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JUPITER

JUPITER. J ustification for the U se of statins in P rimary prevention: an I ntervention T rial E valuating R osuvastatin. Rosuvastatin is not indicated for the treatment of patients with high C-Reactive Protein (CRP).

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JUPITER

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  1. JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Rosuvastatin is not indicated for the treatment of patients with high C-Reactive Protein (CRP). For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  2. 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 (CRESTOR™) in individuals potentially at increased cardiovascular (CV) risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  3. 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 Ridker PM. New Engl J Med 2002; 347: 1557–1565 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  4. 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 Khot UN et al. JAMA 2003; 290: 898–904. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  5. 8 7 6 5 4 3 2 1 0 CRP Epidemiology CRP levels in the US, NHANES 1999-2000 Men Women 33.3 Percentile 50 66.7 CRP, mg/L 30-39 40-49 50-59 60-69 70-79 80+ 30-39 40-49 50-59 60-69 70+ Age (yrs) Age (yrs) Ford ES, Giles WH, Myers GL, Mannino DM. Clin Chem 2003; 49(4):686-90. Ford ES, Giles WH, Mokdad AH, Myers GL. Clin Chem 2004; 50(3):574-81. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  6. CRP contributes to all stages of atherosclerosis Roles of CRP • Endothelial • Dysfunction •  Vasodilation • NO • Endothelial • activation • Monocyte adhesion • Endothelial progenitor cells • Plaque • progression • Monocyte migration • VSMC proliferation • Plaque Rupture • /Thrombosis • Capthinning • TF secretion  Fibrinolysis Progression of atherosclerosis NO: Nitric oxide, VSMC: Vascular Smooth Muscle Cell, TF: Tissue factor Bisoendial RJ, Kastelein JJP, Stroes ESG. Atherosclerosis 2007; 195:e10-18 Packard RRS, Libby P. Clin Chem 2008; 54:24-38 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  7. 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 cardiovascular events CRP is a stronger predictor of future events compared with other markers in women CRP=C-reactive protein; Lp(a)=lipoprotein (a); IL=interleukin; TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; sICAM-1=soluble intercellular adhesion molecule 1; SAA=serum amyloid A; Apo=apolipoprotein; HDL-C=high-density lipoprotein cholesterol Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  8. CRP predicts risk of MI and stroke in 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 infarction*p=0.03 vs quartile 1; ***p<0.001 vs quartile 1 Ridker PM et al. N Engl J Med 1997; 336: 973–979. Quartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14; Quartile 3: 1.15-2.10 ; Quartile 4:  2.11. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  9. Rate of cardiovascular events in women in relation to LDL-C and CRP 100 10 CRP (mg/L) 1 0.1 1.3 2.6 3.9 5.2 6.5 LDL-C (mmol/L) LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive proteinRidker PM et al. N Engl J Med 2002; 347: 1557–1565. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  10. Cardiovascular event-free survival in women using combined LDL-C and CRP measurements 1.00 Low LDL-C, low CRP 0.99 Probability of event-free survival High LDL-C, low CRP 0.98 Low LDL-C, high CRP 0.97 High LDL-C, high CRP 0.96 0 LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive proteinMedian LDL-C=3.2 mmol/L (124 mg/dL) Median CRP=1.5 mg/LRidker PM et al. N Engl J Med 2002; 347: 1557–1565. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  11. LDL-C and CRP as markers of cardiovascular events – the AFCAPS/TexCAPS study Median LDL-C=3.9 mmol/L (149 mg/dL). Median CRP=1.6 mg/L LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; NNT=number needed to treat to prevent one coronary event; na=not applicable. Ridker PM et al. N Engl J Med 2001; 344: 1959–1965. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  12. CRP is a strong independent predictor of future CV events • CRP is a strong independent predictor of cardiovascular events1 • Addition of CRP to the Framingham algorithm improves global cardiovascular risk prediction2 • CRP and LDL-C are complementary biomarkers for identifying at-risk individuals3 1. Ridker PM. JACC 2007;49:2129-38. 2. Ridker PM. JAMA 2007;297:611-9. 3. Ridker PM et al. N Engl J Med 2002; 347: 1557–1565. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  13. 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 Ridker PM. Circulation 2003; 108: 2292–2297 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  14. JUPITER – study design No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <3.36 mmol/L CRP ≥2.0 mg/L Rosuvastatin 20 mg (n~8900) Placebo run-in Placebo (n~8900) Visit:Week: 1–6 2–4 30 413 Final3–4 y 6-month intervals Lead-in/eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA1C CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  15. JUPITER - Study Endpoints • Primary Endpoint • Time to the first occurrence of a major cardiovascular event, composite of: • cardiovascular death • Stroke • MI • unstable angina • arterial revascularisation • Secondary Endpoints: • total mortality • non-cardiovascular mortality • development of diabetes mellitus • development of venous thromboembolic events • bone fractures • discontinuation of study medication due to adverse effects. Ridker PM. Circulation 2003; 108: 2292–2297

  16. JUPITER – study design No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <3.36 mmol/L CRP ≥2.0 mg/L Rosuvastatin 20 mg (n~8900) Placebo run-in Placebo (n~8900) Visit:Week: 1–6 2–4 30 413 Final3–4 y 6-month intervals Lead-in/eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA1C CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  17. JUPITER – study endpoints • Primary • time to the first occurrence of a major cardiovascular event (cardiovascular death, stroke, MI, unstable angina or arterial revascularisation) • Secondary • Efficacy (incident diabetes mellitus, venous thromboembolic events, bone fractures) • Safety (total mortality noncardiovascular mortality, adverse events) Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  18. Major inclusion criteria • Men aged ≥50 years; women aged ≥60 years • Fasting LDL-C levels 3.36 mmol/L, CRP levels ≥2.0 mg/L and TG levels 5.65 mmol/L on initial screening Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  19. Major exclusion criteria • Current use of statinsor other lipid-lowering therapies • Prior history of cardiovascular or cerebrovascular 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 • CK 3 x ULN MI=myocardial infarction; CHD=coronary heart disease; ULN=upper limit of normal Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  20. JUPITER - Major exclusion criteria • Current use of statinsor other lipid-lowering therapies • Current use of hormone replacement therapy • Prior history of cardiovascular or cerebrovascular 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 Ridker PM. Circulation 2003; 108: 2292–2297 CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure Ridker P et al. N Eng J Med 2008;359: 2195-2207

  21. JUPITER - PatientFlow 89,890 subjects screened 17,802 randomized 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  22. 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 (%). Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  23. JUPITER - Baseline laboratory parameters* Rosuvastatin Placebo n=8901 n=8901 Total cholesterol (mg/dL) 4.81 (4.34-5.17) 4.78 (4.37-5.15) LDL cholesterol (mg/dL) 2.69 (2.43-3.08) 2.69 (2.43-3.08) HDL cholesterol (mg/dL) 1.27 (1.03-1.55) 1.27 (1.03-1.55) Triglycerides (mg/dL) 1.33 (0.96-1.91) 1.33 (0.97-1.90) hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2) Glucose(mg/dL)94 (87-102) 94 (88-102) 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 and visits *All values are median (interquartile range) or N (%). Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  24. 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 CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBI Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  25. 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; *Baseline lipid levels are mean values. Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664 Ridker PM et al. N Engl J Med. 2001 344: 1959-65

  26. JUPITER - Primary EndpointTime to first occurrence of a CV death, non-fatal stroke, non-fatalMI, unstable angina or arterial revascularization 9 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 8 7 6 5 Rosuvastatin 20 mg Percent of patients with primary endpoint 4 3 NNT for 2y = 95 5y* = 25 2 1 0 0 1 2 3 4 5 Years Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 Ridker P et al. N Eng J Med 2008;359: 2195-2207 *Extrapolated figure based on Altman and Andersen method

  27. JUPITER - Primary Endpoint 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 Limit Ridker P et al. N Eng J Med 2008;359: 2195-2207

  28. JUPITER – Subgroup analysis Placebo better Rosuvastatin better 0.8 0.4 0.2 1.2 0.6 0 1 Hazard ratio (95% CI) Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  29. JUPITER - Total MortalityDeath from any cause Hazard Ratio 0.80 (95% CI 0.67-0.97) p=0.02 7 Placebo 6 5 Rosuvastatin 20mg Percent total mortality 4 3 2 1 0 0 1 2 3 4 5 Years Number at risk RSV 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246 Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  30. JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;Percentage change between rosuvastatin and placebo 10 LDL-C HDL-C TG hsCRP 4% 0 p<0.001* -10 17% -20 Percentage change from baseline (%) p<0.001 -30 37% -40 p<0.001 50% -50 p<0.001 -60 Ridker P et al. N Eng J Med 2008;359: 2195-2207 *P-value at study completion (48 months) = 0.34 For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

  31. JUPITERTolerability and safety data Placebo Rosuvastatin p-value [n=8901][n=8901] • Adverse Events, (%) • Any serious adverse event 15.5 15.2 0.60 • Muscle weakness, stiffness, pain 15.4 16.0 0.34 • Myopathy 0.1 0.1 0.82 • Rhabdomyolysis 0.0 <0.1* ---- • Newly diagnosed cancer 3.5 3.4 0.51 • Death from cancer 0.7 0.4 0.02 • Gastrointestinal disorders 19.2 19.7 0.43 • Renal disorders 5.4 6.0 0.08 • Bleeding 3.1 2.9 0.45 • Hepatic disorders 2.1 2.4 0.13 • Other events, (%) • Newly diagnosed diabetes** 2.4 3.0 0.01 • Haemorrhagic stroke 0.1 0.1 0.44 *Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359: 2195-2207

  32. JUPITERLaboratory 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**, (mg/dL) 98 (90-106) 98 (91-107) 0.12 GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c # on consecutive visits, ‡ >100% increase from baseline,*at 12 months, **at 24 months, †>trace at 12 months Ridker P et al. N Eng J Med 2008;359: 2195-2207

  33. JUPITER – summary and perspectives • The JUPITER study included patients with low to normal LDL-C who were at increased CV risk as identified by elevated CRP levels and who did not require statin treatment based on current treatment guidelines • A 44% reduction in the primary endpoint of major cardiovascular events (composite of: CV death, MI, stroke, unstable angina, arterial revascularisation) was observed in patients who received rosuvastatin 20 mg compared with placebo (p< 0.00001) • A 20% reduction in total mortality was observed in patients who received rosuvastatin 20 mg compared with placebo (p=0.02), a unique finding for statins in a population without established CHD • In JUPITER, long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants • There was no difference between treatment groups for muscle weakness, cancer, haematological disorders, gastrointestinal, hepatic or renal systems • The results from JUPITER highlight the importance of highly effective statin treatment for these patients with an increased risk of CV disease Ridker P et al. N Eng J Med 2008;359: 2195-2207

  34. Acknowledgements • The JUPITER Steering Committee • P Ridker (Chairman), Boston, MA, USA • A Gotto, New York, NY, USA • P Libby, Boston, MA, USA • J Willerson, Houston, TX, USA • J Genest, Montreal, Canada • The JUPITER Independent Data Monitoring Board • The JUPITER investigators and participating patients • This study is supported by AstraZeneca

  35. DISCLAIMER • This slide presentation may include evolving scientific information that has not been reviewed and approved by Health Canada. These slides are intended for educational purposes only. • AstraZeneca Canada Inc. does not recommend the use of CRESTOR® in any other indication than as described in the Canadian Product Monograph. • INDICATIONS AND CLINICAL USES • CRESTOR® (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol (Total-C), LDL-C, Apo-B, Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including: • Primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia and severe non-familial hypercholesterolemia) • Combined (mixed) dyslipidemia (Type IIb) • Homozygous familial hypercholesterolemia where CRESTOR ® is used either alone or as an adjunct to diet and other lipid lowering treatment such as apheresis • Rosuvastatin is not indicated for the treatment of patients with high C-Reactive Protein (CRP).

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