Antiplatelet Therapy Use and the Risk of Venous Thromboembolic Events in the Double-Blind Raloxifene Use for the Heart (RUTH) Trial C. Duvernoy 1, A. Yeo.

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Antiplatelet Therapy Use and the Risk of Venous Thromboembolic Events in the Double-Blind Raloxifene Use for the Heart (RUTH) Trial C. Duvernoy 1, A. Yeo 2, M. Wong 2, D. Cox 2 H. Kim 1 1 University of Michigan, VA Ann Arbor Healthcare System, Ann Arbor, MI 2 Eli Lilly & Company, Indianapolis, IN

Duvernoy, et al. AHA, 2007 Background  Raloxifene 60 mg/d is approved for osteoporosis prevention and treatment in postmenopausal women, and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and those at high risk for invasive breast cancer. 1  In randomized clinical trials, postmenopausal women who received raloxifene 60 mg/d had a significantly increased risk of venous thromboembolism (VTE) compared to placebo Evista Prescribing Information, Sept Grady D, et al., Ob Gyn 2004; 104: Martino S et al., Curr Med Res Opin 2005; 21: Barrett-Connor E, et al. N Engl J Med 2006;355:

Duvernoy, et al. AHA, 2007 Background  Platelet activation is thought to be involved more in the pathophysiology of arterial thromboses than venous thromboses. 1  Although some data suggest that aspirin may reduce VTE risk associated with estrogen use, 2 other studies suggest it has no effect. 3,4 1. Tan KT and Lip GY. Arch Intern Med. 2003;163: Grady D et al. Ann Intern Med 2000;132: Cushman M et al., JAMA 2004;292: Curb JD et al., Arch Intern Med 2006;166:

Duvernoy, et al. AHA, 2007 Objective  To examine the effects of concomitant antiplatelet (AP) therapy on VTE risk in postmenopausal women who participated in the Raloxifene Use for The Heart (RUTH) trial.

Duvernoy, et al. AHA, 2007 RUTH: Trial Design  International, randomized, double-blind, placebo- controlled trial  177 investigative sites in 26 countries  10,101 postmenopausal women with established coronary heart disease (CHD) or at increased risk for a major coronary event were enrolled  Randomization from June 1998 to August 2000  Median 5.6 years follow-up

Duvernoy, et al. AHA, Lower Extremity Arterial Disease (%) Prior Myocardial Infarction (%) History of CHD (%) Hyperlipidemia (%) Hypertension (%) Diabetes Mellitus (%) BMI (kg/m 2, (mean + SE) Age (years, mean + SE) Placebo (N=5057) Characteristic Raloxifene (N=5044) RUTH: Baseline Characteristics (N=10,101) No statistically significant differences between treatment groups on these characteristics

Duvernoy, et al. AHA, 2007 Antiplatelet (AP) Use in RUTH 3759 (74.5)3709 (73.3)2960 (58.7)2967 (58.7) AP Use 704 (14.0)733 (14.5)156 (3.1)142 (2.8) Non-aspirin Use 3606 (71.5)3545 (70.1)2846 (56.4)2865 (56.7) Aspirin Use Raloxifene n (%) Placebo n (%) Raloxifene n (%) Placebo n (%) During StudyBaseline

Duvernoy, et al. AHA, Lower Extremity Arterial Disease (%) Prior Myocardial Infarction (%) History of CHD (%) Hyperlipidemia (%) Hypertension (%) Diabetes Mellitus (%) BMI (kg/m 2, (mean + SE) Age (years, mean + SE) No AP User* (N=2625) Characteristic AP User (N=7468) Baseline Characteristics by Antiplatelet Use During RUTH *All comparisons between AP users and AP non-users were significant (P<0.01). Within each subgroup of AP users or non-users, characteristics were not significantly different between treatment groups

Duvernoy, et al. AHA, 2007 Endpoint No. of events (%) Hazard Ratio (95% CI) P value Placebo (N=5057) Raloxifene (N=5044) VTE event71 (1.40)103 (2.04)1.44 ( )0.02 Deep vein thrombosis47 (0.93)65 (1.29)1.37 ( )0.10 Pulmonary embolism24 (0.47)36 (0.71)1.49 ( )0.13 RUTH: Venous Thromboembolic Events (VTE) for All Randomized Women (N=10,101) Barrett-Connor E, et al. N Engl J Med 2006;355:

Duvernoy, et al. AHA, 2007 Incidence of VTE by Antiplatelet Use During RUTH HR 1.40 (95% CI 0.99, 1.97) Interaction P=0.82 (n=3709) HR 1.54 (95% CI 0.82, 2.88) (n=3759)(n=1346)(n=1279) Antiplatelet Use No Antiplatelet Use (n=55) (n=78) (n=16) (n=25) Incidence % (n=55) (n=16) (n=78) (n=25) Placebo Raloxifene

Duvernoy, et al. AHA, 2007 Cumulative Incidence of VTE by Treatment Group and Antiplatelet Use Years Cumulative incidence VTE per 1000 woman years Placebo Placebo + AP Raloxifene Raloxifene + AP } HR 1.04 (95% CI 0.66, 1.64) } HR 1.15 (95% CI 0.65, 2.02)

Duvernoy, et al. AHA, 2007 Incidence of VTE by Aspirin Use During RUTH HR 1.40 (95% CI 0.99, 1.99) Interaction P=0.85 (n=3545) HR 1.52 (95% CI 0.83, 2.80) (n=3606)(n=1510)(n=1432) Aspirin Use No Aspirin Use (n=54) (n=76) (n=17) (n=27) Incidence % Placebo Raloxifene (n=54) (n=76) (n=17) (n=27)

Duvernoy, et al. AHA, 2007 Incidence of VTE by Non-Aspirin AP Use During RUTH HR 1.30 (95% CI 0.65, 2.62) Interaction P=0.79 (n=733) HR 1.45 (95% CI 1.04, 2.03) (n=704)(n=4322)(n=4334) Non-Aspirin AP Use No Non-Aspirin AP Use (n=14) (n=18) (n=57) (n=85) Incidence % Placebo Raloxifene (n=14) (n=18) (n=57) (n=85)

Duvernoy, et al. AHA, 2007 Incidence of VTE by Baseline Antiplatelet Use HR 1.44 (95% CI 0.98, 2.10) Interaction P=0.88 (n=2967) HR 1.37 (95% CI 0.83, 2.27) (n=2960)(n=2064)(n=2053) Antiplatelet Use No Antiplatelet Use (n=45) (n=65) (n=26) (n=36) Incidence % Placebo Raloxifene (n=45) (n=65) (n=26) (n=36)

Duvernoy, et al. AHA, 2007 Incidence of VTE by Antiplatelet Use During RUTH Excluding Women with Prior CHD (Primary Prevention Cohort) HR 2.16 (95% CI 1.17, 3.96) Interaction P=0.50 (n=1449) HR 1.57 (95% CI 0.79, 3.11) (n=1482)(n=1110)(n=1019) Antiplatelet Use No Antiplatelet Use (n=15) (n=34) (n=14) (n=20) Incidence % (n=20) Placebo Raloxifene (n=15) (n=34) (n=14)

Duvernoy, et al. AHA, 2007 Incidence of VTE by Antiplatelet Use During RUTH: Women with Established CHD (Secondary Prevention Cohort) HR 1.11 (95% CI 0.72, 1.70) Interaction P=0.48 (n=2260) HR 2.09 (95% CI 0.41, 10.78) (n=2277)(n=236)(n=260) Antiplatelet Use No Antiplatelet Use (n=40) (n=44) (n=2) (n=5) Incidence % (n=2) (n=44) (n=5) Placebo Raloxifene (n=40)

Duvernoy, et al. AHA, 2007 Study Limitations  Post-hoc exploratory analysis  Majority of subjects (~74%) took an antiplatelet (AP) agent during the study  Duration of AP use was not assessed  AP use not randomized; however: AP use did not differ between treatment groups Potential confounders were balanced between treatment groups within AP user and AP non-user subgroups

Duvernoy, et al. AHA, 2007 Conclusions In the study cohort overall:  the increased risk of VTE with raloxifene compared with placebo was not influenced by use of antiplatelet (AP) agents (aspirin or non-aspirin)  the use of AP agents during RUTH was not associated with a reduced incidence of VTE in either the placebo or raloxifene group For women with established CHD only:  the increased VTE risk with raloxifene compared with placebo seems to be mitigated with AP use, but whether this apparent effect is attributable to AP use or to other factors is unknown