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JUPITER AHA November 9, 2008 A Randomized Trial of Rosuvastatin in the Prevention of JUPITER AHA November 9, 2008 A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17, 802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hs. CRP): The JUPITER Trial Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*, Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*, Alberto Lorenzatti*, Jean Mac. Fadyen, Borge Nordestgaard*, James Shepherd*, James Willerson, and Robert Glynn* on behalf of the JUPITER Trial Study Group An Investigator Initiated Trial Funded by Astra. Zeneca, USA * These authors have received research grant support and/or consultation fees from one or more statin manufacturers, including Astra-Zeneca. Dr Ridker is 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 Dade-Behring and Astra. Zeneca.

JUPITER Trial Structure Independent Steering Committee : P Ridker (Chair), F Fonseca, J Genest, JUPITER Trial Structure Independent Steering Committee : P Ridker (Chair), F Fonseca, J Genest, A Gotto, J Kastelein, W Koenig, P Libby, A Lorenzatti, B Nordestgaard, J Shepherd, J Willerson Independent Academic Clinical Coordinating Center: P Ridker, E Danielson, R Glynn, J Mac. Fadyen, S Mora (Boston) Independent Academic Study Statistician: R Glynn (Boston) Independent Data Monitoring Board: R Collins (Chair), K Bailey, B Gersh, G Lamas, S Smith, D Vaughan Independent Academic Clinical Endpoint Committee: K Mahaffey (Chair), P Brown, D Montgomery, M Wilson, F Wood (Durham) With thanks to the clinical development teams worldwide at Astra. Zeneca for their considerable efforts in data collection, site monitoring, and overall study coordination

JUPITER Background and Prior Work Ridker et al NEJM 2008 Current guidelines for the JUPITER Background and Prior Work Ridker et al NEJM 2008 Current guidelines for the prevention of myocardial infarction stroke, and cardiovascular death endorse statin therapy among patients with established vascular disease, diabetes, and among those with hyperlidemia. However, these screening and treatment strategies are insufficient as half of all heart attack and stroke events occur among apparently healthy men and women with average or even low levels of cholesterol.

JUPITER Background and Prior Work Ridker et al NEJM 2008 To improve detection of JUPITER Background and Prior Work Ridker et al NEJM 2008 To improve detection of individuals at increased risk for cardiovascular disease, physicians often measure high sensitivity C-reactive protein (hs. CRP), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low. Prior work has shown that statin therapy reduces hs. CRP, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hs. CRP.

JUPITER Why Consider Statins for Low LDL, high hs. CRP Patients? In 2001, in JUPITER Why Consider Statins for Low LDL, high hs. CRP Patients? In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / Tex. CAPS trial*, we observed that those with low levels of both LDL and hs. CRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1, 448, HR 1. 1, 95% CI 0. 56 -2. 08). Thus, a trial of statin therapy in patients with low cholesterol and low hs. CRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit. In contrast, we also observed within AFCAPS/Tex. CAPS that among those with low LDL but high hs. CRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1, 428, HR 0. 6, 95% CI 0. 34 -0. 98). *Ridker et al N Engl J Med 2001; 344: 1959 -65

JUPITER Why Consider Statins for Low LDL, high hs. CRP Patients? AFCAPS/Tex. CAPS Low JUPITER Why Consider Statins for Low LDL, high hs. CRP Patients? AFCAPS/Tex. CAPS Low LDL Subgroups Low LDL, Low hs. CRP [A] Low LDL, High hs. CRP [B] 0. 5 Statin Effective 1. 0 RR 2. 0 Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/Tex. CAPS that statin therapy might be effective among those with elevated hs. CRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001; 344: 1959 -65

JUPITER Primary Objectives Ridker et al NEJM 2008 Justification for the Use of statins JUPITER Primary Objectives Ridker et al NEJM 2008 Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/d. L (3. 36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hs. CRP > 2 mg/L. To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists.

JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in 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 hs. CRP Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/d. L hs. CRP >2 mg/L 4 -week run-in 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 Ridker et al, Circulation 2003; 108: 2292 -2297.

U r Sw ug itz uay e R rlan om d an C ia U r Sw ug itz uay e R rlan om d an C ia h Es ile to n Is ia El rae Sa l l Bu vad lg or Pa aria na N ma o Ve rwa ne y G zue er la Ar ma ge ny C nti os na ta R Ric us a s Br ia D azil en C ma ol rk om Be bi lg a i M um ex Th P ico e ola N et nd he C rlan So ana ds U uth da ni te Af d r U Ki ica ni ng te d d o St m at es Randomizations (% Total. ) JUPITER 0% 14 15 32 Ridker et al NEJM 2008 17, 802 Patients, 1, 315 Sites, 26 Countries 25% 4021 20% Total Randomized = 17, 802 327 336 345 197 202 204 209 222 253 270 273 83 85 143 162 2873 15% 2497 2020 10% 5% 741 804 987 487

JUPITER Ridker et al NEJM 2008 Inclusion and Exclusion Criteria, Study Flow 89, 863 JUPITER Ridker et al NEJM 2008 Inclusion and Exclusion Criteria, Study Flow 89, 863 Screened 89, 890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/d. L hs. CRP > 2 mg/L 4 week Placebo Run-In 17, 802 Randomized 8, 901 Assigned to 8, 901 Assignedto Rosuvastatin 20 mg Reason for Exclusion LDL > 130 mg/d. L 52 LDL-C > 130 mg/d. L 53 hs. CRP < 2. 0 mg/L 36 hs. CRP < 2. 0 mg/L 37 Withdrew Consent 5 Withdrew 4 Diabetes 1 1 Hypothyroid <1 Hypothyroid Liver Disease <1 TG > 500 mg/d. L <1 Age out of range <1 Age Current Use of HRT <1 Current Use of HRT Cancer <1 Poor Compliance/Other 3 8, 901 Assigned to Placebo 8, 600 Completed Study 8, 864 Completed Study 8, 857 Completed. Study 8, 600 Completed Study 120 Lost tofollow-up 120 Lost to follow-up 44 Lost to 37 Lost to follow-up 8, 901 Included in Efficacy 8, 901 and Safety Analyses (%) 8, 901 Included inin Efficacy 8, 901 Included Efficacy and Safety Analyses

JUPITER Baseline Clinical Characteristics Ridker et al NEJM 2008 Rosuvastatin (N = 8901) Age, JUPITER Baseline Clinical Characteristics Ridker et al NEJM 2008 Rosuvastatin (N = 8901) Age, years (IQR) Female, N (%) Ethnicity, N (%) Caucasian Black Hispanic Blood pressure, mm (IQR) Systolic Diastolic Smoker, N (%) Family History, N (%) Metabolic Syndrome, N (%) Aspirin Use, N (%) Placebo (n = 8901) 66. 0 (60. 0 -71. 0) 3, 426 (38. 5) 66. 0 (60. 0 -71. 0) 3, 375 (37. 9) 6, 358 (71. 4) 1, 100 (12. 4) 1, 121 (12. 6) 6, 325 (71. 1) 1, 124 (12. 6) 1, 140 (12. 8) 134 80 1, 400 997 3, 652 1, 481 134 80 1, 420 1, 048 3, 723 1, 477 (124 -145) (75 -87) (15. 7) (11. 2) (41. 0) (16. 6) All values are median (interquartile range) or N (%) (124 -145) (75 -87) (16. 0) (11. 8) (41. 8) (16. 6)

Ridker et al NEJM 2008 JUPITER Baseline Blood Levels (median, interquartile range) Rosuvastatin (N Ridker et al NEJM 2008 JUPITER Baseline Blood Levels (median, interquartile range) Rosuvastatin (N = 8901) Placebo (n = 8901) hs. CRP, mg/L 4. 2 (2. 8 - 7. 1) 4. 3 (2. 8 - 7. 2) LDL, mg/d. L 108 (94 - 119) HDL, mg/d. L 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/d. L 186 (168 - 200) 185 (169 - 199) Glucose, mg/d. L 94 (87 – 102) 94 (88 – 102) Hb. A 1 c, % 5. 7 (5. 4 – 5. 9) 5. 7 (5. 5 – 5. 9) All values are median (interquartile range). [ Mean LDL = 104 mg/d. L ]

Comparison of the JUPITER trial population to previous statin trials of primary prevention JUPITER Comparison of the JUPITER trial population to previous statin trials of primary prevention JUPITER WOSCOPS AFCAPS 17, 802 6, 595 6, 605 Women (n) 6, 801 0 997 Minority (n) 5, 118 0 350 4. 9 5. 2 Sample size (n) Duration (yrs) Diabetes (%) 1. 9 (max 5) 0 1 6 Baseline LDL-C (mg/d. L) 108 192 150 Baseline HDL-C (mg/d. L) 49 44 36 -40 Baseline TG (mg/d. L) 118 164 158 Baseline hs. CRP (mg/L) >2 NA NA Intervention Rosuvastatin 20 mg Pravastatin 40 mg Lovastatin 10 -40 mg JUPITER Trial Study Group, Am J Cardiol 2007

JUPITER Ridker et al NEJM 2008 hs. CRP decrease 37 percent at 12 months JUPITER Ridker et al NEJM 2008 hs. CRP decrease 37 percent at 12 months 0 12 24 Months 36 HDL (mg/d. L) LDL decrease 50 percent at 12 months HDL increase 4 percent at 12 months TG (mg/d. L) hs. CRP (mg/L) LDL (mg/d. L) Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hs. CRP TG decrease 17 percent at 12 months 48 Months

JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 0. 04 0. 06 - 44 % Rosuvastatin 142 / 8901 0. 00 0. 02 Cumulative Incidence 0. 08 HR 0. 56, 95% CI 0. 46 -0. 69 P < 0. 00001 0 1 2 4 Follow-up (years) Number at Risk Rosuvastatin Placebo 3 8, 901 8, 631 8, 621 8, 412 8, 353 6, 540 6, 508 3, 893 3, 872 1, 958 1, 963 1, 353 1, 333 983 955 544 534 157 174

JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death 0. 08 HR 0. 56, 95% CI 0. 46 -0. 69 P < 0. 00001 Placebo 251 / 8901 0. 04 0. 06 - 44 % Rosuvastatin 142 / 8901 0. 00 0. 02 Cumulative Incidence Number Needed to Treat (NNT 5) = 25 0 1 2 4 Follow-up (years) Number at Risk Rosuvastatin Placebo 3 8, 901 8, 631 8, 621 8, 412 8, 353 6, 540 6, 508 3, 893 3, 872 1, 958 1, 963 1, 353 1, 333 983 955 544 534 157 174

Ridker et al NEJM 2008 JUPITER Grouped Components of the Primary Endpoint HR 0. Ridker et al NEJM 2008 JUPITER Grouped Components of the Primary Endpoint HR 0. 53, CI 0. 40 -0. 69 P < 0. 00001 HR 0. 53, CI 0. 40 -0. 70 P < 0. 00001 0. 06 Arterial Revascularization or Hospitalization for Unstable Angina 0. 05 Myocardial Infarction, Stroke, or Cardiovascular Death 0. 04 0. 03 0. 02 - 47 % Rosuvastatin 0. 00 0. 01 Rosuvastatin Cumulative Incidence 0. 04 0. 03 0. 02 - 47 % 0. 00 Cumulative Incidence Placebo 0. 05 Placebo 0 1 2 3 Follow-up (years) 4

Ridker et al NEJM 2008 JUPITER Individual Components of the Primary Endpoint Rosuvastatin Placebo Ridker et al NEJM 2008 JUPITER Individual Components of the Primary Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* 142 251 0. 56 0. 46 -0. 69 <0. 00001 Non-fatal MI Any MI 22 31 62 68 0. 35 0. 46 0. 22 -0. 58 0. 30 -0. 70 <0. 00001 <0. 0002 Non-fatal Stroke Any Stroke 30 33 58 64 0. 52 0. 33 -0. 80 0. 34 -0. 79 0. 003 0. 002 Revascularization or Unstable Angina 76 143 0. 53 0. 40 -0. 70 <0. 00001 MI, Stroke, CV Death 83 157 0. 53 0. 40 -0. 69 <0. 00001 *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

JUPITER Primary Endpoint – Subgroup Analysis I Ridker et al NEJM 2008 N Men JUPITER Primary Endpoint – Subgroup Analysis I Ridker et al NEJM 2008 N Men Women P for Interaction 11, 001 6, 801 0. 80 Age < 65 Age > 65 8, 541 9, 261 0. 32 Smoker Non-Smoker 2, 820 14, 975 0. 63 Caucasian Non-Caucasian 12, 683 5, 117 0. 57 USA/Canada Rest of World 6, 041 11, 761 0. 51 Hypertension No Hypertension 10, 208 7, 586 0. 53 All Participants 17, 802 0. 25 0. 5 Rosuvastatin Superior 1. 0 2. 0 Rosuvastatin Inferior 4. 0

JUPITER Primary Endpoint – Subgroup Analysis II Ridker et al NEJM 2008 N Family JUPITER Primary Endpoint – Subgroup Analysis II Ridker et al NEJM 2008 N Family HX of CHD No Family HX of CHD P for Interaction 2, 045 15, 684 0. 07 BMI < 25 kg/m BMI 25 -29. 9 kg/m 2 2 BMI > 30 kg/m 4, 073 7, 009 6, 675 0. 70 Metabolic Syndrome No Metabolic Syndrome 7, 375 10, 296 0. 14 Framingham Risk < 10% Framingham Risk > 10% 8, 882 8, 895 0. 99 hs. CRP > 2 mg/L Only 6, 375 2 All Participants 17, 802 0. 25 0. 5 1. 0 Rosuvastatin Superior 2. 0 Rosuvastatin Inferior 4. 0

Ridker et al NEJM 2008 JUPITER Adverse Events and Measured Safety Parameters Event Rosuvastatin Ridker et al NEJM 2008 JUPITER Adverse Events and Measured Safety Parameters Event Rosuvastatin Placebo Any SAE Muscle weakness Myopathy Rhabdomyolysis Incident Cancer Deaths Hemorrhagic stroke 1, 352 1, 421 10 1 298 35 6 1, 337 (15. 5) 1, 375 (15. 4) 9 (0. 1) 0 (0. 0) 314 (3. 5) 58 (0. 7) 9 (0. 1) (15. 2) (16. 0) (0. 1) (0. 01)* (3. 4) (0. 1) P 0. 60 0. 34 0. 82 -0. 51 0. 02 0. 44 GFR (ml/min/1. 73 m 2 at 12 mth) ALT > 3 x. ULN 66. 8 (59. 1 -76. 5) 23 (0. 3) 66. 6 (58. 8 -76. 2) 0. 02 17 (0. 2) 0. 34 Fasting glucose (24 mth) Hb. A 1 c (% at 24 mth) Glucosuria (12 mth) Incident Diabetes** 98 5. 9 36 270 98 5. 8 32 216 (91 -107) (5. 7 -6. 1) (0. 5) (3. 0) *Occurred after trial completion, trauma induced. **Physician reported (90 -106) (5. 6 -6. 1) (0. 4) (2. 4) 0. 12 0. 01 0. 64 0. 01 All values are median (interquartile range) or N (%)

JUPITER Statins and the Development of Diabetes Ridker et al NEJM 2008 HR (95% JUPITER Statins and the Development of Diabetes Ridker et al NEJM 2008 HR (95% CI) WOSCOPS Pravastatin 0. 70 (0. 50– 0. 98) PROSPER Pravastatin 1. 34 (1. 06– 1. 68) HPS Simvastatin 1. 20 (0. 98– 1. 35) ASCOT-LLA Atorvastatin 1. 20 (0. 91– 1. 44) PROVE-IT Atorvastatin 1. 11 (0. 67– 1. 83) VS Pravastatin JUPITER Rosuvastatin 1. 25 (1. 05– 1. 54) 0. 25 0. 5 Statin Better 1. 0 2 Statin Worse 4

Ridker et al NEJM 2008 JUPITER Secondary Endpoint – All Cause Mortality HR 0. Ridker et al NEJM 2008 JUPITER Secondary Endpoint – All Cause Mortality HR 0. 80, 95%CI 0. 67 -0. 97 P= 0. 02 0. 06 Placebo 247 / 8901 0. 04 0. 03 0. 02 Rosuvastatin 198 / 8901 0. 00 0. 01 Cumulative Incidence 0. 05 - 20 % 0 Number at Risk Rosuvastatin 8, 901 Placebo 8, 901 1 2 3 4 Follow-up (years) 8, 847 8, 852 8, 787 8, 775 6, 999 6, 987 4, 312 4, 319 2, 268 2, 295 1, 602 1, 614 1, 192 1, 196 683 684 227 246

JUPITER Conclusions – Efficacy I Ridker et al NEJM 2008 Among apparently healthy men JUPITER Conclusions – Efficacy I Ridker et al NEJM 2008 Among apparently healthy men and women with elevated hs. CRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death. Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials. In this trial of low LDL/high hs. CRP individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced all-cause mortality by 20 percent.

JUPITER Conclusions – Efficacy II Ridker et al NEJM 2008 Benefits of rosuvastatin were JUPITER Conclusions – Efficacy II Ridker et al NEJM 2008 Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hs. CRP and no other major risk factor. Rates of hospitalization and revascularization were reduced by 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers. The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention.

JUPITER Conclusions - Safety Ridker et al NEJM 2008 With regard to safety , JUPITER Conclusions - Safety Ridker et al NEJM 2008 With regard to safety , the JUPITER results show no increase in serious adverse events among those allocated to rosuvastatin 20 mg as compared to placebo in a setting where half of the treated patients achieved levels of LDL< 55 mg/d. L (and 25 percent had LDL < 44 mg/d. L). show no increase in myopathy, cancer, hepatic disorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years show no increase in systematically monitored glucose or glucosuria during follow-up, but small increases in Hb. A 1 c and physician reported diabetes similar to that seen in other major statin trials

JUPITER Ridker et al NEJM 2008 Implications for Primary Prevention A simple evidence based JUPITER Ridker et al NEJM 2008 Implications for Primary Prevention A simple evidence based approach to statin therapy for primary prevention. Among men and women age 50 or over : If diabetic, treat If LDLC > 160 mg/d. L, treat If hs. CRP > 2 mg/L, treat

JUPITER Ridker et al NEJM 2008 Proportional reduction in vascular event rate (95% CI) JUPITER Ridker et al NEJM 2008 Proportional reduction in vascular event rate (95% CI) Predicted Benefit Based on LDL Reduction vs Observed Benefit CTT TNT PROVE-IT A-to-Z IDEAL Mean LDL cholesterol difference between treatment groups (mmol/l) JUPITER PREDICTED

JUPITER Ridker et al NEJM 2008 Predicted Benefit Based on LDL Reduction vs Observed JUPITER Ridker et al NEJM 2008 Predicted Benefit Based on LDL Reduction vs Observed Benefit Proportional reduction in vascular event rate (95% CI) JUPITER OBSERVED CTT TNT PROVE-IT A-to-Z IDEAL Mean LDL cholesterol difference between treatment groups (mmol/l) JUPITER PREDICTED

JUPITER Public Health Implications Ridker et al NEJM 2008 Application of the simple screening JUPITER Public Health Implications Ridker et al NEJM 2008 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. We thank the 17, 802 patients and the >1, 000 investigators worldwide for their personal time, effort, and commitment to the JUPITER trial. www. brighamandwomens. org/jupitertrial