atorvastatin ppt

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



LDL-CGoal:

<160 mg/dL<4.1 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:


*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:


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


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).


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


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


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

atorvastatin ppt

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