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JUPITERJUPITER
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 - RationaleJUPITER - 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 factorsPrevalence of conventional risk factors†† in in patients with CHDpatients 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 CRP is a strong independent predictor of CV events in womenCV 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)HomocysteineIL-6TCLDL-CsICAM-1SAAApoBTC/HDL-CCRPCRP + 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 CRP predicts risk of MI and stroke in apparently healthy menhealthy 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 CV event-free survival in women using combined LDL-C and hsCRP measuresand 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 Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline LDL-C and hsCRPbaseline LDL-C and hsCRP
Study group Rate of cardiovascular events
NNT
Lovastatin Placebo
Low LDL-C/low hsCRP 0.025 0.022 N/A
Low LDL-C/high hsCRP 0.029 0.051 48
High LDL-C/low hsCRP 0.020 0.050 33
High LDL-C/high hsCRP 0.038 0.055 58
Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/LAFCAPS/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 - ObjectiveJUPITER - 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 designJUPITER – study design
LipidsCRP
Tolerability
LipidsCRP
TolerabilityHbA1C
Placebo
run-in
1–6
2–4
30
413 Final 6-monthly
Visit:Week:
Randomisation
LipidsCRP
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; HbA 1c=glycated haemoglobin
Median follow-up 1.9 years
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER - Study EndpointsJUPITER - 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 criteriaJUPITER - 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
89,890 subjects screened 17,802 randomized
Rosuvastatin 20mgn=8,901
Placebon=8,901
Lost to follow upn=44
Completed studyn=8,857
Lost to follow upn=37
Completed studyn=8,864
Ridker P et al. N Eng J Med 2008;359: 2195-2207
Age (years) 66 (60-71) 66 (60-71)
Male sex (%) 61.5 62.1Race (%)
White 71.4 71.1Black 12.4 12.6Hispanic 12.6 12.8Other 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 Placebon=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
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 Placebon=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
Current smoker (%) 15.7 16.0 Family history CHD† (%) 11.2 11.8Metabolic syndrome‡ (%) 41.0 41.8Aspirin 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/NHLBIRidker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER population compared with previous trials JUPITER population compared with previous trials in patients without established CHDin patients without established CHD
AFCAPS WOSCOPS JUPITER
Patients, n 6605 6595 17 802
% male, n 85 100 62
Duration, years 5.2 4.9 1.9
Diabetes, % 6 1 0
Baseline lipids, mg/dL*
total cholesterol
221 272 183
LDL-C 150 192 104
HDL-C 36–40 44 51
triglycerides 158 164 138
hsCRP, mg/L 0.2 NA 4.3
Statin Lovastatin 20–40 mg
Pravastatin 40 mg
Rosuvastatin 20 mgCVD=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
0
1
2
3
4
5
6
7
8
9
0 1 2 3 4 5Years
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 P
erc
en
t of
pati
en
ts w
ith
pri
mary
en
dp
oin
t
Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174
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 5y* = 25
*Extrapolated figure based on Altman and Andersen method
JUPITER - Primary Endpoint Components
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 0.003Fatal 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 HR95% 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
Rosuvastatin better Placebo better
N P- value*
Age 0.32≤ 65 years 8,541>65 yrs 9,261Gender 0.80Males 11,001Females 6,801Race 0.57White 12,683Non-white 5,117Hypertension 0.53Yes 10,208No 7,586Region 0.51US or Canada 6,041Other 11,761Metabolic syndrome 0.14Yes 7,375No 10,296
Family history of CHD 0.07Yes 2,045No 15,684
Framingham risk score 0.99≤10% 8,882>10% 8,895
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)
0
1
2
3
4
5
6
7
0 1 2 3 4 5Years
Placebo
Rosuvastatin 20mg
JUPITER - Total Mortality Death from any cause
Perc
en
t to
tal m
ort
ality
Number at risk RSV 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246
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
JUPITER 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
Perc
en
tag
e c
han
ge
from
baselin
e (
%)
50%
4%
17%
37%
p<0.001
p<0.001*
p<0.001
p<0.001
*P-value at study completion (48 months) = 0.34Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITERTolerability and safety data
Adverse Events, (%) Any serious adverse event 15.5 15.2 0.60Muscle weakness, stiffness, pain 15.4 16.0 0.34Myopathy 0.1 0.1 0.82Rhabdomyolysis 0.0 <0.1* ----Newly diagnosed cancer 3.5 3.4
0.51Death from cancer 0.7 0.4
0.02Gastrointestinal disorders 19.2 19.7
0.43Renal disorders 5.4 6.0
0.08Bleeding 3.1 2.9
0.45Hepatic disorders 2.1 2.4
0.13
Other events, (%)Newly diagnosed diabetes** 2.4 3.0
0.01Haemorrhagic 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
JUPITERLaboratory Safety Data
Laboratory Values, N (%) Serum creatinine‡ 10 (0.10) 16 (0.20) 0.24ALT > 3 x ULN# 17 (0.20) 23 (0.30) 0.34Glycosuria† 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)0.001Fasting 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 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
AcknowledgementsAcknowledgements
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