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A Randomized Trial of Rosuvastatin in the Prevention of Venous
A Randomized Trial of Rosuvastatin in the Prevention of Venous
Presenter Disclosure Information
Presenter Disclosure Information
JUPITER Timeline First randomization: March 14, 2003 Last
JUPITER Timeline First randomization: March 14, 2003 Last
JUPITER Why Pre-specify Incident Venous Thromboembolism
JUPITER Why Pre-specify Incident Venous Thromboembolism
Observational studies of statins & VTE
Observational studies of statins & VTE
JUPITER Why Pre-specify Incident Venous Thromboembolism
JUPITER Why Pre-specify Incident Venous Thromboembolism
JUPITER Inclusion and Exclusion Criteria, Study Flow
JUPITER Inclusion and Exclusion Criteria, Study Flow
JUPITER Symptomatic VTE
JUPITER Symptomatic VTE
JUPITER VTE analysis
JUPITER VTE analysis
JUPITER Baseline Clinical Characteristics
JUPITER Baseline Clinical Characteristics
JUPITER Total Venous Thromboembolism
JUPITER Total Venous Thromboembolism
JUPITER Occurrence of VTE: Primary efficacy analysis
JUPITER Occurrence of VTE: Primary efficacy analysis
JUPITER Venous Thromboembolism – Unprovoked vs Provoked
JUPITER Venous Thromboembolism – Unprovoked vs Provoked
JUPITER Total Venous Thromboembolism – Subgroup Analysis I
JUPITER Total Venous Thromboembolism – Subgroup Analysis I
JUPITER Total Venous Thromboembolism – Subgroup Analysis II
JUPITER Total Venous Thromboembolism – Subgroup Analysis II
JUPITER Occurrence of VTE: Safety analysis
JUPITER Occurrence of VTE: Safety analysis
JUPITER Occurrence of VTE, CVD, and death
JUPITER Occurrence of VTE, CVD, and death
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV
JUPITER VTE + Primary Trial Endpoint
JUPITER VTE + Primary Trial Endpoint
JUPITER VTE + Primary Trial Endpoint + Total Mortality
JUPITER VTE + Primary Trial Endpoint + Total Mortality
VTE is a serious event that occurred about as often as MI and stroke
VTE is a serious event that occurred about as often as MI and stroke
Posted at NEJM
Posted at NEJM

Презентация: «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». Автор: Jean MacFadyen. Файл: «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.ppt». Размер zip-архива: 580 КБ.

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

содержание презентации «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.ppt»
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1 A Randomized Trial of Rosuvastatin in the Prevention of Venous

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, B?rge 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.

JUPITER ACC March 29, 2009

2 Presenter Disclosure Information

Presenter Disclosure Information

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

Robert J Glynn, PhD, ScD; Brigham & Women’s Hospital, Boston, MA

3 JUPITER Timeline First randomization: March 14, 2003 Last

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 ACC March 29, 2009

4 JUPITER 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;25:287-294

5 Observational studies of statins & VTE

Observational studies of statins & VTE

1st Author

Publication

Study

Adj. RR

95% CI

Grady

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

Doggen

J Thromb Haemost 2004

Washington HMO

0.6

0.4-1.1

Lacut

Fund Clin Pharm 2004

France, case-control

0.4

0.2-0.8

Smeeth

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

S?rensen

J Thromb Haemost 2009

Denmark, case-control

0.7

0.6-0.9

6 JUPITER Why Pre-specify Incident Venous Thromboembolism

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

JUPITER Inclusion and Exclusion Criteria, Study Flow

Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L

Ridker et al NEJM 2008

89,890 Screened

17,802 Randomized

17,802 Randomized

8,901 Assigned to Placebo

8,901 Assigned to Rosuvastatin 20 mg

8,857 Completed Study 44 Lost to follow-up

8,864 Completed Study 37 Lost to follow-up

8,901 Included in Efficacy and Safety Analyses

8,901 Included in Efficacy and Safety Analyses

Reason for Exclusion (%) LDL > 130 mg/dL 52 hsCRP < 2.0 mg/L 36 Withdrew Consent 5 Diabetes 1 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

Reason for Exclusion (%) LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 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

4 week Placebo Run-In

8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned to Placebo

8,600 Completed Study 120 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

89,863 Screened

8 JUPITER Symptomatic VTE

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

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 JUPITER Baseline Clinical Characteristics

JUPITER Baseline 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

11 JUPITER Total Venous Thromboembolism

JUPITER Total Venous Thromboembolism

- 43 %

HR 0.57, 95%CI 0.37-0.86 P= 0.007

Glynn et al NEJM 2009

Placebo 60 / 8901

Cumulative Incidence

Rosuvastatin 34 / 8901

0.025

0.020

0.015

0.010

0.005

0.000

0

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 JUPITER Occurrence of VTE: Primary efficacy analysis

JUPITER Occurrence 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 0.09 Provoked VTE 15 29 0.52 0.28-0.96 0.03 Pulmonary embolism 17 22 0.77 0.41-1.45 0.42 DVT only 17 38 0.45 0.25-0.79 0.004

Glynn et al NEJM 2009

13 JUPITER Venous Thromboembolism – Unprovoked vs Provoked

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

Clear clinical benefit in the absence of any bleeding hazard (hemmorrhagic events: rosuvastatin 258, placebo 275, P=0.45)

Unprovoked Venous Thromboembolism

Provoked Venous Thromboembolism

Placebo

Placebo

Rosuvastatin

Rosuvastatin

Follow-up (years)

Follow-up (years)

0.020

0.020

0.015

0.015

Cumulative Incidence

Cumulative Incidence

0.010

0.010

0.005

0.005

0.000

0.000

0

1

2

3

4

0

1

2

3

4

14 JUPITER Total Venous Thromboembolism – Subgroup Analysis I

JUPITER Total Venous Thromboembolism – Subgroup Analysis I

Rosuvastatin Superior

Rosuvastatin Inferior

Incidence Rates

(Placebo)

N

Events

Men

11,001

66

0.37

Women

6,801

28

0.24

Age 50-59 yr

3,689

17

0.24

Age 60-69 yr

8,418

37

0.30

0.41

Age

>

70 yr

5,695

40

Caucasian

12,683

86

0.39

Black, Hispanic, Other

5,117

8

0.11

4,073

15

BMI <25.0 kg/m

0.20

7,009

32

BMI 25.0-29.9 kg/m

0.30

6,674

46

BMI

>

30.0 kg/m

0.40

Waist Circumference(cm)

0.21

Men<100/Women<95

8,586

34

0.41

Men

>

100/Women

>

95

9,049

57

Metabolic Syndrome

7,373

32

0.29

0.34

No Metabolic Syndrome

10,296

60

13

0.22

Smoker

2,820

81

0.34

Non-Smoker

14,975

94

0.32

All Participants

17,802

0.20

0.5

1.0

2.0

4.0

2

2

2

15 JUPITER Total Venous Thromboembolism – Subgroup Analysis II

JUPITER Total Venous Thromboembolism – Subgroup Analysis II

Rosuvastatin Superior

Rosuvastatin Inferior

# of

Incidence Rates

N

Events

(Placebo)

LDLC

<

100 mg/dL

0.30

6,269

33

LDLC > 100 mg/dL

0.33

11,528

61

HDLC (mg/dL)

Men<40, Women<50

0.30

5,689

26

Men

>

40, Women

>

50

0.33

12,112

68

Triglycerides<150 mg/dL

0.32

11,965

66

Triglycerides

>

150 mg/dL

0.32

5,836

28

hsCRP<5 mg/L

0.27

10,458

49

hsCRP

>

5 mg/L

0.39

7,344

45

Time of event

<

24 Months

0.28

17,802

70

Time of event>24 Months

0.53

7,870

24

All Participants

17,802

94

0.32

0.20

0.5

1.0

2.0

4.0

16 JUPITER Occurrence of VTE: Safety analysis

JUPITER Occurrence 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 0.06 Provoked VTE 15 30 0.50 0.27-0.93 0.02 Pulmonary embolism 17 24 0.71 0.38-1.32 0.27 DVT only 18 40 0.45 0.26-0.78 0.003

Glynn et al NEJM 2009

17 JUPITER Occurrence of VTE, CVD, and death

JUPITER Occurrence 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

18 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV

Death

Number Needed to Treat (NNT5) = 25

HR 0.56, 95% CI 0.46-0.69 P < 0.00001

109 Fewer Events

Placebo 251 / 8901

Rosuvastatin 142 / 8901

Cumulative Incidence

0.08

0.06

0.04

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

19 JUPITER VTE + Primary Trial Endpoint

JUPITER VTE + Primary Trial Endpoint

Number Needed to Treat (NNT5) = 21

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

132 Fewer Events

Placebo 305 / 8901

Rosuvastatin 173 / 8901

Cumulative Incidence

Follow-up (years)

0.10

0.08

0.06

0.04

0.02

0.00

0

1

2

3

4

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

JUPITER VTE + Primary Trial Endpoint + Total Mortality

Number Needed to Treat (NNT5) = 18

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

163 Fewer Events

Placebo 483 / 8901

Rosuvastatin 320 / 8901

0.14

0.12

0.10

0.08

Cumulative Incidence

0.06

0.04

0.02

0.00

0

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 VTE is a serious event that occurred about as often as MI and stroke

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 in JUPITER: Conclusions

22 Posted at NEJM

Posted at NEJM

org

JUPITER VTE detailed results

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