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L ipid M anagement i n S troke : S tatin a nd O ther L ipid M odifying A gents. Professor Pierre Amarenco INSERM U-698 and Paris-Diderot University Department of Neurology and Stroke Centre Bichat-Claude Bernard Hospital, Paris, France.

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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

INTERSTROKE: Population-attributable risk forcommon risk factors

*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
Meta-analysis : Statin and Stroke

N total=165 732

Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63


Meta analysis stroke death
Meta-Analysis Stroke Death

Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63


Meta analysis hemorrhagic stroke
Meta-analysis Hemorrhagic stroke

Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63


Stroke risk and ldl lowering
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

N=17,802

LDL-c<130 mg/dL

hsCRP >2 mg/dL

F/U 1.9 yrs

JUPITER

Men >50 yrs

Women >60 yrs

Event

Rosuva *

Placebo *

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

1

1.2

Favours Rosuvastatin Favours Placebo

* N (% randomised)


Secondary end point fatal and nonfatal stroke
Secondary End Point: Fatal and Nonfatal Stroke

Atorvastatin 10 mg Number of events 89 (1.7%)

Placebo Number of events 121 (2.4%)

3

27% reduction

2

Cumulative Incidence (%)

1

HR = 0.73 (0.56-0.96)

p=0.0236

0

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Years

Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58


Cards cumulative hazard for stroke
CARDS:Cumulative Hazard for Stroke

4

Atorvastatin10 mg

48% RiskReduction

In Stroke

Placebo

Placebo n=39

[31% of all first CVD events]

3

(P=0.016)

Cumulative Hazard (%)

2

1

Atorvastatin n=21

[25% of all first CVD events]

0

0

1

2

3

4

4.75

Years from Randomization

Hitman GA, et al. EASD Diabetologia. 2005; Abstract 120

Data 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)

Control

Group 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

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 YearB.I.C.H.A.T. Study DesignLacunarBrain 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

94patients

Double-blind placebo

CVMR

CVMR

3 months

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 Year

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: YearPotential Mechanisms of Benefit

Statin

LDL Reduction

Plaque stabilization:macrophagessmooth muscle cellsimmunologic responselipid coreoxidized LDL

35 to 80% of the benefit

Improved endothelial function

Reduced hemorheologic stress

Reduced platelet aggregation

Reduced thrombotic and

Enhanced fibrinolytic state

Blood pressure reduction

Decrease incidence of MI

and of left ventricular mural

thrombus

Neuroprotection

. Up-regulation NO

. Improves CBF

. Reduces infarct size


Hps no reduction in risk of recurrent stroke in patients with prior cerebrovascular disease
HPS: No Reduction in Risk of YearRecurrent Stroke in Patients With Prior Cerebrovascular Disease

Patient with Event (5)

n=406

n=488

n=169

n=170

Major Vascular Events

Stroke

*29% RR, P=.001

Heart Protection Study Collaborative Group. Lancet. 2004;363:757–767.


Sparcl study design
SPARCL: Study Design Year

Patient Population

Double-Blind Period

Atorvastatin 80 mg/day

  • 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

4,731Patients

Placebo

540 Primary Endpoints

Primary End PointTime 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
LCL-C During Follow-up Year

Baseline LDL-C: 133 mg/dL

+1%

-7%

-38%

-53%

  • Mean on-treatment LDL-C:

    Placebo = 129 mg/dL

    Atorvastatin = 73 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

16% Year

16%RR

Placebo

Atorvastatin

12%

Fatal or Non-Fatal Stroke (%)

8%

4%

Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03

0%

0

1

2

3

4

5

6

Years Since Randomization

Primary Endpoint:Time to Fatal or Non-Fatal Stroke

* 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


Secondary Endpoint: YearTime to Major Coronary Event

8%

6%

35%RR

Major Coronary Event (%)

4%

Placebo

Atorvastatin

2%

Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003

0%

0

1

2

3

4

5

6

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


Gender stroke outcomes
Gender: Stroke Outcomes Year

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
SPARCL Elderly vs Young Year

ELDERLY

YOUNG

STROKE

CV events

Chaturvedi S et al. Neurology. 2008 ;E-pub


Sparcl elderly vs young1
SPARCL Elderly vs Young Year

Chaturvedi S et al. Neurology. 2008 ;E-pub


Ischemic and hemorrhagic stroke post hoc analysis
Ischemic and Hemorrhagic Stroke YearPost hoc analysis

Fatal and Non-fatal Stroke

Unadjusted HR

Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70


Multivariable cox regression model baseline characteristics time varying blood pressure
Multivariable Cox Regression Model YearBaseline Characteristics & Time Varying Blood Pressure

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

Entry Event Year

P-value

HR (95% CI)

Large Vessel

1.23 (0.44, 3.39)

0.6934

0.97 (0.44, 2.17)

0.9473

TIA

4.67 (0.96, 22.6)

Hemorrhagic

0.0556

Small Vessel

5.07 (1.73, 14.9)

0.0031

0.80 (0.30, 2.13)

Unknown

0.6494

-

2

0

2

4

6

8

Impact of Atorvastatin onHemorrhagic stroke by Entry Event

Goldstein LB, Amarenco P et al. Neurology. 2008;70:2864-70

Hazard ratio*

*Adjusted for time since

entry event, gender, and age

Placebo better

Atorvastatin better


Impact of atorvastatin on stroke risk
Impact of Atorvastatin on Stroke Risk Year

HR (95% CI)

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

Stroke

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

3

4

Hazard Ratio

Amarenco et al. Stroke. 2009


Impact of atorvastatin on coronary risk and death
Impact of Atorvastatin Yearon Coronary Risk and Death

HR (95% CI)

p-value

Large Vessel

0.60 (0.29, 1.25)

0.1690

Major

Coronary

Event

TIA

0.70 (0.40, 1.25)

0.2317

Hemorrhagic

1.09 (0.15, 7.93)

0.9324

Small Vessel

0.80 (0.50, 1.27)

0.3407

Unknown

0.43 (0.24, 0.80)

0.0071

P for heterogeneity = 0.360

Large Vessel

0.77 (0.48, 1.22)

0.2657

TIA

0.99 (0.68, 1.45)

0.9615

Death

Hemorrhagic

2.24 (0.67, 7.55)

0.1918

Small Vessel

1.20 (0.86, 1.68)

0.2799

Unknown

0.84 (0.56, 1.27)

0.4035

0

1

2

3

4

Hazard Ratio

Amarenco et al. Stroke. 2009


Benefit risk
Benefit/Risk Year

P=0.002

P=0.03

17.2%

Major Coronary Event

Ischemic Stroke

Hemorrhagic Stroke

Unclassified Stroke

14.1%

13.1%

11.2%

Incidence (%)

Atorvastatinn = 2365

Placebon = 2366

Atorvastatinn = 2365

Placebon = 2366

Stroke

Stroke and Major Coronary Events

Amarenco P, et al. Exp Op Pharmacotherapy. 2007


Ischemic stroke severity last dose 1 month before stroke
Ischemic Stroke Severity: Last Dose Year1 Month Before Stroke

Goldstein LG, Amarenco P et al. Stroke. 2009

Mild

Moderate

Severe

Fatal

Placebo

(n=222)

32.4

13.5

11.3

42.8

42.8

Atorvastatin(n=175)

36.0

6.9

6.3

50.9

50.9

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

Placebo Year

Atorvastatin 80 mg

Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes

100

90

Percentage of Patients Free of End Points

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

5

6

Years since randomization

*Adjusted for entry event, time since entry event, gender, age, and geographic region

Callahan A, Welch KMA, Amarenco P, et al.


Effect of atorvastatin on cv events in sparcl patients with diabetes

100 Year

100

Placebo

Placebo

Atorvastatin 80 mg

Atorvastatin 80 mg

98

98

96

96

94

94

92

92

90

90

88

88

86

86

84

84

82

82

Effect of Atorvastatin on CV EventsIn SPARCL Patients with Diabetes

Any Revascularization

Any CHD Event

Percentage of Patients Free of End Points

Percentage of Patients Free of End Points

RR: 64%

RR: 51%

HR=0.49 (95% CI 0.31, 0.79), P=0.0033*

Log-rank P=0.0027

HR=0.36 (95% CI 0.21, 0.61), P=0.0001*

Log-rank P=0.0001

0

1

2

3

4

5

0

1

2

3

4

5

6

6

Years since randomization

Years since randomization

*Adjusted for entry event, time since entry event, gender, age, and geographic region

Callahan A, Welch KMA, Amarenco P, et al.


Effect of atorvastatin on renal function by glycemic status
Effect of Atorvastatin on Renal YearFunction by Glycemic Status

p = 0.012*

Atorvastatin

2.5

Placebo

2.0

p = 0.001*

1.5

1.0

0.5

p = 0.258†

p < 0.0001†

0.0

Mean Change in eGFR

from Baseline (mL/min/1.73 m2)

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.0

-4.5

p < 0.001*

n=1459 n=1476 n=366 n=359 n=360 n=370

No Diabetes, No MetS

MetS

Diabetes

* Treatment difference

† Difference from baseline


Stroke in patients with carotid stenosis

Placebo Year

Atorvastatin

Stroke in Patients With Carotid Stenosis

100

90

Patients free of fatal or non-fatal stroke (%)

RR: 33%

80

HR=0.67 (95% CI 0.47, 0.94), P=.02*

70

0

1

2

3

4

5

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


Any cardiovascular event in patients with carotid stenosis

100 Year

Placebo

Atorvastatin

90

80

70

60

50

0

1

2

3

4

5

Any Cardiovascular Event inpatients With Carotid Stenosis

Patients free of any cardiovascular event (%)

RR: 42%

HR=0.58 (95% CI 0.46, 0.73), P<.0001

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


Carotid endarterectomy in patients with carotid stenosis

100 Year

Placebo (n=37/514)

Atorvastatin (n=16/493)

98

96

94

92

0

1

2

3

4

5

Carotid Endarterectomy inPatients With Carotid Stenosis

Patients free of carotid endarterectomy (%)

RR: 56%

HR=0.44 (95% CI 0.24, 0.79), P=.006

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


Stroke risk and ldl lowering1
Stroke Risk and LDL Lowering Year

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 lowering2
Stroke Risk and LDL Lowering Year

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 YearStroke Risk

HR (95% CI)

p-value

All Stroke

≥0% Increase

1.00

<50% Decrease

0.89 (0.73, 1.08)

0.2253

≥50% Decrease

0.69 (0.55, 0.87)

0.0016

Ischemic Stroke

≥0% Increase

1.00

<50% Decrease

0.90 (0.73, 1.12)

0.3394

≥50% Decrease

0.67 (0.52, 0.86)

0.0018

Hemorrhagic Stroke

≥0% Increase

1.00

<50% Decrease

0.84 (0.50, 1.40)

0.4716

≥50% Decrease

1.04 (0.61, 1.78)

0.8864

0.4

0.7

1.0

1.3

1.6

1.9

2.2

Note: Percent change effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase

Hazard Ratio (95% CI)

Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204


Time Varying LDL-C and YearStroke Risk

HR (95% CI)

p-value

All Stroke

≥ 100 mg/dL

1.00

70 to < 100 mg/dL

1.01 (0.81, 1.27)

0.9076

< 70 mg/dL

0.72 (0.59, 0.89)

0.0016

0.4

0.7

1.0

1.3

1.6

1.9

2.2

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


Meta analysis intensive ldl c lowering vs standard statin therapy
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
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
Mean Lipids and BP During Follow-up in Atorvastatin and Placebo Groups

TG

150

125

LDL

100

75

Lipids (mg/dl)

50

140.0

HDL

25

139.5

SBP

139.0

138.5

0

0

3

6

12

18

24

30

36

42

48

54

60

66

72

LO

138.0

Time (months)

137.5

Blood Pressure (mm Hg)

137.0

82.0

81.5

81.0

80.5

DBP

80.0

1.0

0.0

0

3

6

12

18

24

30

36

42

48

54

60

66

72

LO

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


Optimal multi targets
Optimal Multi-Targets Placebo Groups

  • 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
Combined Effect of Optimal Lipid & BP Control on Risk of Stroke and MCVE

No.subjects

No (%)events

HR

95% CI

P-value

OverallP-value*

Stroke0 parameters

1 parameter

2 parameters

3 parameters

4 parameters

Major cardiovascular events (MCVE)

0 parameter

1 parameters

2 parameters

3 parameters

4 parameters

662

1156

1926

906

80

662

1156

1926

906

80

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)

1.00

0.982

0.782

0.620

0.354

1.000

0.9030.7250.603

0.247

(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

0.0012

<0.0001

1.0

0.0

0.5

1.5

*P value for differences between number of parameters achieved

Amarenco P, et al. Stroke. 2009


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