Prevention of Coronary Heart

Disease with Pravastatin in Men

with Hypercholesterolemia
James Shepherd, M.D., Stuart M. Cobbe, M.D., Ian Ford,
Ph.D., Christopher G. Isles., M.D., A. Ross Lorimer, M.D.,
Peter W. Macfarlane, Ph. D., James H. McKillop, M.D.,
and Christopher J. Packard, D. Sc., for the West of
Scotland Coronary Prevention Study Group

N Engl J Med 1995;333:1301-7

 Background
• This double-blind study was designed to determine
whether the administration of pravastatin to men
with hypercholesterolemia and no history of
myocardial infarction reduced the combined
incidence of nonfatal myocardial infarction and
death from coronary heart disease

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 West of Scotland Coronary Prevention
Study Group (WOS)
• Randomized, double-blind, placebo controlled
• 6595 men, 45 to 64 years of age
• Average follow-up of 4.9 years (seen at 3 month
intervals)
• Pravastatin (40 mg each evening) vs. placebo

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 WOS
Baseline Characteristics
• Mean lipid levels:
– TC = 272 mg/dL
– LDL = 192 mg/dL
– HDL = 44 mg/dL
– Trigs = 162-164 mg/dL
• 5% of patients with angina
• 3% of patients with claudication
• 8% of patients with abnormal EKG
• 44% current smokers, 34% ex-smokers

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 WOSCOPS:
High Risk Primary Prevention
120
100 Male > 45
Risk Factors...
100
Smoker
• 1 risk factor: 100 %
% of population

80 Hypertensive
• 2 risk factors: 44+ %
Diabetic
60 • 3 risk factors: ?
44
40
• Family history: ?
• Current CHD: 5+ %?
20 16
1
0
Risk Factors
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 Endpoints

Primary
• Non-fatal MI or coronary heart disease death as a first
event
Secondary
• Non-fatal MI
• Coronary heart disease death

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Other Endpoints

• Cardiovascular mortality

• Total mortality

• Coronary revascularization procedures

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 WOS
Reduction in Lipids
• Pravastatin reduced lipid levels by*:
– 20% reduction in TC
– 26% reduction in LDL
– 12% reduction in Trigs
– 5% increase in HDL

*Data analyzed according to the treatment actually received not according to the
intention-to-treat principle

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Effects of Pravastatin Therapy on Plasma
LDL Cholesterol Levels
200
placebo (intention -to-treat)
LDL cholesterol mg/dL

180 placebo (actual treatment)

160 pravastatin (intention-to-treat)

140
pravastatin (actual treatment)
120

100
6 12 18 24 30 36 42 48 54 60
Months
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 Nonfatal MI or CHD Death
(Primary Endpoint)

12
Pravastatin
10 31%
Placebo
Risk
8 Reduction
Percent
with 6 P=0.0001
Events
4

0
0 1 2 3 4 5 6
Years in Study

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Non-Fatal MI
(Secondary Endpoint)

10
Pravastain Placebo
8
31%
Percent 6 Risk
with Reduction
Events 4
P=0.0005
2

0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 CHD Death
(Secondary Endpoint)

2.5
Pravastain Placebo
2 28%
Risk
Percent 1.5 Reduction
with
P=0.13
Events 1

0.5

0
0 1 2 3 4 5 6
Years in Study

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Cardiovascular Death

3.5
3 Pravastain Placebo
32%
2.5 Risk
Percent 2 Reduction
with
Events 1.5 P=0.033
1
0.5
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 Coronary Interventions

Intervention Placebo Pravastatin Risk

(n= 3293) (n=3302) Reductions p-value

Coronary
Angiography 128 90 31% 0.007

PTCA / CABG 80 51 37% 0.009

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Total Mortality
6

5 Pravastain Placebo 22%

Risk
Reduction
4
Percent
with 3 P=0.051
Events
2

0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 WOS
Results/Clinical Events
E vent % R e d u c tio n p v a lu e
N o n f a t a l M I + C H D d e a th 31%  < 0 .0 0 1
D e f in it e n o n f a t a l M I 31%  < 0 .0 0 1
D e f in it e C H D d e a t h 28%  0 .1 3 ( N S )
D e f in it e a n d s u s p e c t e d C H D d e a th 33%  0 .0 4 2
A ll c a r d io v a s c u la r d e a t h s 32%  0 .0 3 3
T o t a l m o r ta lit y 22%  0 .0 5 1 ( N S )
C A B G /P T C A 37%  0 .0 2 9
James Shepherd, et al, N Engl J Med 1995;333:1301-7
 WOS
Conclusions
• “Treatment with pravastatin significantly reduced
the incidence of myocardial infarction and death
from cardiovascular causes without adversely
affecting the risk of death from noncardiovascular
causes in men with moderate hypercholesterolemia
and no history of myocardial infarction.”

James Shepherd, et al, N Engl J Med 1995;333:1301-7

 Projected Benefits
Treatment of 1000 hypercholesterolemic middle aged
men with pravastatin for five years will avoid:
• 14 coronary angiograms
• 8 revascularization procedures
And avoid:
• 20 nonfatal MIs
• 7 CHD deaths
• 2 additional deaths

James Shepherd, et al, N Engl J Med 1995;333:1301-7