Statin Treatment:Revisited, 2008

Yen-Bin Liu, M.D. and Ph.D.

Div of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.National Taiwan University Hospital, Taipei, Taiwan.

Correlation Between Total-C and CHD M t lit i M f S

35

CHD Mortality in Men from Seven Countries

30

35

(%) Northern Europe

S th E

20

25

ity ra

tes Southern Europe,

MediterraneanUnited States

10

15

D m

orta

li

Serbia

0

5CH

D Southern Europe,InlandJapan0

Serum Total-C, mmol/L (mg/dL)

p

2.60(100)

3.25(125)

3.90(150)

4.50(175)

5.15(200)

5.80(225)

6.45(250)

7.10(275)

7.75(300)

8.40(325)

9.05(350)

, ( g )Data are from the Seven Countries Study of 12,467 men from Southern European Countries, the USA and Japan.Verschuren WM et al. JAMA 1995;274:131–136.

Statin Evidence: Expanding BenefitsAcute coronary event

No history of CAD Unstable CAD Stable CAD

AFCAPS / TexCAPS/WOSCOPS

Type 2 DM

4 moMIRACL 2 yPROVIT-TIMI 22Type 2 DM

CARDS

PROVIT TIMI 22

A to Z

4S

CARE/LIPID

3 mo

t = 0

6PROSPER

Elder Age

6 mo5 y

HPS

PROSPER

TNT

Hypertension

ASCOT-LLA / ALLHAT-LLT

Secondary preventionPrimary prevention

yp

Is Lower Better? LDL-C Levels vsE i L d k S i T i l

25 4S PS d ti

Events in Landmark Statin Trials25

20nt

4S-PSecondary preventionPrimary prevention

Si t ti

15

HD

eve

n

CARE-P

LIPID-P4S-S

C S

SimvastatinPravastatinLovastatin

10

5with

CH CARE P

WOSCOPS-SWOSCOPS-PLIPID-S

CARE-S

?0

% OSCO S S

AFCAPS-P

AFCAPS-S?

LDL-C (mg/dL)50 70 90 110 130 150 170 190 210

S = statin treated; P = placebo treated.

( g )

Perspectives: LDL R d ti d CHD E t R tLDL Reduction and CHD Event Rates

David J. Maron, et al. Circulation. 2000;101:207

ASCOT: Non-fatal Myocardial Infarction and Fatal Coronary Heart Diseaseand Fatal Coronary Heart Disease

)4 ‘High risk’ hypertension with TC <250 mg/dL (6.5 mmol/L)

nts

(%

)

3 36% Relative Risk

f p

ati

en

placebo

HR=0.64(0.50–0.83)2

rtio

n o

f

atorvastatin

P=0.0005

1

Pro

po

r 1

0.5 1.0 1.5 2.0 2.5 3.0 3.5

Time (years)

0

0

Sever PS et al, Lancet 2003;361:1149–1158

Time (years)

PROVE-IT: Moderate vs. IntensiveLDL C Reduction Post ACSLDL-C Reduction Post-ACS

t ti 40 HR 0.84 (CI 0.74-0.95, P=0.005)

30

25

pravastatin 40 mgMedian LDL-C reduction 10% LDL-Cachieved 2.45 mmol/L (95 mg/dL)

atorvastatin 80 mgMedian LDL-C reduction 42% LDL-C

20

Median LDL C reduction 42% LDL C achieved 1.60 mmol/L (62 mg/dL) 15

10

5

0 3 18 21 24 27 306 9 12 15

0

Cannon CP et al, NEJM 2004;350:1495

Months of follow-up

TNT: Time to First Major Cardiovascular Event*Cardiovascular Event

HR=0 78 (95% CI 0 69 0 89)0.15

HR=0.78 (95% CI 0.69, 0.89)P=0.0002

en

tsjo

ren

t atorvastatin 10 mg –achieved LDL-C 101 mg/dL (2.6 mmol/L) Relative risk

of

pati

ein

g m

aj

ula

r ev

0.10reduction =22%

ort

ion

op

eri

en

cid

iova

scu

0.05atorvastatin 80 mg –achieved LDL-C 77 mg/dL (2.0 mmol/L)

Pro

po

exp

card

0

0Time (years)

1 2 3 4 5 6

*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

Time (years)

LaRosa JC, et al. N Eng J Med. 2005;352

LDL-C & CHD Events in Statin TrialsNCEP2004

4S - PBO30 NCEP 2001

Eur Joint 2003

4S - Rx20

Secondary Prevention

LIPID Rx

LIPID - PBO

CARE - PBO

20

PROVE-IT - PRATNT - ATV10

TNT - ATV80 HPS - Rx WOSCOPS - PBOAFCAPS PBO

LIPID - Rx

CARE - Rx

CARE PBO

10Primary PreventionHPS - PBO

HPS - Rx

ASCOT - PBO

ASCOT R

PROVE-IT - ATV80

AFCAPS - Rx

AFCAPS - PBO

AFCAPS - Rx

WOSCOPS - Rx

ASCOT - Rx040

(1.0)60

(1.6)80

(2.1)100

(2.6)120

(3.1)140

(3.6)160

(4.1)180

(4.7)200

(5.2)

hi d /d ( l/ )Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269;

LaRosa J et al, N Engl J Med, 2005;352:1425

LDL-C achieved mg/dL (mmol/L)

ATP III Ri k C t i LDL C G lATP III: Risk Categories, LDL-C Goals

Risk Category LDL-C Goal (mg/dL)CHD and CHD risk equivalents <100CHD and CHD risk equivalents (10-year risk >20%)

<100

≥2 i k f t <130≥2 risk factors (10-year risk ≤20%)

<130

0–1 risk factor* <160

*Almost all people with 0–1 risk factor have a 10-year risk <10%;thus, Framingham risk calculations are not necessary.Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

NCEP ATP III : LDL-C Goals (2004 Updates)

High Risk

CHD or CHD risk

Moderately

High Risk

≥ 2 risk

Moderate

Risk

Lower

Risk≥ 2 risk < 2 risk

190

CHD or CHD risk

equivalents

( 10-yr risk

>20% )

≥ 2 risk

factors

( 10-yr risk

10-20% )

≥ 2 risk

factors

( 10-yr risk

<10% )

< 2 risk

factors

Target

160

C le

vel

160

20% ) 10 20% ) 10% )

Target

130Target

130

160mg/dL

Target

100

LDL-

C

130

130mg/dL

or

optional

130mg/dL

100mg/dL

or

optional

100

100mg/dL**

* Therapeutic option in very high-risk patients and in patients with high TG non-HDL-C<100 mg/dL;

70mg/dL*

70

Therapeutic option in very high-risk patients and in patients with high TG, non-HDL-C<100 mg/dL;** Therapeutic option; 70 mg/dL = 1.8 mmol/L; 100 mg/dL = 2.6 mmol/L;

130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

Grundy SM et al. Circulation 2004; 110:227-239

Current Clinical Guidelines : NCEP ATP III

• Initiation threshold for pharmacologic therapy: – LDL-C ≥100 mg/dL (≥2.6 mmol/L) for patients with

diabetes and CVDLDL C ≥130 mg/dL (≥3 4 mmol/L) for diabetes– LDL-C ≥130 mg/dL (≥3.4 mmol/L) for diabetes patients without CVD

» LDL-C levels of <129 mg/dL (<3 4 mmol/L)» LDL C levels of <129 mg/dL (<3.4 mmol/L), drugs may be considered

• Treatment goal: g– LDL-C <70 mg/dL (<1.8 mmol/L) for patients with

diabetes and CVD– LDL-C <100 mg/dL (<2.6 mmol/L) for diabetes

patients without CVD

Do we need another statin?

Even With Dose Titration, Many Patients Fail to A hi LDL C G lAchieve LDL-C Goals The ACCESS Study

8080 Atorvastatin 10Atorvastatin 10––80 mg80 mg

Simvastatin 10Simvastatin 10––40 mg40 mgL t ti 20L t ti 20 80 80

6060

Lovastatin 20Lovastatin 20––80 mg80 mgFluvastatin 20Fluvastatin 20––80 mg80 mg

Pravastatin 10Pravastatin 10––40 mg40 mg

4040

2020

00

At week 54, n=2543 CHD patientsAt week 54, n=2543 CHD patients

Ballantyne CM et al. Ballantyne CM et al. Am J CardiolAm J Cardiol 2001;88:2652001;88:265––269269

Cholesterol Goal Attainment in the Real World: The REALITY Taiwan StudyResults: Proportion Patients Attaining NCEP III Lipid GoalsResults: Proportion Patients Attaining NCEP III Lipid Goals

90%

70%80%90%

63.3%

50%60%70%

42.5%

30%40%50%

24.4%15.9%

10%20%30%

0%10%

Overall CHD/diabetes nonCHD 2+ nonCHD < 2Overall CHD/diabetes nonCHD 2+risk factors

nonCHD < 2risk factors

Rosuvastatin versus Comparators:LDL C Efficacy Across the Dose RangeLDL-C Efficacy Across the Dose RangeThe STELLAR Study

00

Dose, mg (log scale)Dose, mg (log scale)1010 2020 4040 8080

––1010

C f

rom

C

fro

m

%)

%)

XX––3030

––2020

n=485n=485e in

LD

Le in

LD

L--CC

seli

ne (

%se

lin

e (

%

PravastatinPravastatinXX

XX

––4040 XX

n=648n=648Ch

an

ge

Ch

an

ge

bas

bas

SimvastatinSimvastatin

**

––6060

––5050

n=473n=473n=634n=634

††‡‡ RosuvastatinRosuvastatin

AtorvastatinAtorvastatin

Adapted from Jones PH et al. Adapted from Jones PH et al. Am J CardiolAm J Cardiol 2003;92:1522003;92:152––160160

Rosuvastatin versus Comparators:LDL-C Efficacy Across the Dose RangeLDL-C Efficacy Across the Dose RangeThe STELLAR Study

00

Dose, mg (log scale)Dose, mg (log scale)1010 2020 4040 8080

––2020

––1010

LL--C

fro

m

C f

rom

(%

)(%

)

XX

XX––3030

2020

n=485n=485

ge in

LD

Lg

e in

LD

Lb

ase

lin

e (

base

lin

e (

PravastatinPravastatin

**

XX

XX––5050

––4040 XX

n=648n=648

n 634n 634

Ch

an

Ch

an bb

SimvastatinSimvastatin

––6060n=473n=473

n=634n=634

††‡‡ RosuvastatinRosuvastatin

AtorvastatinAtorvastatin

Adapted from Jones PH et al. Adapted from Jones PH et al. Am J CardiolAm J Cardiol 2003;92:1522003;92:152––160160

Results Of DISCOVERY Asia StudyResults Of DISCOVERY Asia StudyResults Of DISCOVERY Asia StudyResults Of DISCOVERY Asia Study

DIDIrect rect SStatin tatin COCOmparisonmparison of LDLof LDL--CC VValues: analues: anppEEvaluationvaluation ofof RRosuvastatinosuvastatin TherapTherapYY

China, Hong Kong, Malaysia, Korea, Taiwan, ThailandN=1 482 with 100 centresN=1 482 with 100 centresN=1,482 with 100 centresN=1,482 with 100 centres

More Patients in RSV Group Reaching 2003 European More Patients in RSV Group Reaching 2003 European LDLLDL--C and TC Target Goals After C and TC Target Goals After g fg f1212--Week TreatmentWeek Treatment

* *

00

3

*P 0 0001

hin

g 2

0C

go

als *P<0.0001

ts r

each

-C &

TC

pati

en

tan

LD

L-ce

nt

of

Eu

rop

ea

Perc E

DISCOVERY A i St dDISCOVERY A i St dDISCOVERY Asia StudyDISCOVERY Asia Study

GALAXY Programme: Areas of Investigation

Atherogenic lipid profile h l i Reduction in CV

AURORAORIONSTELLAR

Atherogenic lipid profile+/- inflammatory markers Atherosclerosis Reduction in CV

morbidity & mortality

CORONAJUPITER

METEORASTEROID

MERCURY IMERCURY II

ORBITALDISCOVERY

COMETSLUNARLUNARPLUTO

POLARISPULSAR

Completed

PULSARECLIPSE

EXPLORER

Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187–1200

Effect of Rosuvastatin on Progression of Carotid Intima

Media ThicknessMedia Thicknessin Low Risk Individuals:

Results of the METEOR Trialesults of the O ial

JAMA. 2007;297:1344-1353.

METEOR Obj tiMETEOR – Objectives

• Primary objective – to assess whether rosuvastatin therapy could slow progression of CIMT compared to placeboprogression of CIMT compared to placebo and/or induce regression of CIMT, in all sites of the carotid arterys tes o t e ca ot d a te y

• Secondary objectives – to assess whether• Secondary objectives – to assess whether rosuvastatin therapy could slow progression of CIMT compared to placebo p g p pand/or induce regression of CIMT, in the common carotid artery, in the carotid bulb and in the internal carotid arterybulb, and in the internal carotid artery

METEOR – Study Designy gDouble blind, placebo controlled, multicenter trial

Rosuvastatin 40 mg6-week

Placebo

6 week run-in/

eligibility

0 6 12 18 24

Randomization

0 6 12 18 24Months

CIMTCIMT

Lipids

Study Population: M j i l i i iMajor inclusion criteria

• Men aged 45 70 years; women aged 55 70 years• Men aged 45–70 years; women aged 55–70 years

• LDL-C ≥120 to <190 mg/dL (3.1 to <4.9 mmol/L) with no coronary heart disease (CHD) risk factor other than age

• LDL-C ≥120 to <160 mg/dL (3.1 to <4.1 mmol/L) with >1 risk factor and a 10-year CHD risk ofwith 1 risk factor and a 10 year CHD risk of <10%

T i l id <500 /dL (<5 7 l/L)• Triglycerides <500 mg/dL (<5.7 mmol/L)

• Maximum CIMT of at least 1.2 mm at any site and yless than 3.5 mm in all sites

St d E d i t P iStudy Endpoints – Primary

• Rate of change (mm/yr) in maximum CIMT based on all measurements of the carotid artery: near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery

Study Endpoints – SecondaryStudy Endpoints – Secondary

• Rate of change (mm/yr) in maximum CIMT of• Rate of change (mm/yr) in maximum CIMT of individual carotid segments – near and far walls of the right and leftof the right and left

– common carotid artery (CCA) – carotid bifurcation (bulb)– internal carotid artery (ICA)

• Rate of change (mm/yr) in mean CIMT of the near and far walls of the right and left CCAg

• Change from baseline in lipids and lipoproteinsS f• Safety

5751 subjects screened for lipids Framingham risk and5751 subjects screened for lipids, Framingham risk, and CIMT eligibility at 61 centers in the USA (24) and Europe (37)

Rosuvastatin 40 mg Placebo

984 randomized

Rosuvastatin 40 mgN = 702

N = 78

PlaceboN = 282

N = 30Did not have follow-up CIMTN = 78 N = 30

ITTN 624 (89%)

ITT

Did not have follow up CIMT

N = 624 (89%) N = 252 (89%)

N = 94 Discontinued after 6 months N = 44

Completed 2 yearsN = 530 (75%)

Completed 2 yearsN = 208 (74%)N 530 (75%) N = 208 (74%)

METEOR – Baseline CharacteristicsMETEOR – Baseline Characteristics

Rosuvastatin PlaceboRosuvastatin(n=702)

Placebo(n=282)

Male gender, n (%) 421 (60) 167 (59)Mean age (SD), years 57 (6.2) 57 (6.0)Mean BMI (SD), kg/m2 27.1 (4.0) 27.5 (4.0)2+ CHD risk factors, n (%) 223 (32) 111 (39)2+ CHD risk factors, n (%) 223 (32) 111 (39)

Smokers, n (%) 22 (3) 16 (6)Hypertension, n (%) 138 (20) 58 (21)HDL-C <40 mg/dL, n (%) 64 (9) 36 (13)

MeanMax CIMT all 12 sites (SD), mm 1.15 (0.19) 1.17 (0.20)( ),LDL-C mg/dL, mean (SD) 155 (24.1) 154 (24.2)

SD=standard deviation; BMI=body mass index; CHD=coronary heart disease; MeanMax=mean of the maximum; CIMT=carotid intima-media thickness; MeanMax=mean of the maximum; CIMT=carotid intima media thickness; LDL-C=low-density lipoprotein cholesterol

Percent Change in Lipids and LipoproteinsPercent Change in Lipids and Lipoproteins

p valuePercent change from baseline (SE)†

Rosuvastatin(n=624)

Placebo(n=252)

p value Rosuvastatin

versus PlaceboLDL-C –48.8 (0.7) –0.3 (1.1) <0.0001

HDL-C 8.0 (0.6) 2.8 (0.9) <0.0001

TC –33.7 (0.5) 0.3 (0.8) <0.0001

TG –15 7 (1 4) 10 1 (2 3) <0 0001TG 15.7 (1.4) 10.1 (2.3) <0.0001

nonHDL-C –45.1 (0.6) 0.0 (0.98) <0.0001

LDL-C/HDL-C –51.2 (0.8) –0.7 (1.2) <0.0001

ApoB/ApoA-I –41.5 (0.8) –4.5 (1.3) <0.0001

METEOR – Primary Endpointy pChange in maximum CIMT for the primary endpoint (12 carotid artery sites) estimated from the statistical model

0.03

0.04m

m)

0.01

0.02

m C

IMT

(m

-0 01

0.00

0 0

Max

imum

0 03

-0.02

-0.01

Placebo (with 95% CI)ange

in M

0 6 12 18 24-0.04

-0.03Rosuvastatin (with 95% CI)Placebo (with 95% CI)

Cha

Time (months)

Rosuvastatin Change over 2 years Primary and Secondary EndpointsEstimated from the model (ITT population)

0 03

0.04

mm

)

0.02

0.03

m C

IMT

(m

0.01

Max

imum

Mean CIMT CCA

Max CIMT ICA

-0.01

0.00

ange

in M

Max CIMT (primary)Mean CIMT CCA

Max CIMT CCAM CIMT B lb

-0.02

Cha

0 6 12 18 24

Max CIMT Bulb

Time (months)

Change in CIMTRosuvastatin versus Placebo

EndpointRosuvastatin

(mm/year) n=624Placebo

(mm/year) p value

Rosuvastatinn=252 vs Placebo

Primary variable

Max CIMT of 12 sites –0.0014 +0.0131 <0.0001

Secondary variablesSecondary variables

Max CIMT of CCA –0.0038 +0.0084 <0.0001

M CIMT f b lb 0 0040 0 0172 0 0001Max CIMT of bulb –0.0040 +0.0172 <0.0001

Max CIMT of ICA +0.0039 +0.0145 0.0228

Mean CIMT of CCA +0.0004 +0.0088 <0.0001

Change in CIMTgRosuvastatin and Placebo vs Baseline

EndpointRosuvastatin

slope (mm/year)

p value Rosuvastatin

versus

Placebo slope

(mm/year)

p value Placebo versus ( y )

n=624 baseline( y )

n=252 baseline

Primary variable

Max CIMT of 12 sites –0.0014 0.32 +0.0131 <0.0001

Secondary variables

Max CIMT of CCA –0.0038 0.004 +0.0084 <0.0001

Max CIMT of bulb 0 0040 0 11 +0 0172 <0 0001Max CIMT of bulb –0.0040 0.11 +0.0172 <0.0001

Max CIMT of ICA +0.0039 0.11 +0.0145 0.0002

Mean CIMT of CCA +0.0004 0.64 +0.0088 <0.0001

METEOR SafetyMETEOR – Safety% subjects with Rosuvastatin (n=700) Placebo adverse events (n=281)

Myalgia 12.7 12.1CK >10 X ULN 0.1‡ 0.7Rhabdomyolysis 0 0

A T 3 X U N 0 6 0 4ALT >3 X ULN 0.6 0.4

Hepatitis 0 0$Proteinuria shift$ 0.3 0.4

Renal failure 0 0

Cardiac SAEs 0.9 0

Neoplasms 1.6 1.1

D th 1/702† 0/282Deaths 1/702† 0/282

Conclusions I• In middle-aged adults with low Framingham risk

and evidence of subclinical atherosclerosisand evidence of subclinical atherosclerosis, rosuvastatin treatment over a 2-year period resulted in:resulted in:

– slowing of the rate of progression of maximum CIMT compared to placeboCIMT compared to placebo

– slowing of the rate of progression in every carotid segment compared to placebosegment compared to placebo

• The decrease in overall CIMT in the rosuvastatin group did not represent statistically significantgroup did not represent statistically significant regression. Significant regression was only observed in the maximum CIMT in the commonobserved in the maximum CIMT in the common carotid artery segment

C l i IIConclusions II

• The placebo group showed significant progression overall and in all carotid segments

• No significant progression was observed in rosuvastatin group overall or in any carotidrosuvastatin group overall or in any carotid segment during the 2 years of treatment

• There was substantial improvement in the lipid profile of the rosuvastatin group consistent

ith i t diwith previous studies

• Rosuvastatin treatment was well toleratedRosuvastatin treatment was well tolerated

ASTEROIDASTEROID

• ASTEROID used intravascular• ASTEROID used intravascular ultrasound (IVUS) to evaluate the effect of rosuvastatin (CRESTOR™) onof rosuvastatin (CRESTOR ) on atherosclerotic disease in patients with coronary artery disease (CAD)coronary artery disease (CAD)

• It investigated whether rosuvastatin canIt investigated whether rosuvastatin can induce regression of the volume of coronary artery atheromacoronary artery atheroma

The IVUS technique can detect angiographically ‘silent’ atheromasilent atheroma

Angiogram IVUSg g US

Little evidence of

No evidence of disease

disease

Atheroma

IVUS=intravascular ultrasoundNissen S, Yock P. Circulation 2001; 103: 604–616

IVUS efficacy measuresEEM Area

Changein Percent Σ n= Σ n

(EEM – Lumen)CSA

–

(EEM – Lumen)CSA

X 100 X 100LumenArea

AtheromaVolume

Σ nEEMCSA

= Σ nEEMCSA

–

(Month 24) (baseline)

X 100 X 100

(EEM – Lumen)

M t di dM t di dMost diseasedMost diseasedcontiguouscontiguous

10 cross10 cross--sectionssections

Σ (EEMCSA - LumenCSA)Normalized*

Total median number cross-number cross-sections

in patient’s pullback

TotalAtheromaVolume

=median number crosssections for all patientsx

* Normalized = adjusting for pullbacks of differing lengths thereby resulting in an equal weighting of each individual patient

Baseline and follow-up IVUS results

Example of regression of atherosclerosis with rosuvastatin in ASTEROID, measured by IVUSrosuvastatin in ASTEROID, measured by IVUS

BaselineIVUSIVUS

Atheroma Area10.16 mm2

Lumen Area6.19 mm2

Follow-upIVUS

24 th Ath A24 monthsrosuvastatin

Atheroma Area5.81 mm2

Lumen Area5.96 mm2

Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

Relationship between LDL-C levels and change in percent atheroma volume for several IVUS trials

1.8

percent atheroma volume for several IVUS trials

REVERSAL R2 = 0.97

1.2

CAMELOT placebo

pravastatinR = 0.97 P<0.001

0.6

Median change in Percent AtheromaVolume A Pl

REVERSAL atorvastatin ProgressionVolume

(%)

0

A-Plus placebo

Progression

Regression

ASTEROID rosuvastatin

1 2

-0.6

g

50 60 80 90 100 110Mean LDL-C (mg/dL)

-1.270 120

Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

Summary

• Rosuvastatin 40mg produced significant regression of atherosclerosis for all three IVUS measures assessedatherosclerosis for all three IVUS measures assessed

• Regression occurred in 4 out of 5 patients and in virtually all subgroups evaluated, including men and women, older and younger patients and in most subgroups defined by lipid levels.

• Regression of atherosclerosis was associated with aRegression of atherosclerosis was associated with a substantial reduction of LDL-C (-53%) combined with a significant increase in HDL-C (15%).

• Analysis of results from ASTEROID and other previously conducted IVUS trials confirms the strong correlation between LDL-C reduction and reduction in atheroma volume

• Rosuvastatin 40mg was well tolerated with a safety profile consistent with the existing extensive safety databaseconsistent with the existing extensive safety database

Rosuvastatin versus Comparators Change in HDL-CChange in HDL CThe STELLAR Study

10

12†

9 5

‡9.6

RosuvastatinAtorvastatinSimvastatin

5 6

8

10

5 7

*7.7

9.5

6.06.8

Pravastatin

C f

rom

%

)

3.2

4.4

5.6

4

6 5.74.8

4.4

2

5.3 5.2

ge in

HD

-ase

lin

e (

%

10 20 40 10 20 40 80 10 20 40 0

22.1

10 20 40 80

Ch

an

g ba

*p<0.002 vs pravastatin 10 mg†p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg

10 20 40 10 20 40 80 10 20 40 10 20 40 80 Dose (mg)

‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mgObserved data in ITT population

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus Comparators Change in TriglyceridesChange in TriglyceridesThe STELLAR Study

Dose (mg)( g)

10 20 40 80 10 20 40 10 20 40 80 10 20 40 0

–5

–11.9

–8.2 –7.7–10

5

TG

fro

m

(%

)

–20.0

9

–17.6

–14.8

–18.2–19.8

–13.2

–20

–15

RosuvastatinAt t tia

ng

e in

Tb

ase

lin

e

–22.6

–26.8–28.2

–23.7

† –26.1

‡

*

–30

–25Atorvastatin

PravastatinSimvastatinC

ha

*p<0.002 vs pravastatin 10, 20 mg

‡

†p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg‡p<0.002 vs simvastatin 40 mg; pravastatin 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin Tolerability and Safety -Wi hd l d Ad EWithdrawals due to Adverse Events

Percentage of patients with an adverse event leading to withdrawalleading to withdrawal

8

7

6

Patients 5

7

2

4(%)

32.9%

2.5% 2.5%3.2%

0

2

t ti i t ti t ti

1

t t ti

10–40 mg10–80 mg10–80 mg10–40 mg

rosuvastatin simvastatin pravastatin(n=3074) (n=1457) (n=1278)

atorvastatin(n=2899)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

Putting Statin Risks and Benefits into ContextPutting Statin Risks and Benefits into Context

DRUGS

Comparing with other risks

Lovastatin20/80 mg

Fluvastatin20/80 mg

Simvastatin20/80 mg

Pravastatin20/80 mg

Atorvastatin10/80 mg

Rosuvastatin10/40 mg

1927 28

35 37

0

10

20n LD

L-C

4612

10 12

12

20

30

40

% R

educ

tion

in

3137*

4018

950

60

%

47

55 55

10 20 40 80 mg

Statin

L-R

educ

tion

(%)

-10-20-30

+10 mg

6%

+20 mg +40 mg

LDL - 6%

- 6% - 6%

-40-50

Adverse ff t

0 51,01,52,02,5

% P

atie

ntseffects

Med Clin North Am. 2000; 84:23

10 mg 20 mg 40 mg 80 mg0

0,5

20 mg 40 mg 80 mg

%

40 mg 80 mgAtorvastatin Lovastatin Simvastatin

20 mg

R l i hi B ChRelationship Between Changesin LDL-C and HDL-C Levels and CHD Risk

1% decreasein LDL-C reduces 1% increasein LDL C reduces

CHD risk by1%

1% increasein HDL-C reduces

CHD risk by2 3%2-3%

Third Report of the NCEP Expert Panel. NIH Publication No 01-3670 2001.http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

INHIBITION OF ATHEROSCLEROSIS BY HDLINHIBITION OF ATHEROSCLEROSIS BY HDLHDL INHIBIT ADHESION MOLECULE EXPRESSIONHDL INHIBIT ADHESION MOLECULE EXPRESSION

MonocyteMonocyte

Vessel LumenVessel LumenLDLLDL

HDL INHIBIT ADHESION MOLECULE EXPRESSIONHDL INHIBIT ADHESION MOLECULE EXPRESSIONHDL INHIBIT MCPHDL INHIBIT MCP--1 EXPRESSION1 EXPRESSION

AdhesionAdhesionM l lM l l EndotheliumEndothelium

LDLLDL

MoleculeMolecule EndotheliumEndotheliumLDLLDLMCPMCP--11

HDL INHIBITHDL INHIBITOXIDATION OF LDLOXIDATION OF LDL

CytokinesCytokines MODIFIED LDLMODIFIED LDL

OXIDATION OF LDLOXIDATION OF LDL

IntimaIntimaMODIFIED LDLMODIFIED LDL

MacrophageMacrophage FoamFoamMacrophageMacrophage Foam Foam CellCellHDL PROMOTE CHOLESTEROL EFFLUXHDL PROMOTE CHOLESTEROL EFFLUX

Statins, High-Density Lipoprotein Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary AtherosclerosisCholesterol, and Regression of Coronary AtherosclerosisCoronary AtherosclerosisCoronary Atherosclerosis

Stephen J. Nicholls, MBBS, PhD; E. Murat Tuzcu, MD; Ilke Stephen J. Nicholls, MBBS, PhD; E. Murat Tuzcu, MD; Ilke Sipahi, MD; Adam W. Grasso, MD; Paul Schoenhagen, MD; Sipahi, MD; Adam W. Grasso, MD; Paul Schoenhagen, MD; p gp g

Tingfei Hu, MS; Kathy Wolski, MPH; Tim Crowe, BS; Tingfei Hu, MS; Kathy Wolski, MPH; Tim Crowe, BS; Milind Y. Desai, MD; Stanley L. Hazen, MD, PhD; Samir Milind Y. Desai, MD; Stanley L. Hazen, MD, PhD; Samir

R. Kapadia, MD; Steven E. Nissen, MDR. Kapadia, MD; Steven E. Nissen, MDR. Kapadia, MD; Steven E. Nissen, MDR. Kapadia, MD; Steven E. Nissen, MD

Published in JAMAPublished in JAMA

February 7 2007February 7 2007February 7, 2007February 7, 2007

Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis:and Regression of Coronary Atherosclerosis: Study Design1455 patients from 4 trials (REVERSAL CAMELOT ACTIVATE ASTEROID) with CAD1455 patients from 4 trials (REVERSAL, CAMELOT, ACTIVATE, ASTEROID) with CAD

undergoing serial intravascular ultrasonography while receiving statin treatment.Post-hoc analysis of raw data from the four prospective, randomized trials. Follow-up at 18 or 24 months.

Exclusion criteria: Target segment selected was required to have no greater than 50% lumen narrowing for a g g q g glength of at least 30 mm and target vessel required to have not previously undergone percutaneous coronary

intervention.

REVERSAL CAMELOT ACTIVATE ASTEROID

n=502

18 or 24 mos. follow-up18 or 24 mos. follow-up

n=240 n=364 n=349

Primary Endpoint: Relationship between changes in LDLPrimary Endpoint: Relationship between changes in LDL--C and C and

pp

HDLHDL--C levels and atheroma burden.C levels and atheroma burden.

Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508. Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

Statins, HDL-Cholesterol, and Regression f C Ath l i R ltof Coronary Atherosclerosis: Results

• In multivariate analysis mean levels of LDL-C (β• In multivariate analysis mean levels of LDL-C (βIn multivariate analysis, mean levels of LDL C (βcoefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (β coefficient, -

In multivariate analysis, mean levels of LDL C (βcoefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (β coefficient, -0.15]) and increases in HDL C (β coefficient, 0.26 [95% confidence interval, -0.41-0.10]) remained independent predictors of atheroma regression.

0.15]) and increases in HDL C (β coefficient, 0.26 [95% confidence interval, -0.41-0.10]) remained independent predictors of atheroma regression.independent predictors of atheroma regression.

• Substantial atheroma regression (≥5% reduction in atheroma volume) was observed in patients with

independent predictors of atheroma regression.• Substantial atheroma regression (≥5% reduction in

atheroma volume) was observed in patients withatheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-

atheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-during treatment and percentage increases of HDL-C greater than the mean (7.5%; P<0.001).during treatment and percentage increases of HDL-C greater than the mean (7.5%; P<0.001).

Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508. Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

Rosuvastatin versus Comparators Change in HDL-CChange in HDL CThe STELLAR Study

10

12†

9 5

‡9.6

RosuvastatinAtorvastatinSimvastatin

5 6

8

10

5 7

*7.7

9.5

6.06.8

Pravastatin

C f

rom

%

)

3.2

4.4

5.6

4

6 5.74.8

4.4

2

5.3 5.2

ge in

HD

-ase

lin

e (

%

10 20 40 10 20 40 80 10 20 40 0

22.1

10 20 40 80

Ch

an

g ba

*p<0.002 vs pravastatin 10 mg†p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg

10 20 40 10 20 40 80 10 20 40 10 20 40 80 Dose (mg)

‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mgObserved data in ITT population

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

HDL V L LDLHDL, Very Low LDL

N Engl J Med 2007;357:1301-10.

Plasma cholesterol transport

LiverLiver VLDLVLDL

CECE

CECE

CECETGTGTGTG FFAFFA

LPLLPLFCFC

CECE CECE

LDLLDL Adipose andAdipose andother tissuesother tissuesFFAFFA

CECETGTG LiverLiver

LDL receptorLDL receptorAdiposeAdiposetissuetissue

LDL receptorLDL receptorCETPtissuetissue

FCFC

CECE

Cell inCell inCECEHDLHDL LCATLCAT

TGTGNewNew

synthesissynthesis

Cell inCell inperipheral tissueperipheral tissue

LCATLCAT

ILLUMINATE trialPfi (N Y k NY) d th l• Pfizer (New York, NY) announced the early termination of the ILLUMINATE trial on December 2, 2006.,

• Phase 3 clinical trial with the CETP inhibitor, torcetrapib, had begun only 18 months earlier.

– enrolling about 15,000 patients – torcetrapib 60 mg plus atorvastatin vs atorvastatin 10-80

mg.mg. – The primary endpoint of the trial was first occurrence of

a major cardiovascular event. t i l h ld b t d• trial should be stopped

– 80 deaths in the torcetrapib/atorvastatin arm vs 51 in the atorvastatin-alone arm (HR, 1.58; 95% CI, 1.14-2.19; P =atorvastatin alone arm (HR, 1.58; 95% CI, 1.14 2.19; P .006)

– rates of MI, revascularization, angina, and heart failure were higher (hazard ratio [HR] 1 25; 95% confidencewere higher (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.09- 1.44; P = .001)

ILLUMINATE t i lILLUMINATE trial

• Mean increase of 72.1% in high-density lipoprotein cholesterol (HDL-C);

• Mean decrease of 24.9% in LDL-C; and

• Small mean decrease of 9% in triglycerides compared with baselinecompared with baseline.

* ll P < 001 t t ti l*all P < .001 vs atorvastatin only

Activation of RAAS

• K+ ↓, Na+↑• HCO3

- ↑3 ↑• serum aldosterone ↑

systolic blood pressure observed in this groupaveraged 4.6 mm Hg, with 21.3% of patients exceeding140/90 mm Hg and 9 0% having a sustained140/90 mm Hg and 9.0% having a sustainedincrease of more than 15 mm Hg.

AntiAnti Atherogenic ParticlesAtherogenic ParticlesAntiAnti--Atherogenic ParticlesAtherogenic Particles

HDLHDL2a2aHDLHDL2b2b HDLHDL3c3cHDLHDL3b3bHDLHDL3a3a

• HDL-Cdysfunctionality• unknown effects of CETP inhibition may have contributedto a mechanism-related adverse outcome.

ENHANCE t i lENHANCE trial• 720 patients with heterozygous familial• 720 patients with heterozygous familial

hypercholesterolemia

• patients treated with ezetimibe/simvastatin 10/80 mg vs patients treated with simvastatin10/80 mg vs patients treated with simvastatin 80 mg alone over a two-year period.

• mean change in the intima media thickness (IMT) measured at three sites in the carotid ( )arteries

ENHANCE trialENHANCE trial

Ezetimibe plus Simvastatin p Ezetimibe plus simvastatin

Simvastatin alone

p

Baseline LDL (mg/dL) 319 318 NSReduction after 2-y

treatment (%)58 41 <0.01

End point Ezetimibe plus i i

Simvastatil pEnd point simvastatin n alone p

Change in mean carotid 0.0111 0.0058 0.29 IMT after 2-y treatment (mm)

Pleiotropic Effects of Statin

(JAMA 1998;279:1643-50.)(JAMA 1998;279:1643-50.)

Direct Cardiac Effects of Lipids and Statinsp

• Mechanical function• Mechanical function

• Electrical stability

Statin Use in DCM (DEFINITE)

[Goldberger et al, J Am Coll Cardiol 2006; 48:1228 –33.]

Statin Use in DCM (DEFINITE)

[Goldberger et al, J Am Coll Cardiol 2006; 48:1228 –33.]

Statin Treatment in Patient with DCM (BEST)

[Domanski et al; Am J Cardiol 2007;99:1448 1450][Domanski et al; Am J Cardiol 2007;99:1448–1450]

COntrolled ROsuvastatin MultiNAtional Trial in Heart Failure

Kjekshus J et al N Eng J Med 2007; 357Kjekshus J et al. N Eng J Med 2007; 357

d i d bl li d l b ll dCORONA - Study DesignA Randomized, Double-Blind, Placebo-Controlled Study with Rosuvastatin in Patients with Chronic

Symptomatic Systolic Heart FailurePatients (n=5011)

Chronic ischaemic systolic End points:

Symptomatic Systolic Heart Failure

Chronic ischaemic systolic heart failure receiving optimal HF treatment (diuretics, ACE inhibitors, ARBs, beta-blocker therapy)

rosuvastatin 10 mg (n=2514)End points:

Time to cardiovascular death, non-fatal MI, non-fatal

Ejection fraction≤0.40 (NYHA class III/IV)or ≤0.35 (NYHA class II)

≥60 years

placebo (n=2497)

MI, non fatal stroke

Total mortality

≥60 years

Visit:Week:

1–8 to –2

2–4 to –2

30

46

5–213 monthly

Final~3 y

Eligibility Optimal HF treatment

instituted

Median follow-up 2.7 yearsPlaceborun-in

instituted

Kjekshus J et al. Eur J Heart Fail 2005;7:1059-1069

CORONA - Study EndpointsPrimary • Time to the first occurrence of cardiovascular death

oror non-fatal MI or non-fatal stroke (time to first event)

Secondaryy• Total mortality • Time to any coronary event (time to first event) • Cardiovascular mortality• Number of hospitalisations for cardiovascular causes Tertiary• Change from baseline in lipid, lipoproteins and

inflammatory markersinflammatory markers• Safety, tolerability, functional state, patient-reported

outcomes, health economics ,

Kjekshus J et al. N Eng J Med 2007; 357 doi 10.1056/NEJMoa0706201

CORONA - Current medications Medication Placebo Rosuvastatin

n=2497 n=2514

Loop diuretic (%) 75 76Loop or thiazide diuretic (%) 88 89 Loop or thiazide diuretic (%) 88 89 Aldosterone antagonist (%) 39 39ACE inhibitor (%) 80 80ACE inhibitor or ARB (%) 92 91Beta-blocker (%) 75 75Digitalis (%) 32 34Digitalis (%) 32 34Antiarrhythmic (%) 12 12Antiplatelet (%) 60 59Antiplatelet (%) 60 59Anticoagulant (%) 34 36Antiplatelet or anticoagulant (%) 90 90

ARB – Angiotensin Receptor Blocker

Kjekshus J et al. N Eng J Med 2007; 357 doi 10.1056/NEJMoa0706201

CORONA - Primary EndpointThe combined endpoint of cardiovascular death or non-fatal MI orThe combined endpoint of cardiovascular death or non fatal MI or non-fatal stroke (time to first event)

30Placebo

Rosuvastatin 10 mg

wit

hn

t

20

tien

ts w

en

dp

oin

An 8% reduction8% reduction was observed in the primary endpoint in

nt

of

pa

mary

e

primary endpoint in patients taking CRESTOR 10mg compared to placebo. Thi diff

Hazard ratio = 0.9295% CI 0.83 to 1.02

p=0 12

10

Perc

en

pri This difference was

not statistically significant (p=0.12)

p=0.12

0 363024181260

Months of follow-upNo. at riskPlacebo 2497 2315 2156 2003 1851 1431 811Rosuvastatin 2514 2345 2207 2068 1932 1484 855

CORONA - Secondary EndpointsT l b f h i li iTotal number of hospitalizationsAmong secondary endpoints, significantly fewer hospitalisations occurred in patients on CRESTOR whether

f

4 074

due to any cause (p=0.007), CV cause (p<0.001), or for worsening heart failure (p=0.01)

4,0743,694

3,000

4,000

Placebo (n=2,497)Rosuvastatin 10 mg (n 2 514)sa

tio

ns

2,464

1,510

2,193

1,5012,000

3,000 Rosuvastatin 10 mg (n=2,514)

osp

italis

1,2991,510

1,1091,501

1,000No

. h

o

p=0.01p=0.007 p<0.001

0Heart failureAll cause CV cause Non-CV cause

Kjekshus J et al. N Eng J Med 2007; 357 doi 10.1056/NEJMoa0706201

CORONAEffects on LDL-C, HDL-C, TG and CRP at 3 months;

Absolute difference between rosuvastatin and placebo

10 LDL-C HDL-C TG CRP

ce

5.0%

-10

0

dif

fere

nc

e (

%)

5.0%

p<0.001

-20

gro

up

d b

ase

lin

e

20.5%

p<0.001

-40

-30

etw

een

fr

om

45%

37.1%

p<0.001

-50

B

p<0.001

CORONACORONATolerability and safety dataTolerability and safety data

Placebo Rosuvastatin[n=2497] [n=2514]no. of pts no. of pts

Discontinuation of study drug1 546 490adverse event2 302 241patient unwilling to continue 162 187p gother reason 82 62

1Hazard ratio 0 88; 95 CI 0 78 to 0 99; p= 0 031Hazard ratio 0.88; 95 CI 0.78 to 0.99; p= 0.032Hazard ratio 0.78; 95 CI 0.66 to 0.92; p= 0.004

Kjekshus J et al. N Eng J Med 2007; 357 doi 10.1056/NEJMoa0706201

CORONACORONALaboratory safety data Placebo RosuvastatinLaboratory safety data

CK > 10 x ULN

Placebo Rosuvastatin[n=2497] [n=2514]no. of pts no. of pts

CK > 10 x ULNCK > 10 x ULN 3 1CK > 10 x ULN and muscle symptoms 1 0

ALT > 3 x ULN At least one occasion 24 25>1 occasion 5 3

Serum creatinineDoubling of serum creatinine 32 23Baseline mg/dL (µmol/L) 1.30 (115)1 1.30 (115)2Baseline mg/dL (µmol/L) 1.30 (115) 1.30 (115)Last visit mg/dL (µmol/L) 1.45 (128)1 1.41 (125)2

1n=1553 2n=1619

Kjekshus J et al. N Eng J Med 2007; 357 doi 10.1056/NEJMoa0706201

CORONA – summary• CORONA was a novel and challenging study in heart failure

patients assessing, for the first time, the effect of statin th bidit d t lit d btherapy on morbidity and mortality, over and above optimised heart failure treatment

• In this elderly heart failure population on extensive heart• In this elderly heart failure population on extensive heart failure medication, rosuvastatin 10 mg did not reduce the primary composite cardiovascular outcome or all-cause mortalitymortality

• There were significantly fewer hospitalizations with rosuvastatin compared with placebo (whether due to anyrosuvastatin compared with placebo (whether due to any cause (p=0.007), cardiovascular causes (p<0.001) or for worsening heart failure (p=0.01)

• In this elderly heart failure population rosuvastatin 10 mg was tolerated in over 2,500 patients with a safety profile similar to placebop

Efficacy Safety

moremore Statins

Evidence Cost EffectivenessEvidence Cost-Effectiveness

Thank you for your attention !y f y

The Pyramid of Recent Statin TrialsThe Pyramid of Recent Statin TrialsRelative Size of the Various

Very high cholesterol with CHD or MI 4S

Segments of the Population

CHD or MI

Moderate high cholesterol in high risk CHD or MI

4S

LIPID, PLAC I / II, KAPS, REGRESS

Normal cholesterol with CHD or MI

CARE

WOSCOPSHigh cholesterol with NO CHD or MI

No history of CHD or MI, average TC

WOSCOPS

AFCAPS/TexCAPS

and LDL-C, but below average HDL-C

High CHD risk patients regardless of the cholesterol or LDL-C level

HPS, ASCOT-LLA

of the cholesterol or LDL C level

Present Status of Statin TreatmentPresent Status of Statin Treatment• For CAD:

– Primary prevention, Secondary prevention– ACS (MIRACL)

• Lipid levels– The lower, the better– Aggressive lipid lowering is associated with

more favorable outcomes (ADVERT)• CHD risk status• CHD risk status

– There has to be a change in emphasis away from the concept of a "normal lipid profile." Instead, the emphasis should be on risk factors predisposing to CADshould be on risk factors predisposing to CAD.

– Present clinicians need to place less emphasis on lipid levels and more importance on risk stratification of the patientpatient.

Vascular Benefits of Statin f f

Ch l t l Bi th ti P thSqualene

Cholesterol Biosynthetic Pathway

synthaseDolicholHMG-CoA

reductase

AcetylCoA

HMG-CoA

Mevalonate Farnesylpyrophosphate Squalene Cholesterol

Farnesyl-transferase

E,E,E-Geranylgeranyl

Farnesylatedproteins

pyrophosphate

Geranylgeranylated Ubiquinones

Rasprotein

Geranylgeranylatedproteins

Ubiquinones

Rho, Rac, Rab, Rapprotein

Pleiotropic Effects of Statin• Improvement of endothelial

function• Plaque modifying effects

– VSMC proliferation and i ti– eNOS expression and activity

– NO synthesis – ET-1 synthesis

migration – VSMC aptosis – Neointimal thickening

• Antioxidant effects• Anti-inflammatory effects

– MØ proliferation and migration

– MØ MMP expression and – LECA – EC adhesion molecules – LK adhesion molecules

psecretion

• Antithrombotic effectsPl t l t ti ti– Proinflammatory cytokines

– HMC II expression

• Antiangiogenic effects

– Platelet activation – TF expression by MØ – SMC & EC PAI-1 expression Antiangiogenic effects

– EC migration – Vascular VEGF expression

– EC tPA expression • Proangiogenic effects

EPC– Vascular MMP expression – EPC

[European Heart Journal 2003, 24: 225–248]

Pleiotropic Effects of Statin

[European Heart Journal 2003, 24: 225–248]

Direct Cardiac Effects of Lipids and Statinsp

• Mechanical function• Mechanical function

• Electrical stability

Systolic Function in Patients with Systolic Function in Patients with Dyslipidemia

LVEF in patients after AMI LVEF in patients with stable angina

Baseline LDL value versus post-M350

l)

350

300

250

LDL

(mg/

d

200

150

100

908070605040302010

100

50

0

[Wang et al; Am J Cardiol, 1998; 81: 531-7]

LVEF(%)

[Wang et al; Am J Cardiol, 1998; 81: 531 7][Wang et al; Atherosclerosis 146 (1999) 117–124]

Reduced positive inotropic response to i t l i ill l f HC bbit

)

16

isoproterenol in papillary muscle from HC rabbits

orce

(fol

d

12

14tr

actil

e fo

8

10

e of

con

t

4

6

Incr

ease

2

4Control group (n=7) Hypercholesterol group(n=10)

Concentration of isoproterenol (M)10(-10)3*10(-10) 10(-9) 3*10(-9) 10(-8) 3*10(-8) 10(-7) 3*10(-7) 10(-6)

0

[Lo et al; submitted]

Decreased Systolic Function in HC RabbitsDecrease in cyclic variation of integrated backscatterDecrease in mitral ring systolic velcityIncrease in Tei indexIncrease in Tei index

HC rabbit

Control rabbit

[Lin, et al; submitted]

Decreased Systolic and Diastolic Function in Single Myocyte from HC Rabbits

[Huang et al, Circulation. 2004;109:97-102.]

Impaired Intracellular Calcium Handling Impaired Intracellular Calcium Handling in Single Myocyte from HC Rabbits

[Huang et al, Circulation. 2004;109:97-102.]

Statin Treatment in Patient with DCM

[Node et al, Circulation. 2003;108:839-843.]

Statin Treatment in Patient with DCM

[Node et al, Circulation. 2003;108:839-843.]

Statins and CRP

[Ann Intern Med. 2003;139:670-682]

Lipid profiles and VT/VF during theVT/VF during the acute stage of MI

[Liu, et al; submitted]

Lipid profiles and VT/VF during h f MI M l i i bl A l i

OROR 95% CI95% CI P value P value the acute stage of MI: Multivariable Analysis

3-month lipid profileT i l id /dlT i l id /dl 1 051 05 0 710 71 1 541 54 0 82460 8246Triglyceride, mg/dl Triglyceride, mg/dl 1.051.05 0.710.71--1.541.54 0.82460.8246LDLLDL--CC, mg/dl, mg/dl 3.893.89 1.741.74--8.698.69 0.0009 0.0009

Difference in 1 & Difference in 1 & 33--monthmonth lipid profilelipid profilep p fp p f

TriglycerideTriglyceride, mg/dl , mg/dl 1.541.54 1.011.01--2.34 2.34 0.04660.0466LDLLDL--C, mg/dlC, mg/dl 1.321.32 0.470.47--3.713.71 0.59900.5990

Mean BP on arrivalMean BP on arrival,, 0.440.44 0.260.26--0.75 0.75 0.0025 0.0025 mmHgmmHgmmHgmmHg

[Liu, et al; submitted]

Hypercholesterolemic Rabbits5 m/o Sacrificed

St d d hfor 8 weeks

Standard chow(n=4)

2 m/oHigh fat and

cholesterol chow ( 3)cholesterol chow (n=3)for 8 weeks

High fat and cholesterol chow for 6 weeks (n=3)

followed by Standard chow for 2 weeks

Blood sampling

(n=3)

Blood samplingHistological study

[Liu et al; Circ Res. 2003 May 30;92(10):1145-52.]

Nerve Sprouting and Sympathetic Hyperinnervation

[Liu et al; Circ Res. 2003 May 30;92(10):1145-52.]

Never Sprouting and Sudden Cardiac Death• There is an association between a

history of spontaneous ventricular arrhythmia and an increasedarrhythmia and an increased density of sympathetic nerves in patients with severe heart failure. (i 6 h i l i )(in 65 human ventricular tissue)

[Cao et al; Circulation. 2000;101:1960-1969.]

• In dogs with MI + cAVB + NGF infusion to L. stellate ganglion

E

C [Cao et al; Circ Res,[Cao et al; Circ Res, 2000; 86:816-821.]

300300Mean of APD80 Max. of APD80

B.A. Rabbit 1 (ms)(ms)

APD and APD Dispersion

250

300

250

300 80 80

* **

*

150

20012000 120 240 360 480 600 720 840 960 1080

150

200HC Rabbit 2

50

100

400 ms 300 ms 200 ms12000 120 240 360 480 600 720 840 960 1080

50

100

400 ms 300 ms 200 ms

60

70Difference of APD8015

SD of APD80Rabbit 1 (ms)(ms)

† † **

30

40

5010

S 12000 120 240 360 480 600 720 840 960 1080

Rabbit 2

10

205

0400 ms 300 ms 200 ms

0400 ms 300 ms 200 ms

HC S

12000 120 240 360 480 600 720 840 960 1080

[Liu et al; Circ Res. 2003 May 30;92(10):1145-52.]

Calcium Inward Current of Myocyte

2-50 -30 -10 10 30 50 70(mv)

Capacitance: 99 pF

-50 -30 -10 10 30 50 70(mv)

S

-4100 ms

1 nA

S

HC

*Capacitance: 144 pF

-10HC

A/p

F)

HC

†IC

a (p

AHC

*

†

†1 nA

-16†

100 ms[Liu et al; Circ Res. 2003 May 30;92(10):1145-52.]

Down-regulated myocardial Cx43 g yprotein expression

HC bbit C t l bbitHC rabbits Control rabbits

[Lin, et al; submitted]

S S 600 S S 280A. EP study at room temperature C. EP study at 37˚C; Isoproterenol 0.1μM

Vulnerability to Ventricular Fibrillation

S1-S1=600 ms, S1-S2=280 ms

HC(1) Onset of Ventricular Fibrillation

HC

S

B EP t d t 37˚C b li

HC

B. EP study at 37˚C; baseline

HC

S1-S1=400 ms, S1-S2=190 ms HC

SHC

(2) Re-initiation after DC shockS1-S1=400 ms, S1-S2=170 ms

S

S

1000 ms

S1-S1=400 ms, S1-S2=250 ms, S2-S3=190 ms

( )S

HC

S1-S1=400 ms, S1-S2=230 ms, S2-S3=170 ms

HC HC

S1000 ms

S3 0 sS

S

[Liu et al; Circ Res. 2003 May 30;92(10):1145-52.]

Lipid-lowering Therapy in AVID study• Patients who had been

resuscitated from near-f t l VF dfatal VF or undergone cardioversion for VT/VF

• In patients with ICD:In patients with ICD:83 patients with LL Rx and 279 without LL Rx

• Mean LVEF ≈ 32%• Comparable β-blocker

use in both group

A more conservative d i i h l ireduction in the relative

risk of VT/VF recurrence of 40% by 16 mof 40% by 16 m.

[Mitchell et al; J Am Coll Cardiol 2003; 42(1): 81-7.]

Heart Rate Variability and Atorvastatin

[Pehlivanidis et al; [Pehlivanidis et al; AtherosclerosisAtherosclerosis 2001; 157: 4632001; 157: 463--9] 9]

C di Eff t f St tiCardiac Effects of Statin

• Reversing the detrimental effects of dyslipidemia on the mechanical function y pand electrical instability of hearts

• Additional cardioprotective effects via pleiotropic effects of statins

Translating results of experimental g f pstudies to clinical practiceStatins always modify serum cholesterol levels• Statins always modify serum cholesterol levels to some extent and , thus, it is impossible to differentiate possible lipid-independent effects p p pfrom those associated with lipid reduction.

• Analysis of lipid-independent effects may be not possible in the in vivo settingnot possible in the in vivo setting

• Direct evidenceVery short term effects which appear within 1st– Very short-term effects which appear within 1st day or hours before changes of lipid levels

– Short-term effect vs. long-term therapiesg p• Indirect evidence

– Similar lipid levels with/without statin treatmentp– Treating normocholesterolemic patients

HPS: Average LDL Difference (mmol/l ± SE) S: ve age iffe ence (mmol/l S )by BASELINE LDL

Baseline feature

STATIN (10,269)

PLACEBO (10,267)

Difference in LDL

LDL (mmol/l)

<3 0 (116 /dl) 1 8 2 7 0 90 ± 0 02<3.0 (116 mg/dl) 1.8 2.7 -0.90 ± 0.02≥3.0<3.5 2.2 3.2 -0.96 ± 0.03 ≥3.5 (135 mg/dl) 2.7 3.7 -1.00 ± 0.03

ALL PATIENTS 2 3 3 3 0 96 ± 0 02ALL PATIENTS 2.3 3.3 -0.96 ± 0.02

Reductions in Total and LDL Ch l lCholesterol

6Atorvastatin 10 mg Placebo

200ol

4

200

150

mg/

dL)

chol

este

rom

ol/L

)1.3 mmol/L

(50mg/dL)

24% reduction

1.0 mmol/L

(39mg/dL)

19% reduction

2

100

(m

Tota

l c (m

20 1 2 34 150

125 )rol

2

3

75

125

100

(mg/

dL)

chol

este

mm

ol/L

) 1.2 mmol/L

(46mg/dL)

35% reduction

1.0 mmol/L

(39mg/dL)

29% reduction

10 1 2 3

75

LDL (

Close-out0 1 2 3Years

Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

Close-out

HPS: Clinical implicationsHPS: Clinical implications

• A statin should be considered for anybody with• A statin should be considered for anybody with a history of CHD, stroke, other occlusive vascular diseases or diabetes, regardless ofvascular diseases or diabetes, regardless of their initial blood cholesterol levels

• There is little (or no) need to measureThere is little (or no) need to measure cholesterol levels before using statin drugs

• Regular safety monitoring (CK ALT) during• Regular safety monitoring (CK, ALT) during statin treatment has little clinical relevance

In fact, statins are the new “safe aspirin”

Eli ibilit C it iALLHAT Eligibility CriteriaALLHAT

Moderate hypercholesterolemia

• LDL 120-189 mg/dLwithout CHDwithout CHD

LDL 100 129 /dL• LDL 100-129 mg/dL with known CHDwith known CHD

LDL-C ALLHATLDL C150

mg/

dL

140 7% *

11%

L-C

in m

120

130

16%

LD

110

120 Usual Care23%

28% 30%

100

110

Pravastatin

28% 30%* Percent decrease from baseline.

0 2 4 6Year of Blood DrawNo. of Participants

Pravastatin 5129 850 572 157Usual Care 5131 508 330 75

All-Cause Mortality% 15

All Cause MortalityR

ate,

%

12

15

orta

lity

9 Usual CarePravastatin

ativ

e M

RR = 0.996

Cum

ula

95% CI = (0.89, 1.11) p = 0.88Pravastatin/Usual Care

0

3

Time to Death, years0 1 2 3 4 5 6

0

No. at Risk

Pravastatin 5170 5088 4956 4809 3819 2173 1132

Usual Care 5185 5104 4994 4845 3832 2179 1138

Results: TH-positive (sympathetic) NerveControl Withdrawal TH Nerve Density

p ( y p )

15000

20000

m2 /m

m2 )

†

10000

15000

*††

ensi

ty (μ

m

5000Statin HC

Ner

ve D

0THTH

Control WithdrawalControl WithdrawalStatin HC

* p<0 05 as compared with HC group; p<0 05 as compared with control group† p<0.05 as compared with HC group; p<0.05 as compared with control group

Ezetimibe + Simvastatin Coadministration Study:

Median % Change From Baseline to Endpoint in C-Reactive Protein

zeti ibe Si vastati Coad i ist atio Study:Effect of EZETROL on CRP

PooledMedian % Change From Baseline to Endpoint in C-Reactive Protein

1012%

Simva Simva Simva Simva

Individual Dose Groups10

ange

1%0

Simva10 mg

Simva20 mg

Simva40 mg

Simva80 mg

0(n=232) (n=227)

(n=62) (n=54)

(n=57) (n=57) (n=55) (n=54) (n=60) (n=62) (n=60) (n=54)

ian

% C

ha

-13%-12%-10 -10

Med

i

-18%

27%†30

-20

-24%29%30

-20

Placebo

-31%‡-27%†

-35%*-40

-30

-40%†

-29%

-36%†-40

-30SimvaEZTROLEZETROL +

*P<0.01 Combination versus statin alone.†P<0.05 Combination versus statin alone.‡P=0.09 Combination versus statin alone.

-40%†Simva

Simva + Placebo EZETROL +Simva