The Importance on Early Time to CV Benefit and What Are the~

CURRICULUM VITAECURRICULUM VITAEDr. Antonia Anna Lukito,Dr. Antonia Anna Lukito, SpJPSpJP, FIHA,, FIHA, FAPSICFAPSIC, FSCAI, FSCAI

EDUCATION:EDUCATION:••Medical Faculty,Medical Faculty, AirlanggaAirlangga University, 1988University, 1988••Cardiology Department, Indonesia University, 1997Cardiology Department, Indonesia University, 1997••Advance CardiologyAdvance Cardiology Course,VictoriaCourse,Victoria Heart Center, Melbourne,Heart Center, Melbourne,

Australia, 1996 & 2000Australia, 1996 & 2000••Pacemaker & Interventional Cardiology, NPacemaker & Interventional Cardiology, Nationalational CCardiacardiac CCenterenter, 2004, 2004••Cardiovascular CT Training, Cologne, Germany, 2005Cardiovascular CT Training, Cologne, Germany, 2005ORGANIZATION:ORGANIZATION:ORGANIZATION:ORGANIZATION:••Scientific & Education Committee of PERKIScientific & Education Committee of PERKI BantenBanten••CommitteeCommittee of PERKIof PERKI PusatPusat••Organization CommitteeOrganization Committeeofof Indonesian Society of Hypertension (Indonesian Society of Hypertension (InaSHInaSH))••OrganizationOrganization CComitteeomittee of Indonesian Society of Interventional Cardiology (ISIC)of Indonesian Society of Interventional Cardiology (ISIC)••Fellow of AsiaFellow of Asia--Pacific Society of InterventionalPacific Society of Interventional CardiologyCardiology (APSIC)(APSIC)••Fellow of Society for Cardivascular Angiography & Interventions (SCAI)Fellow of Society for Cardivascular Angiography & Interventions (SCAI)••Fellow of Indonesian HeartFellow of Indonesian Heart AssociationAssociation (IHA)(IHA)••Member of IDIMember of IDIPROFESSIONAL EXPERIENCES:PROFESSIONAL EXPERIENCES:••Heart Center, Siloam Hospitals,Heart Center, Siloam Hospitals, KarawaciKarawaci••Lecturer of UPH medical facultyLecturer of UPH medical faculty

Vasculoprotective Effect of Statin:Vasculoprotective Effect of Statin:Early Time to CV BenefitEarly Time to CV BenefitEarly Time to CV BenefitEarly Time to CV Benefit

Antonia Anna LukitoAntonia Anna Lukito

Relationship Between Cholesterol and CHD RiskRelationship Between Cholesterol and CHD Risk ::

The Framingham StudyThe Framingham Study

75

100

125

150

CH

Din

cid

en

cep

er

10

00

(Adapted from Castelli WP, 1984)

0

25

50

75

204 205–234 235–264 265–294 295

CH

Din

cid

en

cep

er

10

00

Serum cholesterol (mg/100 mL)

ACSACS

CoronaryCoronaryThrombosisThrombosis

MyocardialMyocardialIschemiaIschemia

Arrhythmia andArrhythmia andLoss of MuscleLoss of Muscle

RemodelingRemodeling

VentricularVentricular

SecondarySecondarypreventionprevention

StrokeStroke

The Cardiovascular Continuum of EventsThe Cardiovascular Continuum of Events

CADCAD

AtherosclerosisAtherosclerosis

Risk FactorsRisk Factors

(( DyslipidemiaDyslipidemia,, BP, DM, InsulinBP, DM, Insulin

Resistance, Platelets, Fibrinogen, etc)Resistance, Platelets, Fibrinogen, etc)Adapted fromAdapted from

DzauDzau et al. Am Heart J. 1991;121:1244et al. Am Heart J. 1991;121:1244--12631263

VentricularVentricularDilatationDilatation

CongestiveCongestiveHeart FailureHeart Failure

EndEnd--stage Heartstage HeartDiseaseDisease

PrimaryPrimarypreventionprevention

PrimaryPrimary PPreventionrevention TTrialsrials

CV Benefits of Intensive and Aggressive LDLCV Benefits of Intensive and Aggressive LDL--C Lowering WithC Lowering WithAtorvastatinAtorvastatin Have Been Shown in Primary Prevention TrialsHave Been Shown in Primary Prevention Trials

CH

De

ven

ts(%

)C

HD

eve

nts

(%)

66

55

88

77

1010

99

AFCAPSAFCAPS--PP

WOSCOPSWOSCOPS--PRPR

WOSCOPSWOSCOPS--PP

CARDSCARDS--ATAT

CARDSCARDS--PP

00

LDLLDL--C (mg/dL)C (mg/dL)

CH

De

ven

ts(%

)C

HD

eve

nts

(%)

y=.0599xy=.0599x 3.39523.3952RR22=.9305=.9305PP=.0019=.0019

22

11

44

33

55

ASCOTASCOT--ATAT

ASCOTASCOT--PP

AFCAPSAFCAPS--PP

AFCAPSAFCAPS--LOLO

CARDSCARDS--ATAT

5555 7575 9595 115115 135135 155155 175175 195195

AT=atorvastatin; LO=lovastatin; P=placebo; PR=pravastatin.AT=atorvastatin; LO=lovastatin; P=placebo; PR=pravastatin.Adapted fromAdapted from O’Keefe JH et al.O’Keefe JH et al. J Am Coll CardiolJ Am Coll Cardiol. 2004;43:2142. 2004;43:2142--2146; Colhoun HM et al.2146; Colhoun HM et al. LancetLancet. 2004;364:685. 2004;364:685--696.696.

AtorvastatinAtorvastatin PravastatinPravastatin PlaceboPlaceboLovastatinLovastatin

--11

CH

De

ven

ts(%

)C

HD

eve

nts

(%)

2020

2525

30304S4S--PP

LIPIDLIPID--PPHPSHPS--PP

4S4S--SS

HPSHPS--SS

CV Benefits of Intensive and Aggressive LDLCV Benefits of Intensive and Aggressive LDL--C Lowering WithC Lowering WithAtorvastatinAtorvastatin Have Been Shown in Secondary Prevention TrialsHave Been Shown in Secondary Prevention Trials

Secondary prevention trialsSecondary prevention trials

ALLIANCEALLIANCE--ATAT

ALLIANCEALLIANCE--UCUC

LDLLDL--C (mg/dL)C (mg/dL)

5050 7070 9090 110110 130130 150150 170170 190190 210210

CH

De

ven

ts(%

)C

HD

eve

nts

(%)

55

1010

1515

y=0.1629xy=0.1629x 4.67764.6776RR22=0.9029=0.9029PP<.0001<.0001

3030

CARECARE--PP

LIPIDLIPID--PRPR

HPSHPS--SS

CARECARE--PRPR

PROVE ITPROVE IT--PRPR

PROVE ITPROVE IT--ATAT

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

AtorvastatinAtorvastatin PlaceboPlaceboPravastatinPravastatin SimvastatinSimvastatin Usual careUsual care

00

Decrease LDL plasma level

Primary Prevention

Secondary Prevention

Statin Mechanism CV eventsReduction

Decrease LDL plasma levelDecrease LDL plasma level

Primary Prevention



HighHigh riskrisk

299/322299/322

OverallOverall

1031/12161031/1216

ATGOAL: Target AchievementATGOAL: Target Achievement

92.9%92.9%

% at goal% at goal % not at goal% not at goal

%at goal%at goal % not at goal% not at goal

84.8%84.8% Moderate riskModerate risk

199/237199/237

Low riskLow risk

533/657533/657

84.0%84.0%

81.1%81.1%

Adapted fromAdapted from MckenneyMckenney JM et al. JJM et al. J CardiovascCardiovasc PharmacolPharmacol 2005;46: 5942005;46: 594--599.599.

AtorvastatinAtorvastatinReduction of LDLReduction of LDL--C across dose rangeC across dose range

Primary PreventionPrimary Prevention Secondary PreventionSecondary Prevention ACSACS

ASCOT-LLA1

10 mg

CARDSCARDS22

10 mg10 mg

REVERSALREVERSAL33

80 mg80 mg

IDEALIDEAL44

80 mg80 mg

TNTTNT55

80 mg80 mg

PROVEPROVE--ITIT66

80 mg80 mg

133 117 150 121 <130 106

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.

Baseline LDLBaseline LDL

On TreatmentOn TreatmentLDL mg/LDL mg/dLdL

133mg/dL

117mg/dL

150mg/dL

121mg/dL

<130mg/dL

106mg/dL

90* 77* 79* 81* 77* 62*

*Data from ASCOT-LLA, TNT, REVERSAL, and IDEAL represent mean levels; CARDS follow up and PROVE IT, median levels

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.

Achieving goals as targetedAchieving goals as targeted


Primary Prevention



ASCOTASCOT--LLA: Study DesignLLA: Study Design

10,30510,305PatientsPatients

Placebo

AtorvastatinAtorvastatin10 mg10 mg

Total CholesterolTotal Cholesterol≤6.5 momol/L≤6.5 momol/L((≤≤250 mg/dL)250 mg/dL)

Composite Primary EndComposite Primary EndComposite Primary EndComposite Primary EndPointPoint

Combined end pointCombined end pointof:of:

•• Nonfatal MINonfatal MI

•• Fatal CHDFatal CHD

Patient PopulationPatient Population

Age 40Age 40––79 years79 years

Hypertension plus 3 or more risk factors includingHypertension plus 3 or more risk factors includingage, smoking, family history of CHD, or low HDLage, smoking, family history of CHD, or low HDL

TC ≤6.5 mmol/L (250 mg/dL)TC ≤6.5 mmol/L (250 mg/dL)

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

ASCOTASCOT--LLA Primary End Point:LLA Primary End Point:Nonfatal MI and Fatal CHDNonfatal MI and Fatal CHD

nn# of# of

EventsEvents

End ofEnd ofTreatmentTreatmentMean LDLMean LDL

AtorvastatinAtorvastatin10 mg10 mg

5,1685,168 100100 90 mg/dL90 mg/dL

33

Cu

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veIn

cid

en

ce(%

)C

um

ula

tive

Inci

de

nce

(%)

36%36%Relative RiskRelative Risk

ReductionReduction

((PP=0.0005)=0.0005)

44

The Event Curves Separate as Early as 90 DaysThe Event Curves Separate as Early as 90 Daysand Diverge Over Timeand Diverge Over Time

PlaceboPlacebo 5,1375,137 154154 126 mg/126 mg/dLdL

11

22

Cu

mu

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veIn

cid

en

ce(%

)C

um

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Inci

de

nce

(%)

HR=0.64 (0.50HR=0.64 (0.50––0.83)0.83)

5.05.0

00

0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.33.3

YearsYears

PlaceboPlacebo

Atorvastatin 10 mgAtorvastatin 10 mg

HR = hazard ratioHR = hazard ratio

In a postIn a post--hoc analysis, a significant difference at 90 days was observed between treatment groupshoc analysis, a significant difference at 90 days was observed between treatment groups

Due to a significant reduction in the primary end point, the trial was stopped after only 3.3 years,Due to a significant reduction in the primary end point, the trial was stopped after only 3.3 years,nearly 2 years earlier than expectednearly 2 years earlier than expected

Adapted from Sever PS, et al.Adapted from Sever PS, et al. Lancet.Lancet. 2003;361:11492003;361:1149--1158.1158.

ASCOTASCOT--LLA Post Hoc TimeLLA Post Hoc Time--toto--Benefit Analysis:Benefit Analysis:Cardiac EventsCardiac Events

Censoring TimeCensoring Time Hazard Ratio (95% CI)Hazard Ratio (95% CI)RiskRisk

Reduction (%)Reduction (%)

Event Rate*Event Rate*

AtorvastatinAtorvastatin PlaceboPlacebo

30 days30 days

90 days90 days

180 days180 days

8383 2.42.4 14.214.2

6767 5.55.5 16.616.6

4848 7.57.5 14.314.3

** Per 1000 patientPer 1000 patient--years.years.

CI = confidence interval.CI = confidence interval.

Reproduced from Sever PS et al.Reproduced from Sever PS et al. Am J CardiolAm J Cardiol. 2005;96(suppl):39F. 2005;96(suppl):39F--44F, with permission.44F, with permission.

180 days180 days

1 year1 year

2 years2 years

End of studyEnd of study

4848 7.57.5 14.314.3

4545 6.66.6 12.012.0

3838 5.95.9 9.59.5

3636 6.06.0 9.49.4

00 0.50.5 1.01.0 1.51.5 2.02.0

AtorvastatinAtorvastatinBetterBetter

PlaceboPlaceboBetterBetter

CARDS: Study DesignCARDS: Study Design

66--week Placebo Runweek Placebo Run--ininPrerandomizationPrerandomization

2,838 Patients2,838 PatientsAtorvastatin 10 mgAtorvastatin 10 mg

Placebo

Placebo

PrerandomizationPrerandomization


Type 2 diabetes with no clinically evident CHDType 2 diabetes with no clinically evident CHD

≥1 other CHD risk factor (smoking, hypertension,≥1 other CHD risk factor (smoking, hypertension,albuminuria, retinopathy) plus LDLalbuminuria, retinopathy) plus LDL--C ≤ 4.1 mmol/LC ≤ 4.1 mmol/L(160 mg/dL) and TG ≤ 6.8 mmol/L (600 mg/dL)(160 mg/dL) and TG ≤ 6.8 mmol/L (600 mg/dL)

Aged 40Aged 40––75 years75 years

Adapted from Colhoun HM, et al.Adapted from Colhoun HM, et al. Diabet Med.Diabet Med. 2002;19:2012002;19:201--211.211.

Composite Primary EndComposite Primary EndComposite Primary EndComposite Primary EndPointPoint

First occurrence ofFirst occurrence of::

•• acute CHD eventacute CHD event

•• coronarycoronaryrevascularizationrevascularizationprocedureprocedure

•• StrokeStroke

1010

1515

CARDS: Primary End PointCARDS: Primary End Point –– Major CV Events*Major CV Events*Acute Coronary Heart Disease Events, CoronaryAcute Coronary Heart Disease Events, Coronary

Revascularization, or StrokeRevascularization, or Stroke

37%37%Relative RiskRelative Risk

ReductionReduction

((PP=0.001)=0.001)

(95% CI: 17(95% CI: 17––52)52)

Cu

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aza

rd(%

)C

um

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Ha

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(%)

nn# of# of

EventsEvents

End ofEnd ofTreatmentTreatment

Median LDLMedian LDL

Atorva 10 mgAtorva 10 mg 1,4281,428 8383 77 mg/dL77 mg/dL

PlaceboPlacebo 1,4101,410 127127 120 mg/120 mg/dLdL

PlaceboPlaceboAtorvastatin 10 mgAtorvastatin 10 mg

0.00.0 1.01.0 2.02.0 3.03.0

55

00

(95% CI: 17(95% CI: 17––52)52)

Cu

mu

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aza

rd(%

)C

um

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Ha

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(%)

% Years% Years

3.93.9

The study was stopped 2 years earlier than anticipated after a median follow up of 3.9 years, due to beneficial effect of atoThe study was stopped 2 years earlier than anticipated after a median follow up of 3.9 years, due to beneficial effect of atorvarvastatinstatin

The results were similar in patients with LDLThe results were similar in patients with LDL--C <120 mg/dL (3.1 mmol/L) andC <120 mg/dL (3.1 mmol/L) and ≥120 mg/dL (3.1 mmol/L)≥120 mg/dL (3.1 mmol/L)

1. Adapted from Colhoun HM, et al.1. Adapted from Colhoun HM, et al. Lancet.Lancet. 2004;364:6852004;364:685--696.696.2. Data on File, Pfizer Inc.2. Data on File, Pfizer Inc.

4.754.75

Trial Stopped EarlyTrial Stopped Early

CARDS Post Hoc TimeCARDS Post Hoc Time--toto--BenefitBenefitAnalysis: Major Cardiovascular EventsAnalysis: Major Cardiovascular Events

HazardHazard

1.5

2

Time (years)

1 2 3 4 4.5

HR = 0.63HR = 0.63

(95% CI = 0.48(95% CI = 0.48--0.83)0.83)

HazardHazardRatioRatio

(95% CI)(95% CI)

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

0

1

0.5

PROVEPROVE--IT*: Study DesignIT*: Study Design

4,1624,162PatientsPatientsPost ACSPost ACS Pravastatin 40 mg

AtorvastatinAtorvastatin 80 mg80 mg

DoubleDouble--Blind PeriodBlind Period

2424--month Treatment Phasemonth Treatment Phase


58 y (mean)58 y (mean)

TC <6.2 mmol/LTC <6.2 mmol/L

Randomized within 10 daysRandomized within 10 daysof ACS event (mean: 7 days)of ACS event (mean: 7 days)

Primary End PointPrimary End Point

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

Adapted from Cannon CP, et al.Adapted from Cannon CP, et al. N Engl J MedN Engl J Med. 2004;350:1495. 2004;350:1495--1504.1504.

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

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

PROVEPROVE--IT*: Changes in LDLIT*: Changes in LDL--CC

8080

100100

120120

--35%35%

C(m

g/d

L)C

(mg

/dL)

95 mg/dL95 mg/dL(2.5 mmol/L)(2.5 mmol/L)

2020

4040

6060

BaselineBaseline 30 days30 days 4 mos4 mos 8 mos8 mos 16 mos16 mos FinalFinal

Time of VisitTime of Visit

Adapted from Cannon CP, et al.Adapted from Cannon CP, et al. N Engl J MedN Engl J Med. 2004; 350:1495. 2004; 350:1495--15041504

Pravastatin 40 mgPravastatin 40 mg 95 mg/dL (2.5 mmol/L)95 mg/dL (2.5 mmol/L)

Atorvastatin 80 mgAtorvastatin 80 mg 62 mg/dL (1.6 mmol/L)62 mg/dL (1.6 mmol/L)

LDL

LDL--

C(m

g/d

L)C

(mg

/dL)

62 mg/dL62 mg/dL(1.6 mmol/L)(1.6 mmol/L)



PROVEPROVE--IT*: Primary End PointIT*: Primary End PointAllAll--Cause Death, NonCause Death, Non--Fatal MI, Unstable Angina RequiringFatal MI, Unstable Angina RequiringHospitalization, Urgent Revascularization, and/or StrokeHospitalization, Urgent Revascularization, and/or Stroke

%P

atie

nts

wit

hEv

en

t*%

Pat

ien

tsw

ith

Eve

nt* 2020

2525

303016%16%

Relative RiskRelative RiskReductionReduction

PP=0.005=0.005

Pravastatin 40 mgPravastatin 40 mgAtorvastatin 80 mgAtorvastatin 80 mg

Separation of the Curves Occurred Within 30 Days and Was Maintained over FollowSeparation of the Curves Occurred Within 30 Days and Was Maintained over Follow--up.up.Statistical Significance was Reached at 180 DaysStatistical Significance was Reached at 180 Days

%P

atie

nts

wit

hEv

en

t*%

Pat

ien

tsw

ith

Eve

nt*

Months of FollowMonths of Follow--upup

3030

00

55

1010

1515

2020

33 66 99 1212 1515 1818 2121 2424 272700

Adapted from Cannon CP, et al.Adapted from Cannon CP, et al. N Engl J MedN Engl J Med. 2004;350:1495. 2004;350:1495--1504.1504.

nnEventsEventsRatesRates

End of TreatmentEnd of TreatmentMedian LDLMedian LDL

Atorvastatin 80 mgAtorvastatin 80 mg 20992099 22.422.4 62 mg/dL62 mg/dL

Pravastatin 40 mgPravastatin 40 mg 20632063 26.326.3 95 mg/95 mg/dLdL




Primary Prevention




Primary Prevention


Statin MechanismMechanism CV eventsReduction

MIRACL vs. A to ZMIRACL vs. A to Z

Outcomes Differ Despite Similar LDLOutcomes Differ Despite Similar LDL--C ReductionsC Reductions

MIRACL A to Z

16%16%

2020

Cu

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ce(%

)C

um

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Inci

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(%)

1515

No differenceNo differencein CV Eventsin CV Eventsin the first 4in the first 4

months of themonths of the2424--month trialmonth trial

Simvastatin 80 mgSimvastatin 80 mgPlaceboPlacebo

1010

1515

2020

Cu

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cid

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)C

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(%)

LIPITOR 80 mgLIPITOR 80 mgPlaceboPlaceboThere will be STATIN benefitsThere will be STATIN benefits

1.6 mmol/L1.6 mmol/L45%45% reductionreduction

1.63 mmol/L1.63 mmol/L40%40% reductionreduction

LDLLDL--C DifferenceC DifferenceBetween ArmsBetween Arms

Schwartz GG, et al. JAMA. 2001;285 Adapted from de Lemos JA et al. JAMA. 2004;292

WeeksWeeks00 44 88 1212 1616

Cu

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)C

um

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(%)

55

1010

0000

55

1010

00 44 88 1212 1616WeeksWeeks

Cu

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um

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Inci

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(%)

than just reducing LDLthan just reducing LDL--CC

Effects ofEffects of StatinsStatins ononHMGHMG--CoACoA ReductaseReductase InhibitionInhibition

Acetyl-CoA + Acetoacetyl-CoA

HMG-CoA

Mevalonate

Isopentanyl PP Important inImportant inSlowerSlower

Early/rapid benefitEarly/rapid benefit((vasculoprotectivevasculoprotective effect)effect)

Statins blockblock

PP=pyrophosphate.PP=pyrophosphate.Adapted from Ray KK, Cannon CP.Adapted from Ray KK, Cannon CP. Curr Opin Lipidol.Curr Opin Lipidol. 2004;15:6372004;15:637--643.643.

Isopentanyl PP

Geranyl PP

Farnesyl PP

SqualeneSqualene

CholesterolCholesterol

GeranylGeranylgeranyl PPgeranyl PP

Related to hepaticRelated to hepaticLDLLDL--C reductionC reduction

Important inImportant invascular cellular responsesvascular cellular responses

PrenylationPrenylation

SlowerSlowerlate benefitlate benefit

Translocates to theTranslocates to thecell membranecell membrane

RhoRho

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

What Accounts for the Added BenefitsWhat Accounts for the Added Benefitsofof AtorvastatinAtorvastatin??

Reduction of

• Endothelial effects

• Anti-inflammatory effects

Reduction oflipids

• Antioxidant effects

• Reduction in plaque progression

• Plaque stabilization

• ↑EPC

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

ShortShort--term Treatment Withterm Treatment With AtorvastatinAtorvastatinimproves Endothelial Function inimproves Endothelial Function in

Postmenopausal Women WithPostmenopausal Women With HypercholesterolemiaHypercholesterolemia

8

10

12

14

FMV

(%)

FMV

(%)

Change in brachial artery flowChange in brachial artery flow--mediatedmediated vasodilationvasodilation (FMV) over time(FMV) over time

††

††††

0

2

4

6

8

Baseline Week 1 Week 2 Week 4 Week 8

Atorvastatin 10 mg

*P*P<.05;<.05; ††PP<.05<.05 vsvs baseline;baseline; ‡‡PP<.001<.001 vsvs atorvastatinatorvastatin..Postmenopausal women (mean age 56.8 years) with hypercholesterolemia were treated withPostmenopausal women (mean age 56.8 years) with hypercholesterolemia were treated with atorvastatinatorvastatin 10 mg (n=20) or the American Heart10 mg (n=20) or the American HeartAssociation step 1 diet (n=10) for 8 weeks. Cholesterol levels and flowAssociation step 1 diet (n=10) for 8 weeks. Cholesterol levels and flow--mediatedmediated vasodilationvasodilation (FMV) were measured at baseline and at 1, 2, 4,(FMV) were measured at baseline and at 1, 2, 4,and 8 weeks.and 8 weeks.

Marchesi S et al.Marchesi S et al. J Cardiovasc PharmacolJ Cardiovasc Pharmacol. 2000;36:617. 2000;36:617--621.621.

FMV

(%)

FMV

(%)

**‡‡ ‡‡ ‡‡

StatinsStatins Significantly Improve Measures ofSignificantly Improve Measures ofInflammation and Endothelial FunctionInflammation and Endothelial Function

Atorvastatin group(80 mg)

Simvastatin group(20 mg)

*

30

40

50

60

Le

ve

ls

**

*†

†

30

40

50

60

Leve

ls

*P<.01 vs baseline; †P<.05 vs baseline.Ox-LDL=oxidized LDL; NO=nitric oxide; CRP=C-reactive protein.Patients (N=97) mean age 61.2±9.7 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.

0

10

20

30

Ox-LDL(U/L)

NO(umol/mL)

CRP(ug/dL)

Fibrinogen(mg/dL)

Le

ve

ls

Baseline 6 months

*

NS

0

10

20

30

Ox-LDL

(U/L)

NO

(umol/mL

CRP

(ug/dL)

Fibrinogen

(mg/dL)Le

vels

Baseline 6 months

LDL

Vessel lumenMonocyte

Adhesionmolecules

Inflammation Promotes Progression of AtherosclerosisInflammation Promotes Progression of Atherosclerosis

Endothelium

CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellularadhesion 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.

Macrophage

molecules(VCAM-1, ICAM-1)

Inflammatory mediators(CRP, CD40/CD40L,

TNF-α, IL-1, IL-6)

IntimaFoamcell

LDL

Ox-LDL

CRP Is a Predictor of Cardiovascular DiseaseCRP Is a Predictor of Cardiovascular Disease

4

5

6

7

8

9

8.7

7.2

6.0

6.0

5.1

4.25.0

Re

lati

veri

sk

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

1

2

3

4

5

1

2

3

4

5

1

2

33.0

2.2

1.7

2.5

3.5

4.2

2.9

2.1

1.4

5.0

3.5

2.5

1.7

1.2

1.0

1.4

2.0

2.9

4.2

Re

lati

veri

sk

AtorvastatinAtorvastatin Reduced HsReduced Hs--CRP Across a Broad Range of PatientsCRP Across a Broad Range of Patients

ATOMIX1

10-40 mg*

(n=50)

DALI2

80 mg

(n=64)

Athyros etal3

20 mg

(n=100)

ASAP4

80 mg

(n=135)

ARBITER5

80 mg

(n=79)

REVERSAL6

80 mg

(n=253)

MIRACL7

80 mg

(n=1186)

PROVE-IT8

80 mg

(n=2099)

Combinedhyperlipidia

Type 2diabetes

Metabolicsyndrome

HeterozygousFH

Statin-eligible§ Stable CHD ACS ACS

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

CRP atbaseline =

§46% with CVDAtorvastatinAtorvastatin has established data for reducing CRP in several trialshas established data for reducing CRP in several trials

baseline =2.5 mg/L†

baseline =3.0 mg/L‡

baseline =4.4 mg/L






1 year 30 weeks 12 months 2 years 12 months 18 months 16 weeks 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 andPROVE-IT vs pravastatin 40 mg*Mean dose of atorvastatin in ATOMIX = 23.5 mg/day†Mean value; ‡Median valueAtorvastatin 80 mg is not approved in all countries and is not an approved starting dose in most countriesLipitor 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

AtorvastatinAtorvastatin Metabolite Dramatically Slows the Rate ofMetabolite Dramatically Slows the Rate ofLDL OxidationLDL Oxidation

Oxidativestress

NativeLDL-C

ModifiedLDL-C

NativeLDL-C

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-34–II-41.

Normalactivity

LDL-C LDL-C

Atherogenic effects• Foam-cell formation• Monocyte mobility

• Chemoattraction

• Endothelial adhesion

• Free-radical production

EFFECTS of STATINS on HUMANEFFECTS of STATINS on HUMANLDL OXIDATIONLDL OXIDATION

Inh

ibit

ion

of

oxL

DL

Inh

ibit

ion

of

oxL

DL

70

60

50

40

30

**

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

Inh

ibit

ion

of

oxL

DL

Inh

ibit

ion

of

oxL

DL

30

20

10

0

-10

-20

COMPARATIVE EFFECTS OF STATINS onCOMPARATIVE EFFECTS OF STATINS onSMALL DENSESMALL DENSE LDLLDL

Inh

ibit

ion

of

TB

AR

SFo

rmat

ion

(%)

20

30

40

50

AtorvastatinMetabolite

Atorvastatinparents

Pravastatin

Rosuvastatin Simvastatin

Probucol

Inh

ibit

ion

of

TB

AR

SFo

rmat

ion

(%)

-10

0

10

20

*P<0.01 vs control (ANOVA Dunnett Multiple Comparison Post-Hoc Test); values = mean +SD (n=3) (Cu2+) = 10uM; drugconcentration = 10uM

Mason et.al (ACC, 2007 New Orleans

Plaque StabilizationPlaque Stabilization

Unstable plaque

Fibrous cap

Stable plaque

Fibrous cap

Lipid core

Inflammatorycells Lipid core

Fewerinflammatory

cells

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

AtorvastatinAtorvastatin Significantly Reduced MMPSignificantly Reduced MMP--9 Levels in a9 Levels in aDoseDose--Dependent MannerDependent Manner

100

150

200

PB

MC

su

pern

ata

nt

9(m

g/L

)

Decrease in supernatantMMP-9 levels

200

100

Change in plasma MMPChange in plasma MMP--9 levels9 levels

PB

MC

sup

ern

ata

nt

9(m

g/L

)

** *

†

*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 allsupernatant and plasma samples.Xu Z et al. Clin Chem. 2004;50:750-753.

0

50

100

Conventionaltherapy

Conventionaltherapy +

atorvastatin 10 mg

PB

MC

su

pern

ata

nt

MM

P-9

(mg

/L)

Baseline After 4 weeks

Atorvastatin concentration (mol/L)

100

0

0 0.1 1 10

PB

MC

sup

ern

ata

nt

MM

P-9

(mg

/L)

†

†

ATROCAP:ATROCAP:AtorvastatinAtorvastatin Reduced PlaqueReduced Plaque ThrombogenicityThrombogenicity

Ch

an

gein

TF

Ag

(pg

/mg)

an

dT

Fa

ctiv

ity

(U/m

g)

†

10

60

110

Change in TF Ag and TF activity

TF Ag TF activity

Atorvastatin 20 mg Placebo

Ch

an

gein

TF

Ag

(pg

/mg)

an

dT

Fa

ctiv

ity

(

*

‡-140

-90

-40

10

*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.

Patient Population:

• Men and women with a historyof CHD

• Angiographic criteria:

•≥20% reduction in lumendiameter in ≥1 coronary

Atorvastatin 80 mg/day

654patients

Double-Blind Period

REVERSALREVERSALStudy DesignStudy Design

diameter in ≥1 coronaryartery lesion

•≤50% reduction in lumendiameter of the left maincoronary artery

•≥1 coronary artery with≤50% stenosis

Pravastatin 40 mg/day

Primary End Point:• Percent change in total plaque volume

18-Month Follow-up with IVUS

(BART at 3 months)

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

REVERSALREVERSAL vsvs ASTEROIDASTEROID

Differentiation REVERSAL ASTEROID

PatientCharacteristic

• Baseline LDL-C 150.2 mg/dL 130.4 mg/dL• Baseline LDL-C

• History of DM

150.2 mg/dL 130.4 mg/dL

20% 13.2%

Drug Comparison Pravastatin 40mg Placebo

Result in Plaque RegressionResult in Plaque Regression

REVERSAL STUDY

Atorvastatin reduce atheroma volumeand increase lumen area

(from 7.7 mm2 to 9.8 mm2)

In REVERSAL,In REVERSAL, atorvastatinatorvastatin 80 mg slowed progression80 mg slowed progression

Ref: Nissen SRef: Nissen S et al.et al. JAMA 2006; 295JAMA 2006; 295

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

ASTEROID STUDY

Rosuvastatin reduce atheroma volumeBUT ALSO reduce lumen area

(from 6.19 mm2 to 5.96 mm2)

In REVERSAL,In REVERSAL, atorvastatinatorvastatin 80 mg slowed progression80 mg slowed progression

of atherosclerosis at 18 monthsof atherosclerosis at 18 months

ESTABLISH: Study DesignESTABLISH: Study Design

Atorvastatin 20 mg

Usual care(cholesterol absorption inhibitor initiated if LDL-C >

150 mg/dL)

Open label period70 PatientsScreening visit*


ACS patients with significant stenosison initial coronary angiography andreceived PCI

150 mg/dL)

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

Composite Primary End PointComposite Primary End Point

To examine early aggressive lipidlowering with atorvastatin VS usualcare in reducing in plaque volume bystabilizing vulnerable plaques

ESTABLISHESTABLISHIVUS Analysis:IVUS Analysis: AtorvastatinAtorvastatin

Before

After 6months

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

Plaque volume 84.1 mm³ to 60.9 mm³Lumen area 10.0 mm² to 10.5 mm²Plaque area 8.6 mm² to 6.4 mm²

ESTABLISHESTABLISHIVUS Analysis: ControlIVUS Analysis: Control

BeforeBefore

After 6After 6monthsmonths

Plaque volume 94.88 mmPlaque volume 94.88 mm³ to³ to 99.499.4 mmmm³³Lumen area 6.2 mm² toLumen area 6.2 mm² to 3.93.9 mm²mm²Plaque area 7.66 mm² toPlaque area 7.66 mm² to 9.09.0 mm²mm²

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

No Significant Association Between Achieved LDL-C andAdverse Events With Atorvastatin 80 mg

Achieved LDL Cholesterol (mg/dL)

Safety Measure>80–100n=256

>60–80n=576

>40–60n=631

40n=193 P Trend

Muscle side effects

Myalgia 6.4 4.3 6.2 5.7 .75

Myositis 0.4 0.6 0.6 0 .64

44CK=creatinine kinase; ULN=upper limit of normal; LFT=liver function test.

Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

Myositis 0.4 0.6 0.6 0 .64

CK >3 ULN 2.3 0.7 1.9 1.0 .18

CK >10 ULN 0 0 0.3 0 .45

Liver side effects

ALT >3 ULN 3.2 3.0 3.2 2.6 .98

Study drug discontinued because of LFT 2.0 2.6 2.4 1.6 .83

No cases of rhabdomyolysis were reported.

ConclusionsConclusions

•• Achieving LDLAchieving LDL--C target is Important, BUT having rapid and fastC target is Important, BUT having rapid and fastclinical benefits is alsoclinical benefits is also IMPORTANTIMPORTANT

•• AtorvastatinAtorvastatin has been shown Target goal’s achievement in severalhas been shown Target goal’s achievement in severalstudiesstudies

•• The early time to CV benefit is shown in severalThe early time to CV benefit is shown in several AtorvastatinAtorvastatin trials:trials:

–– PROVE ITPROVE IT --CARDSCARDS

–– REVERSALREVERSAL --ASCOTASCOT--LLALLA–– REVERSALREVERSAL --ASCOTASCOT--LLALLA

•• Early benefits may be related more to LDLEarly benefits may be related more to LDL--independentindependent((pleiotropicpleiotropic) effects of) effects of statinsstatins, whereas both lipid, whereas both lipid--dependent anddependent and --

independent effectsindependent effects maybemaybe responsible for longerresponsible for longer--term benefitsterm benefits

•• Distinct molecular structures may account for differences inDistinct molecular structures may account for differences inpleiotropicpleiotropic effectseffects

–– these benefits extend beyond any dosethese benefits extend beyond any dose--dependent lipiddependent lipid--loweringloweringeffectseffects

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 CollCardiol. 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.

ConclusionsConclusions

•• Accumulating evidence suggests thatAccumulating evidence suggests that atorvastatinatorvastatinmay havemay have vasculoprotectivevasculoprotective effects beyond lipideffects beyond lipidlowering, including:lowering, including:–– Inhibit process of OxInhibit process of Ox--LDLLDL

–– Reducing CRP and other markers of inflammationReducing CRP and other markers of inflammation–– Reducing CRP and other markers of inflammationReducing CRP and other markers of inflammation

–– Increasing plaque stability by reducing plaque volume andIncreasing plaque stability by reducing plaque volume andoxidativeoxidative stressstress

•• LongLong--term reduction in clinical events andterm reduction in clinical events andatherosclerosis progression is related to reduction inatherosclerosis progression is related to reduction inboth inflammation and lipids (dual goals)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.

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