lipid management in stroke : statin and other lipid modifying agents professor pierre amarenco...
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Lipid Management in Stroke :Statin and Other Lipid Modifying
Agents
Professor Pierre AmarencoINSERM U-698 and Paris-Diderot UniversityDepartment of Neurology and Stroke Centre
Bichat-Claude Bernard Hospital, Paris, France
*For the protective factor of physical activity, the population-attributable risks are provided for individuals who do not participate in regular physical activity.
Risk factor Population-attributable risk, % (99% CI)
Hypertension 34.6 (30.4–39.1)Smoking 18.9 (15.3–23.1)Waist-to-hip ratio (tertile 2 vs tertile 1) 26.5 (18.8–36.0)Dietary risk score (tertile 2 vs tertile 1) 18.8 (11.2–29.7)Regular physical activity 28.5 (14.5–48.5)Diabetes 5.0 (2.6–9.5)Alcohol intake 3.8 (0.9–14.4)Cardiac causes 6.7 (4.8–9.1)Ratio of apolipoprotein B to A1(tertile 2 vs tertile 1)
24.9 (15.7–37.1)
Psychological factors•Stress 4.6 (2.1–9.6)•Depression 5.2 (2.7–9.8)
INTERSTROKE: Population-attributable risk forcommon risk factors
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
JUPITER
64 (0.72%)
143 (1.6%)
251 (2.8%)
Placebo *
48% (21-66)
p=0.00233 (0.37%)Stroke
47% (30-60)76 (0.85%)Revascularisation or Unstable angina
44% (31-54)
p=0.000001142 (1.6%)Primary endpoint
Hazard Ratio Risk Reduction (CI)Rosuva *Event
* N (% randomised)
.2 .4 .6 .8 1 1.2
Favours Rosuvastatin Favours Placebo
68 (0.76%) 54% (30-70)31 (0.35%)Any MI
157 (1.8%) 47% (30-61)83 (0.93%)MI, Stroke, CVdeath
N=17,802LDL-c<130 mg/dLhsCRP >2 mg/dLF/U 1.9 yrs
Men >50 yrsWomen >60 yrs
Secondary End Point: Fatal and Nonfatal Stroke
Atorvastatin 10 mg Number of events 89 (1.7%)
Placebo Number of events 121 (2.4%)
27% reduction
HR = 0.73 (0.56-0.96) p=0.0236
0
1
2
3
0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5
Years
Cu
mul
ativ
e In
cid
ence
(%
)
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Placebo n=39
[31% of all first CVD events]
Atorvastatin n=21
[25% of all first CVD events]
(P=0.016)
CARDS:Cumulative Hazard for Stroke
00
Years from Randomization
Cu
mu
lati
ve H
azar
d (
%)
1 2 3 4 4.75
1
2
3
448% Risk
ReductionIn Stroke
PlaceboAtorvastatin10 mg
Hitman GA, et al. EASD Diabetologia. 2005; Abstract 120Data on file, Pfizer Inc.
Pleiotropic Effects
Studied Parameter Within the Plaque
Lipid contain (Oil Red O)
Ox-LDL (NA59)
Macrophage contain
T-Cell count
SMC
Apoptotic Cells (TUNEL)
ControlGroup n=13
23.9%
22%
25.3%
23.4%
16.9%
32%
Pravastatin Group n=11
8.2%
13.3%
15.3%
11.2%
24.3%
17.7%
P Value
<0.001
<0.001
<0.05
<0.05
<0.05
<0.05
Crisby et al. Circulation 2001
Between-Group LDL Reduction and Carotid-IMT Reduction Per Year
Between-Group LDL Reduction and Carotid-IMT Reduction Per Year
For Each 10% LDL-cholesterolIMT reduction per year = 0.76% (95%CI, 0.34-1.18)
r=0.70 , p=0.0013
Amarenco et al. Stroke 2004;35:2902-9
Patient populationPatient population Lacunar stroke 3 Lacunar stroke 3
months prior randomonths prior rando 2-month Run-in 2-month Run-in
period prior rando:period prior rando: BP treatment to target
guidelines Blood glucose control
if diabetic
Double-blind placeboDouble-blind placebo
94patients
94patients
Atorvastatin 80 mgAtorvastatin 80 mg
Primary end point:Primary end point: Cerebral vasoreactivityCerebral vasoreactivity
3 months3 months3 months3 months
Secondary end point:Secondary end point: Brachial artery vasoreactivityBrachial artery vasoreactivity
Randomization with stratification on hypertensive
and diabetic status
CVMR CVMR
Lacunar Lacunar BB..II..CC..HH..AA..TT. Study Design. Study DesignLLacunar acunar BBrain rain IInfarction, nfarction, CCerebral erebral HHyperreactivity, yperreactivity,
and and AAtorvastatin torvastatin TTrialrial
Lacunar Lacunar BB..II..CC..HH..AA..TT. Study Design. Study DesignLLacunar acunar BBrain rain IInfarction, nfarction, CCerebral erebral HHyperreactivity, yperreactivity,
and and AAtorvastatin torvastatin TTrialrial
Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009
Primary and Secondary Endpoints
TREATMENT BETTERTREATMENT WORSE
PRIMARY ENDPOINT
PRIMARY ENDPOINT
SECONDARY
ENDPOINT
SECONDARY
ENDPOINT
Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009
Stroke:Stroke:Potential Mechanisms of BenefitPotential Mechanisms of Benefit
LDL Reduction
Plaque stabilization:macrophagessmooth muscle cellsimmunologic responselipid coreoxidized LDL
Improved endothelial function
Reduced hemorheologic stress
Reduced platelet aggregation
Reduced thrombotic and
Enhanced fibrinolytic state
Statin
Blood pressure reduction
Decrease incidence of MI
and of left ventricular mural
thrombus
35 to 80% of the benefit
Neuroprotection . Up-regulation NO . Improves CBF . Reduces infarct size
HPS: No Reduction in Risk ofRecurrent Stroke in Patients With Prior Cerebrovascular Disease
*29% RR, P=.001Heart Protection Study Collaborative Group. Lancet. 2004;363:757–767.
Pat
ien
t w
ith
Eve
nt
(5)
n=169 n=170n=406 n=488
Major Vascular Events Stroke
4,731Patients
SPARCL: Study Design
Placebo
540 Primary Endpoints
Atorvastatin 80 mg/day
Double-Blind Period
Source: The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389–395
Primary End PointTime to the First Occurrence of a Fatal or Nonfatal Stroke
Patient Population
205 sites worldwide
Previously documented stroke or TIA within 6 months
No history of CHD
LDL-C levels ≥100 mg/dL and ≤190 mg/dL
0
20
40
60
80
100
120
140
Baseline Month 1 Month 3 Month 6 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Last
Timepoint
Me
an
(m
g/d
L)
LCL-C During Follow-up
Mean on-treatment LDL-C:
Placebo = 129 mg/dL
Atorvastatin = 73 mg/dL
-53%
+1%
-7%
-38%
Baseline LDL-C: 133 mg/dL
Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59
Primary Endpoint:Time to Fatal or Non-Fatal Stroke
Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03
16%RR
Years Since Randomization
Fat
al o
r N
on
-Fat
al S
tro
ke (
%)
0 1 2 3 4 5 60%
4%
8%
12%
16%
PlaceboAtorvastatin
* 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
Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003
Secondary Endpoint:Time to Major Coronary Event
35%RR
Years Since Randomization
Maj
or
Co
ron
ary
Eve
nt
(%)
0 1 2 3 4 5 6
0%
2%
4%
6%
8%
PlaceboAtorvastatin
* 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
Gender: Stroke Outcomes
0.0 0.5 1.0 1.5
Men
Women
Men
Women
Men
Women
Non-fatal Stroke
Fatal Stroke
All Stroke
Treatment Better Placebo Better
Gender X TreatmentInteraction p-value
0.99
0.77
0.23
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
Chaturvedi S et al. Neurology. 2008 ;E-pub
YOUNG ELDERLY
STROKE
CV events
SPARCL Elderly vs Young
Chaturvedi S et al. Neurology. 2008 ;E-pub
Ischemic and Hemorrhagic StrokePost hoc analysis
Years Since Randomization
Isch
em
ic o
r H
em
orr
ha
gic
Str
oke
(%
)
0 1 2 3 4 5 6
0
4
8
12
16Placebo: IschemicAtorvastatin: IschemicPlacebo: HemorrhagicAtorvastatin: Hemorrhagic
Ischemic: HR (95% CI) = 0.79 (0.66, 0.95)
Hemorrhagic: HR (95% CI) = 1.68 (1.09, 2.59)
Unadjusted HR
Fatal and Non-fatal Stroke
Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70
Multivariable Cox Regression ModelBaseline 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
Blood PressurePre-hypertensionStage 1 hypertensionStage 2 hypertension
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
Pre-HTN: SBP 120-139 or DBP 80-89Stage 1: SBP 140-159 or DBP 90-99Stage 2: SBP>160 or DBP>100
Treatment X entry event interaction, p=0.20Treatment X hypertension interaction, p=0.25
Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70
Hazard ratio**Adjusted for time since entry event, gender, and age
-2 0 2 4 6 8
HR (95% CI) P-value
Large Vessel
TIA
Hemorrhagic 0.0556
Small Vessel
Unknown
1.23 (0.44, 3.39)
0.97 (0.44, 2.17)
4.67 (0.96, 22.6)
5.07 (1.73, 14.9)
0.80 (0.30, 2.13) 0.6494
0.0031
0.6934
0.9473
Entry Event
Atorvastatin better Placebo better
Impact of Atorvastatin onHemorrhagic stroke by Entry Event
Goldstein LB, Amarenco P et al. Neurology. 2008;70:2864-70
Impact of Atorvastatin on Stroke Risk
Stroke
Large Vessel
TIA
Hemorrhagic
Small Vessel
Unknown
0.70 (0.49, 1.02)
0.81 (0.57, 1.17)
3.24 (1.01, 10.4)
0.85 (0.64, 1.12)
0.87 (0.61, 1.24)
0.0604
0.2639
0.0482
0.2491
0.4422
0 1 2 3 4
Hazard Ratio
HR (95% CI) p-value
Amarenco et al. Stroke. 2009
P for heterogeneity = 0.421
Impact of Atorvastatinon Coronary Risk and Death
Major Coronary Event
Death
Large Vessel
TIA
Hemorrhagic
Small Vessel
Unknown
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)
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)
0.1690
0.2317
0.9324
0.3407
0.0071
0.2657
0.9615
0.1918 0.2799
0.4035
0 1 2 3 4
Hazard Ratio
HR (95% CI) p-value
Amarenco et al. Stroke. 2009
P for heterogeneity = 0.360
Benefit/Risk
Atorvastatinn = 2365
Placebon = 2366
Atorvastatinn = 2365
Placebon = 2366
Inci
den
ce (
%)
Stroke and Major Coronary Events
Major Coronary Event
Ischemic Stroke
Hemorrhagic Stroke
Unclassified Stroke
Stroke
P=0.03
11.2%13.1%
14.1%
17.2%
P=0.002
Amarenco P, et al. Exp Op Pharmacotherapy. 2007
8.1
Ischemic Stroke Severity: Last Dose 1 Month Before Stroke
Placebo(n=222) 42.8
32.4 11.3 13.5
Mild FatalSevereModerate
Improvement in atorvastatin group (%)
11.7 7.3
Atorvastatin(n=175) 50.9
36.0 6.9 6.3
Proportion of patients (%)
50.9
42.8
Results were similar after adjusting for age, gender, and severity of baseline event (P=0.044)
P = 0.007
*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.
Goldstein LG, Amarenco P et al. Stroke. 2009
Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes
70
100
90
80
Per
cen
tag
e o
f P
atie
nts
F
ree
of
En
d P
oin
ts
Placebo
Atorvastatin 80 mg
0 1 2 3 4 5
Years since randomization6
*Adjusted for entry event, time since entry event, gender, age, and geographic region
HR=0.70 (95% CI 0.50, 0.98), P=0.0387*Log-rank P=0.0377
RR: 30%
Callahan A, Welch KMA, Amarenco P, et al.
Effect of Atorvastatin on CV EventsIn SPARCL Patients with Diabetes
Any CHD Event Any Revascularization
Placebo
Atorvastatin 80 mg
Years since randomization
Per
cen
tag
e o
f P
atie
nts
Fre
e o
f E
nd
P
oin
ts
0 1 2 3 4 5 6
82
100
84
86
88
90
92
94
96
98
Per
cen
tag
e o
f P
atie
nts
Fre
e o
f E
nd
Po
ints
0 1 2 3 4 5 6
82
100
84
86
88
90
92
94
96
98Placebo
Atorvastatin 80 mg
Years since randomization
*Adjusted for entry event, time since entry event, gender, age, and geographic region
HR=0.49 (95% CI 0.31, 0.79), P=0.0033*Log-rank P=0.0027
RR: 51%
HR=0.36 (95% CI 0.21, 0.61), P=0.0001*Log-rank P=0.0001
RR: 64%
Callahan A, Welch KMA, Amarenco P, et al.
Effect of Atorvastatin on Renal Function by Glycemic Status
* Treatment difference† Difference from baseline
No Diabetes, No MetS
AtorvastatinPlacebo
MetS Diabetes
n=1459 n=1476 n=366 n=359 n=360 n=370
p < 0.001*
p = 0.012*
Mea
n C
ha
ng
e in
eG
FR
fr
om
Bas
elin
e (
mL
/min
/1.7
3 m
2) p = 0.001*
-4.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
p = 0.258† p < 0.0001†
Stroke in Patients With Carotid Stenosis
HR=0.67 (95% CI 0.47, 0.94), P=.02*
0 1 2 3 4 5
70
100
90
80
Pat
ien
ts f
ree
of
fata
l o
r n
on
-fat
al s
tro
ke (
%)
Years since randomization
Placebo
Atorvastatin
*: adjusted for entry event, time since entry event, gender, age, and geographical region
RR: 33%
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
0 1 2 3 4 550
80
90
100
60
70
Any Cardiovascular Event inpatients With Carotid Stenosis
HR=0.58 (95% CI 0.46, 0.73), P<.0001
Pat
ien
ts f
ree
of
any
card
iova
scu
lar
even
t (%
)
Years since randomization
Placebo
Atorvastatin
*: adjusted for entry event, time since entry event, gender, age, and geographical region
RR: 42%
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
0 1 2 3 4 5
98
100
92
94
96
Carotid Endarterectomy inPatients With Carotid Stenosis
HR=0.44 (95% CI 0.24, 0.79), P=.006
Pat
ien
ts f
ree
of
caro
tid
en
dar
tere
cto
my
(%)
Placebo (n=37/514)
Atorvastatin (n=16/493)
Years since randomization*: adjusted for entry event, time since entry event, gender, age, and geographical region
RR: 56%
Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub
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
Note: Percent change effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase
0.4 0.7 1.0 1.3 1.6 1.9 2.2
<50% Decrease
≥50% Decrease
<50% Decrease
≥50% Decrease
<50% Decrease
≥50% Decrease
HR (95% CI)
0.89 (0.73, 1.08)
0.69 (0.55, 0.87)
0.90 (0.73, 1.12)
0.67 (0.52, 0.86)
0.84 (0.50, 1.40)
1.04 (0.61, 1.78)
p-value
0.2253
0.0016
0.3394
0.0018
0.4716
0.8864
All Stroke
Ischemic Stroke
Hemorrhagic Stroke
Hazard Ratio (95% CI)
≥0% Increase 1.00
≥0% Increase 1.00
≥0% Increase 1.00
Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204
Time Varying LDL-C and Stroke Risk
Note: Nominal value effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase
0.4 0.7 1.0 1.3 1.6 1.9 2.2
70 to < 100 mg/dL
< 70 mg/dL
HR (95% CI)
1.01 (0.81, 1.27)
0.72 (0.59, 0.89)
p-value
0.9076
0.0016
All Stroke
Hazard Ratio (95% CI)
≥ 100 mg/dL 1.00
Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204
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
SBP
DBP
140.0
139.5
139.0
138.5
137.5
81.5
138.0
137.0
82.0
81.0
80.5
80.01.00.0
LO7266605448423630241812630
Blo
od P
ress
ure
(mm
Hg)
Time (months)
LDL
HDL
TG150
125
100
75
50
25
0LO7266605448423630241812630
Time (months)
Lipi
ds (m
g/dl
)
LO = last observation
Mean Lipids and BP During Follow-up in Atorvastatin and Placebo Groups
Solid lines = atorvastatin 80 mg group; dashed lines = placebo group
Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009
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
Stroke0 parameters1 parameter2 parameters3 parameters4 parameters
Major cardiovascular events (MCVE)0 parameter1 parameters2 parameters3 parameters4 parameters
No.subjects
66211561926
90680
66211561926
90680
No (%)events
93 (14.0)167 (14.4)228 (11.8)
84 (9.3)4 (5.0)
126 (19.0)207 (17.9)290 (15.1)114 (12.6)
4 (5.0)
HR
1.000.9820.7820.6200.354
1.0000.9030.7250.6030.247
95% CI
(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)
P-value
0.88590.04780.00180.0420
0.37040.00290.00010.0059
OverallP-value*
0.0012
<0.0001
0.0 0.5 1.0 1.5
*P value for differences between number of parameters achieved
Amarenco P, et al. Stroke. 2009