landmark statin trials across the spectrum of risk: secondary stroke prevention
DESCRIPTION
Landmark Statin Trials Across the Spectrum of Risk: Secondary Stroke Prevention . Simvastatin in Patients With Prior Cerebrovascular Disease: HPS. 29.8. 24.7*. Simvastatin. Placebo. 10.3. 10.4. (N=488). N=406. N=169. N=170. Major Vasular Events. Stroke. *29% RRR, p =0.001 - PowerPoint PPT PresentationTRANSCRIPT
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.