New Insights into the Biology of Atherosclerosis and Primary Prevention: Controversy and Consensus in the JUPITER Trial

Fundacion Fernandez-CruzXXVIII Leccion Memorial New Insights into the Biology of Atherosclerosis and Primary Prevention: Controversy and Consensus in the JUPITER Trial 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.

Annals Int Med 1961;55:33-50

LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000-2006 LDLC (mg/dl) < 130 mg/dl 130-160 > 160 mg/dl < 3.4 mmol/l >4.1 mmol/l Sachdeva et al, Am Heart J 2009;157:111-7.e2.

Pro-Inflammatory Pathways Pro-Inflammatory Risk Factors ICAM-1 Selectins, HSPs, etc. Primary Pro-Inflammatory Cytokines ( e.g., IL-1, TNF-a ) CRP SAA IL-6 Messenger Cytokine Liver Endothelium and other cells Circulation Circulation 1999;100:1148 1150.

Inflammation, hscrp, and Vascular Prevention Is there evidence that individuals with elevated levels of the inflammatory biomarker hscrp are at high vascular risk even when other risk factors are acceptable? Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received? Is there evidence that reducing inflammation per se will reduce vascular events? Should our guidelines for vascular disease prevention change?

Relative Risk of MI Relative Risk of Stroke hscrp and Risk of Future MI and CVA in Apparently Healthy Men P Trend <0.001 P Trend <0.01 3 2 2 1 1 0 1 2 3 4 Quartile of hs-crp 0 1 2 3 4 Quartile of hs-crp N Engl J Med 1997;336:973 979.

hscrp and Risks of Future MI: Analysis Stratified by Year of Follow-Up 2 Relative Risk (per quartile) 1 0 0-2 2-4 4-6 6 + Years of Study Follow-Up N Engl J Med 1997;336:973-9

hscrp, Aspirin, and Risks of Future Myocardial Infarction 4 3 2 Relative Risk Myocardial Infarction 1 Placebo Aspirin 1 0 4 3 2 Quartile of C-Reactive Protein N Engl J Med 1997;336:973-9

Risk Factors for Future Cardiovascular Events: WHS Lipoprotein(a) Homocysteine IL-6 TC LDLC sicam-1 SAA Apo B TC: HDLC hs-crp hs-crp + TC: HDLC 0 1.0 2.0 4.0 6.0 Relative Risk of Future Cardiovascular Events N Engl J Med 2000;342:836-43

A Direct Comparison of LDL-C and hscrp in the Prediction of First Ever Cardiovascular Events Among 27,939 Women Total Cardiovascular Events MI, CABG, PTCA 5 5 4 4 3 3 2 2 1 1 0 1 2 3 4 5 0 1 2 3 4 5 Ischemic Stroke Cardiovascular Death 5 5 4 4 3 3 2 2 1 1 0 1 2 3 4 5 0 1 2 3 4 5 N Engl J Med 2002;347:1557-65

Relative Risk Relative Risk Relative Risk Relative Risk Markers of Inflammation in the Prediction of Cardiovascular Disease in Women 6.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 High Medium Low Low Total Cholesterol Medium High 5.0 4.0 3.0 2.0 1.0 0.0 High Medium Low Low Total Cholesterol Medium High 6.0 5.0 4.0 3.0 2.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 High Medium Low Low Medium High 1.0 0.0 High Medium Low Low Medium High Total Cholesterol Total Cholesterol NEJM. 2000;342:836 43.

CRP, IL-6 and the Risk for Developing Type-2 Diabetes in the Women s Health Study Fully adjusted BMI-adjusted Crude 16 14 Relative Risk IL-6 16 14 Relative Risk hs-crp 12 12 10 10 8 8 6 6 4 4 2 2 0 1 2 3 4 Quartile of IL-6 0 1 2 3 4 Quartile of hs-crp Pradhan et al JAMA 2001; 286:327-34

CVD Event-Free Survival Probability hscrp, the Metabolic Syndrome, and Future Cardiovascular Events (N = 14,719) 1.00 0.99 0.98 ATP III Metabolic Syndrome - No hscrp < 3.0 0.97 hscrp > 3.0 0.96 0 2 4 6 8 Years of Follow-Up ATP III Metabolic Syndrome - Yes Circulation 2003;107:391-7

Relative Risk of Future CV Events What are the environmental and genetic influences on CRP? 8 7 6 5 4 3 2 1 0 <0.5 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 5.0-10.0 10.0-20.0 >20 low risk moderate risk high risk Circulation 2004;109:1955-59 hscrp (mg/l)

hscrp and Coronary Heart Disease in a General Population of Japanese The Hisayama Study Arima H., et al, Arterioscler Thromb Vasc Biol. 2008;28:1385-91

Women s Genome Health Study GWAS for Plasma C-Reactive Protein Level Am J Hum Genet 2008;82:1185-1192

< 1 mg/l 1 to 3 mg/l > 3 mg/l 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 PHS 1997 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland 2004 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 NHS 2004 HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS 2008 0 1 2 3 0 1 2 3 0 1 2 3 CHS 2005 PIMA 2005 Fully Adjusted Relative Risk 0 1 2 3 hscrp Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated

AHA / CDC Scientific Statement Markers of Inflammation and Cardiovascular Disease: Applications to Clinical and Public Health Practice Circulation January 28, 2003 Measurement of hs-crp is an independent marker of risk and may be used at the discretion of the physician as part of global coronary risk assessment in adults without known cardiovascular disease. Weight of evidence favors use particularly among those judged at intermediate risk by global risk assessment. Circulation 2003; 107:499-511 CR-20

Cambridge Meta-Analysis : Emerging Risk Factors Collaboration CRP and risk of coronary heart disease, stroke, and total mortality 160,309 participants without a history of vascular disease, 54 prospective cohort studies, 1.31 million person-years of exposure, 27,769 fatal or nonfatal outcomes Risk ratio per 1-standard deviation increase (x3) in CRP = 1.63 (1.51-1.76) after adjustment for age and gender, and 1.39 (1.28-1.49) after additional adjustment for smoking, systolic blood pressure, diabetes, BMI, total cholesterol, HDL-cholesterol, and triglycerides. In these multivariable analyses, the RR for a 1-SD increase in CRP (1.39, 1.28-1.49) was of similar magnitude as that of comparable analyses for non-hdlc (1.28, 1.16-1.40) and systolic blood pressure (1.35, 1.25-1.45). In serial measures obtained among 24,222 participants, the regression-dilution ratio for CRP, adjusted for age and gender, was 0.58 (0.52-0.63) indicating year-to-year variability similar to that for systolic blood pressure (0.54, 0.51-0.58), total cholesterol (0.59,0.51-0.58), and HDLC (0.74, 0.70-0.78). Emerging Risk Factors Collaboration, Lancet 2009 (in press) CR-21

Cambridge Meta-Analysis : Emerging Risk Factors Collaboration CRP and risk of coronary heart disease, stroke, and total mortality 160,309 participants without a history of vascular disease, 54 prospective cohort studies, 1.31 million person-years of exposure, 27,769 fatal or nonfatal outcomes The current study has demonstrated that CRP levels are as consistent within individuals over several years as are total cholesterol and systolic blood pressure. In an analysis of 160,000 people without initial vascular disease, we have shown that under a wide range of circumstances CRP concentration has broadly loglinear associations with subsequent risk of coronary heart disease, ischemic stroke, and vascular death (and) the magnitude of these effects is comparable to that of other major established risk factors. Emerging Risk Factors Collaboration, Lancet 2009 (in press) CR-22

Framingham Risk Score Age Blood Pressure Diabetes Smoking Total cholesterol HDL cholesterol Reynolds Risk Score Age Blood Pressure Diabetes Smoking Total cholesterol HDL cholesterol hscrp Parental history of MI JAMA 2007;297:611-9 Circulation 2008

www.reynoldsriskscore.org

Reynolds Risk Score Example II Clinical Example: 72 year old non-diabetic woman, smoker, systolic BP 145 mm Hg, TC 216 mg/dl, HDLC 82 mg/dl, hscrp 7.7 mg/l, and a positive family history for MI. Predicted 10-year risk Framingham Covariates: Reynolds Covariates: 6.9 percent 23.2 percent

Relative Risk Median hs-crp (mg/dl) Inflammation, Statin Therapy, and hscrp: Initial Observations 3 P Trend = 0.005 0.25-21.6% (P=0.004) 0.24 Placebo 2 0.23 0.22 1 0.21 0.20 Pravastatin 0.19 0 Pravastatin Placebo Pravastatin Placebo Inflammation Absent Inflammation Present 0.18 Baseline 5 Years Circulation. 1998;98:839 844. Circulation. 1999;100:230-235.

Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent) Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy 0.00 0.02 0.04 0.06 0.08 0.10 0.00 0.02 0.04 0.06 0.08 0.10 LDLC>70 mg/dl LDLC<70 mg/dl hscrp>2 mg/l hscrp<2 mg/l 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 NEJM 2005;352:20-28. Follow-Up (years)

Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy 0.00 0.02 0.04 0.06 0.08 0.10 LDL > 70 mg/dl, CRP > 2 mg/l LDL > 70 mg/dl, CRP < 2 mg/l LDL < 70 mg/dl, CRP > 2 mg/l LDL < 70 mg/dl, CRP < 2 mg/l 0.0 0.5 1.0 1.5 2.0 2.5 Follow-Up (Years) NEJM 2005;352:20-28.

Probability of Event-free Survival Primary Prevention : Whom Should We Treat? 1.00 0.99 hscrp < 2 mg/l, LDL < 130 mg/dl 0.98 0.97 hscrp < 2 mg/l, LDL > 130 mg/dl hscrp > 2 mg/l, LDL < 130 mg/dl 0.96 hscrp > 2 mg/l, LDL > 130 mg/dl 0.00 0 2 4 6 8 Years of Follow-up N Engl J Med. 2002;347:1157-1165.

hscrp as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study Group Statin Placebo NNT low LDLC / low hscrp 0.025 0.022 ---- low LDLC / high hscrp 0.029 0.051 48 high LDLC / low hscrp 0.020 0.050 33 high LDLC / high hscrp 0.038 0.055 58 N Engl J Med 2001;344:1959-65 Median LDLC = 150 mg/dl Median CRP = 2 mg/l

JUPITER Trial Design 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 No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela

2873 987 204 85 804 32 2020 4021 345 336 487 222* 273 741 209 197 162 270 202 15 143 83 253 14 327 2497 JUPITER JUPITER Enrollment Sites 17,802 Patients Argentina Belgium Brazil Bulgaria Canada Chile Colombia Costa Rica Denmark El Salvador Estonia Germany Israel Mexico Netherlands Norway Panama Poland Romania Russia South Africa Switzerland UK USA Uruguay Venezuela

JUPITER Baseline Clinical Characteristics Rosuvastatin Placebo (N = 8901) (n = 8901) Age, years (IQR) 66.0 (60.0-71.0) 66.0 (60.0-71.0) Female, N (%) 3,426 (38.5) 3,375 (37.9) Ethnicity, N (%) Caucasian 6,358 (71.4) 6,325 (71.1) Black 1,100 (12.4) 1,124 (12.6) Hispanic 1,121 (12.6) 1,140 (12.8) Blood pressure, mm (IQR) Systolic 134 (124-145) 134 (124-145) Diastolic 80 (75-87) 80 (75-87) Smoker, N (%) 1,400 (15.7) 1,420 (16.0) Family History, N (%) 997 (11.2) 1,048 (11.8) Metabolic Syndrome, N (%) 3,652 (41.0) 3,723 (41.8) Aspirin Use, N (%) 1,481 (16.6) 1,477 (16.6) All values are median (interquartile range) or N (%)

JUPITER Baseline Blood Levels (median, interquartile range) Ridker et al NEJM 2008 Rosuvastatin Placebo (N = 8901) (n = 8901) hscrp, mg/l 4.2 (2.8-7.1) 4.3 (2.8-7.2) LDL, mg/dl 108 (94-119) 108 (94-119) mmol/l 2.8 (2.43-3.08) 2.8 (2.43-3.08 HDL, mg/dl 49 (40 60) 49 (40 60) mmol/l 1.27 (1.03-1.55) 1.27 (1.03-1.55) Triglycerides, mg/l 118 (85-169) 118 (86-169) mmol/l 1.33 (0.96-1.91) 1.33 (0.97-1.91) Total Cholesterol, mg/dl 186 (168-200) 185 (169-199) mmol/l 4.82 (4.35-5.18) 4.79 (4.38-5.15) Glucose, mg/dl 94 (87 102) 94 (88 102) mmol/l 5.22 (4.83-5.66) 5.22 (4.88-5.66) HbA1c, % 5.7 (5.4 5.9) 5.7 (5.5 5.9) All values are median (interquartile range) [ Mean LDL = 104 mg/dl (2.69 mmol/l)]

JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hscrp LDL (mg/dl) hscrp (mg/l) 140 60 120 50 100 80 60 40 40 30 20 20 0 LDL decrease 50 percent at 12 months TG (mg/dl) HDL (mg/dl) 10 0 HDL increase 4 percent at 12 months 5 140 4 3 120 100 80 2 60 1 0 hscrp decrease 37 percent at 12 months 0 12 24 36 48 Months 40 20 0 TG decrease 17 percent at 12 months 0 12 24 36 48 Months

JUPITER Additional Aim: Evaluate Long Term Stability of hscrp Among those allocated to placebo and followed over five years, the intraclass correlation coefficient for hscrp repeated every 6 months was 0.56, very similar to that of LDL-C (0.60) and blood pressure (0.59). These data are consistent with multiple prior reports that the month-to-month, year-to-year, and even decade-to-decade variability of hscrp is comparable to that of cholesterol. Glynn et al Clin Chem 2009 CR-37

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence 0.00 0.02 0.04 0.06 0.08 HR 0.56, 95% CI 0.46-0.69 P < 0.00000001 NEJM 2008;359:2195-2207 Number Needed to Treat (NNT 5 ) = 25 0 1 2 3 4 Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

JUPITER Fatal or Nonfatal Myocardial Infarction 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence NEJM 2008;359:2195-2207 HR 0.45, 95%CI 0.30-0.70 P < 0.0002 0 1 2 3 4 Placebo - 55 % Rosuvastatin Follow-up Years

JUPITER Fatal or Nonfatal Stroke 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence NEJM 2008;359:2195-2207 HR 0.52, 95%CI 0.34-0.79 P = 0.002 0 1 2 3 4 Follow-up Years Placebo - 48 % Rosuvastatin

JUPITER Arterial Revascularization / Unstable Angina 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence NEJM 2008;359:2195-2207 HR 0.53, 95%CI 0.40-0.70 P < 0.00001 0 1 2 3 4 Placebo (N = 143) - 47 % Rosuvastatin (N = 76) Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158 8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176

JUPITER Primary Endpoint Subgroup Analysis I NEJM 2008;359:2195-2207 Men Women Age < 65 Age > 65 Smoker Non-Smoker Caucasian Non-Caucasian USA/Canada Rest of World Hypertension No Hypertension All Participants N P for Interaction 11,001 0.80 6,801 8,541 0.32 9,261 2,820 0.63 14,975 12,683 0.57 5,117 6,041 0.51 11,761 10,208 0.53 7,586 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior CR-42

JUPITER Primary Endpoint Subgroup Analysis II NEJM 2008;359:2195-2207 N P for Interaction Family HX of CHD No Family HX of CHD BMI < 25 kg/m 2 BMI 25-29.9 kg/m BMI >30 kg/m Metabolic Syndrome No Metabolic Syndrome Framingham Risk < 10% Framingham Risk > 10% 2 2 2,045 0.07 15,684 4,073 0.70 7,009 6,675 7,375 0.14 10,296 8,882 0.99 8,895 hscrp > 2 mg/l Only 6,375 hscrp > 2 mg/l Only 6,375 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior CR-43

JUPITER Event Reduction at All Levels of Baseline LDLC < 130 mg/dl Baseline Levels N LDLC <100 mg/dl 6,269 LDLC <90 mg/dl 3,687 LDLC <80 mg/dl 2,033 LDLC <70 mg/dl 1,022 LDLC <60 mg/dl 511 All Participants 17,802 0.20 0.5 1.0 2.0 4.0 Rosuvastatin Better Rosuvastatin Worse

JUPITER Event Reduction at All Levels of Baseline hscrp > 2 mg/l Baseline hscrp N >10 _ mg/l 2,503 >9 _ mg/l >8 _ mg/l >7 _ mg/l >6 _ mg/l >5 _ mg/l >4 _ mg/l >3 _ mg/l >2 _ mg/l 3,071 3,839 4,723 5,897 7,425 9,726 12,939 17,802 0.20 0.5 1.0 2.0 Better Worse CR-45

JUPITER Secondary Endpoint All Cause Mortality HR 0.80, 95%CI 0.67-0.97 P= 0.02 Cumulative Incidence NEJM 2008;359:2195-2207 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1 2 3 4 Placebo 247 / 8901-20 % Rosuvastatin 198 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

JUPITER Number Needed to Treat (5 year) Endpoint All Primary Endpoint 25 Primary Endpoint, Mortality 22 MI, Stroke, CABG/PTCA, Death 23 MI, Stroke, Death 31 Benchmarks: Statins for hyperlipidemia 5-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

JUPITER Number Needed to Treat (5 year) Endpoint All FRS<10 FRS>10 Primary Endpoint 25 47 17 Primary Endpoint, Mortality 22 39 16 MI, Stroke, CABG/PTCA, Death 23 42 16 MI, Stroke, Death 31 67 22 Benchmarks: Statins for hyperlipidemia 5-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

Estimated 5-Year NNT Values for the Primary Prevention of Cardiovascular Disease In Middle-Aged Populations 450 400 350 300 250 200 150 100 50 0

Inflammation and Thrombosis Thrombin Resting Endothelial Cell Activated Endothelial Cell Reactive Oxygen Species Resting Platelet Tissue Factor Procoagulant Resting Smooth Muscle Cell Activated Degranulating Platelet Activated Macrophage Pro-inflammatory Cytokines Proliferating Modulated Smooth Muscle Cell Pro-inflammatory Mediators (e.g., CD40L, RANTES, IL-6) Lipid mediators Of inflammation Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol. 2007;14:55-61

Venous Endothelium- transmission electron micrograph

JUPITER Total Venous Thromboembolism Cumulative Incidence 0.000 0.005 0.010 0.015 0.020 0.025 HR 0.57, 95%CI 0.37-0.86 P= 0.007 0 1 2 3 4 Placebo 60 / 8901-43 % Rosuvastatin 34 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

JUPITER Venous Thromboembolism Unprovoked vs Provoked Cumulative Incidence 0.000 0.005 0.010 0.015 0.020 Cumulative Incidence Unprovoked Venous Thromboembolism Provoked Venous Thromboembolism 0.000 0.005 0.010 0.015 0.020 HR 0.61, 95% CI 0.35-1.09 P= 0.09 0 1 2 3 4 Follow-up (years) Placebo Rosuvastatin HR 0.52, 95% CI 0.28-0.97 P= 0.03 0 1 2 3 4 Follow-up (years) Placebo Rosuvastatin Clear clinical benefit in the absence of any bleeding hazard (hemmorrhagic events : rosuvastatin 258, placebo 275, P=0.45)

JUPITER VTE + Primary Trial Endpoint + Total Mortality Cumulative Incidence 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 HR 0.66, 95% CI 0.57-0.76 P < 0.00001 Number Needed to Treat (NNT 5 ) = 18 0 1 2 3 4 Placebo 483 / 8901 163 Fewer Events Rosuvastatin 320 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,624 8,400 6,525 3,880 1,951 1,348 979 536 157 8,901 8,612 8,338 6,486 3,854 1,949 1,320 945 525 170

JUPITER Achieved LDLC, Achieved hscrp, or Both? Is the benefit observed in the JUPITER trial associated with achieving a low level of LDLC, a low level of hscrp or both? Do we need to achieve the dual targets of low LDLC and low hscrp in order to maximize the benefit of statin therapy?

JUPITER Predicted vs Observed Benefit Based on Absolute LDL Reduction Proportional reduction in vascular event rate (95% CI) 55 50 45 40 35 30 25 CTT JUPITER PREDICTED 20 TNT 15 10 A-to-Z IDEAL PROVE-IT 5 0 0 0.5 1 Mean LDL cholesterol difference between treatment groups (mmol/l)

JUPITER Predicted vs Observed Benefit Based on Absolute LDL Reduction Proportional reduction in vascular event rate (95% CI) 55 50 45 40 35 JUPITER OBSERVED 30 25 CTT JUPITER PREDICTED 20 TNT 15 10 A-to-Z IDEAL PROVE-IT 5 0 0 0.5 1 Mean LDL cholesterol difference between treatment groups (mmol/l)

JUPITER LDL reduction, hscrp reduction, or both? Lancet 2009;373:1175-82 N Rate Placebo 7832 1.11 LDL>70mg/dL,hsCRP>2 mg/l 1384 1.11 LDL<70mg/dL,hsCRP>2 mg/l 2921 0.62 LDL>70mg/dL,hsCRP<2 mg/l 726 0.54 LDL<70mg/dL,hsCRP<2 mg/l 2685 0.38 P < 0.001 Placebo 7832 1.11 LDL>70mg/dL,hsCRP>1 mg/l 1874 0.95 LDL<70mg/dL,hsCRP>1 mg/l 4662 0.56 LDL>70mg/dL,hsCRP<1 mg/l 236 0.64 LDL<70mg/dL,hsCRP<1 mg/l 944 0.24 Full Adjusted Hazard Ratio 0.21, 95% CI 0.09-0.52, P < 0.0001 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Better P < 0.001 Rosuvastatin Worse

Clinical Importance of Achieving LDL-C < 70 mg/dl and hscrp < 2 mg/l Following Initiation of Statin Therapy LDL>70, hscrp>2 LDL<70, hscrp>2 LDL>70, hscrp<2 LDL<70, hscrp<2 0 2 4 6 6 8 8 10 0 180 360 540 720 900 Follow-up (days) PROVE IT TIMI 22 NEJM 2005;352:20-28. 10 8 6 4 2 0 0 120 240 360 480 600 Follow-up (days) A to Z Circulation 2006;114:281-8

Can targeted Anti-Inflammatory Therapy Reduce Cardiovascular Risk? Aspirin / Statins Direct CRP inhibitors DMARDs/ MTX TNF / IL-6 Inhibitors IL-1 receptor antagonism 5-LO Inhibitors Leukotriene blockade CCR2/CCR5 Lp-PLA2 inhibition spla inhibition RNAi / anti-sense Immunization strategies

What is the impact of methotrexate, infliximab, and tocilizumab on lipid levels? TC Statins MTX Infliximab tocilizumab LDL HDL TG Chylo CRP

Methotrexate and Mortality in Patients with Rheumatoid Arthritis: Wichita Arthritis Study All Cause Mortality Cardiovascular Mortality Non-Cardiovascular Mortality.2.4.8 1.0 1.5 2.0 4.0 Methotrexate Superior No DMARD Superior Choi et al, Lancet 2002;359:1173-77

LDM and CVD: Observational Evidence Cohort Group HR * (95 % CI) Endpoint Exposure Wichita RA 0.4 (0.2-0.8) Total Mortality LDM Choi 2002 0.3 (0.2-0.7) CV Mortality LDM 0.4 (0.3 0.8) CV Mortality LDM < 15 mg/wk Netherlands RA 0.3 (0.1 0.7) CVD LDM only van Helm 2006 0.2 (0.1 0.5) CVD LDM + SSZ 0.2 (0.1 1.2) CVD LDM + HCQ 0.2 (0.1 0.5) CVD LDM + SSZ + HCQ Miami VA PsA 0.7 (0.6 0.9) CVD LDM Pradanovich 2005 0.5 (0.3 0.8) CVD LDM < 15 mg/wk RA 0.8 (0.7 1.0) CVD LDM 0.6 (0.5 0.8) CVD LDM < 15 mg/wk CORRONA RA 0.6 (0.3 1.2) CVD LDM Solomon 2008 0.4 (0.2 0.8) CVD TNF-inhibitor QUEST-RA RA 0.85 (0.8 0.9) CVD LDM Narango 2008 0.82 (0.7 0.9) MI LDM 0.89 (0.8-1.0) Stroke LDM UK Norfolk RA, PsA 0.6 (0.4 1.0) Total Mortality LDM 2008 0.5 (0.3 1.1) CV Mortality LDM

Cardiovascular Inflammation Reduction Trial (CIRT) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) Open Label Active Run-In VLDM 10 mg/wk Randomized VLDM 10 mg/wk + folate Randomized Placebo mg/wk + folate N = 3,500 N = 3,500 25% RRR, 3.0 year median f/u Nonfatal MI, Nonfatal Stroke, Cardiovascular Death

WOSCOPS, AFCAPS, MEGA, ASCOT, JUPITER Can we use evidence to simplify guidelines for primary prevention? 1. Strong recommendations for diet, exercise, and smoking cessation for any patient with or at risk for cardiovascular disease. 2. If the patient is diabetic or has a very strong family history of premature atherothrombosis, strongly consider treatment with a statin if RRS or FRS > 5 % 3. If LDLC > 160, TC:HDLC > 5, or hscrp > 2, strongly consider treatment with a statin if RRS or FRS > 5 % 4. Beyond these recommendations, referral to lipid specialist or cardiologist for further evaluation.

2009 Canadian Cardiovascular Society (CCS) Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult Primary Goal : LDLC High CAD, CVA, PVD <2mmol/L or 50% reduction Class I Most pts with Diabetes Level A FRS > 20 % RRS > 20 % Moderate FRS 10-19 % <2mmol/L or 50 % reduction Class IIA RRS 10-19 % Level A LDL > 3.5 mmol/l TC/HDLC > 5.0 hscrp > 2 in men >50 yr women > 60 yr Low FRS < 10 % <5mmol/L Class IIA Level A Secondary Targets : TC/HDLC < 4, non HDLC < 3.5 mol/l, hscrp < 2 mg/l, TG < 1.7 mol/l, ApoB/A<0.8 CR-75

JUPITER Primary Endpoint in Intermediate Risk Groups with hscrp >2 mg/l FRS (%) Rosuvastatin Placebo HR (95%CI) 5 10 % 32 (0.50) 59 (0.92) 0.55 (0.36-0.84) 10 20 % 74 (0.95) 145 (1.84) 0.51 (0.39-0.68) None of these patients are currently eligible to receive statin therapy because, using traditional risk factors alone and calculating Framingham 10-year risk, they are less than 20 % AND they already have untreated LDL-C levels below the treatment target in primary prevention (ie < 130 mg/dl). However, they ALL have hscrp > 2 mg/l. CR-76

JUPITER Public Health Implications Exercise, diet, and smoking cessation remain the first interventions for those with elevated LDLC or hscrp. 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. With thanks to the 17,802 patients and the >1,000 physicians worldwide for their effort and commitment to the JUPITER trial program.