JUPITER ACC March 29, 2009 A Randomized Trial of Rosuvastatin in the Prevention of Venous...

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


8,901 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


8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo




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

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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 %


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


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

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Follow-up (years)

0 1 2 3 4

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0.01

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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


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


JUPITEROccurrence of VTE, CVD, and death


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


JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 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

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0.0

40

.06

0.0

8

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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


HR 0.56, 95% CI 0.47-0.68P < 0.00001


0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

80

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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


HR 0.66, 95% CI 0.57-0.76P < 0.00001


0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

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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

JUPITERVTE detailed results

Posted at NEJM.org

JUPITER ACC March 29, 2009 A Randomized Trial of Rosuvastatin in the Prevention of Venous...

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