1. Cost-Effectiveness of hsCRP Screening 1. Adjunct to Global Risk Assessment 2. Method to Monitor Statin Efficacy in Secondary Prevention 3. Method to Target Statin Therapy in Primary Prevention Paul M Ridker, MD Eugene Braunwald Professor of Medicine Harvard Medical School Director, Center for Cardiovascular Disease Prevention Brigham and Women’s Hospital Boston, Massachusetts Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

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

3. Circulation Primary Pro-Inflammatory Cytokines ( e.g., IL-1, TNF-  ) IL-6 IL-6 “Messenger” Cytokine ICAM-1 Selectins, HSPs, etc. Liver Endothelium and other cells Circulation 1999;100:1148–1150. Pro-Inflammatory Pathways Pro-Inflammatory Risk Factors CRPSAA

4. WHS ARIC MONICA PHS HPFSNHS Reykjavik* Framingham Adjusted Relative Risk hsCRP Adds Prognostic Information Beyond the Framingham Risk Score in ALL Major Cohorts Evaluated CHSEPIC-Norfolk 1997 20022004 2005 PIMA

5. Fully Adjusted Relative Risk TC : HDLC RatioApo B 100 : Apo A-I Ratio hsCRP 3 mg/L JAMA 2005;294:326-333 Additive Value of hsCRP Across All Lipid Ratios Risks Adjusted for Age, Blood Pressure, Smoking Status, Body Mass Index, and Diabetes

6. Moving Toward an hs-CRP Modified Framingham Risk Score Calculated Framingham 10-Year Risk Ridker PM, Wilson PW, Grundy S. Circulation 2004;109:2818-2925 hs-CRP mg/L CRP Modified Framingham Risk

7. hsCRP Enters Global Risk Prediction Models Before TC, HDL, 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

8. Comparison of model fit for ATP III risk prediction with and without CRP ATP Prediction Model Without CRP With CRP Liklihood ratio Chi-square Bayes Information Criteria (BIC) BIC weight (posterior probability) Akaike Information Criteria (AIC) AIC weights Nagelkerke’s Generalized R 2 C-statistic Adjusted C-statistic D-statistic Adjusted D-statistic Brier Score Regardless of Measure Used, the Addition of hsCRP Improves Predictive Modeling

9. 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 Risk Without CRP (10 year risk) Proportion Correctly Reclassified 21.3 % 20.0 % 13.9 % Additive Value of hsCRP to Global Risk Prediction Models – Observed Risk and Proportion Correctly Reclassified 32.4% 42.2 % 19.4 % WHSATP-III Between 20 and 40 percent of all individuals with 5 to 20 percent risk by ATP-III are reclassified more accurately and with greater precision by adding hsCRP; these proportions are significantly LARGER than those associated with LDL, HDL, or TG screening

10. Cost-Effectiveness of hsCRP Screening Part 1. Adjunct for Global Risk Assessment: Comparison 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 equal to that of lipid screening then hsCRP screening must be at least as cost effective for broad population screening as is lipid evaluation.

11. The Clinical Issue : hsCRP Reduction and Patient Management There is no hard evidence to date that lowering hsCRP per se will reduce vascular risk. However, all observational evidence indicates that those with lower hsCRP levels after treatment have better short and long term prognosis.

12. Clinical Predictive Value of Very Low as Well as Very High Levels of hsCRP hsCRP (mg/L) Relative Risk of Future CV Events “low risk” “moderate risk” “high risk” Circulation 2004;109:1955-59

13. Follow-Up (years) 0.00.51.01.52.02.5 0.00 0.02 0.04 0.06 0.08 0.10 CRP>2 mg/L CRP<2 mg/L 0.00.51.01.52.02.5 0.00 0.02 0.04 0.06 0.08 0.10 Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent) 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.

14. 0.00.51.01.52.02.50.00.51.01.52.02.50.00.51.01.52.02.50.00.51.01.52.02.5 0.00 0.02 0.04 0.06 0.08 0.10 0.02 0.04 0.06 0.08 0.10 Recurrent Myocardial Infarction or Coronary Death (percent) Follow-Up (Years) LDL > 70 mg/dL, CRP > 2 mg/L LDL 2 mg/L LDL > 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.

15. 0.00.51.01.52.02.50.00.51.01.52.02.50.00.51.01.52.02.50.00.51.01.52.02.5 0.00 0.02 0.04 0.06 0.08 0.10 0.02 0.04 0.06 0.08 0.10 Recurrent Myocardial Infarction or Coronary Death (percent) Follow-Up (Years) LDL > 70 mg/dL, CRP > 2 mg/L LDL 2 mg/L LDL > 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.

16. Nissen et al NEJM 2005; 352:29-38 Effects of LDL Reduction and CRP Reduction on Atherosclerotic Progression Measured By Intravascular Ultrasound : REVERSAL

17. REVERSAL: Regression of Atherosclerosis On Statin Therapy Only Occurs Among Those with CRP Reduction Change in Atheroma Volume (mm 3 ) Nissen et al NEJM 2005; 352:29-38 LDL CRP LDL CRP LDL CRP LDL CRP Progression Regression +8mm 3 +2mm 3 - 1mm 3 - 2mm 3

18. Importance of Achieving Low LDLC and Low hsCRP After Initiation of Statin Therapy : Carotid IMT Regression in ARBITER Kent SM, Taylor AJ. AJC 2003;92:1224-1227 LDL > 130 LDL 100 - 129 LDL 70 - 99 LDL < 70 LDL < 70 hsCRP > 2 LDL < 70 hsCRP < 2 Proportion with IMT Regression

19. Cost-Effectiveness of hsCRP Screening Part 2. High Risk Secondary Prevention to Monitor Statin Efficacy 1.Patients on statin therapy who achieve low hsCRP levels have better clinical outcomes at all levels of achieved LDL-C. 2.The best clinical outcomes are obtained among statin treated patients who achieve the “dual goals” of LDL-C < 70 mg/dL and hsCRP < 2 mg/L. 3.The relationship between achieved LDL-C and achieved hsCRP is highly variable for individual patients and cannot be predicted on the basis of intensity of therapy. 4.Strategies to cost-effectively lower cardiovascular risk with statins may need to measure and monitor hsCRP in a manner analogous to how we currently measure and manage LDL-C.

20. CRP as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study Group StatinPlaceboNNT 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/dL Median CRP = 0.16 mg/dL N Engl J Med 2001;344:1959-65

21. No History of CAD Men >55, Women > 65 LDL-C <130 mg/dL CRP >2 mg/L Rosuvastatin (N =7500) Placebo (N =7500) MI Stroke Unstable Angina CVD Death CABG/PTCA LDL CRP FHS Lipids hs-CRP LFTs Lipids hs-CRP HbA1C JUPITER Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with 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 Lipids hs-CRP LFTs HbA1C JUPITER Investigators, Circulation 2003

22. Estimated Life Expectancy Gains : hsCRP Primary prevention in 35 year old men and women InterventionGains in Life Expectancy (months) MenWomen Statin Therapy for high CRP / low LDL10.2 7.9 Eliminate Smoking10.0 8.0 Reduce DBP to 88 mm Hg13.2 4.8 Eliminate CHD37.239.6 Mammography 50 yr old womenNA 0.8 Pap smear 20 year old womenNA 3.1 Blake G, Kuntz K, JACC 2002;40:49-55

23. Blake G, Kuntz K. Am J Med 2003;114:485-94 “A strategy involving C-reactive protein screening to target statin therapy among middle-aged patients without hyperlipidemia is relatively cost-effective and, in some cases, cost-saving” “Overall, cost-effectiveness ratios were comparable to those reported for primary prevention using statin therapy among those with hyperlipidemia” Cost-Effectiveness of hsCRP Screening Part 3. : Targeting Statin Therapy for Primary Prevention

24. Blake G, Kuntz K, Am J Med 2003;114:485-94 Cost-Effectiveness of hsCRP Screening Part 2 : Targeting Statin Therapy $ / QALY (000) 0-55-1010-1515-2020-25 Ten-year Risk of Coronary Heart Disease Cost Saving Cost Effective Cost Comparable

26. Combined Use of CT Calcium Scores and CRP in the Prediction of Cardiovascular Events: South Bay Heart Watch EBCT Calcium Score Park R, Detrano R, Xiang M, et al. Circulation 2002;106:2073-7 hs-CRP, mg/L Relative Risk

27. hsCRP and Progression of Cerebral Small-Vessel Disease: The Rotterdam Scan Study Quartile of hsCRP At Study Entry Adjusted Odds Ratio* 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

28. hsCRP and SAA Predict Short-Term Progression of Atherosclerosis Lesions in Human Carotid Arteries Schillinger et al, Circulation 2005;111:2203-9 Quintile of hsCRP or SAA at Baseline Adjusted OR for Carotid Progression Adjusted for age, gender, BMI, HbA1c, smoking, BP, LDL-C,, family history, and IMT (N = 1268, 7.5 month f/u)

29. February 23, 2004 1995 – Cholesterol 2005 – Cholesterol and Inflammation

31. Broad Screening: Blood Pressure TC, HDLC, glucose, hsCRP, ABI Targeted Screening: Imaging Statin Monitoring: LDLC, hsCRP

32. “If CRP was half as effective and twice as expensive, physician use would be ten times higher” Moving Toward New National Screening Guidelines