landmark statin trials across the spectrum of risk: secondary stroke prevention
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(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
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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.
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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
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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
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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%
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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%
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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
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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.