1 / 35

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).

alia
Download Presentation

JUPITER

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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).

More Related