Dr.

Antonia Anna Lukito, SpJP SpJP, , FIHA, FAPSIC FAPSIC, , FSCAI

EDUCATION: Medical Faculty, Airlangga University, 1988 Cardiology Department, Indonesia University, 1997 Advance Cardiology Course,Victoria Heart Center, Melbourne, Australia, 1996 & 2000 Pacemaker & Interventional Cardiology, National National Cardiac Center, enter, 2004 Cardiovascular CT Training, Cologne, Germany, 2005 ORGANIZATION: Scientific & Education Committee of PERKI Banten Committee of PERKI Pusat Organization Committee Committeeof of Indonesian Society of Hypertension (InaSH (InaSH) ) Organization Comittee of Indonesian Society of Interventional Cardiology (ISIC) Fellow of AsiaAsia-Pacific Society of Interventional Cardiology (APSIC) Fellow of Society for Cardivascular Angiography & Interventions (SCAI) Fellow of Indonesian Heart Association (IHA) Member of IDI PROFESSIONAL EXPERIENCES: Heart Center, Siloam Hospitals, Karawaci Lecturer of UPH medical faculty

CURRICULUM VITAE

Vasculoprotective Effect of Statin: Early Time to CV Benefit

Antonia Anna Lukito

Relationship Between Cholesterol and CHD Risk : The Framingham Study

150 125 100 75 50 25 0 204 205234 235264 265294 295

CHD incidence per 1000

Serum cholesterol (mg/100 mL)

(Adapted from Castelli WP, 1984)

The Cardiovascular Continuum of Events

ACS
Secondary prevention Coronary Thrombosis

Stroke

Arrhythmia and Loss of Muscle Remodeling

Myocardial Ischemia

CAD Atherosclerosis Primary prevention

Ventricular Dilatation Congestive Heart Failure EndEnd -stage Heart Disease

Adapted from Dzau et al. Am Heart J. 1991;121:12441991;121:1244-1263

Risk Factors ( Dyslipidemia, Dyslipidemia, BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

CV Benefits of Intensive and Aggressive LDL LDL-C Lowering With Atorvastatin Have Been Shown in Primary Prevention Trials

Primary Prevention Trials

10 9 8 7 6 5 4 3 2 1 0 -1 55 75
CARDSCARDS-P WOSCOPSWOSCOPS-P WOSCOPSWOSCOPS-PR CARDSCARDS-AT AFCAPSAFCAPS-LO ASCOTASCOT-P ASCOTASCOT-AT AFCAPSAFCAPS-P

CHD events (%)

y=.0599x 3.3952 R2=.9305 P=.0019 155

Lovastatin

95

115 135 LDL LDL-C (mg/dL)

Pravastatin

175

195
Placebo

Atorvastatin

AT=atorvastatin; LO=lovastatin; P=placebo; PR=pravastatin. Adapted from OKeefe JH et al. J Am Coll Cardiol. 2004;43:21422004;43:2142-2146; Colhoun HM et al. Lancet. 2004;364:6852004;364:685-696.

CV Benefits of Intensive and Aggressive LDLLDL-C Lowering With Atorvastatin Have Been Shown in Secondary Prevention Trials

Secondary prevention trials

30 25
ALLIANCEALLIANCE-UC 4S4S-P

CHD events (%)

20 15 10 5 0 30 50

ALLIANCEALLIANCE-AT 4S4S-S HPSHPS -S PROVE ITIT-AT

HPSHPS -P

LIPIDLIPID-P CARECARE-P

LIPIDLIPID-PR CARECARE-PR PROVE ITIT-PR

y=0.1629x 4.6776 R2=0.9029 P<.0001 150 170

Usual care

70

90

110 130 LDL LDL-C (mg/dL)

Simvastatin

190

210
Placebo

Atorvastatin

Pravastatin

AT=atorvastatin; P=placebo; PR=pravastatin; S=simvastatin; UC=usual care. Adapted from OKeefe JH et al. J Am Coll Cardiol. 2004;43:2142-2146; Koren MJ et al. J Am Coll Cardiol. 2004;44:1772-1779.

Primary Prevention Secondary Prevention

Decrease LDL plasma level

Statin

Mechanism

CV events Reduction

Primary Prevention Secondary Prevention

Decrease LDL plasma level Statin

Mechanism

CV events Reduction

ATGOAL: Target Achievement

Overall 1031/1216
High risk 299/322 92.9%

84.8%

Moderate risk 199/237

84.0%

Low risk

81.1%

% at goal

% not at goal

533/657

%at goal
Adapted from Mckenney JM et al. J Cardiovasc Pharmacol 2005;46: 594594-599.

% not at goal

Atorvastatin Reduction of LDL LDL-C across dose range

Primary Prevention
ASCOT-LLA1 10 mg CARDS2 10 mg

Secondary Prevention
REVERSAL3 80 mg IDEAL4 80 mg TNT5 80 mg

ACS
PROVEPROVE-IT6 80 mg

Baseline LDL

133
mg/dL

117
mg/dL

150
mg/dL

121
mg/dL

<130
mg/dL

106
mg/dL

On Treatment LDL mg/dL mg/dL

90*

77*

79*

81*

77*

62*

Achieving goals as targeted

*Data from ASCOT-LLA, TNT, REVERSAL, and IDEAL represent mean levels; CARDS follow up and PROVE IT, median levels
1. Sever PS, et al. Lancet. 2003;361:1149-1158. 2. Colhoun HM, et al. Lancet. 2004;364:685-696. 3. Nissen SE, et al. JAMA. 2004;291:1071-1080. 4. Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. 5. LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435 6. Pedersen TR, et al. JAMA. 2005;294:2437-2445.

Primary Prevention Secondary Prevention

Decrease LDL plasma level

Statin

Mechanism

CV events Reduction

ASCOT ASCOT-LLA: Study Design

Placebo

10,305 Patients

Total Cholesterol 6.5 momol/L (250 mg/dL) Atorvastatin 10 mg

Patient Population
Age 40 40 79 years Hypertension plus 3 or more risk factors including age, smoking, family history of CHD, or low HDL TC 6.5 mmol/L (250 mg/dL)

Composite Primary End Point

Combined end point of:
Nonfatal MI Fatal CHD

Adapted from Sever PS, et al. Lancet. 2003;361:1149-1158.

ASCOT ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD

The Event Curves Separate as Early as 90 Days and Diverge Over Time
4
n # of Events 100 154 End of Treatment Mean LDL 90 mg/dL 126 mg/dL mg/dL

Cumulative Incidence (%)

Relative Risk Reduction (P=0.0005) HR=0.64 (0.50 (0.50 0.83) Placebo Atorvastatin 10 mg

36%

Atorvastatin 10 mg Placebo

5,168 5,137

0 0.0 0.5 1.0 1.5

Years

2.0

2.5

3.0

3.3

5.0

In a post post-hoc analysis, a significant difference at 90 days was observed between treatment groups HR = hazard ratio Due to a significant reduction in the primary end point, the trial was stopped after only 3.3 years, nearly 2 years earlier than expected

Adapted from Sever PS, et al. Lancet. 2003;361:11492003;361:1149-1158.

ASCOTASCOT-LLA Post Hoc TimeTime-to to-Benefit Analysis: Cardiac Events

Event Rate* Atorvastatin 2.4 5.5 7.5 6.6 5.9 6.0 Placebo 14.2 16.6 14.3 12.0 9.5 9.4

Censoring Time 30 days 90 days 180 days 1 year 2 years End of study 0

Hazard Ratio (95% CI)

Risk Reduction (%) 83 67 48 45 38 36

0.5

1.0

1.5 Placebo Better

2.0

Atorvastatin Better

* Per 1000 patient patient-years. CI = confidence interval. Reproduced from Sever PS et al. Am J Cardiol. 2005;96(suppl):39F 2005;96(suppl):39F-44F, with permission.

CARDS: Study Design

Placebo
2,838 Patients

Atorvastatin 10 mg

6-week Placebo RunRun-in Prerandomization

Placebo

Patient Population
Type 2 diabetes with no clinically evident CHD 1 other CHD risk factor (smoking, hypertension, albuminuria, retinopathy) plus LDLLDL-C 4.1 mmol/L (160 mg/dL) and TG 6.8 mmol/L (600 mg/dL) Aged 40 4075 years
Adapted from Colhoun HM, et al. Diabet Med. 2002;19:2012002;19:201-211.

Composite Primary End Point

First occurrence of: acute CHD event coronary revascularization procedure Stroke

CARDS: Primary End Point Major CV Events* Acute Coronary Heart Disease Events, Coronary Revascularization, or Stroke
15
n # of Events 83 127 End of Treatment Median LDL 77 mg/dL 120 mg/dL mg/dL

Placebo Atorvastatin 10 mg

Cumulative Hazard (%)

Atorva 10 mg

1,428 1,410

10

Placebo

Relative Risk Reduction (P=0.001) (95% CI: 17 17 52)

37%

0 0.0 1.0 2.0 3.0 3.9

Trial Stopped Early
The study was stopped 2 years earlier than anticipated after a median follow up of 3.9 years, due to beneficial effect of ato atorva rvastatin statin The results were similar in patients with LDLLDL-C <120 mg/dL (3.1 mmol/L) and 120 mg/dL (3.1 mmol/L)
1. Adapted from Colhoun HM, et al. Lancet. 2004;364:6852004;364:685-696. 2. Data on File, Pfizer Inc.

4.75

% Years

CARDS Post Hoc TimeTime-to to-Benefit Analysis: Major Cardiovascular Events

2

1.5 Hazard Ratio (95% CI)

1 HR = 0.63 (95% CI = 0.48 0.48-0.83)

0.5

0 1 2 3 4 4.5 Time (years)

Adapted from Colhoun HM et al. Diabetologia. 2005;48:2482-2485, with permission.

PROVE PROVE-IT*: Study Design

Atorvastatin 80 mg 4,162 Patients Post ACS
Double Double-Blind Period

Pravastatin 40 mg
2424-month Treatment Phase

Patient Population
58 y (mean) TC <6.2 mmol/L Randomized within 10 days of ACS event (mean: 7 days)
* PROVE PROVE-IT was sponsored by Bristol Myers Squibb and Sankyo

Primary End Point

Time to Occurrence of: Death, Nonfatal MI, Unstable Angina, Stroke, Revascularization

Atorvastatin is not indicated for secondary prevention of CHD in all countries

Adapted from Cannon CP, et al. N Engl J Med. 2004;350:14952004;350:1495-1504.

PROVEPROVE -IT*: Changes in LDLLDL-C

120

100
LDLLDL -C (mg/dL)

95 mg/dL (2.5 mmol/L)

80

-35%
62 mg/dL (1.6 mmol/L)
Pravastatin 40 mg Atorvastatin 80 mg 95 mg/dL (2.5 mmol/L) 62 mg/dL (1.6 mmol/L)

60

40

20 Baseline 30 days 4 mos Time of Visit

* PROVE PROVE-IT was sponsored by Bristol Myers Squibb and Sankyo

8 mos

16 mos

Final

Atorvastatin is not indicated for secondary prevention of CHD in all countries

Adapted from Cannon CP, et al. N Engl J Med. 2004; 350:1495350:1495-1504

AllAll-Cause Death, NonNon-Fatal MI, Unstable Angina Requiring Hospitalization, Urgent Revascularization, and/or Stroke Separation of the Curves Occurred Within 30 Days and Was Maintained over FollowFollow-up. Statistical Significance was Reached at 180 Days
30 25
% Patients with Event*

PROVE PROVE-IT*: Primary End Point

Pravastatin 40 mg Atorvastatin 80 mg

16% Relative Risk Reduction P=0.005

20 15 10 5 0 0 3 6 9 12 15 18 21 24 27
Atorvastatin 80 mg Pravastatin 40 mg Events Rates 22.4 26.3 End of Treatment Median LDL 62 mg/dL 95 mg/dL mg/dL

n 2099 2063

30

Months of FollowFollow-up
* PROVE PROVE-IT was sponsored by Bristol Myers Squibb and Sankyo

Atorvastatin is not indicated for secondary prevention of CHD in all countries

Adapted from Cannon CP, et al. N Engl J Med. 2004;350:14952004;350:1495-1504.

Primary Prevention Secondary Prevention

Decrease LDL plasma level

Statin

Mechanism

CV events Reduction

Primary Prevention Secondary Prevention

Decrease LDL plasma level

Statin

Mechanism

CV events Reduction

MIRACL vs. A to Z
Outcomes Differ Despite Similar LDLLDL-C Reductions

MIRACL
Cumulative Incidence (%) Cumulative Incidence (%)

A to Z
20 15 10 5
Simvastatin 80 mg Placebo No difference in CV Events in the first 4 months of the 24 24-month trial

20 15 10 5 0 0

LIPITOR 80 mg Placebo

There will be 16% STATIN benefits than just reducing LDLLDL-C

8 Weeks 12 16 0 0 4 8 Weeks 12

16

LDL-C Difference LDLBetween Arms

1.63 mmol/L 40% reduction

1.6 mmol/L 45% reduction

Schwartz GG, et al. JAMA. 2001;285

Adapted from de Lemos JA et al. JAMA. 2004;292

Effects of Statins on HMGHMG-CoA Reductase Inhibition

Acetyl-CoA + Acetoacetyl-CoA HMG-CoA
block

Statins

Mevalonate Slower late benefit Related to hepatic LDL LDL-C reduction Squalene Cholesterol
PP=pyrophosphate. Adapted from Ray KK, Cannon CP. Curr Opin Lipidol. 2004;15:6372004;15:637-643.

Early/rapid benefit (vasculoprotective effect) Important in vascular cellular responses

Isopentanyl PP Geranyl PP Farnesyl PP

Geranyl geranyl PP

Prenylation

Rho

Translocates to the cell membrane

Methods Find Exp Clin Pharmacol 2006, 28(9): 627

What Accounts for the Added Benefits of Atorvastatin Atorvastatin? ?

Endothelial effects Anti-inflammatory effects

Reduction of lipids

Antioxidant effects Reduction in plaque progression Plaque stabilization EPC

Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

Short Short-term Treatment With Atorvastatin improves Endothelial Function in Postmenopausal Women With Hypercholesterolemia
Change in brachial artery flow flow-mediated vasodilation (FMV) over time
14 12

FMV (%)

10 8 6 4 2 0 Baseline Week 1
*

Week 2 Atorvastatin 10 mg

Week 4

Week 8

*P<.05; P<.05 vs baseline; P<.001 vs atorvastatin atorvastatin. . Postmenopausal women (mean age 56.8 years) with hypercholesterolemia were treated with atorvastatin 10 mg (n=20) or the American Heart Association step 1 diet (n=10) for 8 weeks. Cholesterol levels and flowflow-mediated vasodilation (FMV) were measured at baseline and at 1, 2, 4, and 8 weeks.

Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:6172000;36:617-621.

Statins Significantly Improve Measures of Inflammation and Endothelial Function

Atorvastatin group (80 mg) Simvastatin group (20 mg)
*

60 50 40
Levels
*

60 50

Levels

40 30

30 20 10 0
Ox-LDL (U/L) NO (umol/mL) CRP (ug/dL) Fibrinogen (mg/dL) *

NS

20 10 0
Ox-LDL (U/L) NO (umol/mL CRP (ug/dL) Fibrinogen (mg/dL)

Baseline

6 months

Baseline

6 months

*P<.01 vs baseline; P<.05 vs baseline. Ox-LDL=oxidized LDL; NO=nitric oxide; CRP=C-reactive protein. Patients (N=97) mean age 61.29.7 years with previous MI were randomized to either atorvastatin 80 mg (n=47) or simvastatin 20 mg (n=50). Follow-up was 6 months. Aim: to compare intensive vs conventional lipid-lowering therapy on cholesterol levels, inflammation, and endothelial function in patients with CAD. Hognestad A et al. Clin Cardiol. 2004;27:199-203.

Inflammation Promotes Progression of Atherosclerosis

Monocyte LDL

Vessel lumen

Adhesion molecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-, IL-1, IL-6)

Endothelium
LDL

Ox-LDL Foam cell

Intima

Macrophage
CD40L=CD40 ligand; TNF-=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126.

CRP Is a Predictor of Cardiovascular Disease

9 8.7 8 7 6.0 6.0 5.1 5.0 4.2 4.2 3.5 2.9 2.0 1.4 4 3 2 1 1 2 1.0 2.5 1.7 1.2 4 3 2.9 2.1 1.4 5 3.5 2.5 1.7 3.0 2.2 1 4.2 6 5 4 3 2

7.2

Ridker PM. Circulation. 2001;103:1813-1818; Libby P et al. Circulation. 2002;105:1135-1143.

Relative risk

Atorvastatin Reduced Hs Hs-CRP Across a Broad Range of Patients

Athyros et al3 20 mg (n=100) Metabolic syndrome REVERSAL
6

ATOMIX1 10-40 mg* (n=50) Combined hyperlipidia CRP at baseline = 2.5 mg/L 1 year

DALI2 80 mg (n=64) Type 2 diabetes

ASAP4 80 mg (n=135) Heterozygous FH CRP at baseline = 2.1 mg/L 2 years

ARBITER5 80 mg (n=79) Statineligible

80 mg (n=253) Stable CHD

MIRACL7 80 mg (n=1186)

PROVE-IT8 80 mg (n=2099)

ACS

ACS

46% with CVD Atorvastatin has established data for reducing CRP in several trials

CRP at baseline = 3.0 mg/L 30 weeks

CRP at baseline = 4.4 mg/L 12 months

CRP at baseline = 4.3 mg/L 12 months

CRP at baseline = 2.8 mg/L 18 months

CRP at baseline = 11.5 mg/L 16 weeks

CRP at baseline = 12.3 mg/L 2 years

43%
(P<0.001)

47%
(P<0.001)

65%
(P<0.05)

40%
(P<0.001)

51%
(P=0.005)

36%
(P<0.001)

83%
(P<0.0001)

89%
(P<0.001)

% reductions are from baseline; P-values for ATOMIX, Athyros et al and ASAP are vs baseline; for DALI and MIRACL vs placebo; and for ARBITER, REVERSAL and PROVE-IT vs pravastatin 40 mg *Mean dose of atorvastatin in ATOMIX = 23.5 mg/day Mean value; Median value Atorvastatin 80 mg is not approved in all countries and is not an approved starting dose in most countries Lipitor is not indicated to reduce hs-CRP 1. Gomez-Gerique JA, et al. Atherosclerosis. 2002;162:245-51; 2. van de Ree MA, et al. Atherosclerosis. 2003 Jan;166:129-35; 3. Athyros VG, et al. Metabolism. 2005;54:1065-74; 4. van Wissen S, et al. Atherosclerosis. 2002;165: 361-6; 5. Taylor AJ, et al. Circulation. 2002;106:2055-60; 6. Nissen SE et al. JAMA. 2004;291:1071-80; 7. Kinlay S et al. Circulation. 2003;108:1560-6; 8. Cannon CP, et al. N Engl J Med. 2004;350:1495-504

Atorvastatin Metabolite Dramatically Slows the Rate of LDL Oxidation

Native LDL-C
Oxidative stress Native LDL-C Modified LDL-C

Atherogenic effects
Normal activity
Foam-cell formation Monocyte mobility Chemoattraction Endothelial adhesion Free-radical production

Heinecke JW. Am J Cardiol. 2003;91(suppl):12A-16A; Meagher EA, FitzGerald GA. Free Rad Biol Med. 2000;28:1745-1750; Chisolm GM, Steinberg D. Free Rad Biol Med. 2000;28:1815-1826; Mason RP et al. Circulation. 2004;190(suppl II):II-34II-41.

EFFECTS of STATINS on HUMAN LDL OXIDATION

70 60

Inhibition of oxLDL

50 40 30 20 10 0 -10 -20

Atorva-M

Atorva

Lova Simva

Prava

Rosuva

* p<0.005 vs untreated
Adapted from Mason RP et al. Journal of Biology Chemistry 2006;281:9337-9245

COMPARATIVE EFFECTS OF STATINS on SMALL DENSE LDL

50

Inhibition of TBARS Formation (%)

40 30

20

10 0 Atorvastatin Metabolite Atorvastatin parents Pravastatin Rosuvastatin Simvastatin Probucol

-10

*P<0.01 vs control (ANOVA Dunnett Multiple Comparison Post-Hoc Test); values = mean +SD (n=3) (Cu2+) = 10uM; drug concentration = 10uM Mason et.al (ACC, 2007 New Orleans

Plaque Stabilization
Unstable plaque
Fibrous cap Fibrous cap

Stable plaque

Inflammatory cells Lipid core

Fewer inflammatory cells Lipid core

Toschi V et al. Circulation. 1997;95:594-599; Libby P. Circulation. 1995;91:2844-2850.

Atorvastatin Significantly Reduced MMP MMP-9 Levels in a Dose Dose-Dependent Manner

Change in plasma MMPMMP-9 levels Decrease in supernatant MMP-9 levels

200 PBMC supernatant MMP-9 (mg/L)

PBMC supernatant MMP-9 9 (mg/L)

200

150
*

100 50 0
Conventional therapy

100

0
Conventional therapy + atorvastatin 10 mg

0.1 0 1 10 Atorvastatin concentration (mol/L)

Baseline

After 4 weeks

*P<.05; P<.01. PBMC=peripheral blood mononuclear cells. Patients (N=40) with ACS were randomly assigned either to conventional therapy + atorvastatin 10 mg (n=20) or conventional therapy alone (n=20). Peripheral blood was drawn in heparin-coated tubes after an overnight fast at baseline and after 4 weeks. Protein levels of MMP-9 were measured in all supernatant and plasma samples. Xu Z et al. Clin Chem. 2004;50:750-753.

ATROCAP: Atorvastatin Reduced Plaque Thrombogenicity

Change in TF Ag and TF activity
110 60 10 -40 -90 -140
Atorvastatin 20 mg *P=.049 (vs placebo). P=.029 (1st vs 2nd CEA). P=.085 (1st vs 2nd CEA). Cortellaro M et al. Thromb Haemost. 2002;88:41-47.

TF Ag

TF activity

Change in TF Ag (pg/mg) and TF activity ( (U/mg)

Placebo

REVERSAL Study Design

Patient Population:
Men and women with a history of CHD Angiographic criteria: 20% reduction in lumen diameter in 1 coronary artery lesion 50% reduction in lumen diameter of the left main coronary artery 1 coronary artery with 50% stenosis Double-Blind Period

Atorvastatin 80 mg/day 654 patients Pravastatin 40 mg/day

18-Month Follow-up with IVUS (BART at 3 months) Primary End Point: Percent change in total plaque volume

Nissen SE et al. JAMA. 2004;291:1071-1080.

REVERSAL vs ASTEROID
Differentiation
Patient Characteristic Baseline LDL-C History of DM Drug Comparison 150.2 mg/dL 20% Pravastatin 40mg 130.4 mg/dL 13.2% Placebo

REVERSAL

ASTEROID

Result in Plaque Regression

REVERSAL STUDY Atorvastatin reduce atheroma volume and increase lumen area (from 7.7 mm2 to 9.8 mm2)

In REVERSAL, atorvastatin 80 mg slowed progression

Ref: Nissen SE, et.al. JAMA 2004; 291

of atherosclerosis at 18 months
ASTEROID STUDY Rosuvastatin reduce atheroma volume BUT ALSO reduce lumen area (from 6.19 mm2 to 5.96 mm2)

Ref: Nissen S et al. JAMA 2006; 295

ESTABLISH: Study Design

Atorvastatin 20 mg
Screening visit* 70 Patients Open label period
Usual care (cholesterol absorption inhibitor initiated if LDL-C >
150 mg/dL)

Patient Population
ACS patients with significant stenosis on initial coronary angiography and received PCI

Composite Primary End Point

To examine early aggressive lipid

lowering with atorvastatin VS usual care in reducing in plaque volume by stabilizing vulnerable plaques

Okazaki S, et al. Circulation 2004; 110: 1061-1068. *after PCI, IVUS performed

ESTABLISH IVUS Analysis: Atorvastatin

Before

After 6 months

Okazaki et al.Circulation. 2004;110:1061-1068.)

Plaque volume 84.1 mm to 60.9 mm Lumen area 10.0 mm to 10.5 mm Plaque area 8.6 mm to 6.4 mm

ESTABLISH IVUS Analysis: Control

Before

After 6 months

Plaque volume 94.88 mm mm to 99.4 mm mm Lumen area 6.2 mm to 3.9 mm Plaque area 7.66 mm to 9.0 mm
Okazaki et al.Circulation. 2004;110:1061-1068.)

No Significant Association Between Achieved LDL-C and Adverse Events With Atorvastatin 80 mg
Achieved LDL Cholesterol (mg/dL) >80100 >6080 >4060 40 n=256 n=576 n=631 n=193 P Trend 6.4 0.4 2.3 0 3.2 2.0 4.3 0.6 0.7 0 3.0 2.6 6.2 0.6 1.9 0.3 3.2 2.4 5.7 0 1.0 0 2.6 1.6 .75 .64 .18 .45 .98 .83

Safety Measure
Muscle side effects Myalgia Myositis CK >3 ULN CK >10 ULN Liver side effects ALT >3 ULN Study drug discontinued because of LFT

No cases of rhabdomyolysis were reported.

CK=creatinine kinase; ULN=upper limit of normal; LFT=liver function test. Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

44

Conclusions
Achieving LDLLDL-C target is Important, BUT having rapid and fast clinical benefits is also IMPORTANT Atorvastatin has been shown Target goals achievement in several studies The early time to CV benefit is shown in several Atorvastatin trials: PROVE IT -CARDS REVERSAL -ASCOT ASCOT-LLA Early benefits may be related more to LDLLDL-independent (pleiotropic pleiotropic) ) effects of statins statins, , whereas both lipidlipid-dependent and independent effects maybe responsible for longerlonger-term benefits Distinct molecular structures may account for differences in pleiotropic effects
these benefits extend beyond any dosedose-dependent lipidlipid-lowering effects
Sever PS et al. Lancet. 2003;361:1149-1158; Colhoun HM et al. Lancet. 2004;364:685-696; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Koren MJ, Hunninghake DB. J Am Coll Cardiol. 2004;44:1772-1779; Nissen SE et al. JAMA. 2004;291:1071-1080; Smilde TJ et al. Lancet. 2001;357:577-581; Cannon CP et al. Circulation. 2004;110(suppl III);III-499; Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:617621; Ridker PM et al. N Engl J Med. 2005;532:20-28; Walter MF et al. J Am Coll Cardiol. 2004;43(5 pt A):529A; Gupta S. Int J Cardiol. 2004;96:131-139.

Conclusions
Accumulating evidence suggests that atorvastatin may have vasculoprotective effects beyond lipid lowering, including:
Inhibit process of Ox Ox-LDL Reducing CRP and other markers of inflammation Increasing plaque stability by reducing plaque volume and oxidative stress

LongLong-term reduction in clinical events and atherosclerosis progression is related to reduction in both inflammation and lipids (dual goals)
Sever PS et al. Lancet. 2003;361:1149-1158; Colhoun HM et al. Lancet. 2004;364:685-696; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Koren MJ, Hunninghake DB. J Am Coll Cardiol. 2004;44:1772-1779; Nissen SE et al. JAMA. 2004;291:1071-1080; Smilde TJ et al. Lancet. 2001;357:577-581; Cannon CP et al. Circulation. 2004;110(suppl III);III-499; Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:617-621; Ridker PM et al. N Engl J Med. 2005;532:20-28; Walter MF et al. J Am Coll Cardiol. 2004;43(5 pt A):529A; Gupta S. Int J Cardiol. 2004;96:131-139.