Wolfgang Koenig, MD, FACC Dept. of Internal Medicine II - Cardiology

1. 1st „Vulnerable Patient“ Satellite Symposium,American Heart Association Orlando, USA, November 11, 2003 Is the Framingham model sufficient for prediction of coronary events? Should CRP be added to Framingham Risk Score? How about calcium score? Wolfgang Koenig, MD, FACC Dept. of Internal Medicine II - Cardiology University of Ulm Medical Center, Ulm, Germany

2. Low-Risk Intermediate-Risk High-Risk (~35 % of Pts.) (~40% of Pts.) (~25% of Pts.) <6 (10)% 6 (10) -19 % ≥ 20 % over 10 years Identity Test Positive Test Negative 0.5 0.4 0.3 0.2 0.1 0.0 0.05 0.1 0.15 0.2 CHD Risk Assessment in Asymptomatic Patients: Selective Use of Noninvasive Testing Modification of Probability Estimates of CHD by Non-invasive Testing • Assessment by multivariable • statistical models: e.g. • Framingham Risk Score or • PROCAM score • Clear guidelines for high or low • risk subjects, but not so for • those at intermediate risk Post-test Probability of CHD Event in 10 Yrs Pre-test Probability of CHD Event in 10 Yrs modified after Greenland et al. Circulation 2001;104:1863-1867

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

4. C-Reactive Protein Modulates Risk Prediction:MONICA/KORA Augsburg Cohort 1984-98 Methods: Patient Population and Assays • 3,435 men aged 45-74 years, participating in the three MONICA surveys 1984/85, 1989/90, 1994/95 • Exclusion of prevalent CHD • Standardized assessment of cardiovascular risk factors: Total cholesterol, HDL-C, blood pressure, smoking, BMI, physical activity, social class, diabetes mellitus, alcohol consumption. • Endpoint determination according to the MONICA protocol (fatal and non-fatal MI and sudden cardiac death) • Determination of CRP by a hs-IRMA (Hutchinson et al. Clin Chem 2000) with a detection limit of 0.05 mg/L (CV < 12%). • Determination of total cholesterol and HDL-C by routine enzymatic methods (CV < 4%) Koenig et al. AHA 2003

5. CRP mg/L <1.0 1.0 – 3.0 > 3.0 RR of CHD According to the Estimated 10-Yrs Risk Alone and in Combination With CRP: MONICA Augsburg Cohort (N=3,435 Men; 45-74 Yrs; 191 Events; FU 6.6 Yrs) Population at risk 809 914 650 526 536 8 P=0.09 8 P=0.02 7 7 6 6 AIC 2776 AIC 2789 5 5 Multivariable Relative Risk 4 4 P=0.03 3 3 P=0.26 2 2 P=0.20 1 1 18 32 35 50 56 0 0 < 6 6-10 11-14 15-19 20 < 6 6-10 11-14 15-19 20 Framingham Estimate of 10-Year Risk (%) Koenig et al. AHA 2003

6. Risk of a First Coronary Event by Cox Model w/o and With CRP for the FRS With 3 and 5 Categories AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP); AUC, Area under the curve Koenig et al. AHA 2003

7. Coronary Calcification and Atherosclerotic Cardiovascular Disease Events: St. Francis Heart Study • Prospective, longitudinal, population-based study of asymp-tomatic men and women aged 50 to 70 with no prior history, symptoms or signs of atherosclerotic CVD • Subjects on or with indication for lipid-lowering therapy excluded • Coronary calcium measured by EBCT scanning, Agatston method • Events verified by independent Endpoints Adjudication Committee, blinded to coronary calcium score • A total of 5,585 subjects were scanned • Risk factors measured in 1,817 • 4.3 years follow-up, 96% complete • 122 subjects (0.6%/year) with  1 atherosclerotic CVD event Arad et al. ACC, Chicago 2003

8. 32.0 24.0 16.0 8.0 0.0 600 0 1-99 100-199 200-599 Prediction of CVD Events by Coronary Calcium Score: St. Francis Heart Study RR • Baseline Calcium Score and CVD Events: Event 584  775 P < 0.0001 No event 142  381 • Coronary Calcium Score (100 • vs <100) and CVD Events: • All CVD 122 9.5 (6.5-13.8) • All coronary 105 10.7 (7.1-16.3) • MI/coronary death 43 9.9 (5.2-18.9) Events N RR (95% CI) Calcium Score Arad et al. ACC, Chicago 2003

9. 5 1st Tertile 2nd Tertile 3rd Tertile 4 3 2 1 0 < 10 10 to 20 > 20 Prediction of CVD by Coronary Calcium Score vs Framingham Risk Score: St. Francis Heart Study Calcium score vs Framingham risk index prediction of coronary events Area under ROC curveP-value Calcium score 0.81  0.03 < 0.01 Framingham 0.71  0.03 % per year (observed) % per 10 years (predicted) Arad et al. ACC, Chicago 2003

10. Summary and Conclusions • The addition of CRP to a prediction model of the FRS resulted in a better fit of the model containing CRP and significantly improved prediction of incident CHD for the calculated FRS • The latter was particularly true for those at intermediate risk (10-20% over 10 years) • Thus, CRP measurement modulates coronary risk and may therefore modify the physician`s interpretation of the patient`s risk status • Calcium scoring also seems to improve prediction based on the FRS • However, these findings have to be replicated in other populations