HYPERLIPIDAEMIA

1
HYPERLIPIDAEMIA
2
4S

• 4444 patients
• Hx angina or MI
• Cholesterol 5.5-8.0
• Simvastatin 20mg (10-40) vs. placebo
• FU 5 years
• ? total cholesterol 25 ? LDL 35 ? HDL 8
• 30 reduction in overall mortality (p0.0003)
• 42 reduction in CV mortality
• No difference in non-cardiovascular death

Scandinavian Simvastatin Survival Study. Lancet
19943441383-9
3
CARE

• 4159 patients with history of MI
• total cholesterol lt6.2
• LDL 3-4.5
• no history of diabetes
• Pravastatin 40mg od vs. placebo
• FU 5 years
• ? total cholesterol 20 ? LDL 28 ? HDL 5
• No difference in
• overall mortality
• cardiovascular death
• non-cardiovascular death
• MI ? 23 (p0.02)
• CVA ? 31 (p0.03)

NEJM 1996 3351001-9
4
WOSCOPS

• 6595 men
• LDL cholesterol gt6.5
• and LDL cholesterol gt4 after dietary modification
• 5 angina 0 MI
• 78 smokers or ex-smokers
• Pravastatin 40mg od vs. placebo
• FU 5 years
• ? total cholesterol 20 ? LDL 26
• 31 reduction in coronary events
• 32 reduction in cardiovascular death
• No increase in non-cardiovascular death

NEJM 1995 3331301-7
5
LIPIDLong-term intervention with pravastatin in
ischaemic disease

• SECONDARY PREVENTION
• gt 9000 pts in Australia /New Zealand
• Baseline cholesterol 4-7
• Pravastatin 40mg od vs. placebo
• FU 6 years
• ? cholesterol by 1mmol/l
• ? overall CHD mortality (22, 24)
• ? MI (29)
• ? hospitalisation for unstable angina (12)
• ? CABG, PTCA (22,19)

NEJM 1998 Nov 053391349-57
6
Baseline Characteristics
Placebo
Pravastatin
Baseline Lipid Values
n 4502
n 4512
(mmol/L)
Median (25, 75)
Median (25, 75)
Total Cholesterol
5.65 (5.08, 6.20)
5.65 (5.07, 6.22)
LDL Cholesterol
3.88 (3.38, 4.40)
3.88 (3.36, 4.39)
HDL Cholesterol
0.92 (0.79, 1.09)
0.92 (0.79, 1.07)
Triglycerides
1.56 (1.18, 2.12)
1.60 (1.17, 2.21)
TC/HDL Ratio
6.07 (5.12, 7.14)
6.11 (5.13, 7.15)
7
Effects on LipidsIntention-to-Treat Comparison
Averaged Over 5 Years of Treatment
10
5
0
Change
-10
-11
-20
-18
-25
-30
LDL
Total
HDL
Triglycerides
Mean differences between pravastatin and placebo
8
Major Cardiovascular EventsReduction in Relative
Risk
0
10
Reduction in Relative Risk
20
19
Stroke
22
24
24
Total
CHD
CHD
Mortality
Events
Death
30
p 0.048
p lt0.001
p lt0.001
p lt0.001
Not currently a licenced indication for
pravastatin CHD death or non-fatal MI
9
CHD Events
10
Reduction in Relative Risk
20
30
40
10
CHD Mortality
24 reduction
10
p lt0.001
Placebo
Cumulative Risk
5
Pravastatin
0
0
1
2
3
4
5
6
7
Years Since Randomisation
11
Total Mortality
15
22 reduction
Placebo
p lt 0.001
10
Cumulative Risk
Pravastatin
5
0
0
1
2
3
4
5
6
7
Years Since Randomisation
12

Relevance to Clinical Practice
4S (simvastatin)
High Risk CHD Patients
LIPID (pravastatin)
Majority of CHD Patients

• Continuum of Risk

CARE (pravastatin)
Patients at High Risk of CHD
WOSCOPS (pravastatin)
Annual risk of cardiovascular mortality
13
Major Secondary Prevention Trials with Statins
Total Cholesterol Range
mmol/L
8
7
6
5
4
3
LIPID
CARE
4S
14
Illustration of overlap between active and
placebo treated populations
Overlap
patient numbers
placebo
pravastatin
On Treatment LDL Cholesterol
15
WOSCOPS - Investigators Overlap
AnalysisComparison of 4.5 Yr event rates in
patients with on-treatment LDL-C values of
3.6-4.6 mmol/l
9.6
Relative risk reduction 36 (p0.014)
10
8
6.3
4.5 YrCHDEventRate ()
6
4
2
0
On-treatment Placebo mean LDL-C 4.4mmol/l n
1120
On-treatment Pravastatin mean LDL-C 4.1
mmol/l n 1071
Cox Analysis of risk reduction for CHD death or
non-fatal MI adjusting for baseline differences
in risk factors for CHD.
(Packard et al. in press)
16
CARE - Overlap AnalysisComparison of 4.5 Yr
event rates in patients with on-treatment LDL-C
values of 2.6-3.4 mmol/l
Relative risk reduction 28 (P0.01)
19.5
20
13.8
15
4.5 YrCHDEventRate ()
10
5
0
On-treatment Placebo LDL-C 2.9 mmol/l n 652
On-treatment Pravastatin LDL-C 3.1 mmol/l n
643
Cox Analysis of risk reduction for CHD death,
non-fatal MI, CABG or PTCA adjusting for baseline
differences in HDL, diabetes and use of nitrates.
17
Framingham CHD Risk Model
Age, Sex, Smoking, Blood Pressure,Total
Cholesterol, HDL-C, Diabetes
Regression Model
Predicted 4.5 Year Riskof Coronary Event
Anderson et al, 1990 Am Heart J 121293-298.
18
WOSCOPS Investigators Framingham Analysis
Predicted
Actual
0
-10
24
-20
Risk Reduction
-30
35
p 0.026
-40
Packard et al. in press
19
WOSCOPS Investigators Quintile Analysis
(intention to treat)
4.4 yr Event Rate (per 100)
0
5
10
15
0
p0.54
-12
p0.03
Percent Changein LDL Cholesterol
-24
p 0.007
-31
p0.018
-39
p0.0001
Comparison to Placebo by Cox Hazard Method
Packard et al. in press
20
Potential Ancillary Mechanisms for Coronary Event
Reduction

• Plaque stabilisation
• Reduced thrombus formation
• Fibrinogen

Libby. Circulation. 1995912844-50.Falk et al.
Circulation. 199592657-71. Brown. Circulation.
1993871781-1.