Transcript Document

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.
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
JUPITER
ACC March 29, 2009
JUPITER Timeline
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
JUPITER
Why Pre-specify Incident Venous Thromboembolism?
Venous and arterial thrombosis are common, serious, agerelated 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;25:287-294
Observational studies of statins & VTE
1st Author
Publication
Study
Adj. RR
95% CI
Ann Intern Med 2000
Heart & E/P Replacement
0.5
0.2-0.9
Ray
Arch Int Med 2001
Ontario residents 65+ yrs
0.8
0.7-0.9
Yang
Br J Clin Pharm 2002
UK database f-up
Case-control
0.8
1.1
0.3-2.7
0.3-4.3
J Thromb Haemost 2004
Washington HMO
0.6
0.4-1.1
Fund Clin Pharm 2004
France, case-control
0.4
0.2-0.8
Br J Cl Pharm 2008
UK database f-up
1.0
0.9-1.2
Ramcharan
J Thromb Haemost 2009
Holland, case-control
0.5
0.4-0.6
Sørensen
J Thromb Haemost 2009
Denmark, case-control
0.7
0.6-0.9
Grady
Doggen
Lacut
Smeeth
JUPITER
Why Pre-specify Incident Venous Thromboembolism?
Observational Evidence: In non-randomized cohort and casecontrol 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
JUPITER
Ridker et al NEJM 2008
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
Randomized
17,802
Reason for
for Exclusion
Exclusion
Reason
LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor
8,901Assigned
Assigned to
8,901
to
Rosuvastatin
20
mg
Rosuvastatin 20 mg
8,901 Assigned
Assigned toto
8,901
Placebo
Placebo
8,600Completed
Completed Study
8,857
Study
120
Lost
to
follow-up
44 Lost to follow-up
8,864
Study
8,600 Completed
Completed Study
120Lost
Lost to
to follow-up
37
follow-up
8,901
8,901 Included in Efficacy
8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses
and
and Safety
Safety Analyses
Analyses
(%)
(%)
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 ventilationperfusion 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.
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
JUPITER
Baseline Clinical Characteristics
Age, years (IQR)
Female, N (%)
Ethnicity, N (%)
Caucasian
Black
Hispanic
Body mass index ≥ 30 kg/m2, N (%)
Waist circumference (cm)
≥100 (men), ≥95 (women), N (%)
Smoker, N (%)
Metabolic Syndrome, N (%)
hsCRP≥5 mg/L, N (%)
LDL>100 mg/dL, N (%)
HDL<40 (men), <50 (women), N (%)
Glynn et al NEJM 2009
Rosuvastatin
(N = 8901)
66 (60-71)
3,426 (38)
Placebo
(n = 8901)
66 (60-71)
3,375 (38)
6,358 (71)
1,100 (12)
1,121 (13)
3,338 (38)
6,325
1,124
1,140
3,336
4,503 (51)
1,400 (16)
3,652 (41)
3,618 (41)
5,781 (65)
2,833 (32)
4,546 (52)
1,420 (16)
3,723 (42)
3,726 (42)
5,747 (65)
2,856 (32)
All values are median (interquartile range) or N (%)
(71)
(13)
(13)
(38)
JUPITER
Total Venous Thromboembolism
Glynn et al NEJM 2009
0.015
Placebo 60 / 8901
0.005
0.010
- 43 %
Rosuvastatin 34 / 8901
0.000
Cumulative Incidence
0.020
0.025
HR 0.57, 95%CI 0.37-0.86
P= 0.007
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,648
8,652
8,447
8,417
6,575
6,574
3,927
3,943
1,986
2,012
1,376
1,381
1,003
993
548
556
161
182
Glynn et al NEJM 2009
JUPITER
Occurrence of VTE: Primary efficacy analysis
All cases identified by March 30, 2008
Endpoint
Rosuvastatin
Any VTE
34
Unprovoked VTE
Provoked VTE
Pulmonary embolism
DVT only
Placebo
HR
95%CI
P
60
0.57
0.37-0.86
0.007
19
15
31
29
0.61
0.52
0.35-1.09
0.28-0.96
0.09
0.03
17
17
22
38
0.77
0.45
0.41-1.45
0.25-0.79
0.42
0.004
JUPITER
Venous Thromboembolism – Unprovoked vs Provoked
HR 0.61, 95% CI 0.35-1.09
P= 0.09
HR 0.52, 95% CI 0.28-0.96
P= 0.03
0.000
0
Rosuvastatin
0.000
Rosuvastatin
Placebo
0.005
0.005
Placebo
Cumulative Incidence
0.010
0.015
0.020
Provoked Venous Thromboembolism
Cumulative Incidence
0.010
0.015
0.020
Unprovoked Venous Thromboembolism
1
2
Follow-up (years)
3
4
0
1
2
3
Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazard
(hemmorrhagic events: rosuvastatin 258, placebo 275, P=0.45)
4
JUPITER
Total Venous Thromboembolism – Subgroup Analysis I
N
Men
Women
Events
Incidence Rates
(Placebo)
11,001
6,801
66
28
0.37
0.24
3,689
8,418
5,695
17
37
40
0.24
0.30
0.41
12,683
5,117
86
8
0.39
0.11
BMI <25.0 kg/m2
BMI 25.0-29.9 kg/m2
BMI >30.0 kg/m2
4,073
7,009
6,674
15
32
46
0.20
0.30
0.40
Waist Circumference(cm)
Men<100/Women<95
Men>100/Women>95
8,586
9,049
34
57
0.21
0.41
Metabolic Syndrome
No Metabolic Syndrome
7,373
10,296
32
60
0.29
0.34
Smoker
Non-Smoker
2,820
14,975
13
81
0.22
0.34
All Participants
17,802
94
0.32
Age 50-59 yr
Age 60-69 yr
Age >70 yr
Caucasian
Black, Hispanic, Other
0.20
0.5
Rosuvastatin Superior
1.0
2.0
4.0
Rosuvastatin Inferior
JUPITER
Total Venous Thromboembolism – Subgroup Analysis II
# of
N
Events
Incidence Rates
(Placebo)
LDLC < 100 mg/dL
6,269
33
0.30
LDLC > 100 mg/dL
11,528
61
0.33
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
17,802
94
0.32
HDLC (mg/dL)
All Participants
0.20
0.5
Rosuvastatin Superior
1.0
2.0
4.0
Rosuvastatin Inferior
JUPITER
Occurrence of VTE: Safety analysis
Glynn et al NEJM 2009
All cases identified by final closeout visit and unblinding
Endpoint
Rosuvastatin
Any VTE
35
Unprovoked VTE
Provoked VTE
Pulmonary embolism
DVT only
Placebo
HR
95%CI
P
64
0.55
0.36-0.82
0.003
20
15
34
30
0.59
0.50
0.34-1.02
0.27-0.93
0.06
0.02
17
18
24
40
0.71
0.45
0.38-1.32
0.26-0.78
0.27
0.003
JUPITER
Occurrence of VTE, CVD, and death
Endpoint
Rosuvastatin
Placebo
Glynn et al NEJM 2009
HR
95%CI
P
VTE without prior CVD
32
56
0.57
0.37-0.88
0.009
CVD without prior VTE
141
249
0.56
0.46-0.69
<0.001
VTE after CVD
2
4
0.98
0.18-5.34
0.98
173
305
0.56
0.47-0.68
<0.001
7
14
0.88
0.35-2.18
0.78
483
0.66
0.57-0.76
<0.001
First CVD or VTE
Death after VTE
First CVD, VTE or death 320
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
0.06
0.04
109 Fewer Events
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
VTE + Primary Trial Endpoint
0.10
HR 0.56, 95% CI 0.47-0.68
P < 0.00001
0.08
Number Needed to Treat (NNT5) = 21
0.04
0.06
132 Fewer Events
Rosuvastatin 173 / 8901
0.00
0.02
Cumulative Incidence
Placebo 305 / 8901
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,624
8,612
8,400
8,338
6,525
6,486
3,880
3,854
1,951
1,949
1,348
1,320
979
945
536
525
157
170
JUPITER
VTE + Primary Trial Endpoint + Total Mortality
Placebo 483 / 8901
0.10
Number Needed to Treat (NNT5) = 18
0.06
0.08
163 Fewer Events
0.04
Cumulative Incidence
0.12
0.14
HR 0.66, 95% CI 0.57-0.76
P < 0.00001
0.00
0.02
Rosuvastatin 320 / 8901
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,624
8,612
8,400
8,338
6,525
6,486
3,880
3,854
1,951
1,949
1,348
1,320
979
945
536
525
157
170
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
JUPITER
VTE detailed results
Posted at NEJM.org