antiplatelet therapy use and the risk of venous thromboembolic events in the double-blind raloxifene...

Antiplatelet Therapy Use and the Risk Antiplatelet Therapy Use and the Risk of Venous Thromboembolic Events in of Venous Thromboembolic Events in the Double-Blind Raloxifene Use for the Double-Blind Raloxifene Use for

the Heart (RUTH) Trialthe Heart (RUTH) Trial

C. DuvernoyC. Duvernoy11, A. Yeo, A. Yeo22, M. Wong, M. Wong22, D. Cox, D. Cox2 2 H. Kim H. Kim11

1 1 University of Michigan, VA Ann Arbor Healthcare System, Ann Arbor, MIUniversity of Michigan, VA Ann Arbor Healthcare System, Ann Arbor, MI22Eli Lilly & Company, Indianapolis, INEli Lilly & Company, Indianapolis, IN

Duvernoy, et al. AHA, 2007

BackgroundBackground

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. 2-4

1. Evista Prescribing Information, Sept. 20072. Grady D, et al., Ob Gyn 2004; 104: 837-44.3. Martino S et al., Curr Med Res Opin 2005; 21: 1441-52.4. Barrett-Connor E, et al. N Engl J Med 2006;355:125-37.


BackgroundBackground

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;163:2534-25352. Grady D et al. Ann Intern Med 2000;132:689-6963. Cushman M et al., JAMA 2004;292:1573-15804. Curb JD et al., Arch Intern Med 2006;166:772-780


ObjectiveObjective

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.


RUTH: Trial DesignRUTH: 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


10.7Lower Extremity Arterial Disease (%) 10.8

29.0Prior Myocardial Infarction (%) 29.4

49.4History of CHD (%) 50.3

73.6Hyperlipidemia (%) 73.3

77.8Hypertension (%) 77.9

45.8Diabetes Mellitus (%) 45.7

28.7 + 5.1BMI (kg/m2, (mean + SE) 28.8 + 5.2

67.5 + 6.7Age (years, mean + SE) 67.5 + 6.6

Placebo

(N=5057)

Characteristic Raloxifene

(N=5044)

RUTH: Baseline Characteristics RUTH: Baseline Characteristics (N=10,101)(N=10,101)

No statistically significant differences between treatment groups on these characteristics


Antiplatelet (AP) Use in RUTHAntiplatelet (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 Study Baseline


8.5Lower Extremity Arterial Disease (%) 11.5

12.3Prior Myocardial Infarction (%) 35.2

18.9History of CHD (%) 60.8

67.7Hyperlipidemia (%) 75.4

83.1Hypertension (%) 76.0

59.5Diabetes Mellitus (%) 40.9

29.2 + 5.4BMI (kg/m2, (mean + SE) 28.6 + 5.1

66.9 + 6.7Age (years, mean + SE) 67.7 + 6.6

No AP User*

(N=2625)

Characteristic AP User

(N=7468)

Baseline Characteristics by Antiplatelet Baseline Characteristics by Antiplatelet Use During RUTHUse 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


Endpoint

No. of events (%)

Hazard Ratio

(95% CI)P valuePlacebo

(N=5057)

Raloxifene

(N=5044)

VTE event 71 (1.40) 103 (2.04) 1.44 (1.06-1.95) 0.02

Deep vein thrombosis 47 (0.93) 65 (1.29) 1.37 (0.94-1.99) 0.10

Pulmonary embolism 24 (0.47) 36 (0.71) 1.49 (0.89-2.49) 0.13

RUTH: Venous Thromboembolic Events (VTE) for All Randomized Women (N=10,101)

Barrett-Connor E, et al. N Engl J Med 2006;355:125-137


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)

Inci

den

ce

%

(n=55)

(n=16)

(n=78)(n=25)

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene


Cumulative Incidence of VTE by Treatment Cumulative Incidence of VTE by Treatment Group and Antiplatelet UseGroup and Antiplatelet Use

Years

0 1 2 3 4 5 6

Cum

ulat

ive

inci

denc

e V

TE

per

100

0 w

oman

yea

rs

0

5

10

15

20

25

30Placebo

Placebo + AP

Raloxifene

Raloxifene + AP } HR 1.04 (95% CI 0.66, 1.64)

} HR 1.15 (95% CI 0.65, 2.02)


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)

Inci

den

ce

%

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene(n=54)

(n=76)

(n=17)

(n=27)


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)

Inci

den

ce

%

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene

(n=14)

(n=18)

(n=57)

(n=85)


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)


(n=45)

(n=65)

(n=26)

(n=36)

Inci

den

ce

%

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene(n=45)

(n=65)

(n=26)

(n=36)


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)


(n=15)

(n=34)

(n=14)

(n=20)

Inci

den

ce

% (n=20)

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene

(n=15)

(n=34)

(n=14)


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)


(n=40)(n=44)

(n=2)

(n=5)

Inci

den

ce

%

(n=2)

(n=44) (n=5)

00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.0

Placebo

Raloxifene

(n=40)


Study LimitationsStudy 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


ConclusionsConclusions

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

antiplatelet therapy use and the risk of venous thromboembolic events in the double-blind raloxifene...

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