Statins for the Primary Prevention of CVD in Women with Elevated hsCRP or Dyslipidemia: Results from JUPITER and Meta-Analysis of Women from Primary Prevention Statin Trials Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen, Jacques Genest, and Paul M Ridker Brigham and Women’s Hospital Harvard Medical School Boston, MA on behalf of the JUPITER Trial Study Group Circulation 2010; 121:

Sources of Funding The JUPITER Trial is an investigator-initiated study sponsored by AstraZeneca; The sponsor played no role in the conduct of the analyses or drafting of the paper. Author Disclosures Related to this Presentation S Mora:NHLBI (K08 HL094375),Merck, AstraZeneca (Research Grant, Significant) S Mora:NHLBI (K08 HL094375), Merck, AstraZeneca (Research Grant, Significant) RJ Glynn:AstraZeneca, Bristol-Myers Squibb (Research Grant, Significant) J Hsia:Employed by AstraZeneca J Genest: Merck, AstraZeneca,Resverlogix (Research Grant, Significant); Merck, AstraZeneca, GlaxoSmithKline (Speaker’s Fees) PM Ridker: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 that have been licensed to Siemens and AstraZeneca. Dr. Ridker also receives research grant support (Significant) from AstraZeneca, Novartis, Merck, Roche, Sanofi-Aventis, non-financial support from Amgen, PM Ridker: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 that have been licensed to Siemens and AstraZeneca. Dr. Ridker also receives research grant support (Significant) from AstraZeneca, Novartis, Merck, Roche, Sanofi-Aventis, non-financial support from Amgen, and serves as consultant for AstraZeneca, Isis, Merck, Novartis, Sanofi-Aventis, Schering-Plough, Siemens, Novartis, Merck, Isis, and Vascular Biogenics

Background Statins for patients with CVD is established Similar benefit in women, men Relative risk reduction ~20-30% Statins for women with no CVD is controversial Prior meta-analyses: non-significant RR CHD events 0.87 ( ), P=0.17 N = 11, 435 women Walsh and Pignone, JAMA 2004;2243

Objectives 1.Pre-specified analysis in JUPITER for efficacy and safety of rosuvastatin in women and men with elevated hsCRP and non-elevated LDL cholesterol 2. Updated meta-analysis of statin therapy for primary prevention of CVD in women

JUPITER Trial Objective To investigate whether rosuvastatin 20 mg vs placebo decreases major CVD events in apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are at increased vascular risk due to enhanced inflammatory response, with hsCRP > 2 mg/L Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin Ridker PM et al NEJM 2008;2195

Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA > 60 > 50 6,801 women > 60 years 11,001 men > 50 years 1,315 sites, 26 countries 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) 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 Ridker PM et al NEJM 2008;2195

JUPITER Inclusion and Exclusion Criteria, Study Flow 89,863 Screened 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo Reason for Exclusion (%) LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,600 Completed Study 120 Lost to follow-up 8,600 Completed Study 120 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses 89,890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 17,802 Randomized Reason for Exclusion (%) LDL > 130 mg/dL 52 hsCRP < 2.0 mg/L 36 Withdrew Consent 5 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 4 week Placebo Run-In 8,857 Completed Study 44 Lost to follow-up 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,864 Completed Study 37 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses Ridker et al NEJM 2008

Statistical Methods 1.JUPITER Intention to treat sex-specific Cox regression, pre-specified in trial protocol P values from Wilcoxon 2 sample, chi 2, heterogeneity (likelihood ratio tests) 2. Meta-analysis Random-effects regression models, tests for heterogeneity Mora S et al Circulation 2010; 1069

JUPITER Baseline Clinical Characteristics WomenMen (N = 6801)(N = 11001) Age, years (IQR)68.0( )63.0 ( ) Ethnicity, % Caucasian Black Hispanic BMI, kg/m 2 (IQR)29.2 ( )27.9 ( ) Hypertension, % Smoker, % Family History, % Metabolic Syndrome, % All values are median (interquartile range) or % Mora S et al Circulation 2010; 1069

JUPITER Baseline Blood Levels (median, interquartile range) WomenMen (N = 6801)(N = 11001) hsCRP, mg/L4.6( )4.1 (2.7 – 6.8) LDL, mg/dL 109 ( )108( ) HDL, mg/dL54(46 – 66)45(38 – 55) Triglycerides, mg/L118( )118 ( ) Total Cholesterol, mg/dL192 ( )182( ) Glucose, mg/dL93(87 – 101)95(88 – 102) HbA1c, %5.8(5.5 – 6.0)5.6 (5.4 – 5.9) All values are median (interquartile range). Mora S et al Circulation 2010; 1069

JUPITER Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months Women Men Rosuva Placebo Rosuva Placebo hsCRP, mg/L (- 3.6, - 0.6) (- 2.2, +0.8) (- 3.4, - 0.4) (- 2.5, +0.8) LDL, mg/dL (- 65, - 27) (- 7, +17) (- 62, - 29) (- 9, +15) HDL, mg/dL (- 2, + 8) (- 4, + 6) (- 2, + 8) (- 3, + 5) Triglycerides, mg/L (- 44, + 3) (- 23, +21) (- 50, +7) (- 26, +27) Total Cholesterol, mg/dL (- 68, - 27) (- 9, +19) (- 66, - 28) (- 9, +17) All values are median (interquartile range) change from baseline to 12 months Mora S et al Circulation 2010; 1069

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death RosuvaPlacebo No. (Rate)* HR95% CI P for heterogeneity Women39 (0.56)70 (1.04) P= Men103 (0.88) 181 (1.54) P< * Rates are per 100 person-years Mora S et al Circulation 2010; 1069

JUPITER Primary Trial Endpoint : Number Needed to Treat (5-years) RosuvaPlacebo No. (Rate) NNT* Women39 (0.56)70 (1.04)36 Men103 (0.88) 181 (1.54)22 All 142 (0.77)251 (1.36) 25 * Calculated based on the method of Altman and Andersen Mora S et al Circulation 2010; 1069

JUPITER Components of the Primary Endpoint Endpoint Women Men P for Heterogeneity Primary Endpoint Nonfatal MI Nonfatal Stroke – – 0.63 MI, Stroke, CVD Death – – 0.61 Revasc/Unstable Angina – – 0.85 All-cause Death – – 1.03 Mora S et al Circulation 2010; 1069

Rosuvastatin SuperiorRosuvastatin Inferior Women Metabolic Syndrome Yes No ATP-III Risk Factors 0 >1 LDL <100 >100 HDL < 50 >50 Triglycerides <150 >150 hsCRP <5 >5 Time of Event <24 Months >24 Months All Participants 3,157 3,605 3,072 3,716 2,216 4,585 2,451 4,350 4,690 2,111 3,687 3,114 6,801 2,537 6, Age <65 >65 Race/ethnicity White Nonwhite Smoker Yes No Hypertension Yes No BMI < >30.0 Family Hx Yes No N 1,942 4,859 4,197 2, ,283 4,263 2,536 1,412 2,335 3, ,949 # of Events Incidence Rates (Placebo) Mora S et al Circulation 2010; 1069

Rosuvastatin SuperiorRosuvastatin Inferior Incidence Rates Men Age <65 >65 Race or ethnic group White Nonwhite Smoker Yes No Hypertension Yes No BMI < >30.0 Family Hx of CHD Yes No Metabolic Syndrome Yes No ATP-III Risk Factors 0 >1 LDL <100 >100 HDL <40 ≥40 Triglycerides <150 >150 hsCRP <5 >5 Time of Event <24 Months >24 Months All Participants N 6,599 4,402 8,486 2,513 2,305 8,692 5,945 5,050 2,661 4,674 3,631 1,216 9,735 4,218 6,691 3,303 7,683 4,053 6,943 3,238 7,762 7,275 3,725 6,771 4,230 11,001 5,228 11,001 # of Events (Placebo) Mora S et al Circulation 2010; 1069

JUPITER Adverse Events and Measured Safety Parameters Event Women Men Rosuva Placebo Rosuva Placebo Any SAE Muscle weakness Myopathy Rhabdomyolysis Incident Cancer Cancer Deaths Hemorrhagic stroke GFR (ml/min/1.73m 2 at 12 mth) ALT > 3xULN Fasting glucose (24 mth) HbA1c (% at 24 mth) Incident Diabetes* All values are medians or rates per 100 person-years *Physician reported, P for heterogeneity by sex = 0.16 Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women AFCAPS/TexCAPS1998 MEGA2006 JUPITER ( ) P<0.001 P for heterogeneity 0.56 ALL Favors StatinFavors Placebo ( ) ( ) ( ) 21/498 56/ / /499 40/ /3426 RR 95% CI PlaceboStatin Year Women, 240 CVD events Mora S et al Circulation 2010; 1069

Study Limitations JUPITER median follow-up 1.9 years (max 5) Limited long-term safety data for rosuvastatin Low absolute event rates in women <65 years Meta-analysis: degree of LDL cholesterol lowering differed Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis Among apparently healthy women with elevated hsCRP and non-elevated LDL cholesterol, rosuvastatin resulted in similar and significant relative risk reduction in CVD compared with men Women had lower absolute event rates, especially <65 years old Women had more benefit for revascularization / unstable angina, men had more benefit for stroke Subgroup analysis suggested women with family history of premature CHD benefit more than those without family history Higher physician-reported diabetes in women compared with men, but test for heterogeneity by sex non-significant Overall safety in women similar to men Mora S et al Circulation 2010; 1069

JUPITER Conclusions – Meta-Analysis For primary prevention of CVD in women, statin allocation yielded significant relative risk reduction by one third This relative risk reduction is similar to prior results in men for primary prevention and men or women for secondary prevention These findings may have guideline implications for statin therapy in apparently healthy women meeting JUPITER entry criteria, even without high risk Framingham scores Mora S et al Circulation 2010; 1069