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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*, - PowerPoint PPT Presentation
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JUPITERACC March 29, 2009
A Randomized Trial of Rosuvastatin in the Preventionof 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 morestatin 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
JUPITERACC 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
JUPITERWhy 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;25:287-294
Observational studies of statins & VTE
11stst Author Author PublicationPublication StudyStudy Adj. RRAdj. RR 95% CI95% CI
Grady Grady Ann Intern Med 2000Ann Intern Med 2000 Heart & E/P ReplacementHeart & E/P Replacement 0.50.5
0.2-0.90.2-0.9
Ray Ray
Arch Int Med 2001Arch Int Med 2001
Ontario residents 65+ yrsOntario residents 65+ yrs 0.80.8
0.7-0.90.7-0.9
Yang Yang
Br J Clin Pharm 2002Br J Clin Pharm 2002 UK database f-upUK database f-upCase-controlCase-control
0.80.81.11.1
0.3-2.70.3-2.70.3-4.30.3-4.3
DoggenDoggen J Thromb Haemost J Thromb Haemost 20042004 Washington HMOWashington HMO 0.60.6 0.4-1.10.4-1.1
LacutLacut Fund Clin Pharm 2004Fund Clin Pharm 2004 France, case-controlFrance, case-control 0.40.4 0.2-0.80.2-0.8
SmeethSmeeth
Br J Cl Pharm 2008Br J Cl Pharm 2008
UK database f-up UK database f-up 1.01.0 0.9-1.20.9-1.2
RamcharanRamcharan J Thromb Haemost J Thromb Haemost 20092009
Holland, case-controlHolland, case-control 0.50.5
0.4-0.60.4-0.6
SørensenSørensen J Thromb Haemost J Thromb Haemost 20092009
Denmark, case-controlDenmark, case-control 0.70.7
0.6-0.90.6-0.9
JUPITERWhy 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
JUPITERInclusion and Exclusion Criteria, Study Flow
89,863 Screened
17,802 Randomized
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
Reason for Exclusion (%)
LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
8,600 Completed Study120 Lost to follow-up
8,600 Completed Study120 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
89,890 Screened
Men > 50 yearsWomen > 60 yearsNo CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L
17,802 Randomized
Reason for Exclusion (%)
LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3
4 weekPlaceboRun-In
8,857 Completed Study44 Lost to follow-up
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
8,864 Completed Study37 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
Ridker et al NEJM 2008
JUPITERSymptomatic 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.
JUPITERVTE 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
JUPITERBaseline Clinical Characteristics
Rosuvastatin Placebo(N = 8901) (n = 8901)
Age, years (IQR) 66 (60-71) 66 (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 (%)
Glynn et al NEJM 2009
JUPITERTotal Venous Thromboembolism
0 1 2 3 4
0.0
00
0.0
05
0.0
10
0.0
15
0.0
20
0.0
25
Cu
mu
lati
ve In
cid
ence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161
8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182
HR 0.57, 95%CI 0.37-0.86P= 0.007
Placebo 60 / 8901
Rosuvastatin 34 / 8901
- 43 %
Glynn et al NEJM 2009
JUPITEROccurrence of VTE: Primary efficacy analysis
All cases identified by March 30, 2008
Endpoint Rosuvastatin Placebo HR 95%CI P
Any VTE 34 60 0.57 0.37-0.86 0.007
Unprovoked VTE 19 31 0.61 0.35-1.09 0.09Provoked VTE 15 29 0.52 0.28-0.96 0.03
Pulmonary embolism 17 22 0.77 0.41-1.45 0.42DVT only 17 38 0.45 0.25-0.79 0.004
Glynn et al NEJM 2009
JUPITERVenous Thromboembolism – Unprovoked vs Provoked
HR 0.52, 95% CI 0.28-0.96P= 0.03
0 1 2 3 4
0.00
00.
005
0.01
00.
015
0.02
0C
um
ula
tive
Inci
den
ce
Follow-up (years)
0 1 2 3 4
0.00
00.
005
0.01
00.
015
0.02
0C
um
ula
tive
Inci
den
ce
Provoked Venous Thromboembolism
HR 0.61, 95% CI 0.35-1.09P= 0.09
Unprovoked Venous Thromboembolism
Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazard (hemmorrhagic events: rosuvastatin 258, placebo 275, P=0.45)
PlaceboPlacebo
Rosuvastatin
Rosuvastatin
JUPITERTotal Venous Thromboembolism – Subgroup Analysis I
0.20 0.5 1.0 2.0 4.0Rosuvastatin Superior Rosuvastatin Inferior
MenWomen
Age 50-59 yrAge 60-69 yrAge >70 yr
CaucasianBlack, Hispanic, Other
BMI <25.0 kg/m2
BMI 25.0-29.9 kg/m2
BMI >30.0 kg/m2
Waist Circumference(cm)Men<100/Women<95Men>100/Women>95
Metabolic SyndromeNo Metabolic Syndrome
SmokerNon-Smoker
All Participants
N
11,001 6,801
3,689 8,418 5,695
12,683 5,117
4,073 7,009 6,674
8,586 9,049
7,37310,296
2,82014,975
17,802
Events
6628
173740
86 8
153246
3457
3260
1381
94
Incidence Rates(Placebo)
0.370.24
0.240.300.41
0.390.11
0.200.300.40
0.210.41
0.290.34
0.220.34
0.32
JUPITERTotal Venous Thromboembolism – Subgroup Analysis II
0.20 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
LDLC < 100 mg/dL
LDLC > 100 mg/dL
HDLC (mg/dL)
Men<40, Women<50
Men > 40, Women >50
Triglycerides<150 mg/dL
Triglycerides > 150 mg/dL
hsCRP<5 mg/L
hsCRP >5 mg/L
Time of event< 24 Months
Time of event>24 Months
All Participants
N
6,269
11,528
5,689
12,112
11,965
5,836
10,458
7,344
17,802
7,870
17,802
# of
Events
33
61
26
68
66
28
49
45
70
24
94
Incidence Rates
(Placebo)
0.30
0.33
0.30
0.33
0.32
0.32
0.27
0.39
0.28
0.53
0.32
JUPITEROccurrence of VTE: Safety analysis
All cases identified by final closeout visit and unblinding
Endpoint Rosuvastatin Placebo HR 95%CI P
Any VTE 35 64 0.55 0.36-0.82 0.003
Unprovoked VTE 20 34 0.59 0.34-1.02 0.06Provoked VTE 15 30 0.50 0.27-0.93 0.02
Pulmonary embolism 17 24 0.71 0.38-1.32 0.27DVT only 18 40 0.45 0.26-0.78 0.003
Glynn et al NEJM 2009
JUPITEROccurrence of VTE, CVD, and death
Endpoint Rosuvastatin Placebo 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
First CVD or VTE 173 305 0.56 0.47-0.68 <0.001
Death after VTE 7 14 0.88 0.35-2.18 0.78
First CVD, VTE or death 320 483 0.66 0.57-0.76 <0.001
Glynn et al NEJM 2009
JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69P < 0.00001
Number Needed to Treat (NNT5) = 25
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve In
cid
ence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
109 Fewer Events
JUPITERVTE + Primary Trial Endpoint
Placebo 305 / 8901
Rosuvastatin 173 / 8901
HR 0.56, 95% CI 0.47-0.68P < 0.00001
Number Needed to Treat (NNT5) = 21
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
80
.10
Cu
mu
lati
ve I
nci
de
nce
Number at Risk Follow-up (years)Rosuvastatin
Placebo
8,901 8,624 8,400 6,525 3,880 1,951 1,348 979 536 157
8,901 8,612 8,338 6,486 3,854 1,949 1,320 945 525 170
132 Fewer Events
JUPITERVTE + Primary Trial Endpoint + Total Mortality
Placebo 483 / 8901
Rosuvastatin 320 / 8901
HR 0.66, 95% CI 0.57-0.76P < 0.00001
Number Needed to Treat (NNT5) = 18
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cu
mu
lati
ve I
nci
den
ce
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,624 8,400 6,525 3,880 1,951 1,348 979 536 157
8,901 8,612 8,338 6,486 3,854 1,949 1,320 945 525 170
163 Fewer Events
JUPITERVTE 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