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=0.001

Heart 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

Simvastatin

Placebo

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

Fat

al o

r N

on

-Fat

al S

tro

ke,

%

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

Co

ron

ary

Eve

nt,

%

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

den

ce (

%)

Stroke and Major Coronary Events

Major Coronary Event

Ischemic Stroke

Hemorrhagic Stroke

Unclassified 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 region

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

70

100

90

80

Pe

rce

nta

ge

of

Pa

tie

nts

Fre

e o

f E

nd

Po

ints

Placebo

Atorvastatin 80 mg

0 1 2 3 4 5

Years 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

Pat

ien

ts F

ree

of

Fat

al o

r N

on

-Fat

al S

tro

ke, %

Years Since Randomization

Placebo

Atorvastatin

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

Pat

ien

ts F

ree

of

Car

oti

d

En

dar

tere

cto

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

Hem

orr

hag

ic S

tro

ke (

%)

0 1 2 3 4 5 6

0

4

8

12

16

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

Placebo: Ischemic

Atorvastatin: Ischemic

Placebo: Hemorrhagic

Atorvastatin: 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.