“An Examination of the JUPITER Trial”
Moderator
Kevin Winfield, MD
Medical Director
Clear Lake Lipid Center
Houston, TX
Disclosure
• Disclosure of Unlabeled Use and Investigational
Product Discussions:
Dr. Winfield has indicated that his presentation will
not include the discussion of unlabeled uses of
commercial products or products that have not yet
been approved by the FDA for use in the United
States for any purpose.
• Disclosure of Affiliations and Significant
Relationships:
Dr. Winfield has received honoraria related to
speakers’ bureau activities from Novartis,
AstraZeneca, and Abbott Laboratories.
“An Examination of the JUPITER Trial”
Paul Ridker, MD
Director
Center for Cardiovascular
Disease Prevention
Division of Preventive Medicine
Brigham and Women’s Hospital
Boston, MA
Disclosure
• Disclosure of Affiliations and Significant Relationships:
Dr. Ridker has received honoraria related to consulting activities
from Schering-Plough, Sanofi-Aventis, AstraZeneca, Isis, Dade,
Merck & Co., Novartis, Vascular Biogenics.
He has also received grant support from research activities from
National Heart, Lung, and Blood Institute, National Cancer
Institute, American Heart Association, Doris Duke Charitable
Foundation, Leducq Foundation, Donald W. Reynolds
Foundation, James and Polly Annenberg La Vea Charitable
Trusts, AstraZeneca, Novartis, Pharmacia, Roche, SanofiAventis, Abbott Laboratories, Amgen.
Equity: Co-inventor on patients held by Brigham and Women’s
Hospital.
JUPITER
AHA November 9, 2008
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
An Investigator Initiated Trial Funded by AstraZeneca, USA
* These authors have received research grant support and/or consultation fees from one or more
statin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by the
Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in
cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.
Fully Adjusted Relative Risk
hsCRP Adds Prognostic Information Beyond Traditional
Risk Factors in All Major Cohorts Evaluated
3
3
3
3
3
3
3
2
2
2
2
2
2
2
1
1
1
1
1
1
1
0
0
0
0
0
0
0
WHS 2000
PHS 1997
UK 2000
MONICA 2004
ARIC 2004
NHS 2004
Iceland 2004
3
3
3
3
3
3
3
2
2
2
2
2
2
2
1
1
1
1
1
1
1
0
0
0
0
0
0
0
HPFUS 2004
EPIC-N 2005
Strong 2005
< 1 mg/L
Kuopio 2005
CHS 2005
1 to 3 mg/L
PIMA 2005
> 3 mg/L
FHS 2006
What are the environmental and genetic influences on CRP?
Relative Risk of Future CV Events
8
7
6
5
4
3
2
1
0
<0.5
0.5-1.0
“low risk”
1.0-2.0
2.0-3.0
3.0-4.0
4.0-5.0
“moderate risk”
hsCRP (mg/L)
Ridker et al Circulation 2004;109:1955-59
5.0-10.0
10.0-20.0
“high risk”
>20
Inflammation, Statin Therapy, and
hsCRP: Initial Observations
P Trend = 0.005
-21.6% (P=0.004)
0.25
Median hs-CRP (mg/dL)
Relative Risk
3
2
1
0
0.24
Placebo
0.23
0.22
0.21
Pravastatin
0.20
0.19
0.18
Pravastatin Placebo Pravastatin Placebo
Baseline
5 Years
Inflammation Absent Inflammation Present
Circulation. 1998;98:839–844.
Circulation. 1999;100:230-235.
0.10
0.10
hsCRP>2 mg/L
0.06
0.04
0.08
0.06
0.04
0.08
LDLC>70 mg/dL
hsCRP<2 mg/L
0.00
0.02
0.02
LDLC<70 mg/dL
0.00
Recurrent Myocardial Infarction or Coronary Death (percent)
Cumulative Rate of
Clinical Relevance of Achieved LDL and Achieved hsCRP
After Treatment with Statin Therapy
0.0
0.5
1.0
Ridker et al NEJM 2005;352:20-28.
1.5
2.0
2.5
0.0
0.5
Follow-Up (years)
1.0
1.5
2.0
2.5
0.10
Clinical Relevance of Achieved LDL and Achieved hsCRP
After Treatment with Statin Therapy
0.08
LDL > 70 mg/dL, CRP > 2 mg/L
0.06
LDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/L
0.00
0.02
0.04
LDL < 70 mg/dL, CRP < 2 mg/L
0.0
0.5
1.0
1.5
2.0
Follow-Up (Years)
2.5
Ridker et al NEJM 2005;352:20-28.
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).
*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.
Ridker et al, New Engl J Med 2001;344:1959-65
JUPITER
Primary Objectives
Ridker et al NEJM 2008
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.
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)
MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
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
Ridker et al, Circulation 2003;108:2292-2297.
JUPITER
Baseline Clinical Characteristics
Age, years (IQR)
Female, N (%)
Ethnicity, N (%)
Caucasian
Black
Hispanic
Blood pressure, mm (IQR)
Systolic
Diastolic
Smoker, N (%)
Family History, N (%)
Metabolic Syndrome, N (%)
Aspirin Use, N (%)
Rosuvastatin
(N = 8901)
Placebo
(n = 8901)
66.0 (60.0-71.0)
3,426 (38.5)
66.0 (60.0-71.0)
3,375 (37.9)
6,358 (71.4)
1,100 (12.4)
1,121 (12.6)
6,325 (71.1)
1,124 (12.6)
1,140 (12.8)
134
80
1,400
997
3,652
1,481
134
80
1,420
1,048
3,723
1,477
(124-145)
(75-87)
(15.7)
(11.2)
(41.0)
(16.6)
All values are median (interquartile range) or N (%)
(124-145)
(75-87)
(16.0)
(11.8)
(41.8)
(16.6)
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).
[ Mean LDL = 104 mg/dL ]
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
Pravastatin
40 mg
Lovastatin
10-40 mg
JUPITER Trial Study Group, Am J Cardiol 2007
JUPITER
140
60
120
50
100
80
60
40
20
LDL decrease 50 percent at 12 months
HDL (mg/dL)
LDL (mg/dL)
Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP
0
20
10
HDL increase 4 percent at 12 months
140
120
4
3
2
hsCRP decrease 37 percent at 12 months
0
TG (mg/dL)
hsCRP (mg/L)
30
0
5
1
40
100
80
60
40
20
TG decrease 17 percent at 12 months
0
0
12
24
Months
36
48
0
12
24
Months
36
48
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
0.06
0.04
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
0.08
Placebo 251 / 8901
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
0.08
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Placebo 251 / 8901
0.04
0.06
- 44 %
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
Number Needed to Treat (NNT5) = 25
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
JUPITER
Myocardial Infarction, Stroke, Cardiovascular Death
Placebo (N = 157)
0.02
0.03
- 47 %
Rosuvastatin (N = 83)
0.00
0.01
Cumulative Incidence
0.04
0.05
HR 0.53, 95%CI 0.40-0.69
P < 0.00001
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin 8,901
Placebo
8,901
3
8,643
8,633
8,437
8,381
6,571
6,542
3,921
3,918
1,979
1,992
1,370
1,365
998
979
551
550
159
181
JUPITER
Arterial Revascularization / Unstable Angina
0.06
HR 0.53, 95%CI 0.40-0.70
P < 0.00001
0.04
0.02
0.03
- 47 %
Rosuvastatin (N = 76)
0.00
0.01
Cumulative Incidence
0.05
Placebo (N = 143)
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,640
8,641
8,426
8,390
6,550
6,542
3,905
3,895
1,966
1,977
1,359
1,346
989
963
547
538
158
176
JUPITER
Individual Components of the Primary Endpoint
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
JUPITER
Primary Endpoint – 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
1.0
2.0
Rosuvastatin Inferior
4.0
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
2.0
Rosuvastatin Inferior
4.0
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
(91-107)
(5.7-6.1)
(0.5)
(3.0)
*Occurred after trial completion, trauma induced.
**Physician reported
(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
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
1.0
2
Statin Worse
4
JUPITER
Secondary Endpoint – All Cause Mortality
HR 0.80, 95%CI 0.67-0.97
P= 0.02
0.06
Placebo 247 / 8901
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
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
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.
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.
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
JUPITER
Achieved LDLC, Achieved hsCRP, or Both?
Is the benefit observed in the JUPITER
trial associated with achieving
a low level of LDLC,
a low level of hsCRP
or both?
Do we need to achieve the “dual targets”
of low LDLC and low hsCRP in order to
maximize the benefit of statin therapy?
JUPITER
Ridker et al NEJM 2008
Predicted Benefit Based on LDL Reduction vs Observed Benefit
55
Proportional reduction in
vascular event rate (95% CI)
50
45
40
35
30
CTT
25
JUPITER PREDICTED
TNT
20
15
PROVE-IT
A-to-Z
IDEAL
10
5
0
0
0.5
Mean LDL cholesterol difference
between treatment groups (mmol/l)
1
JUPITER
Ridker et al NEJM 2008
Predicted Benefit Based on LDL Reduction vs Observed Benefit
55
50
Proportional reduction in
vascular event rate (95% CI)
JUPITER OBSERVED
45
40
35
30
CTT
25
JUPITER PREDICTED
TNT
20
15
PROVE-IT
A-to-Z
IDEAL
10
5
0
0
0.5
Mean LDL cholesterol difference
between treatment groups (mmol/l)
1
Clinical Importance of Achieving LDL-C < 70 mg/dL and hsCRP < 2 mg/L
Following Initiation of Statin Therapy
LDL<70, hsCRP>2 LDL>70, hsCRP<2
LDL>70, hsCRP>2
LDL<70, hsCRP<2
8
6
6
4
4
2
0
8
2
10
10
0
180
360
540
720
Follow-up (days)
900
0
0
120
240
360
480
Follow-up (days)
PROVE IT – TIMI 22
A to Z
NEJM 2005;352:20-28.
Circulation 2006;114:281-8
600
PROVE IT, A to Z, AFCAPS/TexCAPS, REVERSAL
Dose Correct Use of Statin Therapy Require
Evaluation for both LDLC and hsCRP?
1. LDL-C is a strong,
independent predictor
of future CV events
1. hsCRP is a strong,
independent predictor
of future CV events
2. Statins Lower LDL-C
2. Statins Lower hsCRP
3. The level of LDL-C
achieved after starting
statin therapy predicts
recurrent event rates (ie
“lower is better”)
3. The level of hsCRP
achieved after starting
statin therapy predicts
recurrent event rates (ie
“lower is better”)
Dual Goals for Statin Therapy :
LDL-C < 70 mg/dL and hsCRP < 2 mg/L
JUPITER
Ridker et al NEJM 2008
Implications for Primary Prevention
A simple evidence based approach to statin therapy
for primary prevention.
Among men over 45 and post-menopausal
women:
If diabetic or family history, treat
If LDLC > 160 mg/dL, treat
If hsCRP > 3 mg/L, treat
JUPITER
Public Health Implications
Ridker et al NEJM 2008
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
“An Examination of the JUPITER Trial”
Christie Ballantyne, MD
Chief, Section of Atherosclerosis and Vascular Medicine
Director, Center for Cardiovascular Disease Prevention
Co-Director, Lipid Metabolism and Atherosclerosis Clinic
Methodist DeBakey Heart Center
Baylor College of Medicine
Houston, TX
Disclosure
• Disclosure of Unlabeled Use and Investigational Product
Discussions:
Dr. Ballantyne has indicated that his presentation will not include
the discussion of unlabeled uses of commercial products or
products that have not yet been approved by the FDA for use in
the United States for any purpose.
• Disclosure of Affiliations and Significant Relationships:
Dr. Ballantyne has received honoraria related to speakers’
bureau activities from AstraZenece, Merck, Pfizer, Reliant, and
Schering-Plough. He has also received grant support related to
research activities from Abbott, ActivBiotics, Gene Logic,
GlaxoSmithKline, Integrated Theraputics, Merck, Pfizer,
Schering-Plough, Sanofi-Synthelabo, and Takeda. Dr.
Ballantyne has also received honoraria related to consulting
activities from Abbott, AstraZeneca, Atherogenics, Merck, Merck
Schering-Plough, Novartis, Pfizer, Reliant, Schering-Plough,
Sanfi-Synthelabo, Takeda, and GlaxoSmithKline.