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)