Inflammatory

Markers,Pharmacotherapy,

and

Clinical

TrialsPaul

M.

Ridker,

M.D.,

M.P.H.,andChristie

M.

Ballantyne,

M.D.Is

there

clinical

evidence

thatinflammation

can

be

modified

bypreventive

therapies?hs-CRP,

Aspirin,

and

Risks

of

Future

MI:Adapted

from

Ridker

PM

et

al.

N

Engl

J

Med

1997;336:973-979.?1997

Massachusetts

Medical

Society.

All

rights

reserved.1

2

3

4Quartile

of

C-Reactive

ProteinPhysicians'

Health

StudyAspirinPlaceboRelative

Risk

of

MILow-Dose

Aspirin

Reduces

ThromboxaneB2

but

not

CRPSerumCRP(%

ofBaseline)140120100806040200Placebo(n=11)Feldman

M

et

al.

J

Am

Coll

Cardiol

2001;37:2036-2041.140120100806040200Serum

Thromboxane(%

ofBaseline)ASA

81

mg

qd(n=13)Placebo(n=11)ASA

81

mg

qd(n=13)28

Days31

Days*

p<0.001*

*Reduction

of

Proinflammatory

Cytokinesand

CRP

with

Higher-Dose

Aspirin

inPatients

with

Chronic

Stable

AnginaIkonomidis

I

et

al.

J

Am

Coll

Cardiol

1999;100:793-798.Placebo(n=40)ASA

300

mg(n=40)PMCSF,

pg/mL991(459-1476)843(501-1357)<0.05IL-6,

pg/mL3.5(3.2-4.6)2.9(2.5-3.4)<0.05CRP,

mg/mL1.4(0.54-4.05)1(0.5-3.1)<0.05Elevated

CRP

Levels

in

Obesity:NHANES

1988-1994Percent

with

CRP

0.22mg/dLNormal

OverweightVisser

Met

al.

JAMA

1999;282:2131-2135.ObeseEffects

of

Weight

Loss

on

CRPConcentrations

in

Obese

Healthy

Women83

women

(mean

BMI

33.8,

range28.2-43.8

kg/m2)

placed

onvery

low

fat,

energy-restricted

diet

(6.0

MJ,

15%

fat)

for

12weeksBaseline

CRP

positively

associated

with

BMI

(r=0.281,

p=0.01)CRP

reduced

by

26%

(p<0.001)Average

weight

loss

7.9

kg,

associated

with

change

inCRPChange

in

CRP

correlated

with

change

in

TC

(r=0.240,

p=0.03)but

not

changes

inLDL-C,HDL-C,

or

glucoseAt

12

weeks,

CRP

concentration

highly

correlated

withTG(r=0.287,

p=0.009),

but

not

with

other

lipids

or

glucoseHeilbronn

LK

et

al.

Arterioscler

Thromb

Vasc

Biol

2001;21:968-970.Effects

of

Weight

Loss

in

Obese

Women

onIL-6,

TNF-α,

and

CRPpg/mLmg/LIL-6

TNF-

Bastard

J-P

et

al.

J

Clin

Endocrinol

Metab

2000;85:3338-3342.CRPBeforedietAfter

very

low

caloriediet(mean

BMI

reduction

2.1kg/m2;mean

reduction

in

body

fat

mass

4

kg)p=0.05p=0.6p=0.14Effects

of

n-3

Fatty

Acid

Therapy

on

Lipidsand

sCAMsPercent

ChangeAbe

Y

et

al.Arterioscler

Thromb

Vasc

Biol

1998;18:723-731.TGTCsICAM-1sE-selectinAll

PatientsDMPatients*****

p<0.05Effect

of

ACE

Inhibition

vs.

AngiotensinIIReceptor

Blockade

on

sCAMs

and

CRPinType

1

Diabetics

with

Diabetic

NephropathyAndersen

S

et

al.

Diabetes

Care

2000;23:1031-1032.PlaceboLosartan

50

mgLosartan

100

mgEnalapril

10mgEnalapril

20mg*p<0.05

vs.placebo***sVCAM-1,

ng/mlsICAM-1,

ng/mlEffect

of

ACE

Inhibition

vs.

AngiotensinIIReceptor

Blockade

on

sCAMs

and

CRPinType

1

Diabetics

with

Diabetic

NephropathyPlaceboLosartan

50

mgLosartan

100

mgEnalapril

10mgEnalapril

20mg*p<0.05

vs.placebo**sE-selectin,

ng/mlCRP,

ng/mlAndersen

S

et

al.

Diabetes

Care

2000;23:1031-1032.Effect

of

HRT

on

hs-CRP:

the

PEPI

Study3.02.01.0hs-CRP(mg/dL)012Months36Cushman

M

et

al.

Circulation1999;100:717-722.

1999

Lippincott

Williams

&

Wilkins.CEE

+

MPAcyclicCEE

+

MPAcontinuousCEE

+

MPCEEPlacebohs-CRP

and

Relative

Risk

of

RecurrentRidker

PM

et

al.

Circulation1998;98:839-844.

1998

Lippincott

Williams

&

Wilkins.Relative

RiskQuintile

of

hs-CRP

(range,

mg/dL)12345<0.120.12-0.200.21-0.370.38-0.66>0.66Coronary

Events:

CAREP

Trend

=0.044P=0.02Inflammation,

Pravastatin,

and

RelativeRidker

PM

et

al.

Circulation1998;98:839-844.

1998

Lippincott

Williams

&

Wilkins.Relative

RiskRisk

of

Recurrent

Coronary

Events:

CAREP

Trend

=0.005Pravastatin

PlaceboInflammationAbsentPravastatin

PlaceboInflammationPresentMean

Baseline

(mg/dL)Inflammation

absentInflammation

present250200150100500TC

LDL-CHDL-CTGBaseline

Lipid

Levels

in

Patients

withandwithout

Inflammation:

CARERidker

PM

et

al.

Circulation1998;98:839-844.Long-Term

Effect

of

Pravastatin

on

hs-CRP:CARE

Placebo

and

Pravastatin

GroupsAdapted

from

Ridker

PM

et

al.

Circulation

1999;100:230-235.

1999

Lippincott

Williams

&

Wilkins.PravastatinPlaceboMedian

hs-CRPConcentration

(mg/dL)–21.6%(P=0.007)0.250.240.230.220.210.200.190.18Baseline 5

YearsChange

in

hs-CRP

Concentration

Over

5Years:

CARE

Subgroup

AnalysesPravastatin

PlaceboAll

SubjectsAge

>60

yearsAge

<60yearsBMI

>27

kg/m2BMI

<27

kg/m2SmokersNonsmokersSBP

>128

mm

HgSBP

<128

mm

HgDBP

>78

mm

HgDBP

<78

mm

HgLDL-C

>138mg/dLLDL-C

<138mg/dLHDL-C>35mg/dLHDL-C

<35

mg/dLTriglycerides

>160

mg/dLTriglycerides

<160

mg/dL0.3-0.2

-0.1

0

0.1

0.2Change

in

hs-CRP

over

5

Years

(mg/dL)Ridker

PM

et

al.

Circulation1999;100:230-235.Change

in

hs-CRP

according

to

Observed

Changesin

LDL-C:

CARE

Placebo

and

Pravastatin

GroupsIncrease0–25Decrease0–25Decrease25–50Decrease50–75Decrease>75Change

inhs-CRP(mg/dL)PlaceboPravastatin-0.150.050-0.05-0.100.100.15Change

inLDL-C

(mg/dL)Ridker

PM

et

al.

Circulation1999;100:230-235.

1999

Lippincott

Williams

&

Wilkins.Relative

Risks

of

Future

MI

among

ApparentlyHealthy

Middle-Aged

Men:

Physician’s

Health

Study6.0Lipoprotein(a)HomocysteineTotal

CholesterolFibrinogentPA

AntigenTC:HDL-Chs-CRPhs-CRP

+

TC/HDL-C0

1.0

2.0

4.0Relative

Risk

for

FutureMIRidker

PM.

Ann

Intern

Med

1999;130:933-937.

1999ACP-ASIM.CRP

in

Combination

with

LDL-C

as

a

Methodto

Target

Statin

Therapy

in

PrimaryPrevention:

AFCAPS/TexCAPSMedian

LDL-C

=

149.1mg/dLMedian

CRP

=

0.16

mg/dLRidker

PM

et

al.

N

Engl

J

Med

2001;344:1959-1965.Event

RateStudy

GroupLovastatinPlaceboNNTLow

LDL-C/low

CRP0.0250.022_Low

LDL-C/high

CRP0.0290.05148High

LDL-C/low

CRP0.0200.05033High

LDL-C/high

CRP0.0380.05558CRP

in

Combination

with

TC:HDL-C

Ratio

asa

Method

to

Target

Statin

Therapy

inPrimary

Prevention:

AFCAPS/TexCAPSMedian

TC:HDL-C=5.96Median

CRP

=

0.16

mg/dLRidker

PM

et

al.

N

Engl

J

Med

2001;344:1959-1965.Event

RateStudy

GroupLovastatinPlaceboNNTLow

TC:HDL-C/lowCRP0.0240.025983Low

TC:HDL-C/high

CRP0.0250.05043High

TC:HDL-C/low

CRP0.0210.05035HighTC:HDL-C/high

CRP0.0410.05762hs-CRP: Potential

Clinical

ApplicationsAdjunct

to

lipid

screening

in

the

detectionofindividuals

at

high

risk

for

coronary

arterydiseaseMethod

to

better

target

statin

therapy

inthesetting

of

primary

preventionPotential

prognostic

value

in

acute

coronarysyndromesInflammation

is

likely

to

represent

a

new

targetfor

both

the

treatment

and

prevention

of

acutemyocardial

infarctionStatin

Therapy,

Lipid

Levels,

CRP,

andSurvival

Among

Patients

with

SevereCoronary

Artery

DiseaseHorne

BD

et

al.

J

Am

Coll

Cardiol

2000;36:1774-1780.

2000

Reprinted

with

permission

from

the

American

College

of

Cardiology.Mortality

(%)Low

Medium

HighCRP

TertilesStatinsLow

Medium

HighCRP

TertilesNoStatinsP

Trend

=0.94P

Trend<0.0001Short-Term

Effects

of

Statins

onhs-CRP

LevelsRandomized,

double-blind,

crossover

trial

with22

hyperlipidemic

patients

(LDL-C

>130,

TG

200-600

mg/dL)6

weeks

of

therapy

with

either

simvastatin20mg,

atorvastatin

10

mg,

or

pravastatin

40mg3-week

washout

between

drugsJialal

I

et

al.

Circulation

2001;103:1933-1935.Effect

of

Statin

Therapy

on

Lipid

andLipoprotein

Levels

at

6

WeeksBaselinePravastatinSimvastatinAtorvastatinTC264.3+36.9219.7+37.8*201.0+35.1*191.5+33.5*LDL-C169.7+37.1132.8+35.4*118.3+30.2*113.8+28.4*HDL-C44.7+13.245.8+12.845.7+13.444.8+12.5TG230.3(144-588)178.8(97-1352)164.0(91-400)*162.3(87-581)*Mean

+SD

or

median

(range),

mg/dL*P<0.001

vs.

baselineJialal

I

et

al.

Circulation

2001;103:1933-1935.hs-CRP(mg/L)Effect

of

Statin

Therapy

on

hs-CRP

Levelsat

6WeeksJialal

I

et

al.

Circulation

2001;103:1933-1935.

2001

Lippincott

Williams

&

Wilkins.6543210Baseline*Prava(40

mg/d)Simva(20

mg/d)Atorva(10

mg/d)*p<0.025

vs.

Baseline*

*Effect

of

Cerivastatin

on

CRP

LevelsinPatients

with

HypercholesterolemiaRidker

PM

et

al.

Circulation

2001;103:1191-1193.

2001

Lippincott

Williams

&

Wilkins.Change

at

8

weeks,

%n=785n=162

n=623All

patients 0.4

mg 0.8mgCRP

LDL-C

HDL-CEffect

of

Pravastatin

on

CRP

LevelsinPrimary

and

Secondary

Prevention:

PRINCEChange

in

CRP,

%Primary

Prevention Secondary

Prevention*******Albert

MA

et

al.

JAMA2001;286:64-70.12weeksvs.

baseline24weeksvs.

baseline24

weeks

ITTvs.

placebo*p<.001vs.baseline**p<.005vs.baselineEffect

of

Bezafibrate

with

and

without

Fluvastatinon

Plasma

Fibrinogen,

PAI-1,

and

CRP

in

Patients