Wolfgang Koenig, MD, FACCWolfgang Koenig, MD, FACCDept. of Internal Medicine II - CardiologyDept. of Internal Medicine II - Cardiology

University of Ulm Medical Center, Ulm, GermanyUniversity of Ulm Medical Center, Ulm, Germany

Is the Framingham model sufficient for Is the Framingham model sufficient for prediction of coronary events?prediction of coronary events?

Should CRP be added to Should CRP be added to Framingham Risk Score?Framingham Risk Score?

How about calcium score? How about calcium score?

11stst „Vulnerable Patient“ Satellite Symposium, „Vulnerable Patient“ Satellite Symposium,American Heart Association American Heart Association

Orlando, USA, November 11, 2003Orlando, USA, November 11, 2003

IdentityIdentityTest PositiveTest PositiveTest NegativeTest Negative

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0 0.05 0.1 0.15 0.20.05 0.1 0.15 0.2

Pre-test Probability of CHD Event in 10 YrsPre-test Probability of CHD Event in 10 Yrs

Post

-test

Pro

babi

lity o

f CHD

Eve

nt in

10

Yrs

Post

-test

Pro

babi

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f CHD

Eve

nt in

10

Yrs

modified after Greenland et al. Circulation 2001;104:1863-1867modified after Greenland et al. Circulation 2001;104:1863-1867

Low-Risk Intermediate-Risk High-RiskLow-Risk Intermediate-Risk High-Risk(~35 % of Pts.) (~40% of Pts.) (~25% of Pts.)(~35 % of Pts.) (~40% of Pts.) (~25% of Pts.)

<6 (10)% 6 (10) -19 % ≥ 20 %<6 (10)% 6 (10) -19 % ≥ 20 % over 10 yearsover 10 years

CHD Risk Assessment in CHD Risk Assessment in Asymptomatic Patients: Asymptomatic Patients:

Selective Use of Noninvasive TestingSelective Use of Noninvasive TestingModification of Probability Estimates of Modification of Probability Estimates of

CHD by Non-invasive TestingCHD by Non-invasive Testing

Assessment by multivariable Assessment by multivariable statistical models: e.g.statistical models: e.g. Framingham Risk Score or Framingham Risk Score or PROCAM scorePROCAM score

Clear guidelines for high or low Clear guidelines for high or low risk subjects, but not so for risk subjects, but not so for those at intermediate riskthose at intermediate risk

C-Reactive Protein C-Reactive Protein Modulates Risk PredictionModulates Risk Prediction

Can CRP ChangeCan CRP Change Our Practice? Our Practice?

C-Reactive Protein Modulates Risk Prediction:C-Reactive Protein Modulates Risk Prediction:

MONICA/KORA Augsburg Cohort 1984-98MONICA/KORA Augsburg Cohort 1984-98 3,435 men aged 45-74 years, participating in the three 3,435 men aged 45-74 years, participating in the three

MONICA surveys 1984/85, 1989/90, 1994/95MONICA surveys 1984/85, 1989/90, 1994/95 Exclusion of prevalent CHD Exclusion of prevalent CHD Standardized assessment of cardiovascular risk factors: Standardized assessment of cardiovascular risk factors:

Total cholesterol, HDL-C, blood pressure, smoking, BMI, Total cholesterol, HDL-C, blood pressure, smoking, BMI, physical activity, social class, diabetes mellitus, alcohol physical activity, social class, diabetes mellitus, alcohol consumption.consumption.

Endpoint determination according to the MONICA protocol Endpoint determination according to the MONICA protocol (fatal and non-fatal MI and sudden cardiac death) (fatal and non-fatal MI and sudden cardiac death)

Determination of CRP by a hs-IRMA (Hutchinson et al. Clin Determination of CRP by a hs-IRMA (Hutchinson et al. Clin Chem 2000) with a detection limit of 0.05 mg/L (CV < 12%).Chem 2000) with a detection limit of 0.05 mg/L (CV < 12%).

Determination of total cholesterol and HDL-C by routine Determination of total cholesterol and HDL-C by routine enzymatic methods (CV < 4%)enzymatic methods (CV < 4%)

Methods: Patient Population and AssaysMethods: Patient Population and Assays

Koenig et al. AHA 2003Koenig et al. AHA 2003

< 6 6-10 11-14 15-19 < 6 6-10 11-14 15-19 202000

11

22

33

44

55

66

77

88

< 6 6-10 11-14 15-19 < 6 6-10 11-14 15-19 202000

11

22

33

44

55

66

77

88

P=0.20P=0.20P=0.26P=0.26

P=0.02P=0.02

P=0.03P=0.03

P=0.09P=0.09<1.0<1.01.0 – 3.01.0 – 3.0> 3.0> 3.0

CRP CRP mg/Lmg/L

18 18 32 32 35 50 5635 50 56

Population at risk Population at risk 809 914 650 526 536809 914 650 526 536

Framingham Estimate of 10-Year Risk (%)Framingham Estimate of 10-Year Risk (%)

Mul

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e R

elat

ive

Ris

kM

ultiv

aria

ble

Rel

ativ

e R

isk

AIC 2776AIC 2776AIC 2789AIC 2789

RR of CHD According to the Estimated 10-Yrs RR of CHD According to the Estimated 10-Yrs Risk Alone and in Combination With CRP: Risk Alone and in Combination With CRP:

MONICA Augsburg CohortMONICA Augsburg Cohort(N=3,435 Men; 45-74 Yrs; 191 Events; FU 6.6 Yrs)(N=3,435 Men; 45-74 Yrs; 191 Events; FU 6.6 Yrs)

Koenig et al. AHA 2003Koenig et al. AHA 2003

Risk of a First Coronary Event Risk of a First Coronary Event by Cox Model w/o and With CRP for by Cox Model w/o and With CRP for

the FRS With 3 and 5 Categories the FRS With 3 and 5 Categories FactorFactor Events/nEvents/n HR (95%CI)HR (95%CI) P-valueP-value HR (95%CI)HR (95%CI) P-valueP-value

FRS 1FRS 1 <6<6 18/80918/809 Ref.Ref. Ref.Ref.

(%)(%) 6-19 6-19 117/2090117/2090 2.81 (1.71-4.62)2.81 (1.71-4.62) 2.39 (1.45-3.94)2.39 (1.45-3.94)

20 20 56/53656/536 6.19 (3.64-10.54)6.19 (3.64-10.54) <0.0001<0.0001 4.85 (2.82-8.33)4.85 (2.82-8.33) <0.0001<0.0001

AICAIC 28162816 27972797 ∆∆AIC 19AIC 19

AUCAUC 0.7130.713 0.7400.740 0.00770.0077

FRSFRS 22 <6<6 18/80918/809 Ref.Ref. Ref.Ref.

(%)(%) 6-106-10 32/91432/914 1.63 (0.91-2.90)1.63 (0.91-2.90) 1.46 (0.82-2.61)1.46 (0.82-2.61)

10-1410-14 35/65035/650 2.70 (1.53-4.77)2.70 (1.53-4.77) 2.35 (1.32-4.16)2.35 (1.32-4.16)

15-1915-19 50/52650/526 5.61 (3.27-9.62)5.61 (3.27-9.62) 4.50 (2.59-7.80)4.50 (2.59-7.80)

2020 56/53656/536 6.21 (3.65-10.57)6.21 (3.65-10.57) <0.0001<0.0001 5.01 (2.91-8.62)5.01 (2.91-8.62) <0.0001<0.0001

AICAIC 27892789 27762776 ∆∆AIC 13AIC 13

AUCAUC 0.7350.735 0.7500.750 0.01630.0163

AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP); AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP); AUC, Area under the curve AUC, Area under the curve Koenig et al. AHA 2003Koenig et al. AHA 2003

Coronary Calcification and Atherosclerotic Coronary Calcification and Atherosclerotic Cardiovascular Disease Events: Cardiovascular Disease Events:

St. Francis Heart StudySt. Francis Heart Study Prospective, longitudinal, population-based study of asymp-Prospective, longitudinal, population-based study of asymp-

tomatic men and women aged 50 to 70 with no prior history, tomatic men and women aged 50 to 70 with no prior history, symptoms or signs of atherosclerotic CVDsymptoms or signs of atherosclerotic CVD

Subjects on or with indication for lipid-lowering therapy Subjects on or with indication for lipid-lowering therapy excludedexcluded

Coronary calcium measured by EBCT scanning, Agatston Coronary calcium measured by EBCT scanning, Agatston methodmethod

Events verified by independent Endpoints Adjudication Events verified by independent Endpoints Adjudication Committee, blinded to coronary calcium scoreCommittee, blinded to coronary calcium score

A total of 5,585 subjects were scannedA total of 5,585 subjects were scanned Risk factors measured in 1,817Risk factors measured in 1,817 4.3 years follow-up, 96% complete4.3 years follow-up, 96% complete 122 subjects (0.6%/year) with 122 subjects (0.6%/year) with 1 atherosclerotic CVD event 1 atherosclerotic CVD event

Arad et al. ACC, Chicago 2003Arad et al. ACC, Chicago 2003

0.00.0

8.08.0

16.016.0

24.024.0

32.032.0

00 1-991-99 100-199100-199 200-599200-599 600600

Baseline Calcium Score Baseline Calcium Score and CVD Events:and CVD Events:

EventEvent 584 584 775 775 P < 0.0001P < 0.0001

No event 142 No event 142 381381

Coronary Calcium Score (Coronary Calcium Score (100 100 vs <100) and CVD Events:vs <100) and CVD Events:

All CVDAll CVD 122 122 9.5 (6.5-13.8) 9.5 (6.5-13.8)All coronary 105 10.7 (7.1-16.3)All coronary 105 10.7 (7.1-16.3)MI/coronary death 43MI/coronary death 43 9.9 (5.2-18.9) 9.9 (5.2-18.9)

Prediction of CVD Events by Coronary Prediction of CVD Events by Coronary Calcium Score: St. Francis Heart StudyCalcium Score: St. Francis Heart Study

Arad et al. ACC, Chicago 2003Arad et al. ACC, Chicago 2003

Calcium ScoreCalcium Score

RR

Events N RR (95% CI)Events N RR (95% CI)

00

11

22

33

44

55

< 10< 10 10 to 2010 to 20 > 20> 20

Prediction of CVD by Coronary Calcium Prediction of CVD by Coronary Calcium Score vs Framingham Risk Score: Score vs Framingham Risk Score:

St. Francis Heart Study St. Francis Heart Study

Calcium score vs Calcium score vs Framingham risk index prediction Framingham risk index prediction

of coronary eventsof coronary events

Area underArea under ROC curveROC curve P-valueP-value

Calcium score 0.81 Calcium score 0.81 0.03 0.03< 0.01< 0.01

Framingham 0.71 Framingham 0.71 0.03 0.03

11stst Tertile Tertile22nd nd TertileTertile33rdrd Tertile Tertile

% per 10 years % per 10 years ((predicted)predicted)

% p

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ear

% p

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ear ((

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Arad et al. ACC, Chicago 2003Arad et al. ACC, Chicago 2003

Summary and ConclusionsSummary and Conclusions The addition of CRP to a prediction model of the FRS resulted The addition of CRP to a prediction model of the FRS resulted

in a better fit of the model containing CRP and significantly in a better fit of the model containing CRP and significantly improved prediction of incident CHD for the calculated FRSimproved prediction of incident CHD for the calculated FRS

The latter was particularly true for those at intermediate risk The latter was particularly true for those at intermediate risk (10-20% over 10 years)(10-20% over 10 years)

Thus, CRP measurement modulates coronary risk and may Thus, CRP measurement modulates coronary risk and may therefore modify the physician`s interpretation of the patient`s therefore modify the physician`s interpretation of the patient`s risk statusrisk status

Calcium scoring also seems to improve prediction based on Calcium scoring also seems to improve prediction based on the FRS the FRS

However, these findings have to be replicated in other However, these findings have to be replicated in other populationspopulations