evista – studies overview daniel thiebaud md, medical fellow, global osteoporosis strategy, eli...
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EVISTA – Studies Overview
Daniel Thiebaud MD, Medical Fellow,
Global Osteoporosis Strategy, Eli Lilly, Australia
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Concept of a SERM
SS electiveelective
EE strogenstrogen
RR eceptoreceptor
MModulatorodulator
• Not an estrogen and not a hormoneNot an estrogen and not a hormone• Binds to estrogen receptorsBinds to estrogen receptors• Has estrogen-like effects in some tissuesHas estrogen-like effects in some tissues• Blocks estrogen effects in some tissuesBlocks estrogen effects in some tissues
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Evista Update
• EVA : Evista versus Alendronate • MORE
– New non vertebral fractures– Clinical vertebral fractures (3 and 6 months)
• CORE– Invasive breast cancer and overall safety
• RUTH – STAR timelines
• CHOOSE ASIA Observational study
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Raloxifene versus Alendronate Comparison
EVA Trial
• First ever head-to-head fracture outcome trial• Compare the osteoporotic fracture risk reduction efficacy of
raloxifene and alendronate• Double-blind, randomized, controlled, 5-year trial with raloxifene
60 mg/d vs alendronate 10 mg/d
• Initially planned about 3000 postmenopausal women with osteoporosis. Enrollment terminated on Aug 2004 with 1423 patients randomized, because too slow recruitment
– Calcium 500 mg + vitamin D 400 IU to all patients– Sites in US, Canada, and Puerto Rico
Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97
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Baseline Characteristics
Characteristic Raloxifene
(N=707)
Alendronate
(N=716)
P-value
Age (years) 65.5 65.7 0.56
Caucasian (%) 86.7 86.9 0.83
BMI (kg/m2) 24.8 24.6 0.42
LS BMD (g/cm2) 0.82 0.82 0.79
T-score -2.32 -2.34 0.65
FN BMD (g/cm2) 0.61 0.61 0.98
T-score -2.39 -2.39 0.77
Total Hip BMD (g/cm2)
0.71 0.71 0.71
T-Score -1.99 -2.01 0.64
Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97
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EVA Trial: Incidence of VFx and Non-V Fx
Women with ≥1 new Fx, n(%)Type of Fx ALN, 10mg/d RLX 60mg/d P value
N=713 N=699
Age, yrs 65.7± 7.8 65.5± 7.7 0.56
Vert or Non Vert 22 (3.1) 20 (2.9) 0.84
Vertebrala 8 (3.1) 5 (1.9) 0.53 Moderate/Severe 4 (1.6) 0 0.04 Clinical Vertebral 3 (0.4) 0 0.1
NonVertebral 14 (2.0) 15 (2.2) 0.86 Nonvertebral-Sixb 11 (1.5) 10 (1.4) 0.89
b Includes the clavicule, humerus, wrist, pelvis, hip and leg.
Recker R et al, ASBMR 2005, Abstract in JBMR 2005, 20,Suppl 1,S97
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• Multicenter, double-blind, placebo-controlled trial
• 25 countries, 180 centers, 3 years with 1 year extension
• 7705 postmenopausal women with osteoporosis
• Mean age 66 years
• Raloxifene 60 mg =Evista, 120 mg, or placebo
• All patients given daily elemental calcium (500 mg) and vitamin D (400-600 IU)
• Primary endpoints: radiographic vertebral fracture, BMD, safety
• Secondary endpoints: all osteoporotic fractures, cardiovascular health, breast cancer, cognitive function
Ettinger B et al. JAMA 282:637-45, 1999Cummings SR et al. JAMA 281:2189-97, 1999
MOREMOREMMultiple ultiple OOutcomes of utcomes of RRaloxifene aloxifene EEvaluationvaluation
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Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999,
Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After
Age 5040
30
20
10
50 60 7080
Vertebrae
Hip
Wrist
Age (Years)
Ann
ual i
ncid
ence
pe
r 10
00 w
omen
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Women with and withoutPrevalent Vertebral Fractures
Women withPrevalent Vertebral Fractures
Placebo RLX 60
% o
f Wom
en w
ith
New
Cli
nic
al V
erte
bra
l F
ract
ure
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
RR 0.32 (95% CI, 0.13 - 0.79)
Placebo RLX 600.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
RR 0.34 (95% CI, 0.11 - 0.77)
66%
68%
Risk of New Clinical Vertebral Fractures at 1 Year
Marici et al, Arch. Int med, 2002
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Wom
en w
ith N
ew C
linic
al V
erte
bral
Fra
ctur
e (%
)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.04%(n=1)
0.04%(n=1)
0.04%(n=2)
RR 0.10 (95% CI 0.02-0.41)**
RR 0.10 (95% CI 0.01-0.62)**
RR 0.10 (95% CI 0.01-0.63)**
0.44%(n=10)
Placebo Raloxifene60 mg/d
Raloxifene120 mg/d
RaloxifenePooled
0.44%(n=10)
Effect of Raloxifene on New Clinical Vertebral Fractures at 6 Months
Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.
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Months
0 2 4 6 8 10 12 14 16 18
Wom
en w
ith N
ew
Clin
ical
Ver
tebr
al F
ract
ure
(%
)
0.0
0.2
0.4
0.6
0.8
1.0
PlaceboRaloxifene 60 mg/dRaloxifene 120 mg/d
Cumulative Incidence of New Clinical Vertebral Fractures in the First Year of MORE*
*P=0.007 in the first 6 months foreach raloxifene group compared with placebo
Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.
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Wom
en w
ith N
ew C
linic
al V
erte
bral
Fra
ctur
e (%
)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.04%(n=1)
0.04%(n=1)
0.04%(n=2)
Placebo Raloxifene60 mg/d
Raloxifene120 mg/d
RaloxifenePooled
0.22%(n=5)
RR 0.20 (95% CI 0.03-0.90) *
RR 0.20 (95% CI 0.02-1.31)
RR 0.20 (95% CI 0.02-1.32)
0.22%(n=5)
Effect of Raloxifene on New Clinical Vertebral Fractures at 3 Months
Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.
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Women with severe osteoporosisWomen with severe osteoporosis
• Does raloxifene prevent Does raloxifene prevent multiple newmultiple new vertebral fractures ?vertebral fractures ?
• Does raloxifene prevent Does raloxifene prevent the first severethe first severe vertebral fracture?vertebral fracture?
• Does raloxifene prevent subsequent fracture Does raloxifene prevent subsequent fracture (also non vertebral) when a (also non vertebral) when a severesevere fracture is fracture is present?present?
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Lufkin E et al. North American Menopause Society 12th Annual Meeting Program and Abstract Book, P21, p70, October 4-6, 2001
*p = 0.001
0
0.4
0.8
1.2
PlaceboN=1457
Raloxifene 60 mg/dayN=1401
RR 0.07*(95% CI = 0.01, 0.56)
93%
% o
f Wo
me
n w
ith
2In
cide
nt V
ert
ebra
l Fra
ctu
res 1.6
Effect of Raloxifene on the Risk of 2 or More New Vertebral Fractures in Women
MORE Trial - 3 Years
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Semiquantitative Evaluation of Vertebral Fracture Severity
*Percent reduction in anterior, mid and/or posterior vertebral heightAdapted from: Genant HK et al. J Bone Miner Res 8:1137-1148, 1993
MiddleAnterior Posterior
Fracture Grade
0- Normal
1- Mild(20-25%*)
2- Moderate(26-40%*)
3- Severe
(>40%*)
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Risk of At Least 1 New Moderate/Severe Vertebral Fracture
MORE Trial – 3 Year
% o
f W
omen
with
At
Leas
t 1
New
Mod
erat
e/S
ever
e V
erte
bral
Fra
ctur
e
0
5
10
15
20
RR 0.39 (95% CI 0.17, 0.69)
RR 0.63(95% CI 0.49, 0.83)
WithoutWithout Preexisting PreexistingVertebral FracturesVertebral Fractures
WithWith Prevalent PrevalentVertebral FracturesVertebral Fractures
PlaceboRLX 60 mg/d
61%61%
37%37%
Siris E et al. Osteoporosis Int 13:907, 2002
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Reduction of 47% of at Least 1 New Nonvertebral* Fracture in Women With Baseline SQ Grade 3
MORE Trial - 3 Years
0
5
10
15
20
% o
f W
omen
with
at
Leas
t 1
New
Non
vert
ebra
l Fra
ctur
e
RH=0.53 (95% CI 0.29, 0.99) P=0.04
Placebo Raloxifene 60 mg/d
* Clavicle, humerus, wrist, pelvis, hip, legDelmas PD et al. Bone 2003;33;4:522-532
47%
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Raloxifene prevents Non Vertebral Fracture in Women with 2 Prevalent Vertebral Fractures
(n= 1369, mean age 69y MORE Trial - 3 Years – pooled raloxifene
Nonvertebral Fracture *
Farrerons et al., CTI, 2003;72(4):391(P230)
0
10
20
30
40
% o
f Wo
me
n W
ith a
t Le
ast
1
New
non
-Ve
rteb
ral F
ract
ure RR=0.69 (95% CI 0.48, 0.99)
P<0.05
Placebo Raloxifene
31%
* Clavicle, humerus, wrist, pelvis, hip, leg
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Randomized Studies of Antiresorptives in Postmenopausal Osteoporotic Women*
Risk of Vertebral Fractures
1Data on file, Eli Lilly & Co.2Black DM et al. Lancet 348:1535-1541, 19963Cummings SR et al. JAMA 280:2077-2082, 1998
4Harris ST et al. JAMA 282:1344-1352, 19995Reginster JY et al. Osteoporosis Int 11:83-91, 20006 Chesnut CH et al. Am J Med 109:267-276, 2000
LS BMD** Relative Risk (95% CI)
Raloxifene60 mg/d
Preexisting vertebral fracture (VFx)1
No preexisting VFx1
2.2
2.9
Alendronate
5/10 mg/d
Preexisting VFx2
No preexisting VFx3
6.26.8
Risedronate5 mg/d
Preexisting VFx4
Preexisting VFx5
4.35.9
Calcitonin200 IU/d
Preexisting VFx6 0.7
*Not head -to-head comparison, **vs placebo 0.5 1.00
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Differences in Trial Design: Baseline fracturesCa and Vitamin D Supplementation / Ethical rules
Baseline fractures and age quite different between trials
Differences in calcium and vitamin D supplementation, a regimen that has been shown to reduce the risk of hip fractures, may have also contributed to the different results in hip.
The estimated number of patients who received calcium and vitamin D supplementation in the FIT and WHI HRT trial was 30 -40%.
• All patients in the MORE trial were supplemented in the trial.
• MORE had stringent ethical rules : patients having a fracture or losing too much BMD could discontinue: ¾ more patients discontinued in placebo, strong bias against raloxifene
• Also ¾ more patients took additional bone active drug in 4th year
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Number Needed to Treat (NNT) to Prevent 1 Vertebral Fracture
†Delmas PD, et al. J Clin Endocrinol Metab. 2002; 87:3609-3617.‡Marcus R, et al. Endocrine Rev. 2002;23:16-37.
*Not head-to-head comparisons
Raloxifene 60 mg/d† 4.034
Alendronate 5/10 mg/d‡ 4.260
NNTStudy Duration (Years)
Without Preexisting Vertebral Fracture
Raloxifene 60 mg/d‡ 3.016
Alendronate 5/10 mg/d‡ 2.914
Risedronate 5 mg/d‡ 3.020
With Preexisting Vertebral Fracture
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0
1
2
3
4
5
6
7
8
9
10
RR: 0.11 (0.03-0.51)
6.0%(n=12)
1.0%(n=2) 0.7%
(n=2)
RR: 0.17 (0.04-0.75)
Placebo Raloxifene 60 mg/day
Raloxifene Pooled
Nakamura et a, IBMS-ECTS Geneva, June 2005, and Bone 36, Suppl 2
Japan-China trials: Any New Clinical Fractures
Asian Women with Osteoporosis - One Year
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Raloxifene Bone Efficacy - Summary
• Significant reduction in risk of vertebral fractures • 66% in risk of clinical vertebral fractures during the first year
• 55% in risk of women without preexisting vertebral fractures at 3 years of therapy.
• Efficacy sustained in the 4th year (40-50% reduction).
• 93% in risk of multiple vertebral fractures at 3 yr in those without preexisting vertebral fractures
• 47% in risk of non vertebral fractures in women with severe vertebral fractures or 31% in women with 2 pre-existing fractures
• Improves properties of bone quality
• 34% reduction of non vertebral fractures in MORE+CORE 8 y in women with pre-existing SQ3 fracture
• Easy to use and good tolerability
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MORE, Multiple Outcomes of Raloxifene Evaluation; CORE, Continuing Outcomes Relevant to EVISTA; RUTH, Raloxifene Use for The Heart; STAR, Study of Tamoxifen and Raloxifene; EVA, EVISTA-Alendronate Comparison
0
5000
10000
15000
20000
1,764
7,705
4,011
10,101
19,365
Nu
mb
er
of E
nro
lled
Wo
men
OsteoporosisPrevention
MORE CORE RUTH STAR EVA
1,400 –1y
Completed and Ongoing Large-Scale Raloxifene Clinical Trials
2004
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Breast Cancer
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Effect of Raloxifene on All Breast Cancer
MORE Trial - 4 Years
Years since RandomizationTotal Cases = 77
Arrow denotes annual mammogram (*optional)
Sourced from Cauley J et al. Breast Cancer Res Treatment 65:125-34, 2001
0.0
2.0
1.0
1.5
0.5
% o
f Ran
dom
ize
d P
atie
nts
0 1 2 3 4
RR = 0.38 (95% CI = 0.24-0.58)NNT = 94
62%
*
RLX (pooled)
Placebo
2004
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MORE plus CORE Study Design
0 1 2 3 4 5 6 7 8
Placebo
Raloxifene HCl 60 mg/day
Raloxifene HCl 120 mg/day
Placebo
Raloxifene HCl 60 mg/day
Year
8 Years Total Follow-up
MORE (N=7705)Three Treatment
Groups
CORE (n=4011)Two Treatment
Groups
GapMORE ConclusionCORE Screening
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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CORE Study Objectives
• Determine the effect of raloxifene on incidence of invasive breast cancer over an additional 4 years of therapy (8 years total for MORE + CORE)
• Determine the effect of raloxifene on incidence of invasive, ER(+) breast cancer over the same time period
• Assess the tolerability of raloxifene over 8 years
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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Breast Cancer Assessment
• Clinical breast exams:
• MORE: every 6 months• CORE: every 12 months
• Mammograms:
• MORE: baseline and after 2, 3, and 4 years of treatment
• CORE: baseline and after years 2 and 4 of treatment
• Breast cancer cases adjudicated by an independent committee of physicians blinded to treatment assignment and not affiliated with study sponsor
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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CORE Demographics at MORE Baseline
Mean age, yr 66.5 66.2
Age 60 years (%) 81.581.2
Mean BMI, kg/m2 25.225.3
Caucasian, (%) 95.795.5
Current smoker, (% yes) 16.716.2
Mean time postmenopause, yr 18.718.4
Family history of breast cancer, (%) 12.6
12.0
Hysterectomy, (% yes) 22.721.4
Previous hormone therapy, (%) 29.126.5
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
CORE Enrollees(N = 4011)
65.8
80.1
25.2
96.2
16.0
17.9
11.9
20.4
25.6
Characteristic
MORE Participants(N = 7705)
CORE PrimaryAnalysis Dataset
(N = 5213)
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Incidence of Invasive Breast Cancer4 Years of CORE
Cum
ulat
ive
Inci
denc
e (%
)
0 1 2 3 4
HR 0.41 (95% CI = 0.24-0.71)
Year
0.0
1.0
2.0
3.0
4.0
N=5213
Placebo5.2 per 1000 Women-Yrs
Raloxifene2.1 per 1000 Women-Yrs
p <0.001 59%
Jan 1, 1999Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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Incidence of Invasive Breast Cancer8 Years of MORE plus CORE (N=7705)
Years in Study
0 1 2 3 4 5 6 7 80.0
1.0
2.0
3.0
4.0
HR 0.34 (95% CI = 0.22-0.50)
Placebo4.2 per 1000 Women-Yrs
Raloxifene1.4 per 1000 Women-Yrs
p <0.001
Cu
mu
lati
ve In
cid
enc
e (%
)
66%
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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0
0.5
1
1.5
2
2.5
3
3.5
4
Placebo (N=2576)
Raloxifene (N=5129)
HR 0.24(95% CI = 0.15 to 0.40)
P <.001
HR 1.06(95% CI = 0.43 to 2.59)
P = .90
Inci
den
ce/1
000
wo
man
-yea
rs
ER+ breast cancer
n=44 n=22 n=7 n=15
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
Incidence of Invasive ER+ and ER-
Breast Cancer8 Years of MORE Plus CORE Trials
ER- breast cancer
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Summary of Adverse Outcomes over the 8 Years of MORE-CORE (N=4011)
Percentage of participants who experienced event (n)
P-valuePlacebo(N=1286)
Raloxifene(N=2725)
Mortality 2.3 (29) 1.7 (47) 0.27
All cancers† 8.6 (110) 5.7 (156) 0.001
All cancers† excluding breast cancer 6.3 (81) 4.6 (126) 0.027
Hospitalization 40.9 (526) 38.8 (1057) 0.21
Treatment-emergent AEs 99.0 (1273) 98.6 (2688) 0.45
Treatment-emergent serious AEs 45.5 (585) 42.3 (1154) 0.07
Study discontinuation CORE due to AE 2.4 (31) 1.9 (53) 0.35
†Excluding non-melanoma skin cancersMartino S et al. Curr Med Res Opin 2005
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Summary of Gynecologic AE Data over the 8 Years of MORE-CORE (N=4011)
Percentage of participants who experienced event (n)
P-valuePlacebo(N=1286)
Raloxifene(N=2725)
Uterine cancer†‡ 0.39 (4) 0.32 (7) 0.75
Endometrial hyperplasia‡ 0.29 (3) 0.37 (8) >0.99
Ovarian cancer 0.16 (2) 0.11 (3) 0.66
Postmenopausal bleeding‡§ 5.4 (55) 5.5 (120) 0.87
Vulvovaginal signs and symptoms
5.8 (75) 5.0 (135) 0.26
Martino S et al. Curr Med Res Opin 2005
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Flushing (hot flushes) 89 (6.9) 342 (12.6) <0.001
Leg cramps 152 (11.8) 407 (14.9) 0.008
Peripheral edema 120 (9.3) 288 (10.6) 0.240
Adverse Events Reported During MORE Plus CORE – 8 Years
Number (%)
Placebo Raloxifene p-value(n=1286) (n=2725)
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
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CORE CORE/MORE
N 277 1425 615
Adapted from Siris ES et al; J Bone Miner Res 2005; 20:1514-1522
Raloxifene and Non-Vertebral Fx at 8 yrs:Poisson analyses
SQ 1,2 SQ 3 Prev Fx SQ 1,2 SQ 3
1.0
0.660.78
[0.86,1.17]
[0.43,1.02][0.63, 0.96]
0.94
0.64
[0.44, 0.92]
[0.83, 1.07]
Inci
den
ce R
R (
95%
CI)
at
6 si
tes
Inci
den
ce R
R (
95%
CI)
at
6 si
tes
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FoamCells
FattyStreak
IntermediateLesion Atheroma
FibrousPlaque
ComplicatedLesion
Lipid accumulationEndothelial injury
Pathophysiology of Atherothrombosis
Plaque Rupture
Clinical Events
Inflammation
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Effect of Raloxifene 60 mg/d on Cardiovascular Risk Factors
Bas
elin
e to
6 M
ont
h C
hang
e (
%)
Com
pare
d to
Pla
cebo
-15
-10
-5
0
5
*
**
TotalChol LDL-C HDL-C TG Fibrinogen
-7% -12% 0% -4% -10%
*P<0.05 vs. placeboAdapted from Walsh BW et al., JAMA 1998;279:1445-51
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High-Risk Womenn = 1035
Cumulative Incidence of Cardiovascular EventsMORE Trial – 4 Years
All Enrolled WomenN = 7705
Months Since Randomization
Adapted from Barrett-Connor E et al. JAMA 287:847-57, 2002
0 12 24 3648
14
12
10
8
6
4
20
PlaceboRLX 60 mg/d
0 12 24 36
4
0 12 24 36 48
14
12
10
8
6
2
0
PlaceboRLX 60 mg/d
RR=0.86(95% CI=0.64-1.15)
RR=0.60(95% CI=0.38-0.95)
40%
Total number of events = 272 Total number of events = 97
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RUTH StudyRaloxifene Use for The Heart
• 10,101 patients, DBRCT, placebo vs raloxifene (60 mg/d)• Entry: postmenopausal women at high risk for, or
suffering from, heart disease• Primary endpoints
– Coronary: CHD death, non-fatal MI, or hospitalized acute coronary syndrome other than MI
– Invasive breast cancer
• Length of trial: up to 7.5 years with anticipated completion in 2006
DBRCT= double-blind, randomized, controlled trialCHD=coronary heart diseaseMI=myocardial infarction
Wenger NK, et al. Am J Cardiol.2002;90:1204-1210.
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NSABP-P2 (STAR) StudyStudy of Tamoxifen And Raloxifene
• 19,747 patients, double-blind, randomized – Tamoxifen (20 mg/d) vs raloxifene (60 mg/d)
• Entry: postmenopausal, high risk for invasive breast cancer (lobular carcinoma in situ or 5-year risk of >1.67% by the Gail model)
• Primary endpoint– Invasive breast cancer
• Secondary endpoints:– Uterine safety, nonvertebral fracture, cardiovascular, overall toxicity
and side effects• Started 1999 with final analyses when 327 cases have occurred but
women will continue to be followed; results anticipated in 2006
Vogel V, et al. Clin Breast Cancer. 2002;3:153-159.
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WHI Estrogen-Progestin TrialGlobal Index Assessment of Risk-Benefit
• Defined to summarize important aspects of health benefits vs risks
• Defined for each woman as the earliest occurrence of:
– Coronary heart disease (CHD)
– Pulmonary embolism
– Invasive breast cancer
– Stroke
• Endometrial cancer
• Colorectal cancer
• Hip fracture
• Death due to other causes
Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.
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Global Safety Index Assessing Risk and Benefit
2. Barrett-Connor E. et al., J Bone Minral Res, 2004:Aug; 19,1270-1275.
1. Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.
Not head-to-head trials.
1
1.1
1.2
1.3
WHI1 CEE/MPA
Re
lativ
e R
isk NNH = 88
Increased Increased HarmHarm HR 1.15
95% CI 1.03-1.28
Increased Increased BenefitBenefit
Re
lativ
e R
isk
0.7
0.8
0.9
MORE2
Raloxifene 60 mg/d
NNT = 69
HR 0.75HR 0.7595% CI 0.6-0.9695% CI 0.6-0.96
0.6
1
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Effect of Raloxifene on WHI Global Risk-Benefit Index
0.0
0.5
1.0
1.5
2.0
Eve
nt R
ate
Ann
ualiz
ed %
Placebo Raloxifene60 mg/d
Raloxifene120 mg/d
HR, 0.7595% CI, 0.60-0.96
HR, 0.7595% CI, 0.59-0.95
Barrett-Connor E. et al., J Bone Minral Res, 2004:Aug; 19,1270-1275
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Raloxifene Administration and Tolerability
• Single daily dose (60 mg tablets)• Liver metabolism (glucuronidation)• May be given without regard to meals or time of day
• No adjustment needed for most commonly used concomitant medications
• Can be used with Calcium and Vit D (recommended in patients with fractures)
• No GI side effects
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16.4
4.83.4
25.8
119.9
0
5
10
15
20
25
30
% P
atie
nts
RaloxifeneAlendronate
P<0.001
Turbí C et al. Clin Ther 26:245-256, 2004.
P<0.001
Tolerability With Raloxifene Vs AlendronateIn the Clinical Practice at 12 Months
(n=476)(n=426)
P<0.001
Total Discontinuation DiscontinuationDiscontinuation due to Aes due to GI disorders
2004
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• Primary: To demonstrate that raloxifene is associated with better adherence compared with daily dosing bisphosphonates in Asian postmenopausal women at increased risk of osteoporotic fractures.
• Secondary: To demonstrate that raloxifene therapy is associated with improved:
– treatment satisfaction– quality of life
compared with bisphosphonates.
Comparison of Raloxifene and Bisphosphonates on Adherence, Health Outcomes and Treatment Satisfaction
in Post-Menopausal Asian WomenCHOOSE Asia Observational Study
Objectives:
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005
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Methods - 1
Bisphosphonates (alendronate, risedronate, etidronate)
Raloxifeneor
VISIT 1Baseline
VISIT 26 months
VISIT 312 months
Study Design• One-year, open-label, observational study conducted in:
– Hong Kong– Malaysia– Pakistan– Philippines– Singapore– Taiwan.
• Postmenopausal women aged 55 years or older and at increased risk of osteoporosis.
• Study treatments administered by a physician during the normal course of care:
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Characteristic Raloxifene
N = 707
Bisphosphonates
N = 277
Age (years), Mean ± SD (range) 66.9 ± 8.5 (55-97) 67.7 ± 9.2 (55-91)
Race/ethnicity, n (%):
Chinese
Malay
Filipino
Indian sub-continent
Asian – other
364 (51.5)
6 (0.8)
186 (26.3)
144 (20.4)
7 (1.0)
120 (43.3)
3 (1.1)
79 (28.5)
69 (24.9)
6 (2.2)
Menopause, n (%)
Natural
Surgical
613 (86.7)
94 (13.3)
237 (85.6)
40 (14.4)
No. years since menopause,
Mean ± SD
17.6 ± 9.9 19.2 ± 10.3 *
Baseline fractures, n (%) 307 (43.4) 116 (41.9)
* p<0.05: ANOVA
Patient Baseline Characteristics
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Adherence Patient Discontinuations
Enrolled: N = 984
Raloxifene treatment n = 707
33.1%
6.8%
5.7%
2.8%
1.4%
Completed study Completed study 50.2% 50.2%
Bisphosphonates treatment n = 277
Completed study Completed study 37.5% ** 37.5% **
37.5%
2.9% *
10.1% *
9.7% **
2.2%
Alendronate n = 206
Risedronate n = 71
* p<0.05; ** p<0.01Fisher’s Exact Test
Lost to follow up
Chose to leave
Stopped treatment
Switched treatment
Reason missing
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005
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* Wilcoxon rank sum test
Adherence Treatment Duration (days)
0 100 200 300 400 500
Raloxifene
Bisphosphonates
Mean Period of Exposure to Medication (days)
p<0.05*
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005
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Treatment Satisfaction at 12 months
feel
bet
ter
no effe
ct
feel
wors
e
20
40
60
80
100 p<0.01*
Raloxifene Bisphosphonates
dissa
tisfie
d
no opin
ion
satis
fied
20
40
60
80
100 p<0.01*
* Fisher’s Exact Test
Pe
rce
nt o
f pa
tient
s
Pe
rce
nt o
f pa
tient
s
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005
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Quality of Life – Mean Change in Health State (VAS) Score
2
4
6
8
10M
ean
Ch
ang
e† fr
om
Bas
elin
e to
En
dp
oin
t p<0.01*
* ANCOVA
Raloxifene Bisphosphonates
†Health State score was out of 100
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005
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Incidence of New Fractures
p=0.058*
p<0.01*
There were no new fractures of the clavicle and pelvis for raloxifene or bisphosphonates
* Fisher’s Exact Test
Raloxifene
Bisphosphonates
0
1
2
3
4
5
6
total wrist spine humerus other
Fracture site
Pe
rcen
tag
e o
f o
f n
ew, s
elf-
rep
ort
ed
frac
ture
s