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.

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: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

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.

Prevalence of conventional risk factors † in male patients with CHD None One Two Three Four (0.9%) Total male patients= CHD=coronary heart disease † smoking, hypertension, hypercholesterolaemia and diabetes mellitus Khot UN et al. JAMA 2003; 290: 898– % 43.0% 27.8% 8.9% For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Women CRP Epidemiology CRP levels in the US, NHANES Ford ES, Giles WH, Myers GL, Mannino DM. Clin Chem 2003; 49(4): Ford ES, Giles WH, Mokdad AH, Myers GL. Clin Chem 2004; 50(3): Age (yrs) CRP, mg/L Men Age (yrs) Percentile For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

CRP contributes to all stages 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 Roles of CRP Progression of atherosclerosis Endothelial Dysfunction  Vasodilation  NO Plaque Rupture /Thrombosis  Cap thinning  TF secretion  Fibrinolysis Plaque progression  Monocyte migration  VSMC proliferation Endothelial activation  Monocyte adhesion  Endothelial progenitor cells For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

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– Lp(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA ApoB TC/HDL-C CRP CRP + TC/HDL-C Relative risk of future cardiovascular events For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

CRP predicts risk of MI and stroke in apparently healthy men 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 of CRP Relative risk of ischaemic stroke * Quartile of CRP Relative risk of MI *** Quartile 1: ≤ 0.55 ; Quartile 2: ≤ ; Quartile 3: ; Quartile 4:  For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Rate of cardiovascular events in women in relation to LDL-C and CRP LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein Ridker PM et al. N Engl J Med 2002; 347: 1557– CRP (mg/L) LDL-C (mmol/L) For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

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

LDL-C and CRP as markers of cardiovascular events – the AFCAPS/TexCAPS study Study group Rate of cardiovascular events NNT LovastatinPlacebo Low LDL-C/low CRP na Low LDL-C/high CRP High LDL-C/low CRP High LDL-C/high CRP 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.

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

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.

JUPITER – study design Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Placebo run-in 1 –6 2 – Final 3–4 y 6-month intervals Visit: Week: Randomisation Lipids CRP Tolerability Rosuvastatin 20 mg (n~8900) Placebo (n~8900) Lead-in/ eligibility No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <3.36 mmol/L CRP ≥2.0 mg/L CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c =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.

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

JUPITER – study design Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Placebo run-in 1 –6 2 – Final 3–4 y 6-month intervals Visit: Week: Randomisation Lipids CRP Tolerability Rosuvastatin 20 mg (n~8900) Placebo (n~8900) Lead-in/ eligibility No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <3.36 mmol/L CRP ≥2.0 mg/L CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c =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.

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.

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.

Major exclusion criteria Current use of statins or 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 Ridker PM. Circulation 2003; 108: 2292–2297. Ridker PM. Am J Cardiol 2007; 100: 1659–1664. MI=myocardial infarction; CHD=coronary heart disease; ULN=upper limit of normal For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

JUPITER - Major exclusion criteria Current use of statins or 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:

JUPITER - Patient Flow 89,890 subjects screened 17,802 randomized Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Completed study n=8,857 Lost to follow up n=37 Completed study n=8,864 Ridker P et al. N Eng J Med 2008;359: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Age (years) 66 (60-71) 66 (60-71) Male sex (%) Race (%) White Black Hispanic Other BMI (kg/m 2 ) 28.3 ( ) 28.4 ( ) Systolic BP (mmHg) 134 ( ) 134 ( ) Diastolic BP (mmHg) 80 (75-87) 80 (75-87) Rosuvastatin Placebo n=8901 n=8901 JUPITER - Baseline characteristics * *All values are median (interquartile range) or N (%). Ridker P et al. N Eng J Med 2008;359: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Total cholesterol (mg/dL) 4.81 ( ) 4.78 ( ) LDL cholesterol (mg/dL) 2.69 ( ) 2.69 ( ) HDL cholesterol (mg/dL) 1.27 ( ) 1.27 ( ) Triglycerides (mg/dL) 1.33 ( ) 1.33 ( ) hsCRP (mg/L) 4.2 ( ) 4.3 ( ) Glucose (mg/dL) 94 (87-102) 94 (88-102) HbA 1c (%) 5.7 ( ) 5.7 ( ) Glomerular filtration rate, (ml/min/1.73m 2 ) 73.3 ( ) 73.6 ( ) RosuvastatinPlacebo n=8901 n=8901 JUPITER - Baseline laboratory parameters * 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: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Current smoker (%) Family history CHD † (%) Metabolic syndrome ‡ (%) Aspirin use (%) Medical History Rosuvastatin Placebo n=8901 n=8901 JUPITER - Medical History †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: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

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 : AFCAPSWOSCOPSJUPITER Patients, n % male, n Duration, years5.24.9Ongoing Diabetes, %610 Baseline lipids (mmol/L Total Cholesterol LDL-C HDL-C0.93– Triglycerides hsCRP, mg/L0.2NA4.3 Statin Lovastatin 20–40 mg Pravastatin 40 mg Rosuvastatin 20 mg

Years Placebo Rosuvastatin 20 mg JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Percent of patients with primary endpoint Number at risk RSV Placebo Hazard Ratio 0.56 (95% CI ) P< Ridker P et al. N Eng J Med 2008;359: NNT for 2y = 95 5y* = 25 *Extrapolated figure based on Altman and Andersen method

JUPITER - Primary Endpoint Components Primary Endpoint 251 (1.36) 142 (0.77) <0.001 * (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12) <0.001 * Fatal or non-fatal MI 68 (0.37) 31 (0.17) Non-fatal stroke 58 (0.31) 30 (0.16) Fatal or non-fatal stroke 64 (0.34) 33 (0.18) Arterial Revascularization 131 (0.71) 71 (0.38) < Unstable angina † 27 (0.14) 16 (0.09) CV death, stroke, MI 157 (0.85) 83 (0.45) <0.001 * Revascularization or unstable angina 143 (0.77) 76 (0.41) <0.001 * PlaceboRosuvastatinHR95% CIp-value [n=8901][n=8901] n (rate ** ) HR – Hazard Ratio; CI – Confidence Limit ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < Ridker P et al. N Eng J Med 2008;359:

JUPITER – Subgroup analysis Rosuvastatin better Placebo better NP- value* Age 0.32 ≤ 65 years8,541 >65 yrs9,261 Gender 0.80 Males11,001 Females6,801 Race 0.57 White12,683 Non-white5,117 Hypertension 0.53 Yes10,208 No 7,586 Region 0.51 US or Canada6,041 Other11,761 Metabolic syndrome 0.14 Yes7,375 No10,296 Family history of CHD 0.07 Yes 2,045 No15,684 Framingham risk score 0.99 ≤10%8,882 >10%8, Ridker P et al. N Eng J Med 2008;359: Hazard ratio (95% CI) For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

Years Placebo Rosuvastatin 20mg JUPITER - Total Mortality Death from any cause Percent total mortality Number at risk RSV Placebo Hazard Ratio 0.80 (95% CI ) p=0.02 Ridker P et al. N Eng J Med 2008;359: For complete therapeutic and safety information please consult the CRESTOR ® Product Monograph.

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

JUPITER Tolerability and safety data Adverse Events, (%) Any serious adverse event Muscle weakness, stiffness, pain Myopathy Rhabdomyolysis 0.0 <0.1 * ---- Newly diagnosed cancer Death from cancer Gastrointestinal disorders Renal disorders Bleeding Hepatic disorders Other events, (%) Newly diagnosed diabetes ** Haemorrhagic stroke Placebo Rosuvastatin p-value [n=8901] [n=8901] *Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359:

JUPITER Laboratory Safety Data 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/1.73m 2 ) 66.6 ( ) 66.8 ( ) 0.02 % HbA1c ** 5.8 ( ) 5.9 ( ) Fasting plasma glucose **, (mg/dL) 98 (90-106) 98 (91-107) 0.12 Placebo Rosuvastatin p-value [n=8901] [n=8901] 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:

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< ) 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:

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

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). DISCLAIMER