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OVERALL SURVIVAL. 100 95 90 85 0. Simvastatin (n=2221). Placebo (n=2223). % of patients alive. 30% risk reduction P=0.0003. 01 2345 6. Years since randomization. Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. CORONARY MORTALITY. 200 - PowerPoint PPT Presentation
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OVERALL SURVIVAL
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
% o
f p
atie
nts
ali
ve100
95
90
85
0
Simvastatin(n=2221)
0 1 2 3 4 5 6
Years since randomization
30% risk reduction
P=0.0003
Placebo(n=2223)
CORONARY MORTALITY
Adapted from Kjekshus J et al Am J Cardiol 1995;76(9):64C-68C.
No
. o
f d
eath
s200
150
100
50
0 Placebo(n=2223)
42% risk reduction
P=0.00001
Simvastatin(n=2221)
189
111
CAUSES OF MORTALITY
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
Placebo(n=2223)
Simvastatin(n=2221)
11.5%
8.2%
CoronaryOthercardiovascular
Cancer
Other
100
90
80
70
0
MAJOR CORONARY EVENTS
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
Coronary Death or Nonfatal MI%
of
pat
ien
ts w
ith
ou
t ev
ents
Simvastatin(n=2221)
0 1 2 3 4 5 6
Years since randomization
34% risk reduction
P <0.00001
Placebo(n=2223)
CORONARY EVENTS VS. BASELINE LDL
Coronary Deaths or Nonfatal MIs by Baseline LDL-C Quartiles
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1995;345(8960):1274-1275.
40
35
30
25
20
15
10
5
0
% r
isk
red
uct
ion
<4.39 mmol/L(170 mg/dl)
35%
4.40–4.84 mmol/L(170–187 mg/dl)
4.85–5.34 mmol/L(188–207 mg/dl)
>5.35 mmol/L(207 mg/dl)
33% 32%36%
Baseline LDL-C
SUBGROUP COMPARISON –MAJOR CORONARY EVENTS
Adapted from Miettinen TA et al Circulation 1997;96:4211-4218.
Coronary Death and Nonfatal MI%
of
pat
ien
ts
Men
34%risk reduction
29.5
20.5 21.7
14.7
26.4
18.1
33.4
23.6
Women
34%risk reduction
Age <65
34%risk reduction
Age >65
34%risk reduction
Placebo
Simvastatin
35
30
25
20
15
10
5
0
CORONARY EVENT REDUCTION
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Kjekshus J et al Am J Cardiol 1995;76(9):64C-68C; Data on file, MSD.
Simvastatinbetter
Placebobetter
Age
Gender
Smoking
Hypertension
Diabetes
<60 yrs60–70 yrs
MenWomen
YesNo
YesNo
YesNo
0.2 0.4 0.6 0.8 1.0 1.2
P <0.0001P <0.0001
P <0.00001P=0.01
P=0.00105P=0.00009
P=0.00006P <0.00001
P <0.00169P <0.000001
Relative risk (95% Cl)
MI REDUCTION
Myocardial Infarction
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Data on file, MSD.
No
. o
f p
atie
nts
600
500
400
300
200
100
0Placebo(n=2223)
37% risk reduction
P <0.00001
Simvastatin(n=2221)
369
562
NEED FOR PTCA/CABG
PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graftAdapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
100
90
80
0
% o
f p
atie
nts
wit
ho
ut
PT
CA
or
CA
BG
Simvastatin(n=2221)
0 1 2 3 4 5 6
Years since randomization
37% risk reduction
P <0.00001Placebo(n=2223)
HOSPITAL DAYS
Adapted from Pedersen TR et al Circulation 1996;93(10):1796-1802.
Cardiovascular Hospital DaysN
o.
of
card
iova
scu
lar
ho
spit
al d
ays
16,000
12,000
8000
4000
0 Placebo(n=2223)
34% reduction
P <0.0001
Simvastatin(n=2221)
15,089
9951
ATHEROSCLEROSIS
• Coronary arteries
• Carotid arteries
• Femoral arteries
Atherosclerosis is a widespread disease affecting all vascular beds including
STROKE/TIA
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
28% risk reduction
P=0.033
6
5
4
3
2
1
0
% o
f p
atie
nts
Simvastatin(n=2221)
Placebo(n=2223)
Years
0 1 2 3 4 5 6
48% risk reduction
P=0.009
CAROTID BRUITS*
*A post-hoc analysis of 4S
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
2.5
2.0
1.5
1.0
0.5
0
% o
f p
atie
nts
Simvastatin(n=2221)
Placebo(n=2223)
Years
0 1 2 3 4 5 6
0 1 2 3 4 5 6
INTERMITTENT CLAUDICATION*
*A post-hoc analysis of 4S
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
New or Worsening Intermittent Claudication
38% risk reduction
P=0.008
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
% o
f p
atie
nts
Simvastatin(n=2221)
Placebo(n=2223)
Years
ANGINA PECTORIS*
*A post-hoc analysis of 4S
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
New or Worsening Angina Pectoris
0 1 2 3 4 5 6
26% risk reduction
P<0.0001
40
35
30
25
20
15
10
5
0
% o
f p
atie
nts
Simvastatin(n=2221)
Placebo(n=2223)
Years
DEVELOPMENT OF HEART FAILURE
Adapted from Kjekshus J et al J Card Fail 1997;3(4):249-254.
100
98
96
94
92
90
0
% w
ith
ou
t C
HF
Simvastatin(n=2221)
6 12 18 24 30 36 42 48 54 60 66 72
21% risk reduction
P <0.015
Placebo(n=2223)
Months since randomization
CHOLESTEROL PARAMETERS
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Data on file, MSD.
Simvastatin 20 mg, Week 6
20
10
0
–10
–20
–30
–40
Mea
n %
ch
ang
e
LDL-C Total C HDL-C Triglycerides
P <0.0001
–38%
+8%
–28%
–15%
PATIENT FOLLOW-UP
Placebo Simvastatin(n=2223) (n=2221)
Lost to follow-up 0% 0%
Treatment discontinuations 13% 10%
Adverse effects 6% 6%
Personal reasons/other 7% 5%
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
TRANSAMINASES AND CK
AST = aspartate aminotransferase; ALT = alanine aminotransferase; CK = creatine kinase; ULN = upper limit of normal
Adapted from Pedersen TR et al Arch Intern Med 1996;156:2085-2092.
Elevations Occurring More than Once during 5.4 Years of Therapy
Placebo SimvastatinNo. (%) No. (%)
AST >3 ULN 7 (0.3) 5 (0.2)
ALT >3 ULN 12 (0.6) 14 (0.7)
CK >10 ULN 0 0
CONCOMITANT CARDIOVASCULARTHERAPY – BASELINE
Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.
SimvastatinPlacebo 20–40 mg
Drug Class/Therapy No. No.
Aspirin 815 822
Beta blockers 1266 1258
Calcium antagonists 668 712
Isosorbide mono/dinitrate 727 684
Thiazides 138 151
LONG-TERM SAFETY
• Simvastatin had an excellent five-year safety profile
• Adverse experiences similar to placebo
• Only one reversible case of myopathy reported
• Incidence of liver enzyme elevations similar to that of placebo
• No interactions reported with beta blockers, calcium-channel blockers, aspirin, and thiazides
• No increase in cancer overall or at any particular site
• No previously unrecognized adverse effects observed
Adapted from Pedersen TR et al Arch Intern Med 1996;156:2085-2092.
4S provided the largest and longest follow-up of patients treated with simvastatin (5.4 median years)