Transcript Document

JUPITER Trial Presented during AHA 2008 Scientific Sessions
A Randomized Trial of Rosuvastatin in the Prevention
of 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
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 lipidlowering 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 infarction
stroke, 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 for
cardiovascular 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/L
AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=highsensitivity 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
6605
6595
17 802
% male
85
100
62
Duration, years
5.2
4.9
1.9
6
1
0
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
1.78
1.85
1.56
0.2
NA
4.3
Lovastatin
Pravastatin
Rosuvastatin
20–40 mg
40 mg
20 mg
Patients, n
Diabetes, %
Baseline lipids,
mmol/L*
triglycerides
hsCRP, mg/L
Statin
CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=highdensity 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.
Comparison of the JUPITER Trial Population to
Previous Statin Trials of Primary Prevention
JUPITER
WOSCOPS
AFCAPS
17,802
6,595
6,605
Women (n)
6,801
0
997
Minority (n)
5,118
0
350
4.9
5.2
Sample size (n)
Duration (yrs)
Diabetes (%)
1.9 (max 5)
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
20 mg
Adapted from JUPITER Trial Study Group, Am J Cardiol 2007.
Pravastatin
40 mg
Lovastatin
10-40 mg
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?
AFCAPS/TexCAPS Low LDL Subgroups
LowLDL,
LDL,Low
LowhsCRP
hsCRP
Low
[A]
LowLDL,
LDL,High
HighhsCRP
hsCRP
Low
[B]
0.50.5
StatinEffective
Effective
Statin
1.01.0
RR
2.02.0
StatinNot
NotEffective
Effective
Statin
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.
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.
JUPITER: Trial Design
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
4-week
run-in
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
Adapted from Ridker et al. Circulation 2003;108:2292-97.
MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
JUPITER – Study Design
No history of CAD
Rosuvastatin 20 mg (n=8901)
men ≥50 yrs
Placebo
women ≥60 yrs
run-in
LDL-C <130 mg/dL
Placebo (n=8901)
CRP ≥2.0 mg/L
Visit:
Week:
1
–6
2
–4
Lead-in/
eligibility
3
0
4
13
6-monthly
Final
Randomisation
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
Lipids
CRP
Tolerability
HbA1C
Median follow-up 1.9 years
CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol;
CRP=C-reactive protein; HbA1c=glycated haemoglobin
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
JUPITER: 17,802 Patients, 1,315 Sites, 26 Countries
25%
4021
Randomizations (% Total.)
20%
Total Randomized = 17,802
2873
15%
2497
2020
10%
804
5%
741
14
15 32
336 345
253 270 273 327
222
209
197
202
204
83 85 143 162
0%
Adapted from Ridker et al. NEJM 2008.
487
987
JUPITER - Patient Flow
89,890 subjects screened
17,802 randomised
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
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890
Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L
4 week
Placebo
Run-In
17,802
Randomized
17,802 Randomized
8,901 Assigned
Assigned to
8,901
to
Rosuvastatin
20
mg
Rosuvastatin 20 mg
Reason for
for Exclusion
Exclusion
Reason
LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP
<
2.0
mg/L
36
hsCRP < 2.0 mg/L
37
Withdrew Consent
Consent
54
Withdrew
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG
>
500
mg/dL
<1
TG > 500 mg/dL
<1
Age out
out of
of range
range
<1
Age
Current
Use
of
HRT
<1
Current Use of HRT
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor
8,901
to
8,901Assigned
Assigned to
Placebo
Placebo
8,600Completed
CompletedStudy
Study
8,857
120
Lost
follow-up
44
Lost
totofollow-up
8,864
Study
8,600 Completed
Completed Study
120Lost
Lostto
to follow-up
follow-up
37
8,901
8,901Included
Includedin
inEfficacy
Efficacy
and
Safety
Analyses
and Safety Analyses
8,901Included
Includedin
inEfficacy
Efficacy
8,901
andSafety
SafetyAnalyses
Analyses
and
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.
JUPITER - Baseline Characteristics*
Rosuvastatin
n=8901
Age (years)
Male sex (%)
Race (%)
White
Black
Hispanic
Other
BMI (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Placebo
n=8901
66 (60-71)
61.5
66 (60-71)
62.1
71.4
12.4
12.6
3.6
28.3 (25.3-32.0)
134 (124-145)
80 (75-87)
71.1
12.6
12.8
3.5
28.4 (25.3-32.0)
134 (124-145)
80 (75-87)
*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
(N = 8901)
Placebo
(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).
Adapted from Ridker et al. NEJM 2008.
[ Mean LDL = 104 mg/dL ]
JUPITER - Baseline laboratory parameters*
Rosuvastatin
n=a8901
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
hsCRP (mg/L)
Glucose (mmol/L)
HbA1c(%)
Glomerular filtration rate,
(ml/min/1.73m2)
Placebo
n=8901
4.81 (4.34-5.17)
2.79 (2.43-3.08)
1.27 (1.03-1.55)
a1.33 (0.96-1.91)
4.2 (2.8-7.1)
5.2 (4.8-5.7)
5.7 (5.4-5.9)
4.78 (4.37-5.15)
2.79 (2.43-3.08)
1.27 (1.03-1.55)
1.33 (0.97-1.91)
4.3 (2.8-7.2)
5.2 (4.9-5.7)
5.7 (5.5-5.9)
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 visits
*All values are median (interquartile range) or N (%).
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Medical History
Medical History
Current smoker (%)
Family history CHD† (%)
Metabolic syndrome‡ (%)
Aspirin use (%)
Rosuvastatin
n=8901
15.7
11.2
41.0
16.6
Placebo
n=8901
16.0
11.8
41.8
16.6
†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
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin
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.
Adapted from Ridker et al. NEJM 2008.
hsCRP decrease 37 percent at 12 months
0
12
24
Months
Adapted from Ridker et al. NEJM 2008.
36
HDL (mg/dL)
LDL decrease 50 percent at 12 months
TG (mg/dL)
hsCRP (mg/L)
LDL (mg/dL)
JUPITER: Effects of Rosuvastatin 20 mg on LDL,
HDL, TG, and hsCRP
HDL increase 4 percent at 12 months
TG decrease 17 percent at 12 months
48
Months
JUPITER: Adverse Events and Measured Safety Parameters
Event
Rosuvastatin
Placebo
Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke
1,352
1,421
10
1
298
35
6
1,337 (15.5)
1,375 (15.4)
9 (0.1)
0 (0.0)
314 (3.5)
58 (0.7)
9 (0.1)
(15.2)
(16.0)
(0.1)
(0.01)*
(3.4)
(0.4)
(0.1)
P
0.60
0.34
0.82
-0.51
0.02
0.44
GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN
66.8 (59.1-76.5)
23 (0.3)
66.6 (58.8-76.2) 0.02
17 (0.2)
0.34
Fasting glucose (24 mth)
HbA1c (% at 24 mth)
Glucosuria (12 mth)
Incident Diabetes**
98
5.9
36
270
98
5.8
32
216
*Occurred after trial completion, trauma induced.
**Physician reported
Adapted from Ridker et al. NEJM 2008.
(91-107)
(5.7-6.1)
(0.5)
(3.0)
(90-106)
(5.6-6.1)
(0.4)
(2.4)
0.12
0.01
0.64
0.01
All values are median (interquartile range) or N (%)
JUPITER: Grouped Components
of the Primary End Point
HR 0.53, CI 0.40-0.69
P<0.00001
HR 0.53, CI 0.40-0.70
P<0.00001
0.06
Arterial Revascularization or
Hospitalization for Unstable Angina
0.05
Myocardial Infarction, Stroke, or
Cardiovascular Death
0.04
0.03
0.02
Rosuvastatin
0.00
0.00
- 47 %
0.01
Rosuvastatin
Cumulative Incidence
0.04
0.03
0.02
- 47 %
0.01
Cumulative Incidence
Placebo
0.05
Placebo
0
1
2
3
Follow-up (years)
Adapted from Ridker et al. NEJM 2008.
4
0
1
2
3
Follow-up (years)
4
JUPITER: Individual Components
of the Primary End Point
Endpoint
Rosuvastatin
Placebo
HR
95%CI
P
Primary Endpoint*
142
251
0.56
0.46-0.69
<0.00001
Non-fatal MI
Any MI
22
31
62
68
0.35
0.46
0.22-0.58
0.30-0.70
<0.00001
<0.0002
Non-fatal Stroke
Any Stroke
30
33
58
64
0.52
0.52
0.33-0.80
0.34-0.79
0.003
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
*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
Adapted from Ridker et al. NEJM 2008.
JUPITER: Primary End Point – Subgroup Analysis I
N
Men
Women
P for Interaction
11,001
6,801
0.80
Age < 65
Age > 65
8,541
9,261
0.32
Smoker
Non-Smoker
2,820
14,975
0.63
Caucasian
Non-Caucasian
12,683
5,117
0.57
USA/Canada
Rest of World
6,041
11,761
0.51
Hypertension
No Hypertension
10,208
7,586
0.53
All Participants
17,802
0.25
0.5
Rosuvastatin Superior
Adapted from Ridker et al. NEJM 2008.
1.0
2.0
Rosuvastatin Inferior
4.0
JUPITER - Primary End Point
Time to first occurrence of a CV death, non-fatal stroke, non-fatal
MI, unstable angina or arterial revascularisation
Hazard Ratio 0.56
(95% CI 0.46-0.69)
P<0.00001
Cumulative Incidence
0.08
Placebo
0.06
Rosuvastatin 20 mg
0.04
NNT for 2 yrs = 95
5 yrs* = 25
0.02
0.00
0
Number at risk
Rosuvastatin 8901
Placebo
8901
1
2
3
4
5
538
531
157
174
Years
8412
8353
3893
3872
*Extrapolated figure based on Altman and Andersen method
Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.
1353
1333
JUPITER: Primary Endpoint – Subgroup Analysis II
N
Family HX of CHD
No Family HX of CHD
P for Interaction
2,045
15,684
0.07
BMI < 25 kg/m
BMI 25-29.9 kg/m 2
2
BMI >30 kg/m
4,073
7,009
6,675
0.70
Metabolic Syndrome
No Metabolic Syndrome
7,375
10,296
0.14
Framingham Risk < 10%
Framingham Risk > 10%
8,882
8,895
0.99
hsCRP > 2 mg/L Only
hsCRP > 2 mg/L Only
6,375
6,375
2
All Participants
17,802
0.25
0.5
1.0
Rosuvastatin Superior
Adapted from Ridker et al. NEJM 2008.
2.0
Rosuvastatin Inferior
4.0
0.06
JUPITER: Secondary End Point – All Cause Mortality
Placebo 247 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
0.04
0.03
0.02
Rosuvastatin 198 / 8901
0.00
0.01
Cumulative Incidence
0.05
- 20 %
0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901
1
2
3
4
Follow-up (years)
8,847
8,852
Adapted from Ridker et al. NEJM 2008.
8,787
8,775
6,999
6,987
4,312
4,319
2,268
2,295
1,602
1,614
1,192
1,196
683
684
227
246
JUPITER: Statins and the Development of Diabetes
HR
(95% CI)
WOSCOPS
Pravastatin
0.70 (0.50–0.98)
PROSPER
Pravastatin
1.34 (1.06–1.68)
HPS
Simvastatin
1.20 (0.98–1.35)
ASCOT-LLA
Atorvastatin
1.20 (0.91–1.44)
PROVE-IT
Atorvastatin
1.11 (0.67–1.83)
VS
Pravastatin
JUPITER
Rosuvastatin
1.25 (1.05–1.54)
0.25
0.5
Statin Better
Adapted from Ridker et al. NEJM 2008.
1.0
2
Statin Worse
4
Proportional reduction in
vascular event rate (95% CI)
JUPITER: Predicted Benefit Based on
LDL Reduction vs Observed Benefit
CTT
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol difference
between treatment groups (mmol/L)
Adapted from Ridker et al. NEJM 2008.
JUPITER PREDICTED
JUPITER: Predicted Benefit Based
on LDL Reduction vs Observed Benefit
Proportional reduction in
vascular event rate (95% CI)
JUPITER OBSERVED
CTT
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol difference
between treatment groups (mmol/L)
Adapted from Ridker et al. NEJM 2008.
JUPITER PREDICTED
Prevalence of conventional risk factors†
in male patients with CHD
Four
Three
(0.9%)
None
8.9%
19.4%
Two
27.8%
43.0%
One
Total male patients=87 869
CHD=coronary heart disease
†smoking, hypertension, hypercholesterolaemia and diabetes mellitus
Adapted from Khot et al. JAMA 2003;290:898-904.
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
1.0
2.0
4.0
6.0
Relative risk of future CV events
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
Adapted from Blake GJ, Ridker PM. Circ Res 2001;89:763-71.
CRP predicts risk of MI and stroke
in apparently healthy men
3.5
2.0
***
3.0
1.5
2.5
Relative
risk
of MI
*
Relative
risk of
ischaemic
stroke
2.0
1.5
1.0
1.0
0.5
0.5
0
0
1
2
3
4
Quartile of CRP
CRP=C-reactive protein; MI=myocardial infarction
Quartile 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
Adapted from Ridker et al. N Engl J Med 1997;336:973-79.
1
2
3
Quartile of CRP
4
CV event-free survival in women using
combined LDL-C and hsCRP measures
1.00
0.99
Probability
of eventfree
survival
0.98
Low LDL-C, low hsCRP
High LDL-C, low hsCRP
Low LDL-C, high hsCRP
0.97
0.96
High LDL-C, high hsCRP
0
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
Adapted from Ridker et al. N Engl J Med 2002;347:1557-65.
JUPITER: Subgroup Analysis
Placebo better
Rosuvastatin better
0.57
Race
White
Non-white
12,683
5,117
0.53
Hypertension
Yes
No
10,208
7,586
0.51
Region
US or Canada
Other
6,041
11,761
0.14
Metabolic syndrome
Yes
No
7,375
10,296
0.07
Family history of CHD
Yes
No
2,045
15,684
0.99
Framingham risk score
≤10%
>10%
8,882
8,895
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
1.2
11,001
6,801
1
Males
Females
0.8
0.80
Gender
0.6
8,541
9,261
0.4
≤ 65 years
>65 yrs
0.2
Age
P- value
0.32
0
N
Hazard ratio (95% CI)
JUPITER - Total Mortality
Cumulative Incidence
Death from any cause
Hazard Ratio 0.80
(95% CI 0.67-0.97)
P=0.02
0.06
Placebo
Rosuvastatin 20 mg
0.04
0.02
0.00
0
Number at risk
Rosuvastatin 8901
Placebo
8901
1
2
3
4
5
676
681
227
246
Years
8787
8775
4312
4319
1602
1614
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
10
LDL-C
TG
hsCRP
4%
0
Percentage change
from baseline (%)
HDL-C
P<0.001*
-10
17%
-20
P<0.001
-30
37%
-40
-50
P<0.001
50%
P<0.001
-60
*P-value at study completion (48 months) = 0.34
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER - Laboratory Safety Data
Laboratory Values, N (%)
Serum creatinine‡
ALT > 3 x ULN#
Glycosuria†
Placebo
Rosuvastatin
[n=8901]
[n=8901]
10 (0.10)
17 (0.20)
32 (0.40)
Laboratory Values, median values (IQR)
GFR*, (mL/min/1.73m2)
66.6 (58.8-76.2)
% HbA1c**
5.8 (5.6-6.1)
Fasting plasma glucose** (mmol/L) 5.4 (5.0-5.9)
P value
16 (0.20) 0.24
23 (0.30) 0.34
36 (0.50) 0.64
66.8 (59.1-76.5) 0.02
5.9 (5.7-6.1) 0.001
5.4 (5.1-5.9)0.12
‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months
GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c; IQR = interquartile range
Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.
JUPITER: Conclusions – Efficacy I
Among apparently healthy men and women with elevated
hsCRP 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 not
currently qualify for statin therapy, rosuvastatin significantly
reduced 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 reduced
by 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 those
allocated to rosuvastatin 20 mg as compared to placebo
in a setting where half of the treated patients achieved
levels of LDL< 55 mg/dL (and 25 percent had LDL < 44
mg/dL).
show no increase in myopathy, cancer, hepatic
disorders, renal disorders, or hemorrhagic stroke with
treatment duration of up to 5 years.
show no increase in systematically monitored glucose or
glucosuria during follow-up, but small increases in
HbA1c and physician reported diabetes similar to that
seen 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 investigators
worldwide for their personal time, effort, and commitment
to the JUPITER trial.
www.brighamandwomens.org/jupitertrial
Adapted from Ridker et al. NEJM 2008.
JUPITER: Implications for Primary Prevention
A simple evidence based approach to statin therapy
for primary prevention.
Among men and women age 50 or over :
If diabetic, treat
If LDLC > 160 mg/dL, treat
If hsCRP > 2 mg/L, treat
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
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.