SHAPE Society

1. Wolfgang Koenig, MD, FACCWolfgang Koenig, MD, FACC
Dept. 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 forIs the Framingham model sufficient for
prediction of coronary events?prediction of coronary events?
Should CRP be added toShould 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 AssociationAmerican Heart Association
Orlando, USA, November 11, 2003Orlando, USA, November 11, 2003

2. IdentityIdentity
Test PositiveTest Positive
Test 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-testProbabilityofCHDEventin10YrsPost-testProbabilityofCHDEventin10Yrs
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 inCHD Risk Assessment in
Asymptomatic Patients:Asymptomatic Patients:
Selective Use of Noninvasive TestingSelective Use of Noninvasive Testing
Modification of Probability Estimates ofModification of Probability Estimates of
CHD by Non-invasive TestingCHD by Non-invasive Testing
 Assessment by multivariableAssessment by multivariable
statistical models: e.g.statistical models: e.g.
Framingham Risk Score orFramingham Risk Score or
PROCAM scorePROCAM score
 Clear guidelines for high or lowClear guidelines for high or low
risk subjects, but not so forrisk subjects, but not so for
those at intermediate riskthose at intermediate risk

3. C-Reactive ProteinC-Reactive Protein
Modulates Risk PredictionModulates Risk Prediction
Can CRP ChangeCan CRP Change
Our Practice?Our Practice?

4. 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 three3,435 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 CHDExclusion 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, alcoholphysical activity, social class, diabetes mellitus, alcohol
consumption.consumption.
 Endpoint determination according to the MONICA protocolEndpoint 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. ClinDetermination 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 routineDetermination 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

5. < 6 6-10 11-14 15-19< 6 6-10 11-14 15-19 ≥≥2020
00
11
22
33
44
55
66
77
88
< 6 6-10 11-14 15-19< 6 6-10 11-14 15-19 ≥≥2020
00
11
22
33
44
55
66
77
88
P=0.20P=0.20
P=0.26P=0.26
P=0.02P=0.02
P=0.03P=0.03
P=0.09P=0.09
<1.0<1.0
1.0 – 3.01.0 – 3.0
> 3.0> 3.0
CRPCRP mg/Lmg/L
1818 3232 35 50 5635 50 56
Population at riskPopulation at risk
809 914 650 526 536809 914 650 526 536
Framingham Estimate of 10-Year Risk (%)Framingham Estimate of 10-Year Risk (%)
MultivariableRelativeRiskMultivariableRelativeRisk
AIC 2776AIC 2776AIC 2789AIC 2789
RR of CHD According to the Estimated 10-YrsRR 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

6. Risk of a First Coronary EventRisk of a First Coronary Event
by Cox Model w/o and With CRP forby Cox Model w/o and With CRP for
the FRS With 3 and 5 Categoriesthe 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.
(%)(%) 6-196-19 117/2090117/2090 2.81 (1.71-4.62)2.81 (1.71-4.62) 2.39 (1.45-3.94)2.39 (1.45-3.94)
≥≥2020 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 curveAUC, Area under the curve Koenig et al. AHA 2003Koenig et al. AHA 2003

7. Coronary Calcification and AtheroscleroticCoronary 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 therapySubjects on or with indication for lipid-lowering therapy
excludedexcluded
 Coronary calcium measured by EBCT scanning, AgatstonCoronary calcium measured by EBCT scanning, Agatston
methodmethod
 Events verified by independent Endpoints AdjudicationEvents 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) with122 subjects (0.6%/year) with ≥≥ 1 atherosclerotic CVD event1 atherosclerotic CVD event
Arad et al. ACC, Chicago 2003Arad et al. ACC, Chicago 2003

8. 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 ScoreBaseline Calcium Score
and CVD Events:and CVD Events:
EventEvent 584584 ±± 775775
P < 0.0001P < 0.0001
No event 142No event 142 ±± 381381
 Coronary Calcium Score (Coronary Calcium Score (≥≥100100
vs <100) and CVD Events:vs <100) and CVD Events:
All CVDAll CVD 122122 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 CoronaryPrediction 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)

9. 00
11
22
33
44
55
< 10< 10 10 to 2010 to 20 > 20> 20
Prediction of CVD by Coronary CalciumPrediction of CVD by Coronary Calcium
Score vs Framingham Risk Score:Score vs Framingham Risk Score:
St. Francis Heart StudySt. Francis Heart Study
Calcium score vsCalcium score vs
Framingham risk index predictionFramingham risk index prediction
of coronary eventsof coronary events
Area underArea under
ROC curveROC curve P-valueP-value
Calcium score 0.81Calcium score 0.81 ±± 0.030.03
< 0.01< 0.01
Framingham 0.71Framingham 0.71 ±± 0.030.03
11stst
TertileTertile
22ndnd
TertileTertile
33rdrd
TertileTertile
% per 10 years% per 10 years ((predicted)predicted)
%peryear%peryear((observed)observed)
Arad et al. ACC, Chicago 2003Arad et al. ACC, Chicago 2003

10. Summary and ConclusionsSummary and Conclusions
 The addition of CRP to a prediction model of the FRSThe addition of CRP to a prediction model of the FRS
resulted in a better fit of the model containing CRP andresulted in a better fit of the model containing CRP and
significantly improved prediction of incident CHD for thesignificantly improved prediction of incident CHD for the
calculated FRScalculated FRS
 The latter was particularly true for those at intermediate riskThe 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 mayThus, CRP measurement modulates coronary risk and may
therefore modify the physician`s interpretation of thetherefore modify the physician`s interpretation of the
patient`s risk statuspatient`s risk status
 Calcium scoring also seems to improve prediction based onCalcium scoring also seems to improve prediction based on
the FRSthe FRS
 However, these findings have to be replicated in otherHowever, these findings have to be replicated in other
populationspopulations