.3
36.0
50.950.9
Fatal
13.5
6.9 6.3
P = 0.007
Proportion of patients (%)
Improvement in
atorvastatin group (%)
8.1
11.7 7.3
Results were similar after adjusting for age, gender, and severity of
baseline event (P=0.044)
*Percent of patients with no recurrent event is not shown to scale. Subjects with missing severity for first
event are excluded. Stroke severity determined by Rankin Scale: 0/1=mild, 2/3=moderate, 4/5=severe.
Effect of Atorvastatin on Stroke In
SPARCL Patients with Diabetes
Percentage of Patients
Free of End Points
100
Atorvastatin 80 mg
Placebo
90
RR: 30%
80
HR=0.70 (95% CI 0.50, 0.98), P=0.0387*
Log-rank P=0.0377
70
0
1
2
3
4
Years since randomization
*Adjusted for entry event, time since entry
event, gender, age, and geographic region
Callahan A, Welch KMA, Amarenco P, et al.
5
6
Any CHD Event
Percentage of Patients Free of End Points
Percentage of Patients Free of End Points
Effect of Atorvastatin on CV Events
In SPARCL Patients with Diabetes
100
Atorvastatin 80 mg
98
Placebo
96
94
92
90
88
RR: 51%
86
84 HR=0.49 (95% CI 0.31, 0.79), P=0.0033*
82
0
Log-rank P=0.0027
1
2
3
4
5
Years since randomization
6
Any Revascularization
100
Atorvastatin 80 mg
98
Placebo
96
94
92
90
RR: 64%
88
86
84 HR=0.36 (95% CI 0.21, 0.61), P=0.0001*
82
Log-rank P=0.0001
0
1
2
3
4
5
Years since randomization
*Adjusted for entry event, time since entry
event, gender, age, and geographic region
Callahan A, Welch KMA, Amarenco P, et al.
6
Effect of Atorvastatin on Renal
Function by Glycemic Status
p = 0.012*
Atorvastatin
Placebo
2.5
Mean Change in eGFR
from Baseline (mL/min/1.73 m2)
2.0
p = 0.001*
1.5
1.0
0.5
p = 0.258† p < 0.0001†
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
p < 0.001*
-4.5
n=1459 n=1476
No Diabetes, No MetS
* Treatment difference
† Difference from baseline
n=366
MetS
n=359
n=360
Diabetes
n=370
Stroke in Patients With
Carotid Stenosis
Atorvastatin
Patients free of fatal or
non-fatal stroke (%)
100
Placebo
90
RR: 33%
80
HR=0.67 (95% CI 0.47, 0.94), P=.02*
70
0
1
2
3
4
Years since randomization
*: adjusted for entry event, time since entry event, gender, age, and geographical region
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
5
Any Cardiovascular Event in
patients With Carotid Stenosis
Patients free of any
cardiovascular event (%)
100
Atorvastatin
Placebo
90
80
70
RR: 42%
60
HR=0.58 (95% CI 0.46, 0.73), P<.0001
50
0
1
2
3
4
Years since randomization
*: adjusted for entry event, time since entry event, gender, age, and geographical region
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
5
Carotid Endarterectomy in
Patients With Carotid Stenosis
Atorvastatin (n=16/493)
100
Patients free of carotid
endarterectomy (%)
Placebo (n=37/514)
98
RR: 56%
96
94
HR=0.44 (95% CI 0.24, 0.79), P=.006
92
0
1
2
3
4
Years since randomization
*: adjusted for entry event, time since entry event, gender, age, and geographical region
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
5
Stroke Risk and LDL Lowering
Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95%
CI 6.3 to 33.5%, p<0.001)
N total=165 732
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Stroke Risk and LDL Lowering
Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95%
CI 6.3 to 33.5%, p<0.001)
N total=165 732
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Time Varying LDL-C and
Stroke Risk
HR (95% CI)
p-value
All Stroke
≥0% Increase
1.00
<50% Decrease
≥50% Decrease
0.89 (0.73, 1.08)
0.69 (0.55, 0.87)
0.2253
0.0016
Ischemic Stroke
≥0% Increase
1.00
<50% Decrease
≥50% Decrease
0.90 (0.73, 1.12)
0.67 (0.52, 0.86)
0.3394
0.0018
Hemorrhagic Stroke
≥0% Increase
1.00
<50% Decrease
≥50% Decrease
0.84 (0.50, 1.40)
1.04 (0.61, 1.78)
0.4716
0.8864
0.4
Note: Percent change effects from Cox proportional hazards
models with adjustment for gender and baseline age with
reference group = no change or increase
0.7
1.0
1.3
Hazard Ratio (95% CI)
Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204
1.6 1.9 2.2
Time Varying LDL-C and
Stroke Risk
HR (95% CI)
p-value
All Stroke
≥ 100 mg/dL
1.00
70 to < 100 mg/dL
< 70 mg/dL
1.01 (0.81, 1.27)
0.72 (0.59, 0.89)
0.9076
0.0016
0.4
0.7
1.0
1.3
Hazard Ratio (95% CI)
Note: Nominal value effects from Cox proportional hazards
models with adjustment for gender and baseline age with
reference group = no change or increase
Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204
1.6 1.9 2.2
Meta-analysis: Intensive LDL-C Lowering
vs. Standard Statin Therapy
Fatal and Nonfatal STROKE
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Meta-analysis: Intensive Lipid-Lowering
vs. Standard Statin Therapy
MAJOR CARDIOVASCULAR EVENTS
Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63
Mean Lipids and BP During Follow-up in
Atorvastatin and Placebo Groups
TG
150
140.0
139.5
Blood Pressure (mm Hg)
Lipids (mg/dl)
LDL
100
75
50
HDL
25
0
SBP
139.0
125
0 3 6
12
18
24
30
36
42
48
54
60
66
72
LO
138.5
138.0
137.5
137.0
82.0
81.5
81.0
80.5
80.0
1.0
0.0
DBP
0 3 6
Time (months)
Solid lines = atorvastatin 80 mg group; dashed lines = placebo group
Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009
LO = last observation
12
18
24
30
36
42
Time (months)
48
54
60
66
72
LO
Optimal Multi-Targets

LDL-C <70 mg/dL (NCEP-III, high risk)

TG <150 mg/dL (normal ATP-III level)

HDL-C >50 mg/dL (NCEP-III)

BP <120/80 mm Hg (JNC-7)
Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009
Combined Effect of Optimal Lipid & BP Control on
Risk of Stroke and MCVE
No.
subjects
No (%) HR
events
Stroke
0 parameters
1 parameter
2 parameters
3 parameters
4 parameters
662
1156
1926
906
80
93 (14.0)
167 (14.4)
228 (11.8)
84 (9.3)
4 (5.0)
1.00
0.982
0.782
0.620
0.354
Major cardiovascular events (MCVE)
0 parameter
1 parameters
2 parameters
3 parameters
4 parameters
662
1156
1926
906
80
126 (19.0)
207 (17.9)
290 (15.1)
114 (12.6)
4 (5.0)
1.000
0.903
0.725
0.603
0.247
0.0
0.5
1.0
95% CI
P-value Overall
P-value*
0.0012
(0.761, 1.266)
(0.612, 0.998)
(0.459, 0.837)
(0.130, 0.963)
(0.723, 1.128)
(0.587, 0.896)
(0.466, 0.781)
(0.091, 0.669)
0.8859
0.0478
0.0018
0.0420
0.3704
0.0029
0.0001
0.0059
<0.0001
1.5
*P value for differences between number of parameters achieved
Amarenco P, et al. Stroke. 2009