atorvastatin ppt
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Atorvastatin: Effective Therapy fora Broad Range of Dyslipidemias
NCEP Guidelines for LDL Cholesterol
For individualswith:
No CHD and<2 CHD riskfactors
No CHD and>2 CHD riskfactors
EstablishedCHD
Trial of dietarytherapy andcounselling:
6-12months
3-6months
6-12weeks
Initiate drugtherapy ifLDL-C remains:
>190 mg/dL>4.9 mmol/L
>160 mg/dL>4.1 mmol/L
>130 mg/dL>3.4 mmol/L
LDL-CGoal:
<160 mg/dL<4.1 mmol/L
<130 mg/dL<3.4 mmol/L
<100 mg/dL<2.6 mmol/L
NCEP. Circulation. 1994;89:1329-1445.
Major Studies Showing Relationship Between Cholesterol Levels and CHD Risk
(Pre-Statin Studies)
Study type
Size of cohort
Conclusions
Epidemiologic
5127 (original)
1% in cholesterol =2% in CHD risk
FraminghamHeart Study
Observational
361,662
Continuous, gradedassociation betweencholesterol level and CHDrisk starting at 180 mg/dL
MRFIT Screenees
Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.
Major Studies Showing a Beneficial Effect of Lipid-Lowering Therapy on CHD Risk
Lipid Research Clinics Program. JAMA. 1984;251:351-364.Frick MH et al. N Engl J Med. 1987;317:1237-1245.
LRC-CPPT
Prospectivecomparative
Gemfibrozil
TC 9%LDL-C 8%HDL-C 10%TG 34%
34% in risk of fatal and nonfatal MI or cardiac death
Helsinki Heart Study
Prospectivecomparative
Cholestyramine
TC 9%LDL-C 13%
19% in risk of nonfatal MI or fatal CHD
Study type
Treatment
Effect on lipids
Impact on CHD risk
(Pre-Statin Studies)
4S Results
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
*P=0.0003; †P<0.00001.
30% in risk of total (all-cause) mortality*
34% in risk of major coronary events†
42% in risk of definite and suspected CHD death
Changes in lipids:
� 25% in Total-C — 8% in HDL-C� 35% in LDL-C� 10% in TG
WOSCOPS Results
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
31% in risk of nonfatal MI or CHD death*
33% in risk of definite and suspected CHD death†
22% in risk of all-cause mortality‡
Changes in lipids:
� 20% in Total-C — 5% in HDL-C� 26% in LDL-C� 12% in TG
*P<0.001; †P=0.042; ‡P=0.051.
CARE: Preliminary Results
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:
� 20% in Total-C — 5% in HDL-C� 28% in LDL-C� 14% in TG
Braunwald E, Pfeffer MA, Sacks FM. Presented at the 45th ACC; March 26, 1996; Orlando Fla.
*P=0.002; †P=0.007; ‡P=0.0001.
Benefits of Hypolipidemic Treatment
% Reduction inRisk of
Cardiac End Points
0%
20%
40%
70%10 13 26 35 60
LRC-CPPT
WOSCOPS
4S
?
% LDL-C Reduction
Chemical Structure of Atorvastatin
N
– 2+
NHC
OCH
CH3CH3
F
CH2
CH2
CHCH2
CHCH2
OH OHO
O
• Ca
2
Cholesterol Biosynthesis Pathway
HMG-CoAHMG-CoAreductasereductase
SqualeneSqualenesynthasesynthase
AcetylCoA
HMG-CoA
Mevalonate Farnesylpyrophosphate
Squalene Cholesterol
Farnesylatedproteins
Dolichol
E,E,E-Geranylgeranylpyrophosphate
Geranylgeranylatedproteins
Ubiquinones
Rasprotein
Farnesyl-transferase
Mechanism of Action of Atorvastatin
Conclusions Based on Animal Studies
Auerbach BJ et al. Atherosclerosis. 1995;115:173-180.Krause BR. Newton RS. Atherosclerosis. 1995;117:237-244.
EH rabbits: LDL production
EHT rats: VLDL production
Guinea pigs: LDL production
Atorvastatin inhibits hepatic production of major apo B-containing lipoproteins as shown in these animal models –
Atorvastatin Clinical Development
0 500 1000 1500 2000 2500 3000
25
6
6
No. ofStudies
N=3150 Phase III
N=380 Phase II
N=154 Phase I
No. of Subjects
Atorvastatin Dose-Response Study
Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.
Mean Percent Change in LDL-C at 6 Weeks
10
-70
-60
-50
-40
-30
-20
-10
0
%
7.6
4144
50
61
Placebo 10 mg 20 mg 40 mg 80 mg
* **
*
*P<0.05 vs placebo.
Bakker-Arkema RG et al. JAMA. 1996;275:128-133, and data on file, Parke-Davis (981-38).
Atorvastatin in Hypertriglyceridemia
56 hypertriglyceridemic patients, 26-74 y/o
4-week, randomized, double-blind, placebo-controlled, parallel
Atorvastatin 5, 20, 80 mg
Mean baseline LDL-C: 119 mg/dL (3.1 mmol/L)
Mean baseline TG: 603 mg/dL (6.8 mmol/L)
Mean baseline HDL-C: 32 mg/dL (0.8 mmol/L)
Design and Baseline Lipids
Atorvastatin in Hypertriglyceridemia
Mean Percent Change in Lipids at 4 Weeks
*P<0.05 vs placebo; †P<0.05 vs 5-mg dose.
-50
-40
-30
-20
-10
0
10
20
TG LDL-C HDL-C
%
*
*
9
26
32
*
49
13 12
46
*
*†
*†
1
17
33
41
PlaceboAtorvastatin 5 mgAtorvastatin 20 mgAtorvastatin 80 mg
Bakker-Arkema RG et al. JAMA. 1996;275:128-133.
Atorvastatin vs Lovastatin
Mean Percent Change in Lipids at 16 Weeks
Bakker-Arkema RG et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-08).
17
4
5
*
*
VLDL-C
6
17
4*
*
TG
*
36
1
27
*
LDL-C
-40
-30
-20
-10
0
10
%
PlaceboAtorvastatin 10 mgLovastatin 20 mg
*
27
1
19
*
Total-C
7 71*
HDL-C
*
28
3
20
*
Apo B
*PŠ0.05 vs atorvastatin.
Atorvastatin vs Pravastatin
Egros F et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-09).
Mean Percent Change in Lipids at 16 Weeks
Atorvastatin 10 mg
Pravastatin 20 mg
-40
-30
-20
-10
0
10
%
HDL-CTotal-C
*
LDL-C
*
Apo B
*
TG
*
*PŠ0.05.
86
25
17
35
24
27
16 17
9
Bracs P et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-37).
Atorvastatin vs Simvastatin
Mean Percent Change in Lipids at 16 Weeks
Atorvastatin 10 mg
Simvastatin 10 mg
-40
-30
-20
-10
0
10
%
HDL-C
7 7
Total-C
29
24
*
Apo B
3430
LDL-C
37
30
**
-23
TG
15
23
*
*PŠ0.05.
Mean Percent Reduction in LDL-C in Fredrickson Type II Patients in Five Clinical Trials
40 mg
50
981-04
20 mg
44 45
981-04 981-07
10 mg
39 4135
981-04981-13 981-43
80 mg
5761
981-04981-44
0
-10
-20
-30
-40
-50
-60
-70
Atorvastatin Dose
%Reductionin LDL-C
Black DM. Intl Congress Series No. 1066. 1995:307-310, and data on file, Parke-Davis.
Atorvastatin: LDL-C Reduction vs Other Statins
Adapted from Black DM. Intl Congress Series No. 1066. 1995:307-310.
Lovastatin
0
-20
-30
-40
-50
-60
-7010 20 40 60 800
%Change
in LDL-C
Dose (mg/d)
Pravastatin
Fluvastatin
Simvastatin
Atorvastatin
Total-C
*
45
Atorvastatin in Heterozygous FH Patients
Marais AD et al. Atherosclerosis. 1994;109:316.
Percent Change in Lipids at 6 Weeks
LDL-C
*
57
HDL-C
*25
TG
†
34
40
20
0
-20
-40
-60
%
*P<0.001; †P<0.01.
-35
-30
-25
-20
-15
-10
-5
0
Atorvastatin Efficacy in Homozygous FH
Marais AD et al. 12th DALM Symposium; Nov 7-10, 1995; Houston, Tex.
Receptor Negative (N=2)Baseline LDL-C: 498 mg/dL
(12.9 mmol/L)
PercentReductionin LDL-C
3
Receptor Defective (N=6)Baseline LDL-C: 521 mg/dL
(13.5 mmol/L)
22
35
17
AtorvastatinSimvastatin
Atorvastatin in Postmenopausal Women
Heinonen T et al. Atherosclerosis. 1996.
7 5
Mean Percent Change in Lipids at 12 Weeks
4346
*
9
LDL-C-50
-40
-30
-20
-10
0
10
20
%
30
PlaceboAtorvastatin 10 mgPlacebo + Estradiol 1 mgAtorvastatin 10 mg+ Estradiol 1 mg
Total-C
1
3
31 30
HDL-C
161142
TG
9
*P<0.05 vs estradiol.
*
*
7
*
Best JD et al. Atherosclerosis. 1994;109:312, and data on file, Parke-Davis (981-13).
AtorvastatinSimvastatin
HDL-C
88
TG
15
27
Total-C
24
30
*
LDL-C
30
39
*
%Change
10
0
-10
-20
-30
-40
*P<0.01.
Atorvastatin vs Simvastatin in NIDDM
Effects on Lipids at 4 Weeks
Titrate to LDL-C Š100 mg/dLŠ2.6 mmol/L
Primary: incidence rate of ischemic events, time to ischemic event Secondary: all-cause mortality, lipid profile, angina classification, QOL Economic assessment of outcomes
LDL-C 130 mg/dL (3.4 mmol/L)� TG Š400 mg/dL (4.5 mmol/L) Asymptomatic to
moderately symptomatic 1 lesion 50%-90%�
stenosis
Efficacy Parameters
Patient Population (N=320):RecanalizationProcedure
Atorvastatin 80 mg/d
0 18
UsualCare+
Month
Atorvastatin Medical Therapy vs Recanalization (AVERT)
McCormick L et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-68).
Atorvastatin Safety Summary
Administered to >3000 participants in clinical trials worldwide
3 serious adverse events possibly attributable to atorvastatin have been reported
ALT elevations >3x ULN: <1% overall
No incidence of myopathy
<2% withdrawn due to associated adverse events
Data on file, Parke-Davis.
Atorvastatin: Conclusions
Atorvastatin has a positive dose-response relationship over the range of 10-80 mg
LDL-C reductions from 40% to 60%
Effective in the broadest range of patients, including hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and homozygous FH
Safe and well tolerated in studies up to 2 years
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