Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP Screening

1. Adjunct to Global Risk Assessment1. Adjunct to Global Risk Assessment2. Method to Monitor Statin Efficacy in Secondary Prevention2. Method to Monitor Statin Efficacy in Secondary Prevention

3. Method to Target Statin Therapy in Primary Prevention3. Method to Target Statin Therapy in Primary Prevention

Paul M Ridker, MDPaul M Ridker, MDEugene Braunwald Professor of MedicineEugene Braunwald Professor of Medicine

Harvard Medical SchoolHarvard Medical SchoolDirector, Center for Cardiovascular Disease PreventionDirector, Center for Cardiovascular Disease Prevention

Brigham and Women’s HospitalBrigham and Women’s HospitalBoston, MassachusettsBoston, Massachusetts

Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospitalthat relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

Pasceri and Yeh, Circulation 100:2124-2126, 1999

Circulation

Primary Pro-Inflammatory Primary Pro-Inflammatory Cytokines Cytokines

( e.g., IL-1, TNF-( e.g., IL-1, TNF-)) IL-6IL-6““Messenger” Messenger” CytokineCytokineICAM-1ICAM-1

Selectins, HSPs, Selectins, HSPs, etc.etc.

LiverLiverEndotheliumEndotheliumand other cellsand other cells

Circulation 1999;100:1148–1150.

Pro-Inflammatory PathwaysPro-Inflammatory Pathways

Pro-Inflammatory Risk Pro-Inflammatory Risk FactorsFactors

CRPCRPSAASAA

0

1

2

< 1 1 - 3 > 30

1

2

< 1 1 - 3 > 3

WHS

0

1

2

< 1 1 - 3 > 30

1

2

< 1 1 - 3 > 3

ARICMONICAPHS

0

1

2

< 1 1 - 3 > 30

1

2

< 1 1 - 3 > 3

HPFSNHS

0

1

2

1 2 3

Reykjavik*

Fra

min

gham

Ad j

u ste

d R

e la t

ive

Ri s

khsCRPhsCRP Adds Prognostic Information Beyond the Adds Prognostic Information Beyond the

Framingham Risk Score in ALL Major Cohorts EvaluatedFramingham Risk Score in ALL Major Cohorts Evaluated

0

1

2

<1 1-3 >3

CHS

0

1

2

<1 1-3 >3

EPIC-Norfolk

1997 2002 2004 2004 2004

2004 2004 2005 2005

0

1

2

<1 1-3 >3

2005

PIMA

0

1

2

3

4

Low Medium High

Fully

Adj

uste

d R

elat

ive

Ris

k

0

1

2

3

4

Low Medium High

TC : HDLC Ratio Apo B100 : Apo A-I Ratio

hsCRP < 1 mg/L hsCRP 1 to 3 mg/L hsCRP > 3 mg/L

JAMA 2005;294:326-333

Additive Value of hsCRP Across All Lipid RatiosRisks Adjusted for Age, Blood Pressure, Smoking Status, Body Mass Index, and Diabetes

0.0

5.0

10.0

15.0

20.0

25.0

30.0

10-20 5-10 <5 <0.50.5-1.0

1.0-3.03.0-10.0

>10.0

Moving Toward an hs-CRP Modified Moving Toward an hs-CRP Modified Framingham Risk ScoreFramingham Risk Score

Calculated Framingham 10-Year RiskCalculated Framingham 10-Year Risk

Ridker PM, Wilson PW, Grundy S. Circulation 2004;109:2818-2925

hs-CRP mg/Lhs-CRP mg/LC

RP

Mod

ified

Fra

min

gham

Ris

kC

RP

Mod

ified

Fra

min

gham

Ris

k

hsCRP Enters Global Risk Prediction Models hsCRP Enters Global Risk Prediction Models Before Before TC, TC, HDL, and LDLCHDL, and LDLC

Variable LR Chi -Square

Model with age plus:

SBP 100.60

Ln(CRP) 86.72

Current smoking 74.04

Ln(HDL) 70.19

Ln(Total Cholesterol) 36.72

LDL 31.13

Variable LR Chi - Square

Model with age, SBP, smoking plus:

Ln(CRP) 44.05

Ln(HDL) 41.89

Ln(Total Cholesterol) 26.28

LDL 22.94

N Cook 2005

Comparison of model fit for ATP III risk prediction with and Comparison of model fit for ATP III risk prediction with and without CRPwithout CRP

ATP Prediction Model Without CRP With

CRP

Liklihood ratio Chi-squareBayes Information Criteria (BIC)BIC weight (posterior probability)Akaike Information Criteria (AIC)AIC weightsNagelkerke’s Generalized R2

C-statisticAdjusted C-statisticD-statisticAdjusted D-statisticBrier Score

Regardless of Measure Used, the Addition of hsCRP Improves Predictive Modeling

0-<5% 5-<10% 10-<20% 20%+

5-<10% 2.4% 7.8% 15.2% - 10-<20% - 6.8% 11.5% 19.8%

20%+ - - 18.8% 27.1%

Global Risk With CRP (10 year risk)Global RiskWithout CRP(10 year risk)

ProportionCorrectly

Reclassified

21.3 %

20.0 %

13.9 %

Additive Value of hsCRP to Global Risk Prediction Models – Additive Value of hsCRP to Global Risk Prediction Models – Observed Risk and Proportion Correctly ReclassifiedObserved Risk and Proportion Correctly Reclassified

32.4%

42.2 %

19.4 %

WHS ATP-III

Between 20 and 40 percent of all individuals with 5 to 20 percent risk by ATP-IIIare reclassified more accurately and with greater precision by adding hsCRP; these

proportions are significantly LARGER than those associated with LDL, HDL, or TG screening

Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP ScreeningPart 1. Adjunct for Global Risk Assessment: Part 1. Adjunct for Global Risk Assessment:

Comparison to TC, LDL, or HDLComparison to TC, LDL, or HDL

Since the predictive value of hsCRP is equal to or superior to that of TC, LDL-C, or HDLC;

and since the cost of hsCRP is less than or equalto that of lipid screening

then hsCRP screening must be at least as cost effective for broad population screening

as is lipid evaluation.

The Clinical Issue : hsCRP Reduction and Patient The Clinical Issue : hsCRP Reduction and Patient ManagementManagement

There is no hard evidence to date that lowering There is no hard evidence to date that lowering hsCRP hsCRP per seper se will reduce vascular risk. will reduce vascular risk.

However, However, allall observational evidence indicates that observational evidence indicates that those with lower hsCRP levels after treatment have those with lower hsCRP levels after treatment have better short and long term prognosis.better short and long term prognosis.

Clinical Predictive Value of Very Low as Well Clinical Predictive Value of Very Low as Well as Very High Levels of hsCRPas Very High Levels of hsCRP

0

1

2

3

4

5

6

7

8

<0.5 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 5.0-10.0 10.0-20.0 >20

hsCRP (mg/L)

Rela

tive

Risk

of F

utur

e CV

Eve

nts

“low risk” “moderate risk” “high risk”

Circulation 2004;109:1955-59

Follow-Up (years)0.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

CRP>2 mg/L

CRP<2 mg/L

0.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

C

umul

ativ

e R

ate

of

Rec

urre

nt M

yoca

rdia

l Inf

arct

ion

or C

oron

ary

Dea

th (p

erce

nt)

LDLC>70 mg/dL

LDLC<70 mg/dL

Clinical Relevance of Achieved LDL and Achieved CRP

After Treatment with Statin Therapy

NEJM 2005;352:20-28.

0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

0.02

0.04

0.06

0.08

0.10

Rec

urre

nt M

yoca

rdia

l Inf

arct

ion

or C

oron

ary

Dea

th (p

erce

nt)

Follow-Up (Years)

LDL > 70 mg/dL, CRP > 2 mg/L

LDL < 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/L

LDL < 70 mg/dL, CRP < 2 mg/L

Clinical Relevance of Achieved LDL and Achieved CRP

After Treatment with Statin Therapy

NEJM 2005;352:20-28.

0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

0.02

0.04

0.06

0.08

0.10

Rec

urre

nt M

yoca

rdia

l Inf

arct

ion

or C

oron

ary

Dea

th (p

erce

nt)

Follow-Up (Years)

LDL > 70 mg/dL, CRP > 2 mg/L

LDL < 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/L

LDL < 70 mg/dL, CRP < 2 mg/L

Clinical Relevance of Achieved LDL and Achieved CRP

After Treatment with Statin Therapy

LDL < 70 mg/dL, CRP < 1 mg/L

NEJM 2005;352:20-28.

Nissen et al NEJM 2005; 352:29-38

Effects of LDL Reduction and CRP Reduction on AtheroscleroticProgression Measured By Intravascular Ultrasound : REVERSAL

REVERSAL: Regression of Atherosclerosis On REVERSAL: Regression of Atherosclerosis On Statin Therapy Only Occurs Among Those with Statin Therapy Only Occurs Among Those with

CRP ReductionCRP Reduction

-4

-2

0

2

4

6

8

10

Cha n

g e i n

Ath

e ro m

a Vo

lum

e (m

m3 )

Nissen et al NEJM 2005; 352:29-38

LDLCRP

LDLCRP

LDLCRP

LDLCRP

Progression

Regression

+8mm3

+2mm3

- 1mm3

- 2mm3

Importance of Achieving Low LDLC and Low hsCRP After Initiation Importance of Achieving Low LDLC and Low hsCRP After Initiation of Statin Therapy : Carotid IMT Regression in ARBITERof Statin Therapy : Carotid IMT Regression in ARBITER

01020304050607080

Kent SM, Taylor AJ. AJC 2003;92:1224-1227

LDL > 130

LDL 100 - 129

LDL70 - 99

LDL< 70

LDL< 70

hsCRP> 2

LDL< 70

hsCRP < 2

Prop

o rti

on w

ith

I MT

Regr

ess i

on

Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP ScreeningPart 2. High Risk Secondary Prevention to Monitor Part 2. High Risk Secondary Prevention to Monitor

Statin EfficacyStatin Efficacy

1.1. Patients on statin therapy who achieve low hsCRP levels have Patients on statin therapy who achieve low hsCRP levels have better clinical outcomes at all levels of achieved LDL-C.better clinical outcomes at all levels of achieved LDL-C.

2.2. The best clinical outcomes are obtained among statin treated The best clinical outcomes are obtained among statin treated patients who achieve the patients who achieve the “dual goals”“dual goals” of LDL-C < 70 mg/dL of LDL-C < 70 mg/dL andand hsCRP < 2 mg/L.hsCRP < 2 mg/L.

3.3. The relationship between achieved LDL-C and achieved hsCRP The relationship between achieved LDL-C and achieved hsCRP is highly variable for individual patients and cannot be predicted is highly variable for individual patients and cannot be predicted on the basis of intensity of therapy. on the basis of intensity of therapy.

4.4. Strategies to cost-effectively lower cardiovascular risk with Strategies to cost-effectively lower cardiovascular risk with statins may need to measure and monitor hsCRP in a manner statins may need to measure and monitor hsCRP in a manner analogous to how we currently measure and manage LDL-C.analogous to how we currently measure and manage LDL-C.

CRP as a Method to Target Statin Therapy in Primary CRP as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPSPrevention: AFCAPS/TexCAPS

Study Group Statin Placebo NNT

low LDLC / low CRP 0.025 0.022 ----

low LDLC / high CRP 0.029 0.051 48

high LDLC / low CRP 0.020 0.050 33

high LDLC / high CRP 0.038 0.055 58

Median LDLC = 149 mg/dLMedian CRP = 0.16 mg/dL

N Engl J Med 2001;344:1959-65

No History of CADMen >55, Women > 65 LDL-C <130 mg/dL

CRP >2 mg/L

Rosuvastatin (N =7500)

Placebo (N =7500)

MIStroke

Unstable Angina

CVD DeathCABG/PTCA

LDLCRPFHS

Lipidshs-CRP LFTs

Lipidshs-CRPHbA1C

JUPITERJUPITERRandomized Trial of Rosuvastatin in the Primary Randomized Trial of Rosuvastatin in the Primary

Prevention of Cardiovascular Events Among Individuals Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL-C and Elevated Levels of CRPwith Low Levels of LDL-C and Elevated Levels of CRP

4 week Run-in

Screening Visit

Randomization Visit

Safety Visit

Bi-Annual Follow-Up Visits

End of Study Visit

Lipidshs-CRP LFTsHbA1C

JUPITER Investigators, Circulation 2003

Estimated Life Expectancy Gains : hsCRPEstimated Life Expectancy Gains : hsCRPPrimary prevention in 35 year old men and womenPrimary prevention in 35 year old men and women

Intervention Gains in Life Expectancy (months)Men Women

Statin Therapy for high CRP / low LDL 10.2 7.9

Eliminate Smoking 10.0 8.0Reduce DBP to 88 mm Hg 13.2 4.8Eliminate CHD 37.2 39.6

Mammography 50 yr old women NA 0.8Pap smear 20 year old women NA 3.1

Blake G, Kuntz K, JACC 2002;40:49-55

Blake G, Kuntz K. Am J Med 2003;114:485-94

“A strategy involving C-reactive protein screening totarget statin therapy among middle-aged patients

without hyperlipidemia is relatively cost-effective and, in some cases, cost-saving”

“Overall, cost-effectiveness ratios were comparableto those reported for primary prevention

using statin therapy among those with hyperlipidemia”

Cost-Effectiveness of hsCRP Screening Cost-Effectiveness of hsCRP Screening Part Part 3.3. : Targeting Statin Therapy for Primary : Targeting Statin Therapy for Primary

PreventionPrevention

Blake G, Kuntz K, Am J Med 2003;114:485-94

Cost-Effectiveness of hsCRP Screening Cost-Effectiveness of hsCRP Screening Part 2 : Part 2 : Targeting Statin TherapyTargeting Statin Therapy

0102030405060708090

100

$500/yr $1000/yr$

/ QAL

Y (0

00)

0-5 5-10 10-15 15-20 20-25Ten-year Risk of Coronary Heart Disease

CostSaving

CostEffective

CostComparable

Atherosclerosis Test

Very Low Risk3

Negative Test• CCS =0• CIMT<50th percentile

LowerRisk

ModerateRisk

Positive Test• CCS ≥1• CIMT 50th percentile or Carotid Plaque

ModeratelyHigh Risk

HighRisk

VeryHigh Risk

No Risk Factors5 + Risk Factors • CCS <100 & <75th% • CIMT <1mm & <75th%

& No Carotid Plaque

• Coronary Calcium Score (CCS)or

• Carotid IMT (CIMT) & Carotid Plaque4

• CCS 100-399 or >75th%• CIMT 1mm or >75th%

or <50% Stenotic Plaque

• CCS >100 & >90th%or CCS 400

• 50% Stenotic Plaque6

IndividualizedIndividualizedIndividualized5-10 years5-10 yearsRe-test Interval

<70 mg/dl<100 mg/dl<70 Optional

<130 mg/dl<100 Optional

<130 mg/dl<160 mg/dlLDLTarget

All >75y receive unconditional treatment2

Apparently Healthy Population Men>45y Women>55y1

ExitExit

Myocardial IschemiaTest

NoAngiography

Follow Existing Guidelines

Yes

The 1st S .H .A .P .E . GuidelineTowards the National Screening for Heart Attack Prevention and Education (SHAPE) Program

Step 1

Step 2

Step 3Optional

CRP>4mg

ABI<0.9

0.0

2.0

4.0

6.0

8.0

High Medium Low <4.0

>4.0

Combined Use of CT Calcium Scores and CRP in the Combined Use of CT Calcium Scores and CRP in the Prediction of Cardiovascular Events: Prediction of Cardiovascular Events:

South Bay Heart WatchSouth Bay Heart Watch

EBCT Calcium ScoreEBCT Calcium Score

Park R, Detrano R, Xiang M, et al. Circulation 2002;106:2073-7

hs-CRP, mg/L

hs-CRP, mg/L

Rel

ativ

e R

isk

Rel

ativ

e R

isk

hsCRP and Progression of Cerebral Small-Vessel hsCRP and Progression of Cerebral Small-Vessel Disease:Disease:

The Rotterdam Scan StudyThe Rotterdam Scan Study

0

0.5

1

1.5

2

2.5

3

3.5

1 2 3 4

Quartile of hsCRP At Study Entry

Adju

sted

Odd

s Rat

io*

Van Dijk et al, Circulation 2005;112:900-905

Periventricular WML Progression

Subcortical WML Progression

*Adjusted for age, sex, diabetes, smoking, BMI, HTN, TC:HDLC, carotid plaques, and IMT

hsCRP and SAA Predict Short-Term Progression ofhsCRP and SAA Predict Short-Term Progression ofAtherosclerosis Lesions in Human Carotid ArteriesAtherosclerosis Lesions in Human Carotid Arteries

Schillinger et al, Circulation 2005;111:2203-9

0

1

2

3

4

1 2 3 4 5

SAAhsCRP

Quintile of hsCRP or SAA at Baseline

Adj u

sted

OR

for

Car o

tid

P rog

res s

ion

Adjusted for age, gender, BMI, HbA1c, smoking, BP, LDL-C, , family history, and IMT

(N = 1268, 7.5 month f/u)

February 23, 2004

1995 – Cholesterol

2005 – Cholesteroland Inflammation

Broad Screening: Blood Pressure

TC, HDLC, glucose, hsCRP, ABI

Targeted Screening: Imaging

Statin Monitoring:

LDLC, hsCRP

“If CRP was half as effectiveand twice as expensive,physician use would be

ten times higher”

Moving Toward New National Screening Guidelines