TM © 1999 Professional Postgraduate Services ® Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors.

TM

© 1999 Professional Postgraduate Services®

Perspectives on Lipid-Lowering Therapy With HMG-CoA

Reductase Inhibitors

TM


AcetylCoA

HMG-CoA

Mevalonate Farnesylpyrophosphate

Squalene Cholesterol

Squalenesynthase

Dolichol

HMG-CoAreductase

Rasprotein

Farnesyl-transferase

Farnesylatedproteins

E,E,E-Geranylgeranylpyrophosphate

Geranylgeranylatedproteins

Ubiquinones

Cholesterol Biosynthetic Pathway

TM


Agents LDL-C HDL-C VLDL-C

Bile acid sequestrants clearance (modest ) secretion

Niacin synthesis clearance synthesis

Fibric acid derivatives (modest ) synthesis clearance

HMG-CoA reductase clearance (modest ) clearanceinhibitors (statins) synthesis*

* with atorvastatin

Metabolic Effects of Lipid-Lowering Agents on Lipoproteins

Adapted from Levy et al. Circulation. 1993;87:III45-III53.

TM


Lovastatin1987 Pravastatin

1991

Simvastatin1991

Fluvastatin1993

H3

C

OHO

O

O O

N

F

OOHOH

O- Na+

HO

HO

O

O

COONaO

H

H3

C

O

O

HO

O

O

H3

C

Chemical Structures of Older Statins

TM


Atorvastatin

Cerivastatin

F

OOHOH

ONa

N

CH3O

O

OHOH

NNHC

O

F

O-

Ca+

2

H3C CH3

CH

CH2 CH2 CH2

CH2 CH CH

Chemical Structures of Newer Statins

TM


* Not FDA approved.

Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin Cerivastatin TC LDL-C

— 10 20 20 40 0.2* 22 27

10 20 40 40 80 0.4 27 34

20 40 80 32 41

40 80 37 48

80 160* 42 55

Dose (mg) of agent % Reduction

Comparative Efficacy of Available Statins

Roberts WC. Am J Cardiol. 1997;80:106-107.Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

TM


Cerivastatin 0.1 mg bidCerivastatin 0.2 mg qpmPlacebo

* Significantly different from placebo (P<0.05).† Significantly different from 0.1 mg bid (P<0.05).

Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

Mean % + after 4 wk

TC LDL-C HDL-C TG ApoB

5.3

-29.4

2.3

-23.0

-1.4 -1.2-3.1

-0.4

-11.6

-18.9-21.4

-25.7

-11.6

-21.9

-0.01

-30

-25

-20

-15

-10

-5

0

5

10

*

**

*†

**

*

*†

Lipid Lowering With Cerivastatin in Primary Hypercholesterolemia

TM


-40

-30

-20

-10

0

10

20

LDL-C TC LDL-C Lova TC Lova

%+

Insull W et al. JACC. 1997;29(suppl A):46A.

Dose (mg)

0 0.05 0.1 0.15 0.2 0.25 0.3 40

Cerivastatin: TC and LDL-C Lowering in Patients With Primary Hypercholesterolemia

TM


-70

-60

-50

-40

-30

-20

-10

0

Baseline Week 2 Week 4 Last DB visit

Mean % +in LDL-C

at 6 wk

P<0.05.DB=double blind.

Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.

10 mg20 mg

40 mg

80 mg

Atorvastatin Dose-Response Relationship in Primary Hypercholesterolemia

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* Significantly less than atorvastatin 10 mg (P<0.02).† Significantly less than atorvastatin 20 mg (P<0.01).‡ Significantly greater than mg-equivalent dose of comparative agents (P0.01).Jones P et al. Am J Cardiol. 1998;81:582-587.

-60

-50

-40

-30

-20

-10

0

0 10 20 30 40 50 60 70 80 90

Atorvastatin

Fluvastatin

Lovastatin

Pravastatin

Simvastatin

Dose range (mg)

Mean% LDL-Creduction

*

**

*

** *

†

† †‡

‡

‡

The CURVES Trial: A Comparison of LDL-C Lowering Among Statins

TM


Mean % LDL-C reduction

Atorvastatin (10 mg)*Simvastatin (10 mg)*Pravastatin (20 mg)*Lovastatin (20 mg)*Fluvastatin (20 mg)*

-40

-30

-20

-10

0

-38†

-28†-24†

-29†

-17†

*Most commonly prescribed doses. Source: IMS NPA Plus™, December 1996.†Significantly less than atorvastatin 10 mg (P<0.01).

Jones PH et al. Am J Cardiol. 1998;81:582-587.

The CURVES Trial: Comparative LDL-C Reductions

TM

© 1999 Professional Postgraduate Services®Davidson M et al. Am J Cardiol. 1997;79:1475-1481.

-36

1*

-27*

-40

-30

-20

-10

0

10

74

55

7

0

20

40

60

80

100

Placebo Atorvastatin 10 mg Lovastatin 20 mg

% Patients reaching NCEP LDL-C target†

*P<0.05 vs atorvastatin.†<160 mg/dL (<2RFs) 95% vs 86% <130 mg/dL (>2RFs) 67% vs 42% <100 mg/dL (CHD) 18% vs 3%

Mean % in LDL-C+

Reaching NCEP Goals for LDL-C:Atorvastatin vs Lovastatin

TM


Atorvastatin 10 mg Pravastatin 20 mg

Bertolini S et al. Atherosclerosis. 1997;130:191-197.

-35

-23*

-40

-30

-20

-10

0

10

65

19*

0

20

40

60

80

100

*P<0.05 vs atorvastatin.

% Patients reaching LDL-C target (<130 mg/dL)Mean % in LDL-C+

Reaching NCEP Goals for LDL-C:Atorvastatin vs Pravastatin

TM

© 1999 Professional Postgraduate Services®Dart A et al. Am J Cardiol. 1997;80:39-44.

*P<0.05 vs atorvastatin.

Mean % in LDL-C+

-37-30*

-40

-30

-20

-10

0

10

46

27

0

20

40

60

80

100

% Patients reaching LDL-C target (<130 mg/dL)

Atorvastatin 10 mg Simvastatin 10 mg

Reaching NCEP Goals for LDL-C:Atorvastatin vs Simvastatin

TM

© 1999 Professional Postgraduate Services®Bakker-Arkema RG et al. JAMA. 1996;275:128-133.

Mean % + in lipidsat 4 wk

*P<0.05 vs placebo.†P<0.05 vs 5-mg dose.

% Lipid levels at 4 wk

-9

-1

69

-32

13

-46-41

12

-17

-26

-33

-50

-40

-30

-20

-10

0

10

20

PlaceboAtorvastatin 5 mgAtorvastatin 20 mgAtorvastatin 80 mg

*

BaselineTG=603 mg/dL

BaselineLDL-C=119 mg/dL

BaselineHDL-C=32 mg/dL

TG LDL-C HDL-C

*

*

*†

*†

*

Impact of Atorvastatin on Lipids in Patients With Hypertriglyceridemia

TM

© 1999 Professional Postgraduate Services®Marais AD et al. 12th DALM Symposium; November 7-10, 1995.

-22

-35

-17

-3

-35

-30

-25

-20

-15

-10

-5

0

Atorvastatin

Simvastatin

% Reduction in LDL-C

Receptor negative (N=2)Baseline LDL-C: 498 mg/dL

(12.9 mmol/L)

Receptor defective (N=6)Baseline LDL-C: 521 mg/dL

(13.5 mmol/L)

Impact of Statin Therapy on LDL-C in Patients With Homozygous FH

TM

© 1999 Professional Postgraduate Services®Marais AD et al. Arterioscler Thromb Vasc Biol. 1997;17:1527-1531.

% +

% Change in lipids at 6 wk

-45*

-57*

-34

25*

-60

-40

-20

0

20

40

TC LDL-C HDL-CTG

†

*P<0.001.†P<0.01.

Impact of Statin Therapy on LDL-C in Patients With Heterozygous FH

TM

© 1999 Professional Postgraduate Services®PEPI Writing Group. JAMA. 1995;273:199-208.

Impact of Estrogen and Progestin on Cholesterol Concentrations

PlaceboCEE onlyCEE + MP (cyc)CEE + MPA (cyc)CEE + MPA (con)

-16

-14

-12

-10

-8

-6

-4

-2

0

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Time (yr)

% +in LDL-C

-4

-2

0

2

4

6

8

10

12

14

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Time (yr)

% +in HDL-C

TM


1

9

2

-3

-9

11

-30

-5

-46

16

4*

-43*

-7*

-31*

7

-50

-40

-30

-20

-10

0

10

20

Placebo

Atorvastatin 10 mg

Placebo + estradiol 1 mg

Atorvastatin 10 mg +estradiol 1 mg

Heinonen TM et al. 66th Congress, European Atherosclerosis Society. July 13-17, 1996.

Mean %+ at 12 wk

*P<0.05 vs placebo.

% Lipid levels at 12 wk

TC LDL-C HDL-CTG

Impact of Atorvastatin on Lipids in Postmenopausal Women

TM


E+P Simvastatin

%+

*P < 0.001.HRT=hormone replacement therapy; E=estrogen; P=medroxyprogesterone.

Darling GM et al. N Engl J Med. 1997;337:595-601.

-14

-24

7

-27

29

-26*

-36*

7

0

-14

-40

-30

-20

-10

0

10

20

30

40

TC LDL-C

HDL-C

TG

Lp(a)

Effects of HRT and Simvastatin Compared in Hypercholesterolemic Postmenopausal Women

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HERS: Combined HRT Does Not Decrease All-Cause Mortality

Log rank P=0.56*0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate.Hulley S et al. JAMA. 1998;280:605-613.

Incidence (%)

Follow-up, yr (No. at risk)

0

5

10

15

0(2,763)

1(2,720)

2(2,666)

3(2,595)

4(1,590)

5(130)

Estrogen-Progestin*

Placebo

TM


HERS: Primary CHD Events

Data from Blumenthal RS, Post WS. Mediguide to Heart Diseases. 1999;2:1-7.

Events/1,000women-years


0

10

20

30

40

50

60

1 2 3 (4-5)

Placebo

HRT

(2,763) (2,720) (2,666) (1,590®130)

52%¯25%

TM


HERS: HDL-C Distribution in a Cohort With CHD

0

10

20

30

40

50

60

70

80

Low Normal High

Postmenopausalwomen*

(%)

HDL-C (mg/dL)

<35 35–59 60*Mean age 67 years.

8

72

20

Bittner V et al. Am Heart J. 2000;139:288-296.

TM


Log rank P=0.91.* Combined incidence of nonfatal MI and CHD death.† 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate.Hulley S et al. JAMA. 1998;280:605-613.

HERS: Combined HRT Does Not Reduce Primary CHD End Points*

Estrogen-Progestin*

Placebo

0(2,763)

1(2,631)

2(2,506)

3(2,392)

4(1,435)

5(113)

Incidence (%)


0

5

10

15

TM


HERS: Primary CHD Events

Data from Hulley S et al. JAMA. 1998;280:605-613.

0

10

20

30

40

50

60Placebo

HRT

1 2 3 (4-5)Yr

Events/1,000women-years

P for time trend=0.009

TM


CRP(mg/dL)

Box plots show 10th, 25th, 50th, 75th, and 90th percentile cutpoints of CRP distribution for each study group.CRP=C-reactive protein.

Ridker PM et al. Circulation. 1999;100:713-716.

HRT Effects on C-Reactive Protein Levels

1.2

1.0

0.8

0.6

0.4

0.2

0.0

Men Women Women Women Women(n=291) no HRT any HRT estrogen estrogen plus

(n=311) (n=182) alone progestin (n=99) (n=83)

P=0.001 P=0.003 P=0.03

TM


HRT Effects on C-Reactive Protein Levels: PEPI Trial Subgroup

Cushman M et al. Circulation. 1999;100:717-722.

0 12 36

Placebo

CEE only

CEE + MP (cyc)

CEE + MPA (cyc)

CEE + MPA (con)

CRP(mg/L)

0

1

1.5

2

2.5

3

Time (mo)

P=0.0001

CRP = C-reactive protein

TM


-1.2

-5.2-6.4

-9.7

-1

-6.2

-10.1

-14.1

-4.7-3.1 -3.7

-4.5

0 0

3.2

0.5

-15

-10

-5

0

5

Placebo 30 mg 60 mg 150 mg

TC LDL-C HDL-C TG

Delmas PD et al. N Engl J Med. 1997;337:1641-1647.

%+

Raloxifene: Effects on Lipids in Postmenopausal Women

TM


Patients recommended for angioplastyCAD 1 lesion 50% stenosis

LDL-C 115 mg/dL (3.0 mmol/L)TG 500 mg/dL (5.6 mmol/L); LVEF 40%Bruce protocol treadmill test or 20-W/min

bicycle exercise test 4 min

Atorvastatin 80 mg/d+

usual medical therapy (n=164)

Angioplasty+

usual care, including lipid lowering (n=177)

18 months• Occurrence of ischemic events (death from cardiac causes, nonfatal MI, CVA, CABG,

angioplasty, worsening angina verified by objective evidence resulting in hospitalization, resuscitation after cardiac arrest)

• Time to first ischemic event

• Change in lipid parameters

• Safety

Pitt B et al. N Engl J Med. 1999;341:70-76.

AVERT: Study Design and Inclusion Criteria

TM


Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

AVERT: Major Exclusion Criteria• Left main disease or

3-vessel disease

• Unstable angina

• MI within previous 14 days

• Known ejection fraction <40% or NYHA Class III or IV heart failure

• Previous CABG, unless grafts were patent and patient did not have 3-vessel disease

• CABG recommended based on current angiogram

• Percutaneous revascularization in previous 6 months

• Known hypersensitivity to HMG-CoA reductaseinhibitors

• AST/ALT >2 x ULN

• CPK >3 x ULN or unexplained elevations

TM



AVERT: Overview of Study Procedures

Treatment phase

• Patients randomized to atorvastatin

– discontinued other lipid-lowering medication and immediately began atorvastatin 80 mg/d

• Patients randomized to angioplasty/usual care (UC)

– underwent angioplasty followed by “usual care”

• usual care may or may not have included lipid-lowering therapy (eg, diet, behavior modification, or medication)

• angioplasty may or may not have included stenting

• usual care was determined by investigator or patient’s primary physician

TM

© 1999 Professional Postgraduate Services®Pitt B et al. N Engl J Med. 1999;341:70-76.

– angioplasty (other than the original procedure in angioplasty/usual care group)

– worsening angina verified by objective evidence resulting in hospitalization

CVA=cerebrovascular accident.

AVERT: Primary Efficacy Assessment

• Incidence of an ischemic event in each treatment group

• Ischemic event was defined as occurrence of one of the following:

– cardiac death

– resuscitation aftercardiac arrest

– nonfatal MI

– CVA

– CABG

TM



AVERT: Secondary Efficacy Assessments• Time from randomization to ischemic event

• Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a)

• All-cause mortality

• Change from baseline in angina class

• Worsening angina with objective evidence

• Change in quality of life

• Economic assessment

TM


Atorvastatin (n=164) Angioplasty/UC (n=177)

Age (yr), mean 59 58Gender

Male 130 (79%) 157 (89%) Female 34 (21%) 20 (11%)

Mean ejection fraction 61% 61%Nature of CHDSingle vessel 94 (57%) 99 (56%)Double vessel 70 (43%) 78 (44%)

Mean % stenosis 80% 81%Mean no. of risk factors 2.5 2.5Prior MI 73 (45%) 70 (40%)Patients with target lesionLAD 70 (43%) 53 (30%)LCX 59 (36%) 63 (36%)RCA 59 (36%) 64 (36%)

CCS Angina ClassAsymptomatic 29 (18%) 27 (15%)Class I 74 (45%) 70 (40%)Class II 60 (37%) 77 (44%)Class III 1 (1%) 2 (1%)Class IV 0 (0%) 1 (1%)


AVERT: Baseline Patient Characteristics

TM


Number (%) of patients experiencing an ischemic event

Atorvastatin Angioplasty/UCn=164 n=177 %

Any Ischemic event 22 (13) 37 (21) -36*

Death 1 (0.6) 1 (0.6)Resuscitated cardiac arrest 0 (0.0) 0 (0.0)Nonfatal MI 4 (2.4) 5 (2.8)CVA 0 (0.0) 0 (0.0)CABG 2 (1.2) 9 (5.1)Revascularization 18 (11.0) 21 (11.9)Worsening angina with objectiveevidence & hospitalization 11 (6.7) 25 (14.1)

*P=0.048 vs an adjusted significance level of 0.045.


AVERT: Ischemic Events

TM


* P=0.048 vs an adjusted significance level of 0.045 atorvastatin vs angioplasty/UC.Data from Pitt B et al. N Engl J Med. 1999;341:70-76.

0

5

10

15

20

25

Atorvastatin Angioplasty/UC

% of patientswith an

ischemic event

13%

21%

-36% difference*

(P=0.048)

n=22 of 164 n=37 of 177

AVERT: Ischemic Events

TM


0

5

10

15

20

25

0 6 12 18

P=0.03Cumulative incidence

(%)

Time since randomization (months)


Atorvastatin (n=164)

Angioplasty/UC (n=177)

AVERT: Time to First Ischemic Event

TM


*Significantly different from angioplasty/UC (P<0.05).† Baseline values represented patients at randomization without a washout period from existing lipid-lowering therapy.Note: 73% of angioplasty/UC-treated patients were on lipid-lowering medication.Pitt B et al. N Engl J Med. 1999;341:70-76.

mg/dL(mmol/L)

Atorvastatin end of studyAngioplasty/UC baseline†

Angioplasty/UC end of study

Atorvastatin baseline†

10%

0

50

100

150

200

250

LDL-C TC TG HDL-C

18%

31% *

46% *

10%

11% *

8% 11%

(6.5)

(2.6)

(3.9)

(5.2)

(1.3)

AVERT: Summary of Lipid Parameters

TM


0

5

10

15

20

0-6 months >6-18 months

Atorvastatin

Angioplasty/UC

24% difference46%

difference

% of patientswith an

ischemic event

7%6%

10%11%


AVERT: Incidence of First Ischemic Event by Time

TM

© 1999 Professional Postgraduate Services®Pitt B et al. N Engl J Med. 1999;341:70-76.

AVERT: Safety Evaluation

• Elevations in AST or ALT (consecutive elevations >3 x ULN)

– 4 (2.4%) atorvastatin-treated patients

– none in angioplasty/UC-treated patients

• Elevations in CPK (>10 x ULN)

– none in either treatment group

• There were no clinically significant differences in adverse event rates between the two treatment groups

– in this study, eight patients discontinued atorvastatin treatment due to an adverse event, seven of which remained in the study

TM


• Reduces ischemic events by 36%

• Delays the time to first event

• Is safe

• Can delay or prevent the need for percutaneous revascularization


Aggressive lipid lowering with atorvastatin in stable CAD patients:

AVERT: Conclusions

TM


Lovastatin Study Groups I through IV. Arch Intern Med. 1993;153:1079-1087.Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP II). September 1993; NIH Publication 93-3095.

Safety Summary for HMG-CoA Reductase Inhibitors• Excellent patient acceptance

• Few drug-drug interactions

• Few side effects

– most common are gastrointestinal: mild to moderate

– at high doses, elevated ALT/AST in 1% to 2%

– myopathy reported in 0.1% (CK >10 x ULN)

• Only rare cases of toxicity

• No increases in total or non-CHD mortality

TM


C=control; T=treatment; A=aggressive; M=moderate.

Yusuf S, Anand S. Circulation. 1996;93:1774-1776.

5

10

15

20

25

Post-treatment TC (mg/dL)

5-yr CVevents (%)

CARE-T

Post-CABG-A 4S-T

CARE-C

Post-CABG-M 4S-C

155 174 193 212 232 251 271

Risk of CHD Events and Level of Cholesterol

TM


PI=placebo; Rx=treatment

Shepherd J et al. N Engl J Med. 1995;333:1301-1307.4S Study Group. Lancet. 1995;345:1274-1275.Sacks FM et al. N Engl J Med. 1996;335:1001-1009.Downs JR et al. JAMA. 1998;279:1615-1622.Tonkin A. Presented at AHA Scientific Sessions, 1997.

Mean LDL-C level at follow-up (mg/dL)

Relation Between CHD Events and LDL-C in Recent Statin Trials

0

5

10

15

20

25

30

90 110 130 150 170 190 210

% withCHD event CARE-Rx

LIPID-Rx

4S-Rx

CARE-PILIPID-PI

4S-PI

2° Prevention

1° Prevention

WOSCOPS-PI

WOSCOPS-RxAFCAPS/TexCAPS-Rx

AFCAPS/TexCAPS-PI

TM © 1999 Professional Postgraduate Services ® Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors.

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