1. Presenter Disclosure Information Paul M Ridker, MD, FACC 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 that have been licensed to Seimens and AstraZeneca. Dr Ridker is the Principal Investigator of JUPITER, an investigator initiated trial funded by AstraZeneca. Dr Ridker has served as a consultant to AstraZeneca, Novartis, Merck, Schering Plough, ISIS, Vascular Biogenics (modest). Dr Ridker has received grant support from the NHLBI, the NCI, the Donald W Reynolds Foundation, the Doris Duke Foundation, the Leducq Foundation, AstraZeneca, SanofiAventis, Novartis and Merck (significant)

2. Controversies in Prevention: The JUPITER Trial Will it Change Your Practice? Primary Results and Implications Paul M Ridker, MD, MPH Eugene Braunwald Professor of Medicine Director, Center for Cardiovascular Disease Prevention Brigham and Women’s Hospital Harvard Medical School, Boston, MA USA 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.

3. Sachdeva et al, Am Heart J 2009;157:111-7.e2. LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006 LDLC (mg/dL) 130-160> 160< 130

4. Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER Trial Design Placebo (N=8901) Baseline LDLC 104 mg/dL Baseline HDLC 49 mg/dL Baseline hsCRP 4.2 mg/L Women6,800 Non-Caucasian5,000 Ridker et al, NEJM 2008359:2195-07

5. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174

6. JUPITER Myocardial Infarction, Stroke, Cardiovascular Death Placebo (N = 157) Rosuvastatin (N = 83) HR 0.53, 95%CI 0.40-0.69 P < 0.00001 - 47 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6438,4376,5713,9211,9791,370998551159 8,9018,6338,3816,5423,9181,9921,365979550181

7. JUPITER Fatal or Nonfatal Myocardial Infarction Rosuvastatin Placebo - 55 % 01234 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence HR 0.45, 95%CI 0.30-0.70 P < 0.0002

8. JUPITER Fatal or Nonfatal Stroke Rosuvastatin Placebo - 48 % 01234 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence HR 0.52, 95%CI 0.34-0.79 P = 0.002

9. JUPITER Bypass Surgery / Angioplasty Placebo (N = 131) Rosuvastatin (N = 71) HR 0.54, 95%CI 0.41-0.72 P < 0.00001 - 46 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6408,4266,5503,9051,9661,359989547158 8,9018,6418,3906,5423,8951,9771,346963538176

10. JUPITER All Cause Mortality Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,8478,7876,9994,3122,2681,6021,192683227 8,9018,8528,7756,9874,3192,2951,6141,196684246

11. JUPITER Primary Endpoint – Understudied or “Low Risk” Subgroups 0.250.51.02.04.0 Rosuvastatin SuperiorRosuvastatin Inferior Women Age > 70 Framingham Risk < 10 % Black, Hispanic, Other LDLC < 100 mg/dL No Hypertension All Participants N HR (95%CI) 6,8010.54 (0.37-0.80) 5,6950.61 (0.46-0.82) 8,882 0.56 (0.38-0.83) 5,1170.63 (0.41-0.98) 6,2690.66 (0.47-0.92) 7,5860.62 (0.44-0.87) 17,8020.56 (0.46-0.69) BMI < 25 mg/m2 4,0730.59 (0.40-0.87) No metabolic Syndrome10,296 0.49 (0.37-0.65) Elevated hsCRP Only 6,375 0.63 (0.44-0.92) Understudied Subgroups “Low Risk” Subgroups

12. JUPITER Primary Endpoint According to Baseline Glucose Levels HR 0.51, 95% CI 0.40-0.67 P < 0.0001 Normal Fasting Glucose HR 0.69, 95% CI 0.49-0.98 P= 0.04 Impaired Fasting Glucose 01234 Follow-up Years 0.00 0.02 0.04 0.06 0.08 0.10 Cumulative Incidence 01234 Follow-up Years Rosuvastatin Placebo

13. JUPITER Number Needed to Treat (5 year) Endpoint All Primary Endpoint25 Primary Endpoint, Mortality22 MI, Stroke, CABG/PTCA, Death23 MI, Stroke, Death31 Benchmarks: Statins for hyperlipidemia5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330

14. JUPITER Number Needed to Treat (5 year) Endpoint AllMenWomen Primary Endpoint252236 Primary Endpoint, Mortality221933 MI, Stroke, CABG/PTCA, Death231935 MI, Stroke, Death312559 Benchmarks: Statins for hyperlipidemia5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330

15. JUPITER Number Needed to Treat (5 year) Endpoint AllFRS 10 Primary Endpoint254717 Primary Endpoint, Mortality223916 MI, Stroke, CABG/PTCA, Death234216 MI, Stroke, Death316722 Benchmarks: Statins for hyperlipidemia5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330

16. JUPITER WOSCOPS AFCAPS/TexCAPS HTN - Diuretics HTN – Beta Blockers Aspirin - Men Aspirin - Women Estimated 5-Year NNT Values for the Primary Prevention of Cardiovascular Disease In Middle-Aged Populations

17. JUPITER Can we improve and simplify guidelines for primary prevention? www.reynoldsriskscore.org

18. JUPITER Can we simplify guidelines for statin therapy? 1. Strong recommendations for diet, exercise, and smoking cessation for any patient with or at risk for cardiovascular disease. 2. If there is prior MI, stroke, or known CVD, treat 3. If the patient is diabetic or has a very strong family history of premature atherothrombosis, treat 4. If LDLC > 160, TC:HDLC > 6, or hsCRP > 2, treat 5. Beyond these recommendations, referral to lipid specialist or cardiologist for further evaluation.

19. JUPITER ACC 2009 - Late Breaking Clinical Trial Data Do statins have antithrombotic or fibrinolytic effects? Late Breaking Clinical Trials II Sunday 2:00 PM Hall A2 A Randomized Trial of Rosuvastatin in the Prevention of Venous Thormboembolism: The JUPITER Trial Is the benefit observed in the JUPITER trial associated with achieving a low level of LDLC,a low level of hsCRP, or both? Late Breaking Clinical Trials V Monday 2:00 PM Hall A2 Dual Treatment Targets for LDLC and CRP After Initiation Of Rosuvastatin: The JUPITER Trial

20. JUPITER Public Health Implications However, application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone. Simplified guidelines that advocate combined lifestyle and pharmacologic therapy in those groups where trial evidence clearly supports a net benefit have the potential to greatly improve patient care and public health. Exercise, diet, and smoking cessation remain the first interventions for those with elevated LDLC or hsCRP. With thanks to the 17,802 patients and the >1,000 physicians worldwide for their effort and commitment to the JUPITER trial program.