A Randomized Trial of Rosuvastatin in the Preventionof Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels of C-Reactive Protein (hsCRP):
The JUPITER Trial
Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest,Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby,
Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn
on behalf of the JUPITER Trial Study Group
JUPITER Trial Presented during AHA 2008 Scientific Sessions
Independent Steering Committee :P Ridker (Chair), F Fonseca, J Genest, A Gotto, J Kastelein, W Koenig, P Libby, A Lorenzatti, B Nordestgaard, J Shepherd, J Willerson
Independent Academic Clinical Coordinating Center: P Ridker, E Danielson, R Glynn, J MacFadyen, S Mora (Boston)
Independent Academic Study Statistician: R Glynn (Boston)
Independent Data Monitoring Board: R Collins (Chair), K Bailey, B Gersh, G Lamas, S Smith, D Vaughan
Independent Academic Clinical Endpoint Committee: K Mahaffey (Chair), P Brown,D Montgomery, M Wilson, F Wood (Durham)
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 in individuals potentially at increased cardiovascular risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
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
Adapted from: Ridker PM. Circulation 2003; 108: 2292-97.Ridker PM. Am J Cardiol 2007; 100: 1659-64.Ridker PM. New Engl J Med 2002; 347: 1557-65.Ridker PM. Am J Cardiol 2003;92(suppl):17K-22K.
JUPITER: Background and Prior Work
Current guidelines for the prevention of myocardial infarctionstroke, and cardiovascular death endorse statin therapy among patients with established vascular disease, diabetes, and among those with hyperlidemia.
However, these screening and treatment strategies are insufficient as half of all heart attack and stroke events occur among apparently healthy men and women with average or even low levels of cholesterol.
Adapted from Ridker et al .NEJM 2008.
JUPITER: Background and Prior Work
To improve detection of individuals at increased risk forcardiovascular disease, physicians often measure high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low.
Prior work has shown that statin therapy reduces hsCRP, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hsCRP.
Adapted from Ridker et al. NEJM 2008.
Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline 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
Adapted from Ridker et al. N Engl J Med 2001;344:1959-65.
JUPITER population compared with previous trials in patients without established CHD
AFCAPS WOSCOPS JUPITER
Patients, n 6605 6595 17 802
% male 85 100 62
Duration, years 5.2 4.9 1.9
Diabetes, % 6 1 0
Baseline lipids, mmol/L*
total cholesterol 5.72 7.03 4.73
LDL-C 3.88 4.97 2.69
HDL-C 0.93–1.03 1.14 1.32
triglycerides 1.78 1.85 1.56
hsCRP, mg/L 0.2 NA 4.3
StatinLovastatin
20–40 mg
Pravastatin
40 mg
Rosuvastatin
20 mg
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; AFCAPS=Airforce/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS=West of Scotland Coronary Prevention Study; *Baseline lipid levels are mean values.
Adapted from: Ridker et al. Am J Cardiol 2007;100:1659-64. Ridker et al. N Engl J Med. 2001;344:1959-65.
JUPITER WOSCOPS AFCAPS
Sample size (n) 17,802 6,595 6,605
Women (n) 6,801 0 997
Minority (n) 5,118 0 350
Duration (yrs) 1.9 (max 5) 4.9 5.2
Diabetes (%) 0 1 6
Baseline LDL-C (mg/dL) 108 192 150
Baseline HDL-C (mg/dL) 49 44 36-40
Baseline TG (mg/dL) 118 164 158
Baseline hsCRP (mg/L) > 2 NA NA
Intervention Rosuvastatin Pravastatin Lovastatin20 mg 40 mg 10-40 mg
Adapted from JUPITER Trial Study Group, Am J Cardiol 2007.
Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention
JUPITER: Why Consider Statins for Low LDL, high hsCRP Patients?
In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI 0.56-2.08). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit.
In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI 0.34-0.98).
Adapted from *Ridker et al. N Engl J Med 2001;344:1959-65.
JUPITER: Why Consider Statins for Low LDL, High hsCRP Patients?
However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.
Adapted from Ridker et al. New Engl J Med 2001;344:1959-65.
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
[A]
[B]
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
AFCAPS/TexCAPS Low LDL Subgroups
RR
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.
Adapted from Ridker et al. Circulation 2003;108:2292-97.
Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke
UnstableUnstable AnginaAngina
CVD DeathCVD DeathCABG/PTCACABG/PTCA
JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP
4-week 4-week run-inrun-in
Adapted from Ridker et al. Circulation 2003;108:2292-97.
No Prior CVD or DMMen >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L
JUPITER: Trial Design
Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
JUPITER – 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; HbA1c=glycated haemoglobin
Median follow-up 1.9 years
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
JUPITER: 17,802 Patients, 1,315 Sites, 26 Countries
4021
2873
2497
2020
987804
741487
34533632727327025322220920420219716214385833215140%
5%
10%
15%
20%
25%
Urugu
ay
Switzer
land
Roman
ia
Chile
Eston
ia
Israe
l
El Salv
ador
Bulgar
ia
Panam
a
Norway
Venez
uela
Germ
any
Argen
tina
Costa
Rica
Russia
Brazil
Denm
ark
Colom
bia
Belgium
Mex
ico
Poland
The N
ethe
rland
s
Canad
a
South
Afri
ca
United
King
dom
United
Sta
tes
Ra
nd
om
iza
tio
ns
(%
To
tal.
) Total Randomized = 17,802
Adapted from Ridker et al. NEJM 2008.
JUPITER - Patient Flow
89,890 subjects screened 17,802 randomised
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
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Inclusion and Exclusion Criteria, Study Flow
89,863 Screened
17,802 Randomized
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
Reason for Exclusion (%)
LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
8,600 Completed Study120 Lost to follow-up
8,600 Completed Study120 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
89,890 Screened
Men > 50 yearsWomen > 60 yearsNo CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L
17,802 Randomized
Reason for Exclusion (%)
LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
4 weekPlaceboRun-In
8,857 Completed Study44 Lost to follow-up
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
8,864 Completed Study37 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
Adapted from Ridker et al. NEJM 2008.
JUPITER - Major Exclusion Criteria
Current use of statins or other lipid-lowering therapies
Current use of post menopausal hormone replacement therapy
Prior history of cardiovascular or cerebrovaascular 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
CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure
Adapted from: Ridker et al. N Eng J Med 2008;359:2195-207. Ridker PM. Circulation 2003;108:2292-97.
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 (%).
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
JUPITER:Baseline Blood Levels (median, interquartile range)
Rosuvastatin Placebo(N = 8901) (n = 8901)
hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119) 108 (94 - 119)
HDL, mg/dL 49 (40 – 60) 49 (40 – 60)
Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169)
Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199)
Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)
HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9)
All values are median (interquartile range). [ Mean LDL = 104 mg/dL ]
Adapted from Ridker et al. NEJM 2008.
Total cholesterol (mmol/L) 4.81 (4.34-5.17) 4.78 (4.37-5.15)
LDL cholesterol (mmol/L) 2.79 (2.43-3.08) 2.79 (2.43-3.08)
HDL cholesterol (mmol/L) 1.27 (1.03-1.55) 1.27 (1.03-1.55)
Triglycerides (mmol/L) a1.33 (0.96-1.91) 1.33 (0.97-1.91)
hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)
Glucose (mmol/L) 5.2 (4.8-5.7) 5.2 (4.9-5.7)
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=a8901 n=8901
JUPITER - Baseline laboratory parameters*
For hsCRP, values are the average of the values obtained at two screening visits*All values are median (interquartile range) or N (%).
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
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 coronary heart disease (CHD) defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of American Heart Association and the National Heart, Lung, and Blood Institute
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Study End Points
Primary End Point– Time to the first occurrence of a major cardiovascular event, composite of:
• cardiovascular death• Stroke• MI• unstable angina• arterial revascularisation
Secondary End Points:– total mortality– non-cardiovascular mortality– development of diabetes mellitus– development of venous thromboembolic events – bone fractures– discontinuation of study medication due to adverse effects.
Adapted from Ridker et al. Circulation 2003;108:2292-97.
JUPITER: Primary Objectives
To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 2 mg/L.
To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists.
Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
Adapted from Ridker et al. NEJM 2008.
hsC
RP
(m
g/L
)L
DL
(m
g/d
L)
Months0 12 24 36 48
TG
(m
g/d
L)
HD
L (
mg
/dL
)
Months
JUPITER: Effects of Rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP
LDL decrease 50 percent at 12 months
hsCRP decrease 37 percent at 12 months
HDL increase 4 percent at 12 months
TG decrease 17 percent at 12 months
Adapted from Ridker et al. NEJM 2008.
JUPITER: Adverse Events and Measured Safety Parameters
Event Rosuvastatin Placebo P
Any SAE 1,352 (15.2) 1,337 (15.5) 0.60Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34Myopathy 10 (0.1) 9 (0.1) 0.82Rhabdomyolysis 1 (0.01)* 0 (0.0) --Incident Cancer 298 (3.4) 314 (3.5) 0.51Cancer Deaths 35 (0.4) 58 (0.7) 0.02Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02ALT > 3xULN 23 (0.3) 17 (0.2) 0.34
Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64Incident Diabetes** 270 (3.0) 216 (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)**Physician reported
Adapted from Ridker et al. NEJM 2008.
JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death
Placebo 251/8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69P<0.00001
- 44 %
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve In
cid
ence
Number at Risk Follow-up (years)
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
Adapted from Ridker et al. NEJM 2008.
JUPITER: Grouped Components of the Primary End Point
HR 0.53, CI 0.40-0.70P<0.00001
Rosuvastatin
Placebo
Myocardial Infarction, Stroke, orCardiovascular Death
Arterial Revascularization orHospitalization for Unstable
Angina
HR 0.53, CI 0.40-0.69P<0.00001
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cu
mu
lati
ve In
cid
ence
Follow-up (years)
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
Cu
mu
lati
ve In
cid
ence
Follow-up (years)
Placebo
Rosuvastatin
- 47 %- 47 %
Adapted from Ridker et al. NEJM 2008.
JUPITER: Individual Components of the Primary End Point
*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
Endpoint Rosuvastatin Placebo HR 95%CI P
Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001
Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002
Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002
Revascularization or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001
MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001
Adapted from Ridker et al. NEJM 2008.
JUPITER: Primary End Point – Subgroup Analysis I
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
MenWomen
Age < 65Age > 65
SmokerNon-Smoker
CaucasianNon-Caucasian
USA/CanadaRest of World
HypertensionNo Hypertension
All Participants
N P for Interaction
11,001 0.80 6,801
8,541 0.32 9,261
2,820 0.6314,975
12,683 0.57 5,117
6,041 0.5111,761
10,208 0.53 7,586
17,802
Adapted from Ridker et al. NEJM 2008.
0.00
0.02
0.04
0.06
0.08
0 1 2 3 4 5Years
Placebo
Rosuvastatin 20 mg
JUPITER - Primary End PointTime to first occurrence of a CV death, non-fatal stroke, non-fatal
MI, unstable angina or arterial revascularisation C
um
ula
tive
Inci
den
ce
Number at riskRosuvastatin 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
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
NNT for 2 yrs = 95 5 yrs* = 25
*Extrapolated figure based on Altman and Andersen method
JUPITER - Primary End Point 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 Interval
** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual P-value was <0.00001
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
JUPITER: Primary Endpoint – Subgroup Analysis II
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Family HX of CHDNo Family HX of CHD
BMI < 25 kg/m2
BMI 25-29.9 kg/mBMI > 30 kg/m
Metabolic SyndromeNo Metabolic Syndrome
Framingham Risk < 10%Framingham Risk > 10%
hsCRP > 2 mg/L Only
All Participants
N P for Interaction
2,045 0.0715,684
4,073 0.70 7,009 6,675
7,375 0.1410,296
8,882 0.99 8,895
6,375
17,802
2
2
hsCRP > 2 mg/L Only 6,375
Adapted from Ridker et al. NEJM 2008.
JUPITER: Secondary End Point – All Cause Mortality
Placebo 247 / 8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97P= 0.02
- 20 %
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cu
mu
lati
ve I
nci
den
ce
Number at Risk Follow-up (years)
RosuvastatinPlacebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
Adapted from Ridker et al. NEJM 2008.
JUPITER: Statins and the Development of Diabetes
0.25 0.5 1.0 2 4
WOSCOPS Pravastatin
HPS Simvastatin
ASCOT-LLA Atorvastatin
JUPITER Rosuvastatin
PROVE-IT Atorvastatin VS
Pravastatin
0.70 (0.50–0.98)
1.20 (0.98–1.35)
1.20 (0.91–1.44)
1.11 (0.67–1.83)
1.25 (1.05–1.54)
Statin Better Statin Worse
HR (95% CI)
PROSPER Pravastatin 1.34 (1.06–1.68)
Adapted from Ridker et al. NEJM 2008.
JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit
Adapted from Ridker et al. NEJM 2008.
Pro
port
iona
l red
uctio
n in
va
scul
ar e
vent
rat
e (9
5% C
I)
Mean LDL cholesterol differencebetween treatment groups (mmol/L)
IDEAL
TNT
A-to-Z
CTT
PROVE-IT
JUPITER PREDICTED
JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit
Pro
po
rtio
na
l re
du
ctio
n in
va
scu
lar
eve
nt
rate
(9
5%
CI)
Mean LDL cholesterol differencebetween treatment groups (mmol/L)
IDEAL
TNT
A-to-Z
CTT
PROVE-IT
JUPITER PREDICTED
JUPITER OBSERVED
Adapted from Ridker et al. NEJM 2008.
Prevalence of conventional risk factors† in male patients with CHD
None
One
Two
Three
Four (0.9%)
Total male patients=87 869CHD=coronary heart disease†smoking, hypertension, hypercholesterolaemia and diabetes mellitus
19.4%
43.0%
27.8%
8.9%
Adapted from Khot et al. JAMA 2003;290:898-904.
CRP is a strong independent predictorof 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
Adapted from Blake GJ, Ridker PM. Circ Res 2001;89:763-71.
CRP predicts risk of MI and strokein apparently healthy men
CRP=C-reactive protein; MI=myocardial infarctionQuartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14;Quartile 3: 1.15-2.10 ; Quartile 4: 2.11.*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
***
Adapted from Ridker et al. N Engl J Med 1997;336:973-79.
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
Adapted from Ridker et al. N Engl J Med 2002;347:1557-65.
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
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
Hazard ratio (95% CI)
0.00
0.02
0.04
0.06
0 1 2 3 4 5Years
Placebo
Rosuvastatin 20 mg
JUPITER - Total Mortality Death from any cause
Cu
mu
lati
ve In
cid
ence
Number at riskRosuvastatin 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
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
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
Per
cen
tag
e ch
ang
e fr
om
bas
elin
e (%
)
50%
4%
17%
37%
P<0.001
P<0.001*
P<0.001
P<0.001
*P-value at study completion (48 months) = 0.34
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Tolerability 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
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Laboratory 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) 0.001
Fasting plasma glucose** (mmol/L) 5.4 (5.0-5.9) 5.4 (5.1-5.9)0.12
Placebo Rosuvastatin P value[n=8901] [n=8901]
GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c; IQR = interquartile range
‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Conclusions – Efficacy I
Among apparently healthy men and women with elevatedhsCRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death.
Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials.
In this trial of low LDL/high hsCRP individuals who do notcurrently qualify for statin therapy, rosuvastatin significantlyreduced all-cause mortality by 20 percent.
Adapted from Ridker et al. NEJM 2008.
JUPITER: Conclusions – Efficacy II
Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP and no other major risk factor.
Rates of hospitalization and revascularization were reducedby 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers.
The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention.
Adapted from Ridker et al. NEJM 2008.
JUPITER: Conclusions - Safety
With regard to safety , the JUPITER results show no increase in serious adverse events among thoseallocated to rosuvastatin 20 mg as compared to placeboin a setting where half of the treated patients achievedlevels of LDL< 55 mg/dL (and 25 percent had LDL < 44mg/dL).
show no increase in myopathy, cancer, hepaticdisorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years.
show no increase in systematically monitored glucose orglucosuria during follow-up, but small increases inHbA1c and physician reported diabetes similar to thatseen in other major statin trials.
Adapted from Ridker et al. NEJM 2008.
JUPITER – Summary
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.
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Public Health Implications
Application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone.
We thank the 17,802 patients and the >1,000 investigatorsworldwide for their personal time, effort, and commitmentto the JUPITER trial.
www.brighamandwomens.org/jupitertrial
Adapted from Ridker et al. NEJM 2008.
JUPITER: Implications for Primary Prevention
Among men and women age 50 or over :
If diabetic, treatIf LDLC > 160 mg/dL, treat
If hsCRP > 2 mg/L, treat
A simple evidence based approach to statin therapyfor primary prevention.
Adapted from Ridker et al. NEJM 2008.
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
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