LDL-C Goal:
6-12 months
3-6 months 6-12 weeks
Major Studies Showing Relationship Between Cholesterol Levels and CHD Risk
(Pre-Statin Studies)
Framingham Heart Study MRFIT Screenees
Study type
Size of cohort Conclusions
Epidemiologic
5127 (original) 1% in cholesterol = 2% in CHD risk
Observational
361,662 Continuous, graded association between cholesterol level and CHD risk starting at 180 mg/dL
Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.
Effect on lipids
TC 9% LDL-C 13%
Lipid Research Clinics Program. JAMA. 1984;251:351-364. Frick MH et al. N Engl J Med. 1987;317:1237-1245.
4S Results
8% in HDL-C
WOSCOPS Results
5% in HDL-C
24% in risk of fatal CHD or nonfatal MI* 25% in risk of fatal or nonfatal MI 27% in need for coronary revascularization Changes in lipids:
5% in HDL-C
*P=0.002; P=0.007; P=0.0001. Braunwald E, Pfeffer MA, Sacks FM. Presented at the 45th ACC; March 26, 1996; Orlando Fla.
20%
LRC-CPPT WOSCOPS
40%
4S
CH
CH2 N CH2
OH CH CH2
OH CH CH2
Ca 2+
NHC
HMG-CoA reductase
Squalene synthase
Dolichol
Acetyl CoA
HMGCoA
Mevalonate
Farnesyl pyrophosphate
Squalene
Cholesterol
Ras protein
Farnesyltransferase
Farnesylated proteins
Atorvastatin inhibits hepatic production of major apo B-containing lipoproteins as shown in these animal models
EH rabbits:
LDL production
EHT rats:
Guinea pigs:
VLDL production
LDL production
Auerbach BJ et al. Atherosclerosis. 1995;115:173-180. Krause BR. Newton RS. Atherosclerosis. 1995;117:237-244.
N=154 Phase I
No. of 6 Studies
25
500
1000
1500
No. of Subjects
2000
2500
3000
0
-10 -20 % -30 -40 -50 -60 -70
7.6
41
44
50
61
*
Placebo 10 mg 20 mg 40 mg 80 mg
Atorvastatin in Hypertriglyceridemia
Design and Baseline Lipids
56 hypertriglyceridemic patients, 26-74 y/o 4-week, randomized, double-blind, placebo-controlled, parallel Atorvastatin 5, 20, 80 mg Mean baseline LDL-C: Mean baseline TG: 119 mg/dL (3.1 mmol/L) 603 mg/dL (6.8 mmol/L)
Atorvastatin in Hypertriglyceridemia
Mean Percent Change in Lipids at 4 Weeks
20 10 0
9
1 17 26 32 4
*
13
12
*
33
*
46
* * LDL-C
* HDL-C
Atorvastatin vs Lovastatin
Mean Percent Change in Lipids at 16 Weeks
10
1
*
3
*
4 5
*
4 6
* 7 7
1
0 -10 %
19
*
17
17 20
-20
27
*
27 28
* *
36
LDL-C
Apo B
VLDL-C
TG
HDL-C
*P0.05 vs atorvastatin. Bakker-Arkema RG et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-08).
Atorvastatin vs Pravastatin
Mean Percent Change in Lipids at 16 Weeks
10
6 0 9 -10 % -20 25 * -30 35 17 24 27 * 16 17 * Atorvastatin 10 mg Pravastatin 20 mg
*
-40 Total-C LDL-C Apo B TG HDL-C
*P0.05. Egros F et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-09).
Atorvastatin vs Simvastatin
Mean Percent Change in Lipids at 16 Weeks
10
7 7
0 -10 % -20
29
24 30 34 37 30 23 -23
Atorvastatin 10 mg
15
Simvastatin 10 mg
-30 -40
* Total-C LDL-C
* Apo B TG HDL-C
*P0.05. Bracs P et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-37).
Mean Percent Reduction in LDL-C in Fredrickson Type II Patients in Five Clinical Trials
0 -10 -20 % Reduction in LDL-C
98113 98104 98143 98104 98107 98104 98144 98104
-30
39 -40 -50 -60 -70 10 mg 41
35 44 45 50 57 61
20 mg 40 mg Atorvastatin Dose
80 mg
Black DM. Intl Congress Series No. 1066. 1995:307-310, and data on file, Parke-Davis.
Atorvastatin
10
20
40 Dose (mg/d)
60
80
Adapted from Black DM. Intl Congress Series No. 1066. 1995:307-310.
*
25
45 57 LDL-C TG HDL-C
-15
-20 -25 -30 -35 22
17
Atorvastatin Simvastatin
35
Marais AD et al. 12th DALM Symposium; Nov 7-10, 1995; Houston, Tex.
*
9 7 7 5 9 2 4 11
16
*
43
46
HDL-C
8
0
% Change
15 Atorvastatin Simvastatin
30
30
39
27
*
-40
Total-C
LDL-C
TG
HDL-C
*P<0.01. Best JD et al. Atherosclerosis. 1994;109:312, and data on file, Parke-Davis (981-13).
LDL-C 130 mg/dL (3.4 mmol/L) TG 400 mg/dL (4.5 mmol/L) Asymptomatic to moderately symptomatic 1 lesion 50%-90% stenosis
Recanalization Procedure
Atorvastatin 80 mg/d 0
Efficacy Parameters
Primary: incidence rate of ischemic events, time to ischemic event Secondary: all-cause mortality, lipid profile, angina classification, QOL Economic assessment of outcomes
Atorvastatin: Conclusions