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JUPITER ACC March 29, 2009

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*,

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JUPITER ACC March 29, 2009

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  1. 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 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

  4. 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

  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 Ridker et al NEJM 2008 89,890 Screened 89,863 Screened 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 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 Placebo 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 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 8,600 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. JUPITER Baseline Clinical Characteristics Glynn et al NEJM 2009 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 (%)

  11. JUPITER Total Venous Thromboembolism Glynn et al NEJM 2009 HR 0.57, 95%CI 0.37-0.86 P= 0.007 0.025 0.020 Placebo 60/ 8901 0.015 - 43 % Cumulative Incidence 0.010 Rosuvastatin 34 / 8901 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 Glynn et al NEJM 2009 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

  13. JUPITER Venous Thromboembolism – Unprovoked vs Provoked Unprovoked Venous Thromboembolism Provoked Venous Thromboembolism HR 0.61, 95% CI 0.35-1.09 P= 0.09 HR 0.52, 95% CI 0.28-0.96 P= 0.03 0.020 0.020 0.015 0.015 Cumulative Incidence Cumulative Incidence Placebo 0.010 0.010 Placebo 0.005 0.005 Rosuvastatin Rosuvastatin 0.000 0.000 0 1 2 3 4 0 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. JUPITER Total Venous Thromboembolism – Subgroup Analysis I 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 2 4,073 15 BMI <25.0 kg/m 0.20 2 7,009 32 BMI 25.0-29.9 kg/m 0.30 2 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 Rosuvastatin Superior Rosuvastatin Inferior

  15. JUPITER Total Venous Thromboembolism – Subgroup Analysis II # 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 Rosuvastatin Superior Rosuvastatin Inferior

  16. 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 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

  17. JUPITER Occurrence of VTE, CVD, and death Glynn et al NEJM 2009 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

  18. JUPITER Primary Trial Endpoint :MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 P < 0.00001 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 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 HR 0.56, 95% CI 0.47-0.68 P < 0.00001 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 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

  20. JUPITER VTE + Primary Trial Endpoint + Total Mortality HR 0.66, 95% CI 0.57-0.76 P < 0.00001 Placebo 483 / 8901 0.14 Number Needed to Treat (NNT5) = 18 0.12 163 Fewer Events 0.10 0.08 Cumulative Incidence 0.06 Rosuvastatin 320 / 8901 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. 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

  22. JUPITER VTE detailed results Posted at NEJM.org

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