JUPITER TRIAL TALK

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Published on January 8, 2009

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Slide 1: Expanding The Orbit of Statin Therapy Dr. Tang Sie Hing Consultant Interventional Cardiologist Chief, Cardiology Department Normah Medical Specialist Centre, Kuching. JUPITER : JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Ridker P et al. N Eng J Med 2008;359: 2195-2207 JUPITER : 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 JUPITER - Rationale : 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 Prevalence of conventional risk factors† in patients with CHD : Prevalence of conventional risk factors† in patients with CHD None One Two Three Four (0.9%) Total patients=87 869CHD=coronary heart disease †smoking, hypertension, hypercholesterolaemia and diabetes mellitus 19.4% 43.0% 27.8% 8.9% Khot UN et al. JAMA 2003; 290: 898–904 CRP is a strong independent predictor of CV events in women : CRP is a strong independent predictor of CV events in women 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 0 Lp(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA ApoB TC/HDL-C CRP CRP + TC/HDL-C Relative risk of future CV events 1.0 2.0 4.0 6.0 Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771 CRP predicts risk of MI and stroke in apparently healthy men : CRP predicts risk of MI and stroke in apparently healthy men CRP=C-reactive protein; MI=myocardial infarction*p=0.02 versus quartile 1; ***p<0.001 versus quartile 1 Quartile of CRP Relativerisk of ischaemicstroke 0 0.5 1.0 1.5 2.0 1 2 3 4 * Quartile of CRP Relative risk of MI 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 1 2 3 4 *** Ridker PM et al. N Engl J Med 1997; 336: 973–979 CV event-free survival in women using combined LDL-C and hsCRP measures : CV event-free survival in women using combined LDL-C and hsCRP measures 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 1.00 0.99 0.98 0.97 0.96 0 Low LDL-C, low hsCRP High LDL-C, high hsCRP High LDL-C, low hsCRP Low LDL-C, high hsCRP Probability of event-free survival Ridker PM et al. N Engl J Med 2002; 347: 1557–1565 Efficacy of Lovastatin in AFCAPS/TexCAPS subgroups by baseline LDL-C and hsCRP : 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 Ridker PM et al. N Engl J Med 2001; 344: 1959–1965 JUPITER - Objective : 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 JUPITER – study design : JUPITER – study design Lipids CRP Tolerability Lipids CRP Tolerability HbA1C Placebo run-in 1–6 2–4 30 413 Final 6-monthly Visit:Week: Randomisation Lipids CRP Tolerability Rosuvastatin 20 mg (n=8901) Placebo (n=8901) Lead-in/eligibility No history of CAD men =50 yrs women =60 yrs LDL-C <130 mg/dL CRP =2.0 mg/L CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin Median follow-up 1.9 years Ridker P et al. N Eng J Med 2008;359: 2195-2207 JUPITER - Study Endpoints : 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 - Major inclusion criteria : JUPITER - Major inclusion criteria Men aged =50 years; women aged =60 years Fasting LDL-C levels ? 130 mg/dL (3.4 mmol/L) , CRP levels =2.0 mg/L and TG levels ? 500 mg/dL (5.7 mmol/L) on initial screening. Ridker PM. Circulation 2003; 108: 2292–2297 JUPITER - Major exclusion criteria : 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: 2195-2207 JUPITER - Patient Flow : 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: 2195-2207 Slide 17: 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) 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: 2195-2207 Slide 18: Total cholesterol (mg/dL) 186 (168-200) 185 (169-199) LDL cholesterol (mg/dL) 108 (94-119) 108 (94-119) HDL cholesterol (mg/dL) 49 (40-60) 49 (40-60) Triglycerides (mg/dL) 118 (85-169) 118 (86-169) 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) Rosuvastatin Placebo 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: 2195-2207 Slide 19: 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 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: 2195-2207 JUPITER population compared with previous trials in patients without established CHD : 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 JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization : 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 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Ridker P et al. N Eng J Med 2008;359: 2195-2207 NNT for 2y = 95 4y = 31 5y* = 25 *Extrapolated figure based on Altman and Andersen method 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Follow-up (years) Number at Risk Rosuvastatin Placebo 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 JUPITER - Primary Endpoint Components : JUPITER - Primary Endpoint Components Primary Endpoint 251 (1.36) 142 (0.77) 0.56 0.46-0.69 <0.001* 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* Placebo Rosuvastatin HR 95% CI p-value [n=8901] [n=8901] n (rate**) n (rate**) HR – Hazard Ratio; CI – Confidence Limit ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001 Ridker P et al. N Eng J Med 2008;359: 2195-2207 JUPITER – Subgroup analysis : JUPITER – Subgroup analysis Rosuvastatin better Placebo better 0 0.2 0.4 0.6 0.8 1 1.2 Ridker P et al. N Eng J Med 2008;359: 2195-2207 Hazard ratio (95% CI) JUPITER - Total Mortality Death from any cause : Placebo Rosuvastatin 20mg JUPITER - Total Mortality Death from any cause Hazard Ratio 0.80 (95% CI 0.67-0.97) p=0.02 Ridker P et al. N Eng J Med 2008;359: 2195-2207 0 1 2 3 4 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months; Percentage change between rosuvastatin and placebo : JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months; Percentage change between rosuvastatin and placebo -60 -50 -40 -30 -20 -10 0 10 LDL-C HDL-C TG hsCRP Percentage change from baseline (%) 50% 4% 17% 37% p<0.001 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: 2195-2207 JUPITER Tolerability and Safety data : JUPITER Tolerability and Safety data 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** (216) 2.4 (270) 3.0 0.01 Haemorrhagic stroke 0.1 0.1 0.44 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: 2195-2207 JUPITER Laboratory Safety Data : 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/1.73m2) 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 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: 2195-2207 JUPITER – summary and perspectives : 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 THANK YOU : THANK YOU

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