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Expanding The Orbit of Statin

Therapy
Dr. Tang Sie Hing
Consultant Interventional
Cardiologist
Chief, Cardiology Department
Normah Medical Specialist Centre,

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 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  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 .

hypercholesterolaemia and diabetes mellitus Khot UN et al. Prevalence of conventional risk factors† in patients with CHD Four (0.0% One Total patients=87 869 CHD=coronary heart disease †smoking.4% 27. hypertension.8% Two 43.9%) Three None 8. JAMA 2003. 290: 898–904 .9% 19.

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CRP=C-reactive protein. HDL-C=high-density lipoprotein cholesterol. sICAM-1=soluble intercellular adhesion molecule 1. Circ Res 2001. CV=cardiovascular.0 2. SAA=serum amyloid A. Lp(a)=lipoprotein (a).0 4. Ridker PM.0 6. CRP is a strong independent predictor of CV events in women Lp(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA ApoB TC/HDL-C CRP CRP + TC/HDL-C 0 1. 89: 763–771 . TC=total cholesterol Blake GJ. LDL-C=low-density lipoprotein cholesterol.0 Relative risk of future CV Apo=apolipoprotein. IL=interleukin.

336: 973–979 .5 2. CRP predicts risk of MI and stroke in apparently healthy men 3.5 2. MI=myocardial infarction *p=0.5 0.0 *** 1.0 Relative risk of 1.5 0 0 1 2 3 4 1 2 3 4 Quartile of Quartile of CRP CRP CRP=C-reactive protein. N Engl J Med 1997.0 * 3.0 stroke 0.0 1.5 ischaemi risk c 1.001 versus quartile 1 Ridker PM et al.5 Relative 2.02 versus quartile 1. ***p<0.

00 LDL-C and hsCRP measures Low LDL-C. LDL-C=low-density lipoprotein cholesterol Median LDL-C=3. high hsCRP 0. low hsCRP free 0.99 Probability of event. High LDL-C.96 High LDL-C. high hsCRP 0 CV=cardiovascular. hsCRP=high-sensitivity C-reactive protein. low hsCRP 0. N Engl J Med 2002.97 0.2 mmol/L (124 mg/dL) Ridker PM et al.98 survival Low LDL-C. CV event-free survival in women using combined 1. 347: 1557–1565 .

Median hsCRP=1.6 mg/L AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study. N Engl J Med 2001. NNT=number needed to treat to prevent one coronary event Ridker PM et al.9 mmol/L (149 mg/dL). N/A=not applicable. LDL- C=low-density lipoprotein cholesterol. hsCRP=high-sensitivity C-reactive protein. 344: 1959–1965 . Efficacy of Lovastatin in AFCAPS/TexCAPS subgroups by Median LDL-C=3.

Circulation 2003. 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. 108: 2292–2297 .

LDL-C=low-density lipoprotein cholesterol. CRP=C-reactive protein. N Eng J Med 2008. HbA1c=glycated haemoglobin Ridker P et al.9 years CAD=coronary artery disease.0 mg/L Placebo (n=8901) Visit: 1 2 3 4 Week: –6 –4 0 13 6-monthly Final Lead-in/ Randomisation Lipids Lipids Lipids eligibility CRP CRP CRP Tolerability Tolerability Tolerability HbA1C Median follow-up 1. JUPITER – study design No history of CAD Rosuvastatin 20 mg (n=8901) men ≥50 yrs Placeb women ≥60 yrs o LDL-C <130 mg/dL run-in CRP ≥2.359: 2195-2207 .

108: 2292–2297 . Circulation 2003.Study Endpoints  Primary Endpoint  Time to the first occurrence of a major cardiovascular event. JUPITER . 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.

women aged ≥60 years Fasting LDL-C levels 130 mg/dL3.0 mg/L and TG levels 500 mg/dL(5.4 mmol/L).7 mmol/L) on initial screening. Circulation 2003. JUPITER .Major inclusion Men aged ≥50 years. Ridker PM. 108: 2292–2297 . CRP levels ≥2.

Major exclusion  Current use of statins or other lipid-lowering therapies  Current use of hormone replacement therapy  Prior history of cardiovascular or cerebrovascular events.359: 2195-2207 . N Eng J Med 2008. such as severe arthritis. ULN = upper limit of normal. CK = creatinine kinase. or CHD-risk equivalents  Chronic inflammatory condition. SBP = systolic blood pressure. Circulation 2003. lupus or inflammatory bowel disease and/or treatment with immunosuppressants  Uncontrolled:  hypertension: SBP > 190 mmHg or DBP > 100 mmHg  hypothyroidism: TSH > 1. 108: 2292–2297 CHD = coronary heart disease.5 x ULN  CK 3 x ULN  Serum creatinine > 2. unstable angina. such as MI. prior arterial revascularisation or stroke. alcohol or drug abuse Ridker PM. JUPITER . DBP = diastolic blood pressure Ridker P et al.0 mg/dL  Evidence of hepatic dysfunction (ALT > 2 x ULN)  History of prior malignancy.

802 randomized Rosuvastatin 20mg Placebo n=8.901 Lost to follow up Lost to follow up n=44 n=37 Completed study Completed study n=8. N Eng J Med 2008.901 n=8. JUPITER .857 n=8.890 subjects screened 17.Patient Flow 89.359: 2195-2207 .864 Ridker P et al.

0) 28.4 (25.359: 2195-2207 .Baseline characteristics* Rosuvastatin Placebo n=8901 n=8901 Age (years) 66 (60-71) 66 (60-71) Male sex (%) 61.3 (25.6 12.1 Race (%) White 71.1 Black 12.6 3.6 Hispanic 12.0) 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 (%).3-32.4 71.5 BMI (kg/m2) 28.8 Other 3.5 62. JUPITER . N Eng J Med 2008. Ridker P et al.3-32.4 12.

9) Glomerular filtration rate.6-83.3 (2. Ridker P et al. values are the average of the values obtained at two screening and visits *All values are median (interquartile range) or N (%).359: 2195-2207 .7 (5. JUPITER .1) 4. N Eng J Med 2008.2 (2.3 (64.8-7.7) 73.1) For hsCRP.6-84.Baseline laboratory Rosuvastatin Placebo n=8901 n=8901 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) 4.9) 5.4-5.2) Glucose (mg/dL) 94 (87-102) 94 (88-102) HbA1c(%) 5.6 (64.7 (5.5-5.8-7.73m2) 73. (ml/min/1.

0 41.Medical History Medical History Rosuvastatin Placebo Current smoker (%) 15. < 65 yrs (female).7 16.0 Family history CHD† (%) 11.8 Metabolic syndrome‡ (%) 41.2 11.359: 2195-2207 . JUPITER .6 16. N Eng J Med 2008.6 †Family history of premature CHD defined as first degree relative with CHD at age < 55 yrs (male). ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBI Ridker P et al.8 Aspirin use (%) 16.

LDL-C=low-density lipoprotein cholesterol. CHD=coronary heart disease. hsCRP=high sensitivity C-reactive protein. 100: 1659–1664 Ridker PM et al. *Baseline lipid levels are mean values. Am J Cardiol 2007. Ridker PM et al. N Engl J Med.JUPITER population compared with previous trials in patients without established CHD CVD=cardiovascular disease. HDL-C=high- density lipoprotein cholesterol. 2001 344: 1959-65 .

00001 Cumulative Incidence .90 1 8.Primary Endpoint Time to first occurrence of a CV death.96 3 1.62 2 8. non-fatal stroke.41 6.04 0 NNT for 2y = 95 .359: 2195-2207 .54 (years) 1.08 Placeb Hazard Ratio 0.00 0 0 1 2 3 4 Number at Risk Follow-up Rosuvastati 8. unstable angina or arterial . N Eng J Med 2008.02 4y = 31 0 5y* = 25 .56 0 o (95% CI 0.89 1.35 98 54 15 n Placeb 1 8.87 8 1.90 8.63 8.50 3 3.35 0 6.33 3 95 4 53 7 17 o 1 1 3 8 2 3 3 5 4 4 *Extrapolated figure based on Altman and Andersen method Ridker P et al. JUPITER .46-0. non-fatal MI.69) P<0.06 0 Rosuvastatin 20 mg .95 3.

69 <0.53 ** Rates are per 100 person years.002 Arterial Revascularization 131 (0.38) 0.40-0.10 0.52 0.54 0.003 Fatal or non-fatal stroke 64 (0. MI 157 (0.359: 2195-2207 .80 0.77) 0.72 <0.46 0.32-1.37) 31 (0.59 0.33) 22 (0. † Hospitalisation due to*unstable angina.56 0.45) 0.001* Fatal or non-fatal MI 68(0. stroke. *Actual p-value was < 0.30- 0.34) 33 (0. CI – Confidence Limit Ridker P et al.Primary Endpoint Placebo Rosuvastatin HR 95% CI p- value [n=8901] [n=8901] Primary Endpoint 251 (1.001* Non-fatal MI 62 (0.0002 Non-fatal stroke 58 (0.41-0.58 <0.31) 30 (0.16) 0.69 <0.00001 0.85) 83 (0.70 0.35 0. JUPITER . N Eng J Med 2008.09 CV death.46-0.33-0.18) 0.34-0.52 0.14) 16 (0.09) 0.22-0.17) 0.12) 0.79 0.001 HR – Hazard Ratio.36) 142 (0.71) 71 (0.0001 Unstable angina† 27 (0.

N Eng J Med 2008. 0 1 Hazard ratio (95% CI) Ridker P et al. 4 0. 8 0.359: 2195-2207 . 2 1.JUPITER – Subgroup analysis Rosuvastatin better Placebo better 2 0. 6 0.

19 3 68 7 24 o 1 2 5 7 9 5 4 6 4 6 Ridker P et al. N Eng J Med 2008.80 (95% CI 0.29 2 1.04 0 .05 0 Cumulative Incidence Rosuvastatin 20mg .Total Mortality .26 1.31 8 2.19 68 22 n Placeb 1 8.61 2 1.00 0 0 1 2 3 4 Number at Risk Follow-up Rosuvastati 8.77 9 6.97) Placeb p=0.60 1.359: 2195-2207 .02 0 .90 8. JUPITER .06 Death from any cause 0 Hazard Ratio 0.90 7 8.02 o .01 0 .99 (years) 4.31 2.03 0 .84 8.85 7 8.67-0.78 6.98 2 4.

Percentage change between rosuvastatin and placebo 10 LDL-C HDL-C TG hsCR P 4% 0 Percentage change from baseline (%) p<0. JUPITER Effects on LDL-C.001* -10 17% -20 p<0.00 -60 *P-value at study completion (48 months) = 0.00 50% -50 p<0.359: 2195-2207 . N Eng J Med 2008. TG and hsCRP at 12 months. HDL-C.00 -30 37% -40 p<0.34 Ridker P et al.

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stiffness. **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008.2 19.9 0.08 Bleeding 3.5 15.1 0.0 0.02 Gastrointestinal disorders 19.1 2.34 Myopathy 0. (%) Any serious adverse event 15.4 0.4 6.4 0.1 2.5 3.4 16.2 0.13 *Occurred after trial completion.7 0.0 <0.7 0.45 Hepatic disorders 2.0 0.359: 2195-2207 .51 Death from cancer 0. pain 15.60 Muscle weakness.1 0.1* ---- Newly diagnosed cancer 3. JUPITER Tolerability and Safety data Placebo Rosuvastatin p- value [n=8901] [n=8901] Adverse Events.4 0.43 Renal disorders 5.82 Rhabdomyolysis 0.

34 Glycosuria† 32 (0. **at 24 months. median values (IQR) GFR*. *at 12 months. ‡ >100% increase from baseline.64 Laboratory Values.1) 5.359: 2195-2207 . N Eng J Med 2008.20) 23 (0.00 Fasting plasma glucose**.24 ALT > 3 x ULN# 17 (0.8 (5.JUPITER Laboratory Safety Data Placebo Rosuvastatin p- value [n=8901] [n=8901] Laboratory Values.1-76.20) 0. †>trace at 12 months Ridker P et al.9 (5. HbA1c = Haemoglobin A1c # on consecutive visits.6-6. (mg/dL) 98 (90-106) 98 (91-107) GFR = Glomerular filtration rate. N (%) Serum creatinine‡ 10 (0.2) 66.30) 0.50) 0.10) 16 (0. (mL/min/1.5) 0.40) 36 (0.02 % HbA1c** 5.73m2) 66.8 (59.8-76.7-6.1) 0.6 (58.

 A 20% reduction in total mortality was observed in patients who received rosuvastatin 20 mg compared with placebo (p=0.00001). haematological disorders.  In JUPITER. 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. unstable angina.  A 44% reduction in the primary endpoint of major cardiovascular events (composite of: CV death.02). a unique finding for statins in a population without established CHD. arterial revascularisation) was observed in patients who received rosuvastatin 20 mg compared with placebo (p< 0. MI.  The results from JUPITER highlight the importance Ridker P et al.359: 2195-2207 . gastrointestinal. long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants. cancer.  There was no difference between treatment groups for muscle weakness. hepatic or renal systems. stroke.of highly N Eng effective J Med 2008.

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