Landmark Statin Trials Across the Spectrum of Risk:

Secondary Stroke Prevention

2

(N=488)

Simvastatin in Patients With Prior Cerebrovascular Disease: HPS

*29% RRR, p=0.001Heart Protection Study Collaborative Group. Lancet. 2004;363:757-767.

N=169 N=170N=406

24.7*

Major Vasular Events

29.8

10.3 10.4

SimvastatinPlacebo

Stroke

3

SPARCL Trial of Secondary StrokePrevention: Study Design

540 Primary End Points

4731 Patients

• 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

Patient Population

Primary End Point Time to the First Occurrence of a Fatal or Nonfatal Stroke

Atorvastatin 80 mg/day

SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395.

Pravastatin 40 mg

Double-Blind Period

4

SPARCL Primary End Point: Time to Fatal or Nonfatal Stroke

* Treatment effect from Cox proportional hazards models with prespecified adjustment for geographical region, entry event, time since entry event, gender, and baseline age.Amarenco P et al. N Engl J Med. 2006;355:549-559.

Placebo (n= 2366)Mean LDL-C = 128 mg/dL (3.3 mmol/L)

Atorvastatin 80 mg (n= 2635)Mean LDL-C = 73 mg/dL (1.9 mmol/L)

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

16%RR

Years Since Randomization

Fata

l or N

on-F

atal

Str

oke,

%

0 1 2 3 4 5 6

12%

16%PlaceboAtorvastatin

8%

4%

0%

5

* Treatment effect from Cox proportional hazards models with prespecified adjustment for geographical region, entry event, time since entry event, gender, and baseline age.Amarenco P et al. N Engl J Med. 2006;355:549-559.

5

SPARCL Secondary End Point:Time to Major Coronary Event

Years Since Randomization

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

35%RR

Maj

or C

oron

ary

Even

t, %

0 1 2 3 4 5 60%

2%

4%

6%

8%

PlaceboAtorvastatin

6

SPARCL: Benefit/Risk

0%

4%

8%

12%

16%

20%

Atorvastatinn = 2365

Placebon = 2366

Atorvastatinn = 2365

Placebon = 2366

Inci

denc

e (%

)

Stroke and Major Coronary Events

Major Coronary EventIschemic StrokeHemorrhagic StrokeUnclassified Stroke

P = 0.03

11.2%13.1% 14.1%

17.2%

P=0.002

Amarenco P. Exp Op Pharmacotherapy. 2007;8:2789-2797.

Stroke

7

Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes

*Adjusted for entry event, time since entry event, gender, age, and geographic regionCallahan A, Welch KMA, Amarenco P, et al.

70

100

90

80

Perc

enta

ge o

f Pat

ient

s Fr

ee o

f End

Poin

ts

PlaceboAtorvastatin 80 mg

0 1 2 3 4 5Years Since Randomization

6

HR = 0.70 (95% CI, 0.50, 0.98), P = 0.0387*Log-rank P = 0.0377

RR: 30%

8

SPARCL: Stroke in Patients With Carotid Stenosis

* Adjusted for entry event, time since entry event, gender, age, and geographical region.Sillesen H et al. Stroke. 2008;39;3297-3302.

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

0 1 2 3 4 5

70

100

90

80

Patie

nts

Free

of F

atal

or

Non

-Fat

al S

trok

e, %

Years Since Randomization

PlaceboAtorvastatin

RR: 33%

9

SPARCL: Carotid Endarterectomy inPatients with Carotid Stenosis

* Adjusted for entry event, time since entry event, gender, age, and geographical region.Sillesen H et al. Stroke. 2008;39;3297-3302.

0 1 2 3 4 5

98

100

92

94

96

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

Patie

nts

Free

of C

arot

id

Enda

rter

ecto

my,

%

Placebo (n=37/514)Atorvastatin (n=16/493)

Years Since Randomization

RR: 56%

10

*Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event,gender, and baseline age.HR, hazard ratio; CI, confidence interval.The SPARCL Investigators: N Engl J Med: 2006;355:549-559.

SPARCL: Prespecified andPost-Hoc Analyses

Prespecified AnalysisAtorvastatin

(n=2365)n (%)

Placebo(n=2366)

n (%)HR

(95% CI) P-value

Primary Endpoint 265 (11.2) 311 (13.1) 0.84(0.71, 0.99) .03

Fatal Stroke 24 (1.0) 41 (1.7) 0.57(0.35, 0.95) .03

Non-fatal Stroke 247 (10.4) 280 (11.8) 0.57(0.73, 1.03) .11

Post-Hoc Analysis

Ischemic 218 (9.2) 274 (11.6) 0.78(0.66, 0.94) .01

Hemorrhagic 55 (2.3) 33 (1.4) 1.66(1.08, 2.55) .02

11Goldstein LB et al. Neurology. 2008 ;70:2364-2370.

SPARCL: Ischemic and Hemorrhagic Stroke Post hoc Analysis

Unadjusted HR

Fatal and Nonfatal Stroke

Ischemic: HR (95% CI = 0.79 (0.66, 0.95)

Years Since Randomization

Isch

emic

or H

emor

rhag

ic S

trok

e (%

)

0 1 2 3 4 5 60

4

8

12

16

Hemorrhagic: HR (95% CI = 1.68 (1.09, 2.59)

Placebo: IschemicAtorvastatin: IschemicPlacebo: HemorrhagicAtorvastatin: Hemorrhagic

12

SPARCL: Multivariable Cox RegressionModel Baseline Characteristics

Risk of hemorrhage OR (95% CI) p

Atorvastatin treatment 1.68 (1.09, 2.59) 0.02

Hemorrhage as entry event 5.65 (2.82, 11.30) <0.001

Male sex 1.79 (1.13, 2.84) 0.01

Age (10 yr increments) 1.42 (1.16, 1.74) 0.001

History of Htn 1.41 (0.88, 2.25) 0.15

Goldstein LB er al. Neurology. 2008;70:2364-2370.