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A Randomized Trial of Rosuvastatin in the Prevention

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 (hsCRP): The JUPITER Trial Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest,

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A Randomized Trial of Rosuvastatin in the Prevention

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  1. 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 (hsCRP): The JUPITER Trial Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest, Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby, Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn on behalf of the JUPITER Trial Study Group

  2. 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 MacFadyen, 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)

  3. JUPITER • JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP • It assessed the long-term impact of rosuvastatin in individuals potentially at increased cardiovascular risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  4. JUPITER - Rationale • Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C • hsCRP predicts cardiovascular disease independent of LDL-C levels • Along with improved screening there is a need to examine the use of lipid-lowering agents as a method of reducing the risk of cardiovascular events Adapted from: Ridker PM. Circulation 2003; 108: 2292-97. Ridker PM. Am J Cardiol 2007; 100: 1659-64. Ridker PM. New Engl J Med 2002; 347: 1557-65. Ridker PM. Am J Cardiol 2003;92(suppl):17K-22K.

  5. JUPITER: Background and Prior Work 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. Adapted from Ridker et al .NEJM 2008.

  6. JUPITER: Background and Prior Work To improve detection of individuals at increased risk for cardiovascular disease, physicians often measure high sensitivity C-reactive protein (hsCRP), 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 hsCRP, 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 hsCRP. Adapted from Ridker et al. NEJM 2008.

  7. Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline LDL-C and hsCRP Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/L AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event Adapted from Ridker et al. N Engl J Med 2001;344:1959-65.

  8. JUPITER population compared with previous trials in patients without established CHD CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; AFCAPS=Airforce/Texas Coronary Atherosclerosis Prevention Study;WOSCOPS=West of Scotland Coronary Prevention Study; *Baseline lipid levels are mean values. Adapted from: Ridker et al. Am J Cardiol 2007;100:1659-64. Ridker et al. N Engl J Med. 2001;344:1959-65.

  9. Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention JUPITER WOSCOPS AFCAPS Sample size (n) 17,802 6,595 6,605 Women (n) 6,801 0 997 Minority (n) 5,118 0 350 Duration (yrs) 1.9 (max 5) 4.9 5.2 Diabetes (%) 0 1 6 Baseline LDL-C (mg/dL) 108 192 150 Baseline HDL-C (mg/dL) 49 44 36-40 Baseline TG (mg/dL) 118 164 158 Baseline hsCRP (mg/L) > 2 NA NA Intervention Rosuvastatin Pravastatin Lovastatin 20 mg 40 mg 10-40 mg Adapted from JUPITER Trial Study Group, Am J Cardiol 2007.

  10. JUPITER: Why Consider Statins for Low LDL, high hsCRP Patients? In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP 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 hsCRP 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/TexCAPS that among those with low LDL but high hsCRP, 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). Adapted from *Ridker et al. N Engl J Med 2001;344:1959-65.

  11. JUPITER: Why Consider Statins for Low LDL, High hsCRP Patients? AFCAPS/TexCAPS Low LDL Subgroups Low LDL, Low hsCRP Low LDL, High hsCRP Low LDL, Low hsCRP Low LDL, High hsCRP [A] [B] 0.5 2.0 1.0 0.5 2.0 1.0 RR Statin Effective Statin Not Effective Statin Effective Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP 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. Adapted from Ridker et al. New Engl J Med 2001;344:1959-65.

  12. JUPITER - Objective The primary objective was to investigate whether long-term treatment with rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C but at increased cardiovascular risk as identified by elevated CRP levels. Adapted from Ridker et al. Circulation 2003;108:2292-97.

  13. JUPITER: Trial Design JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP MI Stroke Unstable Angina CVD Death CABG/PTCA Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP>2 mg/L Placebo (N=8901) 4-week run-in 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 Adapted from Ridker et al. Circulation 2003;108:2292-97.

  14. JUPITER – Study Design No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <130 mg/dL CRP ≥2.0 mg/L Rosuvastatin 20 mg (n=8901) Placebo run-in Placebo (n=8901) Visit:Week: 1–6 2–4 30 413 Final 6-monthly Lead-in/eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA1C Median follow-up 1.9 years CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

  15. JUPITER: 17,802 Patients, 1,315 Sites, 26 Countries 25% 4021 20% Total Randomized = 17,802 2873 15% 2497 2020 Randomizations (% Total.) 10% 987 804 5% 741 487 345 336 327 270 273 253 222 209 197 202 204 162 143 83 85 32 14 15 0% Chile Canada Panama Poland Russia Estonia Israel Mexico Uruguay Romania Norway Bulgaria El Salvador Belgium Costa Rica Germany Colombia Denmark Brazil Venezuela Argentina South Africa United States Switzerland United Kingdom The Netherlands Adapted from Ridker et al. NEJM 2008.

  16. JUPITER - PatientFlow 89,890 subjects screened 17,802 randomised Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Lost to follow up n=37 Completed study n=8,857 Completed study n=8,864 Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  17. JUPITER: Inclusion and Exclusion Criteria, Study Flow 89,890 Screened 89,863 Screened 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 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 Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 4 week Placebo Run-In 17,802 Randomized 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,857 Completed Study 44 Lost to follow-up 8,864 Completed Study 37 Lost to follow-up 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 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses Adapted from Ridker et al. NEJM 2008.

  18. JUPITER - Major Exclusion Criteria • Current use of statinsor other lipid-lowering therapies • Current use of post menopausal hormone replacement therapy • Prior history of cardiovascular or cerebrovaascular events, such as MI, unstable angina, prior arterial revascularisation or stroke, or CHD-risk equivalents • Chronic inflammatory condition, such as severe arthritis, lupus or inflammatory bowel disease and/or treatment with immunosuppressants • Uncontrolled: • hypertension: SBP > 190 mmHg or DBP > 100 mmHg • hypothyroidism: TSH > 1.5 x ULN • CK 3 x ULN • Serum creatinine > 2.0 mg/dL • Evidence of hepatic dysfunction (ALT > 2 x ULN) • History of prior malignancy, alcohol or drug abuse CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure Adapted from: Ridker et al. N Eng J Med 2008;359:2195-207. Ridker PM. Circulation 2003;108:2292-97.

  19. JUPITER - Baseline Characteristics* Rosuvastatin Placebo n=8901 n=8901 Age (years) 66 (60-71) 66 (60-71) Male sex (%) 61.5 62.1 Race (%) White 71.4 71.1 Black 12.4 12.6 Hispanic 12.6 12.8 Other 3.6 3.5 BMI (kg/m2)28.3 (25.3-32.0) 28.4 (25.3-32.0) Systolic BP (mmHg) 134 (124-145) 134 (124-145) Diastolic BP (mmHg) 80 (75-87) 80 (75-87) *All values are median (interquartile range) or N (%). Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

  20. JUPITER: Baseline Blood Levels (median, interquartile range) 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) HDL, mg/dL 49 (40 – 60) 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199) Glucose, mg/dL 94 (87 – 102) 94 (88 – 102) HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ] Adapted from Ridker et al. NEJM 2008.

  21. JUPITER - Baseline laboratory parameters* Rosuvastatin Placebo n=a8901 n=8901 Total cholesterol (mmol/L) 4.81 (4.34-5.17) 4.78 (4.37-5.15) LDL cholesterol (mmol/L) 2.79 (2.43-3.08) 2.79 (2.43-3.08) HDL cholesterol (mmol/L) 1.27 (1.03-1.55) 1.27 (1.03-1.55) Triglycerides (mmol/L) a1.33 (0.96-1.91) 1.33 (0.97-1.91) hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2) Glucose(mmol/L)5.2 (4.8-5.7) 5.2 (4.9-5.7) HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9) Glomerular filtration rate, (ml/min/1.73m2) 73.3 (64.6-83.7) 73.6 (64.6-84.1) For hsCRP, values are the average of the values obtained at two screening visits *All values are median (interquartile range) or N (%). Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  22. JUPITER - Medical History Medical HistoryRosuvastatin Placebo n=8901 n=8901 Current smoker (%) 15.7 16.0 Family history CHD†(%) 11.2 11.8 Metabolic syndrome‡(%) 41.0 41.8 Aspirin use (%) 16.6 16.6 †Family history of premature coronary heart disease (CHD) defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of American Heart Association and the National Heart, Lung, and Blood Institute Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  23. JUPITER - Study End Points Primary End Point Time to the first occurrence of a major cardiovascular event, composite of: cardiovascular death Stroke MI unstable angina arterial revascularisation Secondary End Points: total mortality non-cardiovascular mortality development of diabetes mellitus development of venous thromboembolic events bone fractures discontinuation of study medication due to adverse effects. Adapted from Ridker et al. Circulation 2003;108:2292-97.

  24. JUPITER: Primary Objectives 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/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 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. Adapted from Ridker et al. NEJM 2008.

  25. JUPITER: Effects of Rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL (mg/dL) HDL (mg/dL) LDL decrease 50 percent at 12 months HDL increase 4 percent at 12 months hsCRP (mg/L) TG (mg/dL) hsCRP decrease 37 percent at 12 months TG decrease 17 percent at 12 months 0 12 24 36 48 Months Months Adapted from Ridker et al. NEJM 2008.

  26. JUPITER: Adverse Events and Measured Safety Parameters Event Rosuvastatin Placebo P Any SAE 1,352 (15.2) 1,337 (15.5) 0.60 Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34 Myopathy 10 (0.1) 9 (0.1) 0.82 Rhabdomyolysis 1 (0.01)* 0 (0.0) -- Incident Cancer 298 (3.4) 314 (3.5) 0.51 Cancer Deaths 35 (0.4) 58 (0.7) 0.02 Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44 GFR (ml/min/1.73m2 at 12 mth)66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02 ALT > 3xULN 23 (0.3) 17 (0.2) 0.34 Fasting glucose (24 mth)98 (91-107) 98 (90-106) 0.12 HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01 Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64 Incident Diabetes** 270 (3.0) 216 (2.4) 0.01 *Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%) **Physician reported Adapted from Ridker et al. NEJM 2008.

  27. JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death Placebo 251/8901 HR 0.56, 95% CI 0.46-0.69 P<0.00001 0.08 0.06 - 44 % Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Adapted from Ridker et al. NEJM 2008.

  28. JUPITER: Grouped Components of the Primary End Point Myocardial Infarction, Stroke, or Cardiovascular Death Arterial Revascularization or Hospitalization for Unstable Angina HR 0.53, CI 0.40-0.70 P<0.00001 HR 0.53, CI 0.40-0.69 P<0.00001 0.05 0.06 Placebo Placebo 0.05 0.04 0.04 - 47 % 0.03 Cumulative Incidence Cumulative Incidence - 47 % 0.03 0.02 0.02 Rosuvastatin Rosuvastatin 0.01 0.01 0.00 0.00 0 1 2 3 4 0 1 2 3 4 Follow-up (years) Follow-up (years) Adapted from Ridker et al. NEJM 2008.

  29. JUPITER: Individual Components of the Primary End Point Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001 Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001 Any MI 31 68 0.46 0.30-0.70 <0.0002 Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003 Any Stroke 33 64 0.52 0.34-0.79 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 Adapted from Ridker et al. NEJM 2008.

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

  31. JUPITER - Primary End PointTime to first occurrence of a CV death, non-fatal stroke, non-fatalMI, unstable angina or arterial revascularisation Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 0.08 0.06 Cumulative Incidence Rosuvastatin 20 mg 0.04 NNT for 2 yrs = 95 5 yrs* = 25 0.02 0.00 0 1 2 3 4 5 Years Number at risk Rosuvastatin 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 *Extrapolated figure based on Altman and Andersen method Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

  32. JUPITER - Primary End Point Components • Placebo Rosuvastatin HR 95% CI P value [n=8901][n=8901] • n (rate**) n (rate**) Primary Endpoint 251 (1.36) 142 (0.77) 0.56 0.46-0.69 <0.001* (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12) 0.35 0.22-0.58 <0.001* Fatal or non-fatal MI 68 (0.37) 31 (0.17) 0.46 0.30-0.70 0.0002 Non-fatal stroke 58 (0.31) 30 (0.16) 0.52 0.33-0.80 0.003 Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52 0.34-0.79 0.002 Arterial Revascularization 131 (0.71) 71 (0.38) 0.54 0.41-0.72 <0.0001 Unstable angina† 27 (0.14) 16 (0.09) 0.59 0.32-1.10 0.09 CV death, stroke, MI 157 (0.85) 83 (0.45) 0.53 0.40-0.69 <0.001* Revascularization or unstable angina 143 (0.77) 76 (0.41) 0.53 0.40-0.70 <0.001* ** Rates are per 100 person years;† Hospitalisation due to unstable angina; *Actual P-value was <0.00001 HR=Hazard Ratio; CI =Confidence Interval Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

  33. JUPITER: Primary Endpoint – Subgroup Analysis II N P for Interaction Family HX of CHD 2,045 0.07 No Family HX of CHD 15,684 2 4,073 0.70 BMI < 25 kg/m 7,009 BMI 25-29.9 kg/m 2 6,675 BMI > 30 kg/m 2 Metabolic Syndrome 7,375 0.14 No Metabolic Syndrome 10,296 Framingham Risk < 10% 8,882 0.99 Framingham Risk > 10% 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 Adapted from Ridker et al. NEJM 2008.

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

  35. 0.25 0.5 1.0 2 4 JUPITER: Statins and the Development of Diabetes HR (95% CI) WOSCOPS Pravastatin 0.70 (0.50–0.98) 1.34 (1.06–1.68) PROSPER Pravastatin 1.20 (0.98–1.35) HPS Simvastatin 1.20 (0.91–1.44) ASCOT-LLA Atorvastatin PROVE-IT Atorvastatin VS Pravastatin 1.11 (0.67–1.83) JUPITER Rosuvastatin 1.25 (1.05–1.54) Statin Better Statin Worse Adapted from Ridker et al. NEJM 2008.

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

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

  38. Prevalence of conventional risk factors†in male patients with CHD Four (0.9%) Three None 8.9% 19.4% Two 27.8% 43.0% One Total male patients=87 869CHD=coronary heart disease †smoking, hypertension, hypercholesterolaemia and diabetes mellitus Adapted from Khot et al. JAMA 2003;290:898-904.

  39. CRP is a strong independent predictorof CV events in women Lp(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA ApoB TC/HDL-C CRP CRP + TC/HDL-C 1.0 2.0 4.0 6.0 0 Relative risk of future CV events Apo=apolipoprotein; CRP=C-reactive protein;CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular adhesion molecule 1; TC=total cholesterol Adapted from Blake GJ, Ridker PM. Circ Res 2001;89:763-71.

  40. CRP predicts risk of MI and strokein apparently healthy men 3.5 2.0 * *** 3.0 1.5 2.5 Relativerisk of ischaemicstroke Relative risk of MI 2.0 1.0 1.5 1.0 0.5 0.5 0 0 1 2 3 4 1 2 3 4 Quartile of CRP Quartile of CRP CRP=C-reactive protein; MI=myocardial infarctionQuartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14; Quartile 3: 1.15-2.10 ; Quartile 4:  2.11. *P=0.02 versus quartile 1; ***P<0.001 versus quartile 1 Adapted from Ridker et al. N Engl J Med 1997;336:973-79.

  41. CV event-free survival in women using combined LDL-C and hsCRP measures 1.00 Low LDL-C, low hsCRP 0.99 Probability of event-free survival High LDL-C, low hsCRP 0.98 Low LDL-C, high hsCRP 0.97 High LDL-C, high hsCRP 0.96 0 CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol Median LDL-C=3.2 mmol/L (124 mg/dL) Median CRP=1.5 mg/L Adapted from Ridker et al. N Engl J Med 2002;347:1557-65.

  42. JUPITER - Total MortalityDeath from any cause Hazard Ratio 0.80 (95% CI 0.67-0.97) P=0.02 Placebo 0.06 Rosuvastatin 20 mg 0.04 Cumulative Incidence 0.02 0.00 0 1 2 3 4 5 Years Number at risk Rosuvastatin 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246 Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  43. JUPITER - Laboratory Safety Data Placebo Rosuvastatin P value [n=8901][n=8901] • Laboratory Values, N (%) • Serum creatinine‡ 10 (0.10) 16 (0.20) 0.24 • ALT > 3 x ULN# 17 (0.20) 23 (0.30) 0.34 • Glycosuria† 32 (0.40) 36 (0.50) 0.64 • Laboratory Values, median values (IQR) • GFR*, (mL/min/1.73m2) 66.6 (58.8-76.2) 66.8 (59.1-76.5) 0.02 • % HbA1c** 5.8 (5.6-6.1) 5.9 (5.7-6.1) 0.001 • Fasting plasma glucose**(mmol/L) 5.4 (5.0-5.9) 5.4 (5.1-5.9) 0.12 ‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c; IQR = interquartile range Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

  44. JUPITER: Conclusions – Efficacy I Among apparently healthy men and women with elevated hsCRP 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 hsCRP individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced all-cause mortality by 20 percent. Adapted from Ridker et al. NEJM 2008.

  45. JUPITER: Conclusions – Efficacy II Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP 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. Adapted from Ridker et al. NEJM 2008.

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