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