1
An Examination of the JUPITER Trial
Moderator Kevin Winfield, MD Medical Director
Clear Lake Lipid Center Houston, TX
2
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.

3
An Examination of the JUPITER Trial
Paul Ridker, MD Director Center for
Cardiovascular Disease Prevention Division of
Preventive Medicine Brigham and Womens Hospital
Boston, MA
4
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, Sanofi-Aventis, Abbott
  Laboratories, Amgen.
• Equity Co-inventor on patients held by Brigham
  and Womens Hospital.

5
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 Womens Hospital
that relate to the use of inflammatory biomarkers
in cardiovascular disease that have been
licensed to Dade-Behring and AstraZeneca.
6
hsCRP Adds Prognostic Information Beyond
Traditional Risk Factors in All Major Cohorts
Evaluated
lt 1 mg/L
1 to 3 mg/L
gt 3 mg/L
7
What are the environmental and genetic influences
on CRP?
Relative Risk of Future CV Events
low risk
moderate risk
high risk
hsCRP (mg/L)
Ridker et al Circulation 20041091955-59
8
Inflammation, Statin Therapy, and hsCRP Initial
Observations
P Trend 0.005
-21.6 (P0.004)
3
0.25
0.24
Placebo
2
0.23
0.22
Relative Risk
Median hs-CRP (mg/dL)
0.21
1
Pravastatin
0.20
0.19
0
0.18
Pravastatin
Placebo
Pravastatin
Placebo
Baseline
5 Years
Inflammation Absent
Inflammation Present
Circulation. 1999100230-235.
Circulation. 199898839844.
9
Clinical Relevance of Achieved LDL and Achieved
hsCRP After Treatment with Statin Therapy
0.10
0.10
hsCRPgt2 mg/L
LDLCgt70 mg/dL
0.08
0.08
0.06
0.06
hsCRPlt2 mg/L
0.04
0.04
LDLClt70 mg/dL
0.02
0.02
0.00
0.00
0.0
0.5
1.0
1.5
2.0
2.5
0.0
0.5
1.0
1.5
2.0
2.5
Follow-Up (years)
Ridker et al NEJM 200535220-28.
10
Clinical Relevance of Achieved LDL and Achieved
hsCRP After Treatment with Statin Therapy
LDL gt 70 mg/dL, CRP gt 2 mg/L
LDL gt 70 mg/dL, CRP lt 2 mg/L
LDL lt 70 mg/dL, CRP gt 2 mg/L
LDL lt 70 mg/dL, CRP lt 2 mg/L
Ridker et al NEJM 200535220-28.
11
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 (N1,448, 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
(N1,428, HR 0.6, 95 CI 0.34-0.98).
Ridker et al N Engl J Med 20013441959-65
12
JUPITER Why Consider Statins for Low LDL, high
hsCRP Patients?
AFCAPS/TexCAPS Low LDL Subgroups
Low LDL, Low hsCRP Low LDL, High hsCRP
Low LDL, Low hsCRP Low LDL, High hsCRP
A
B
2.0
0.5
1.0
2.0
0.5
1.0
RR
Statin Effective
Statin Not Effective
Statin Effective
Statin Not Effective
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 20013441959-65
13
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 lt 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 gt 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.
14
JUPITER Trial Design
JUPITERMulti-National Randomized Double Blind
Placebo Controlled Trial of Rosuvastatin in the
Prevention of Cardiovascular EventsAmong
Individuals With Low LDL and Elevated hsCRP
MI Stroke Unstable Angina CVD Death CABG/PTCA
Rosuvastatin 20 mg (N8901)
No Prior CVD or DM Men gt50, Women gt60 LDL lt130
mg/dL hsCRP gt2 mg/L
Placebo (N8901)
4-week run-in
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 20031082292-2297.
15
JUPITER Baseline Clinical Characteristics
Rosuvastatin Placebo (N
8901) (n 8901) Age, years (IQR) 66.0 (60.0-
71.0) 66.0 (60.0-71.0) Female, N () 3,426
(38.5) 3,375 (37.9) Ethnicity, N ()
Caucasian 6,358 (71.4) 6,325 (71.1)
Black 1,100 (12.4) 1,124 (12.6)
Hispanic 1,121 (12.6) 1,140 (12.8) Blood
pressure, mm (IQR) Systolic 134 (124-145) 1
34 (124-145) Diastolic 80 (75-87) 80 (75-87
) Smoker, N () 1,400 (15.7) 1,420 (16.0) Fami
ly History, N () 997 (11.2) 1,048 (11.8) Metab
olic Syndrome, N () 3,652 (41.0) 3,723 (41.8) A
spirin Use, N () 1,481 (16.6) 1,477 (16.6) Al
l values are median (interquartile range) or N
()
16
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
17
Comparison of the JUPITER trial population to
previous statin trials of primary prevention
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) gt 2
NA NA Intervention Rosuvastatin Prav
astatin Lovastatin 20 mg 40 mg 10-40
mg
JUPITER Trial Study Group, Am J Cardiol 2007
18
JUPITER Effects of rosuvastatin 20 mg on LDL,
HDL, TG, and hsCRP
LDL (mg/dL)
HDL (mg/dL)
LDL decrease 50 percent at 12 months
HDL increase 4 percent at 12 months
hsCRP (mg/L)
TG (mg/dL)
hsCRP decrease 37 percent at 12 months
TG decrease 17 percent at 12 months
0
12
24
36
48
Months
Months
19
JUPITER Primary Trial Endpoint MI, Stroke,
UA/Revascularization, CV Death
Placebo 251 / 8901
0.08
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00
0
1
2
3
4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174
20
JUPITER Primary Trial Endpoint MI, Stroke,
UA/Revascularization, CV Death
HR 0.56, 95 CI 0.46-0.69 P lt 0.00001
Placebo 251 / 8901
0.08
Number Needed to Treat (NNT5) 25
- 44
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00
0
1
2
3
4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174
21
JUPITER Myocardial Infarction, Stroke,
Cardiovascular Death
HR 0.53, 95CI 0.40-0.69 P lt 0.00001
0.05
Placebo (N 157)
0.04
- 47
0.03
Cumulative Incidence
0.02
Rosuvastatin (N 83)
0.01
0.00
0
1
2
3
4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,643
8,437
6,571
3,921
1,979
1,370
998
551
159
Placebo
8,901
8,633
8,381
6,542
3,918
1,992
1,365
979
550
181
22
JUPITER Arterial Revascularization / Unstable
Angina
HR 0.53, 95CI 0.40-0.70 P lt 0.00001
0.06
Placebo (N 143)
0.05
0.04
- 47
Cumulative Incidence
0.03
0.02
Rosuvastatin (N 76)
0.01
0.00
0
1
2
3
4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,640
8,426
6,550
3,905
1,966
1,359
989
547
158
Placebo
8,901
8,641
8,390
6,542
3,895
1,977
1,346
963
538
176
23
JUPITER Individual Components of the Primary
Endpoint
Endpoint Rosuvastatin Placebo HR 95CI
P Primary Endpoint 142 251 0.56
0.46-0.69 lt0.00001 Non-fatal MI 22 62 0.35
0.22-0.58 lt0.00001 Any MI 31 68 0.46
0.30-0.70 lt0.0002 Non-fatal Stroke 30 58 0.5
2 0.33-0.80 0.003 Any Stroke 33 64 0.52
0.34-0.79 0.002 Revascularization or
Unstable Angina 76 143 0.53 0.40-0.70 lt0.00001
MI, Stroke, CV Death 83 157 0.53
0.40-0.69 lt0.00001
Nonfatal MI, nonfatal stroke,
revascularization, unstable angina, CV death
24
JUPITER Primary Endpoint Subgroup Analysis I
N
P for Interaction
Men
11,001
0.80
Women
6,801
Age
lt
65
8,541
0.32
Age gt 65
9,261
Smoker
2,820
0.63
Non-Smoker
14,975
Caucasian
12,683
0.57
Non-Caucasian
5,117
USA/Canada
6,041
0.51
Rest of World
11,761
Hypertension
10,208
0.53
No Hypertension
7,586
All Participants
17,802
0.25
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior
25
JUPITER Primary Endpoint Subgroup Analysis II
N
P for Interaction
Family HX of CHD
2,045
0.07
No Family HX of CHD
15,684
2
4,073
0.70
BMI lt 25 kg/m
7,009
BMI 25-29.9 kg/m
2
6,675
BMI
gt
30 kg/m
2
Metabolic Syndrome
7,375
0.14
No Metabolic Syndrome
10,296
Framingham Risk
lt
10
8,882
0.99
Framingham Risk gt 10
8,895
hsCRP gt 2 mg/L Only
6,375
hsCRP gt 2 mg/L Only
6,375
All Participants
17,802
0.25
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior
26
JUPITER Adverse Events and Measured Safety
Parameters
Event Rosuvastatin Placebo P Any
SAE 1,352 (15.2) 1,337 (15.5) 0.60 Muscle
weakness 1,421 (16.0) 1,375 (15.4) 0.34 Myopath
y 10 (0.1) 9 (0.1) 0.82 Rhabdomyol
ysis 1 (0.01) 0 (0.0) -- Incident
Cancer 298 (3.4) 314 (3.5) 0.51 Cancer
Deaths 35 (0.4) 58 (0.7) 0.02 Hemor
rhagic 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) 0.02 ALT gt
3xULN 23 (0.3) 17 (0.2) 0.34 Fastin
g glucose (24 mth) 98 (91-107)
98 (90-106) 0.12 HbA1c ( at 24 mth) 5.9
(5.7-6.1) 5.8 (5.6-6.1) 0.01 Glucosuria (12
mth) 36 (0.5) 32 (0.4) 0.64 Incident
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
27
JUPITER Statins and the Development of Diabetes
HR (95 CI)
WOSCOPS Pravastatin
0.70 (0.500.98)
1.34 (1.061.68)
PROSPER Pravastatin
1.20 (0.981.35)
HPS Simvastatin
1.20 (0.911.44)
ASCOT-LLA Atorvastatin
PROVE-IT Atorvastatin VS Pravastatin
1.11 (0.671.83)
JUPITER Rosuvastatin
1.25 (1.051.54)
Statin Better
Statin Worse
28
JUPITER Secondary Endpoint All Cause Mortality
HR 0.80, 95CI 0.67-0.97 P 0.02
Placebo 247 / 8901
0.06
- 20
0.05
0.04
Cumulative Incidence
0.03
Rosuvastatin 198 / 8901
0.02
0.01
0.00
0
1
2
3
4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,847
8,787
6,999
4,312
2,268
1,602
1,192
683
227
Placebo
8,901
8,852
8,775
6,987
4,319
2,295
1,614
1,196
684
246
29
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.
30
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.
31
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 LDLlt 55 mg/dL (and 25
percent had LDL lt 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
32
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?
33
JUPITER Predicted Benefit Based on LDL Reduction
vs Observed Benefit
Ridker et al NEJM 2008
Proportional reduction in vascular event rate
(95 CI)
CTT
JUPITER PREDICTED
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol differencebetween treatment
groups (mmol/l)
34
JUPITER Predicted Benefit Based on LDL Reduction
vs Observed Benefit
Ridker et al NEJM 2008
JUPITER OBSERVED
Proportional reduction in vascular event rate
(95 CI)
CTT
JUPITER PREDICTED
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol differencebetween treatment
groups (mmol/l)
35
Clinical Importance of Achieving LDL-C lt 70 mg/dL
and hsCRP lt 2 mg/L Following Initiation of Statin
Therapy
LDLgt70, hsCRPgt2
LDLlt70, hsCRPgt2
LDLgt70, hsCRPlt2
LDLlt70, hsCRPlt2
Recurrent Myocardial Infarction or Death
(percent)
0
540
720
900
180
360
Follow-up (days)
Follow-up (days)
A to Z Circulation 2006114281-8
PROVE IT TIMI 22 NEJM 200535220-28.
36
PROVE IT, A to Z, AFCAPS/TexCAPS, REVERSALDose
Correct Use of Statin Therapy Require Evaluation
for both LDLC and hsCRP?

• 1. LDL-C is a strong, independent predictor of
  future CV events
• 2. Statins Lower LDL-C
• 3. The level of LDL-C achieved after starting
  statin therapy predicts recurrent event rates (ie
  lower is better)

1. hsCRP is a strong, independent predictor of
future CV events 2. Statins Lower hsCRP 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 lt 70 mg/dL
and hsCRP lt 2 mg/L
37
JUPITER Implications for Primary Prevention
Ridker et al NEJM 2008
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 gt 160
mg/dL, treat If hsCRP gt 3 mg/L, treat
38
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 gt1,000
investigators worldwide for their personal time,
effort, and commitment to the JUPITER trial.
www.brighamandwomens.org/jupitertrial
39
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
40
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.