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 Womens 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 & Womens Hospital, Boston, MA The following relationship exists related to this presentation: Research GrantAstraZenecaSignificant Level The Brigham & Womens 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 1 st Author PublicationStudy Adj. RR 95% CI Grady Ann Intern Med 2000 Heart & E/P Replacement 0.50.2-0.9 Ray Arch Int Med 2001 Ontario residents 65+ yrs 0.80.7-0.9 Yang Br J Clin Pharm 2002 UK database f-up Case-control0.81.10.3-2.70.3-4.3 Doggen J Thromb Haemost 2004 Washington HMO 0.60.4-1.1 Lacut Fund Clin Pharm 2004 France, case-control 0.40.2-0.8 Smeeth Br J Cl Pharm 2008 UK database f-up 1.00.9-1.2 Ramcharan J Thromb Haemost 2009 Holland, case-control 0.50.4-0.6 Sørensen J Thromb Haemost 2009 Denmark, case-control 0.70.6-0.9

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 89,863 Screened 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 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 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 89,890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 17,802 Randomized 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 4 week Placebo Run-In 8,857 Completed Study 44 Lost to follow-up 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 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 Ridker et al NEJM 2008

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 RosuvastatinPlacebo (N = 8901)(n = 8901) Age, years (IQR)66 (60-71)66 (60-71) Female, N (%)3,426 (38)3,375(38) Ethnicity, N (%) Caucasian6,358(71)6,325(71) Black1,100(12)1,124(13) Hispanic1,121(13)1,140(13) Body mass index 30 kg/m 2, 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) hsCRP5 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 01234 0.000 0.005 0.010 0.015 0.020 0.025 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6488,4476,5753,9271,9861,3761,003548161 8,9018,6528,4176,5743,9432,0121,381993556182 HR 0.57, 95%CI 0.37-0.86 P= 0.007 Placebo 60 / 8901 Rosuvastatin 34 / 8901 - 43 % Glynn et al NEJM 2009

12. JUPITER Occurrence of VTE: Primary efficacy analysis All cases identified by March 30, 2008 Endpoint RosuvastatinPlaceboHR 95%CI P Any VTE 34 600.57 0.37-0.86 0.007 Unprovoked VTE 19 310.61 0.35-1.09 0.09 Provoked VTE 15 290.52 0.28-0.96 0.03 Pulmonary embolism 17 220.77 0.41-1.45 0.42 DVT only 17 380.45 0.25-0.79 0.004 Glynn et al NEJM 2009

13. JUPITER Venous Thromboembolism – Unprovoked vs Provoked HR 0.52, 95% CI 0.28-0.96 P= 0.03 01234 0.000 0.005 0.010 0.015 0.020 Cumulative Incidence Follow-up (years) 01234 0.000 0.005 0.010 0.015 0.020 Cumulative Incidence Provoked Venous Thromboembolism HR 0.61, 95% CI 0.35-1.09 P= 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) Placebo Rosuvastatin

14. JUPITER Total Venous Thromboembolism – Subgroup Analysis I 0.200.51.02.04.0 Rosuvastatin SuperiorRosuvastatin Inferior Men Women Age 50-59 yr Age 60-69 yr Age>70 yr Caucasian Black, Hispanic, Other BMI <25.0 kg/m 2 BMI 25.0-29.9 kg/m 2 BMI>30.0 kg/m 2 Waist Circumference(cm) Men<100/Women<95 Men>100/Women>95 Metabolic Syndrome No Metabolic Syndrome Smoker Non-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 7,373 10,296 2,820 14,975 17,802 Events 66 28 17 37 40 86 8 15 32 46 34 57 32 60 13 81 94 Incidence Rates (Placebo) 0.37 0.24 0.30 0.41 0.39 0.11 0.20 0.30 0.40 0.21 0.41 0.29 0.34 0.22 0.34 0.32

15. JUPITER Total Venous Thromboembolism – Subgroup Analysis II 0.200.51.02.04.0 Rosuvastatin SuperiorRosuvastatin 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 0.27 0.39 0.28 0.53 0.32

16. JUPITER Occurrence of VTE: Safety analysis All cases identified by final closeout visit and unblinding Endpoint RosuvastatinPlaceboHR 95%CI P Any VTE 35 640.55 0.36-0.82 0.003 Unprovoked VTE 20 340.59 0.34-1.02 0.06 Provoked VTE 15 300.50 0.27-0.93 0.02 Pulmonary embolism 17 240.71 0.38-1.32 0.27 DVT only 18 400.45 0.26-0.78 0.003 Glynn et al NEJM 2009

17. JUPITER Occurrence of VTE, CVD, and death Endpoint RosuvastatinPlaceboHR 95%CI P VTE without prior CVD 32 560.57 0.37-0.88 0.009 CVD without prior VTE 141 2490.56 0.46-0.69 <0.001 VTE after CVD 2 40.98 0.18-5.34 0.98 First CVD or VTE 173 3050.56 0.47-0.68 <0.001 Death after VTE 7 140.88 0.35-2.18 0.78 First CVD, VTE or death 320 4830.66 0.57-0.76 <0.001 Glynn et al NEJM 2009

18. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174 109 Fewer Events

19. JUPITER VTE + Primary Trial Endpoint Placebo 305 / 8901 Rosuvastatin 173 / 8901 HR 0.56, 95% CI 0.47-0.68 P < 0.00001 Number Needed to Treat (NNT 5 ) = 21 01234 0.00 0.02 0.04 0.06 0.08 0.10 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6248,4006,5253,8801,9511,348979536157 8,9018,6128,3386,4863,8541,9491,320945525170 132 Fewer Events

20. JUPITER VTE + Primary Trial Endpoint + Total Mortality Placebo 483 / 8901 Rosuvastatin 320 / 8901 HR 0.66, 95% CI 0.57-0.76 P < 0.00001 Number Needed to Treat (NNT 5 ) = 18 01234 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6248,4006,5253,8801,9511,348979536157 8,9018,6128,3386,4863,8541,9491,320945525170 163 Fewer Events

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