1. A Randomized Trial of Rosuvastatin in the Prevention
JUPITER
ACC March 29, 2009
A Randomized Trial of Rosuvastatin in the Prevention
of Venous Thromboembolism:
The JUPITER Trial
Robert Glynn*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,
Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,
Alberto Lorenzatti*, Jean MacFadyen, Børge Nordestgaard*,
James Shepherd*, James Willerson, and Paul Ridker*
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.

2. Presenter Disclosure Information
Robert J Glynn, PhD, ScD; Brigham & Women’s Hospital, Boston, MA
The following relationship exists related to this presentation:
Research Grant AstraZeneca Significant Level
The Brigham & Women’s Hospital holds patents related to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Dade-Bering and AstraZeneca

3. JUPITER Timeline JUPITER ACC March 29, 2009
First randomization: March 14, 2003
Last randomization: December 15, 2006
Termination for efficacy: March 30, 2008
Last patient visit: August 20, 2008
Trial results:
Primary end point: November 9, 2008
Pre-specified VTE end point: March 29, 2009
hsCRP and LDL reductions and end points: March 30, 2009

4. Why Pre-specify Incident Venous Thromboembolism?
JUPITER
Why Pre-specify Incident Venous Thromboembolism?
Venous and arterial thrombosis are common, serious, age-related events that often co-occur and share some risk factors
Controversies persist regarding the nature and extent of their shared pathways and whether treatments of demonstrated efficacy for one condition have consistent benefits for the primary or secondary prevention of the other
Benefits of statins might accrue not only through effects on lipids but also through influence on thrombosis and inflammation. Specifically, statins downregulate the blood coagulation cascade through decreased tissue factor expression, which leads to reduced thrombin formation*
*Undas, Brummel-Ziedins, Mann. ATVB 2005;25:

5. Observational studies of statins & VTE
1st Author
Publication
Study
Adj. RR
95% CI
Grady
Ann Intern Med 2000
Heart & E/P Replacement
0.5
Ray
Arch Int Med 2001
Ontario residents 65+ yrs
0.8
Yang
Br J Clin Pharm 2002
UK database f-up
Case-control
1.1
Doggen
J Thromb Haemost 2004
Washington HMO
0.6
Lacut
Fund Clin Pharm 2004
France, case-control
0.4
Smeeth
Br J Cl Pharm 2008
1.0
Ramcharan
J Thromb Haemost 2009
Holland, case-control
Sørensen
Denmark, case-control
0.7
Ischemic stroke top vs bottom quartile: PHS, Framingham, CHS, Honolulu
Gussekloo: fatal stroke for CRP of 5-10 mg/L vs those with <5 mg/L
NHANES: Risk of stroke for those in the highest tertile of CRP versus those with undetectable CRP levels (>0.55 mg/dL vs  0.21 mg/dL).
WHS: Risk of ischemic stroke for those in the highest versus the lowest tertile.
ARIC: Risk of ischemic stroke for those in the CDC/AHA defined high risk category (CRP > 3.0 mg/L) versus those in the CDC/AHA low risk category (CRP < 1.0 mg/L).
Rotterdam study: top vs bottom quartile for total stroke (similar results for ischemic and hemorrhagic stroke).

6. JUPITER
Why Pre-specify Incident Venous Thromboembolism?
Observational Evidence: In non-randomized cohort and case-control studies and registries, statins have often, but not always, been associated with reduced risk of VTE.
These studies cannot exclude indication bias. Many included prevalent statin users, and poor health affects the decision to initiate and persist in therapy. They also did not consider the possibility that the reduction in VTE events is secondary to a statin-induced reduction in arterial hospitalizations.
Similar evidence from observational studies indicated benefits for statins on mortality in heart failure, but trials (CORONA, GISSI) refuted this hypothesis
Clear need for a prospective randomized trial

7. JUPITER Inclusion and Exclusion Criteria, Study Flow Men > 50 years
Ridker et al NEJM 2008
89,890 Screened
89,863 Screened
Reason for Exclusion (%)
LDL-C > 130 mg/dL
hsCRP < 2.0 mg/L
Withdrew Consent
Diabetes
Hypothyroid <1
Liver Disease <1
TG > 500 mg/dL <1
Age out of range <1
Current Use of HRT <1
Cancer <1
Poor Compliance/Other
Reason for Exclusion (%)
LDL > 130 mg/dL
hsCRP < 2.0 mg/L
Withdrew Consent
Diabetes
Hypothyroid <1
Liver Disease <1
TG > 500 mg/dL <1
Age out of range <1
Current Use of HRT <1
Cancer <1
Poor Compliance/Other 3
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 to
Rosuvastatin 20 mg
8,901 Assigned to
Rosuvastatin 20 mg
8,901 Assigned to
Placebo
8,901 Assigned to
Placebo
8,600 Completed Study
120 Lost to follow-up
8,857 Completed Study
44 Lost to follow-up
8,864 Completed Study
37 Lost to follow-up
8,600 Completed Study
120 Lost to follow-up
8,901 Included in Efficacy
and Safety Analyses
8,901 Included in Efficacy
and Safety Analyses
8,901 Included in Efficacy
and Safety Analyses
8,901 Included in Efficacy
and Safety Analyses

8. JUPITER
Symptomatic VTE
Symptomatic venous thromboembolism was a pre-specified secondary end point
Upon identification of a new VTE case, site investigators indicated the source of confirmation (venous ultrasonogram or venogram for DVT; angiogram, CT scan, or ventilation-perfusion scan for PE)
Initiation and indication for anticoagulation therapy also noted
Unprovoked VTE: no trauma, hospitalization, or surgery within 3 months before diagnosis, and no malignancy diagnosed before or up to 3 months after the VTE
Unprovoked and provoked VTE, pulmonary embolism and deep vein thrombosis alone were tertiary end points.

9. JUPITER
VTE analysis
Primary efficacy analyses counted all events diagnosed by March 30, 2008 according to the intention to treat principle
Safety analyses also included additional events before the closeout visit and unblinding
Competing risks analyses compared effects of rosuvastatin on first VTE versus first primary cardiovascular event
Estimates of net clinical benefits considered the impact on the number needed to treat (NNT) of inclusion of VTE in a composite with the primary cardiovascular event, and also with total mortality

10. Baseline Clinical Characteristics
JUPITER
Baseline Clinical Characteristics
Glynn et al NEJM 2009
Rosuvastatin Placebo
(N = 8901) (n = 8901)
Age, years (IQR) (60-71) (60-71)
Female, N (%) 3,426 (38) 3,375 (38)
Ethnicity, N (%)
Caucasian 6,358 (71) 6,325 (71)
Black 1,100 (12) 1,124 (13)
Hispanic 1,121 (13) 1,140 (13)
Body mass index ≥ 30 kg/m2, N (%) 3,338 (38) 3,336 (38)
Waist circumference (cm)
≥100 (men), ≥95 (women), N (%) 4,503 (51) 4,546 (52)
Smoker, N (%) 1,400 (16) 1,420 (16)
Metabolic Syndrome, N (%) 3,652 (41) 3,723 (42)
hsCRP≥5 mg/L, N (%) 3,618 (41) 3,726 (42)
LDL>100 mg/dL, N (%) 5,781 (65) 5,747 (65)
HDL<40 (men), <50 (women), N (%) 2,833 (32) 2,856 (32)
All values are median (interquartile range) or N (%)

11. Total Venous Thromboembolism
JUPITER
Total Venous Thromboembolism
Glynn et al NEJM 2009
HR 0.57, 95%CI
P= 0.007
0.025
0.020
Placebo 60 / 8901
0.015
- 43 %
Cumulative Incidence
0.010
Rosuvastatin 34 / 8901
0.005
0.000 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,648
8,447
6,575
3,927
1,986
1,376
1,003
548
161
Placebo
8,901
8,652
8,417
6,574
3,943
2,012
1,381
993
556
182

12. Occurrence of VTE: Primary efficacy analysis
JUPITER
Occurrence of VTE: Primary efficacy analysis
Glynn et al NEJM 2009
All cases identified by March 30, 2008
Endpoint Rosuvastatin Placebo HR 95%CI P
Any VTE
Unprovoked VTE
Provoked VTE
Pulmonary embolism
DVT only

13. Venous Thromboembolism – Unprovoked vs Provoked
JUPITER
Venous Thromboembolism – Unprovoked vs Provoked
Unprovoked Venous Thromboembolism
Provoked Venous Thromboembolism
HR 0.61, 95% CI
P= 0.09
HR 0.52, 95% CI
P= 0.03
0.020
0.020
0.015
0.015
Cumulative Incidence
Cumulative Incidence
0.010
Placebo
0.010
Placebo
0.005
0.005
Rosuvastatin
Rosuvastatin
0.000
0.000 1 2 3 4 1 2 3 4
Follow-up (years)
Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazard
(hemmorrhagic events: rosuvastatin 258, placebo 275, P=0.45)

14. Total Venous Thromboembolism – Subgroup Analysis I
JUPITER
Total Venous Thromboembolism – Subgroup Analysis I
Incidence Rates N
Events
(Placebo)
Men
11,001 66
0.37
Women
6,801 28
0.24
Age yr
3,689 17
0.24
Age yr
8,418 37
0.30
Age
>
70 yr
5,695 40
0.41
Caucasian
12,683 86
0.39
Black, Hispanic, Other
5,117 8
0.11
BMI <25.0 kg/m 2
4,073 15
0.20
BMI kg/m 2
7,009 32
0.30
BMI
>
30.0 kg/m 2
6,674 46
0.40
Waist Circumference(cm)
Men<100/Women<95
8,586 34
0.21
Men
>
100/Women
> 95
9,049 57
0.41
Metabolic Syndrome
7,373 32
0.29
No Metabolic Syndrome
10,296 60
0.34
Smoker
2,820 13
0.22
Non-Smoker
14,975 81
0.34
All Participants
17,802 94
0.32
0.20
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior

15. Total Venous Thromboembolism – Subgroup Analysis II
JUPITER
Total Venous Thromboembolism – Subgroup Analysis II
# of
Incidence Rates N
Events
(Placebo)
LDLC
<
100 mg/dL
6,269 33
0.30
LDLC > 100 mg/dL
11,528 61
0.33
HDLC (mg/dL)
Men<40, Women<50
5,689 26
0.30
Men
>
40, Women
> 50
12,112 68
0.33
Triglycerides<150 mg/dL
11,965 66
0.32
Triglycerides
>
150 mg/dL
5,836 28
0.32
hsCRP<5 mg/L
10,458 49
0.27
hsCRP
>
5 mg/L
7,344 45
0.39
Time of event
<
24 Months
17,802 70
0.28
Time of event>24 Months
7,870 24
0.53
All Participants
17,802 94
0.32
0.20
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior

16. Occurrence of VTE: Safety analysis
JUPITER
Occurrence of VTE: Safety analysis
Glynn et al NEJM 2009
All cases identified by final closeout visit and unblinding
Endpoint Rosuvastatin Placebo HR 95%CI P
Any VTE
Unprovoked VTE
Provoked VTE
Pulmonary embolism
DVT only

17. Occurrence of VTE, CVD, and death
JUPITER
Occurrence of VTE, CVD, and death
Glynn et al NEJM 2009
Endpoint Rosuvastatin Placebo HR 95%CI P
VTE without prior CVD
CVD without prior VTE <0.001
VTE after CVD
First CVD or VTE <0.001
Death after VTE
First CVD, VTE or death <0.001

18. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
HR 0.56, 95% CI
P <
Placebo 251 / 8901
0.08
Number Needed to Treat (NNT5) = 25
0.06
109 Fewer Events
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00 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

19. JUPITER VTE + Primary Trial Endpoint
HR 0.56, 95% CI
P <
Placebo 305 / 8901
0.10
Number Needed to Treat (NNT5) = 21
0.08
132 Fewer Events
0.06
Cumulative Incidence
0.04
Rosuvastatin 173 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,624
8,400
6,525
3,880
1,951
1,348
979
536
157
Placebo
8,901
8,612
8,338
6,486
3,854
1,949
1,320
945
525
170

20. JUPITER VTE + Primary Trial Endpoint + Total Mortality
HR 0.66, 95% CI
P <
Placebo 483 / 8901
0.14
0.12
Number Needed to Treat (NNT5) = 18
0.10
163 Fewer Events
0.08
Cumulative Incidence
0.06
0.04
Rosuvastatin 320 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,624
8,400
6,525
3,880
1,951
1,348
979
536
157
Placebo
8,901
8,612
8,338
6,486
3,854
1,949
1,320
945
525
170

21. JUPITER
VTE in JUPITER: Conclusions
VTE is a serious event that occurred about as often as MI and stroke in the JUPITER study
Rosuvastatin was associated with a significant 43 percent reduction in risk of VTE with no increase in bleeding.
This benefit was comparable in magnitude and independent of the effect on arterial events
Widening the treatment target to include prevention of VTE and death in addition to arterial thrombosis increases the estimated benefit of statin use