Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes
in The Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and
Other Factors
Peter Collins, Lori Mosca, Mary Jane Geiger, Deborah Grady, Marcel Kornitzer, Messan G.
Amewou-Atisso, Mark B. Effron, Sherie A. Dowsett, Elizabeth Barrett-Connor and Nanette K.
Wenger
Circulation. 2009;119:922-930; originally published online February 9, 2009;
doi: 10.1161/CIRCULATIONAHA.108.817577
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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Coronary Heart Disease
Effects of the Selective Estrogen Receptor Modulator
Raloxifene on Coronary Outcomes in The Raloxifene Use
for the Heart Trial
Results of Subgroup Analyses by Age and Other Factors
Peter Collins, MD; Lori Mosca, MD, MPH, PhD; Mary Jane Geiger, MD, PhD; Deborah Grady, MD;
Marcel Kornitzer, MD; Messan G. Amewou-Atisso, PhD; Mark B. Effron, MD;
Sherie A. Dowsett, PhD; Elizabeth Barrett-Connor, MD; Nanette K. Wenger, MD
Background—The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor
modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease
or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over
time and for 24 subgroups (17 predefined, 7 post hoc).
Methods and Results—Postmenopausal women (n⫽10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d
or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary
heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the
incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age
categories defined in the Women’s Health Initiative randomized trials. The effect of raloxifene on the incidence
of coronary events differed significantly by age (interaction P⫽0.0118). The incidence of coronary events in
women ⬍60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo
(84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P⫽0.003; absolute risk reduction, 36 per
1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary
events in women ⱖ60 and ⬍70 or ⱖ70 years of age.
Conclusions—In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was
similar across the prespecified subgroups. (Circulation. 2009;119:922-930.)
Key Words: coronary disease 䡲 hormones 䡲 raloxifene 䡲 randomized controlled trial 䡲 risk factors 䡲 women
R
aloxifene, a benzothiophene selective estrogen receptor
modulator, reduces the risk of vertebral fracture and the
incidence of invasive breast cancer1–5 in postmenopausal
women. Its effects on the arterial system include a decrease in
total and low-density lipoprotein (LDL) cholesterol and
levels of inflammatory markers.6,7 Raloxifene induces coronary artery and cardiac myocyte relaxation8,9 through stimulation of endothelial nitric oxide synthase10 and/or effects on
plasma membrane ion channels.9,11 These actions could
potentially translate into a reduction in the incidence of
coronary heart disease (CHD) events in postmenopausal
women.
Editorial p 912
Clinical Perspective p 930
In epidemiological studies, postmenopausal estrogen use
has been associated with a reduction in the risk of CHD.12
This effect was believed to be mediated by the effect of
estrogen on cardiovascular risk factors such as lipids and
nonlipid factors.13–16 On the basis of these observations and
the effects of raloxifene on cardiovascular risk factors, the
Raloxifene Use for The Heart (RUTH) trial was designed to
evaluate the effect of raloxifene on the incidence of coronary
events in postmenopausal women with documented CHD
Received April 10, 2008; accepted November 17, 2008.
From the Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK (P.C.); Department of Medicine,
Columbia University College of Physicians and Surgeons, New York, NY (L.M.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, Ind
(M.J.G., M.G.A.-A., M.B.E., S.A.D.); Departments of Medicine, University of California, San Francisco, and the San Francisco VA Medical Center, San
Francisco (D.G.); Department of Epidemiology and Health Promotion, School of Public Health, Brussels Free University, Brussels, Belgium (M.K.);
Departments of Family and Preventive Medicine and of Medicine, University of California–San Diego, La Jolla, Calif (E.B.-C.); and Emory University
School of Medicine, Atlanta, Ga (N.K.W.).
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00190593.
Correspondence to Professor Peter Collins, Department of Cardiology, Royal Brompton and Harefield NHS Trust and NHLI, Imperial College London,
Sydney St, London SW3 6NP, UK. E-mail [email protected]
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.817577
922
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Collins et al
(n⫽5034) or CHD risk factors (n⫽5067). RUTH was an
international, multicenter, randomized, double-blind,
placebo-controlled clinical trial that enrolled 10 101 postmenopausal women to receive either raloxifene 60 mg or
placebo daily.17
Although randomized trials have failed to show a reduced
risk of CHD events with hormone therapy (HT), this may
reflect the timing of the initiation of therapy. HT and
raloxifene may not be effective in older women. A similar
lack of effect on cardiovascular events by statin therapy in
elderly women has been demonstrated in one study.18 This
may be due to changes in the underlying biological characteristics of the vessel wall and vascular responses to estrogen
and related molecules in older, more atherosclerotic vessels.19
To investigate this hypothesis, we specifically evaluated, in a
post hoc analysis, the effect of raloxifene on the incidence of
coronary events in women ⬍60 years of age in the RUTH
trial and by discrete age at study entry in a manner similar to
that reported in the Women’s Health Initiative and Nurses’
Health Study of postmenopausal women and HT.20 –22
The overall findings of the RUTH trial have been reported.4 In the present report, we provide detailed results of the
effect of raloxifene on coronary outcomes in women with
CHD risk factors or established CHD and for 24 subgroups
defined according to demographics, clinical characteristics,
and selected biomarkers. We also report the effect of raloxifene on coronary outcomes over time.
Methods
Study Population, Recruitment, and Follow-Up
Between June 1998 and August 2000, 10 101 women were randomized at 177 sites in 26 countries. Eligible women were ⱖ55 years of
age, ⱖ1 year postmenopausal, and at increased risk for CHD events
or with established CHD.17 Participants were required to have a
cardiovascular risk score of ⱖ4 according to a point system that took
into account the presence of risk factors for myocardial infarction
(MI) and coronary death identified through epidemiological study.
Points were awarded as follows: established CHD⫽4 points; arterial
disease of the leg⫽4 points; age of at least 70 years⫽2 points;
diabetes mellitus (self-reported diabetes mellitus and use of oral
hypoglycemic medication or insulin or fasting serum glucose ⬎140
mg/dL at visit 1)⫽3 points; cigarette smoking (self-reported smoking of an average of ⱖ10 cigarettes a day over the 6 months before
visit 1)⫽1 point; hypertension (self-reported hypertension and use of
antihypertensives or systolic blood pressure ⬎160 mm Hg or diastolic blood pressure ⬎95 mm Hg on at least 2 measurements)⫽1
point; and hyperlipidemia (use of lipid-lowering medications, a
fasting LDL cholesterol ⬎160 mg/dL, or fasting high-density lipoprotein [HDL] cholesterol ⬍45 mg/dL with fasting triglycerides
⬎250 mg/dL)⫽1 point.17 Further details of the trial design have been
published.4,17,23
The primary end points of RUTH were a combined coronary end
point, defined as coronary death, nonfatal MI, and hospitalized acute
coronary syndrome (ACS) other than MI, whichever occurred first,
and invasive breast cancer. Women were followed up for a minimum
of 5 years after the last participant was enrolled. ECGs were recorded
at baseline, at years 2 and 4, and at the final visit for the assessment
of silent MI. Fasting biochemical and lipid assays were performed at
baseline, at years 1 and 5, and at the final visit. Fibrinogen levels
were measured in a subset of women enrolled in US centers.
Throughout the study, the Executive Committee communicated to all
investigators the need to implement the standards of cardiovascular
care according to published guidelines.
Raloxifene and Coronary Outcomes
923
End-Point Ascertainment
The Coronary Primary End Point Committee comprised 10 independent cardiologists, none of whom were employees of Eli Lilly and
Co. This committee, which was blinded to treatment assignment,
adjudicated all investigator-reported events of coronary death, nonfatal MI, or hospitalized ACS other than MI.
An event was adjudicated as an MI if at least one of the following
criteria was present: (1) ischemic symptoms and cardiac enzyme
levels ⬎2 times the upper limit of normal with or without new or
equivocal changes on ECG, (2) new Q waves with or without
ischemic symptoms (ie, including silent MI) or cardiac enzyme
levels ⬎2 times the upper limit of normal, and (3) new Q waves or
markedly abnormal levels of cardiac enzymes after invasive coronary procedures. Hospitalized ACS was defined as hospitalization
for or the development during hospitalization of one of the following: cardiac symptoms with new ST-T changes on ECG or cardiac
enzyme levels above the upper limit of normal but ⬍2 times the
upper limit of normal or troponin above the upper limit of normal.
An event was adjudicated as coronary death if it was due to acute MI,
a coronary artery procedure, or heart failure in the presence of
coronary artery disease or if death was sudden or unwitnessed.
Myocardial revascularization was defined as coronary artery
bypass graft or catheter-based coronary revascularization, whereas
noncoronary arterial revascularization was defined as carotid and
lower-extremity revascularization. All events were required to be
documented by a procedure report or an equivalent document.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Statistical Analysis
Baseline characteristics were compared between treatment groups
and between women with CHD risk factors and women with
established CHD through the use of 1-way ANOVA for continuous
variables and ␹2 tests for categorical variables.
Outcomes analyses followed the intention-to-treat principle and
were based on independently adjudicated components of the primary
coronary end point. A log-rank test was used to compare the
incidence of coronary events between treatment groups. Statistical
significance for treatment group differences in the incidence of
coronary events was tested at the 2-sided level of ␣⫽0.0423,
obtained from an ␣ spending rule that accounted for the multiplicity
of the coronary end point and the 3 planned interim analyses. For all
other analyses, statistical significance for treatment effect was tested
at ␣⫽0.05 for a nominal probability value. In RUTH, the power
calculations were based on assumptions of a 20.0% relative reduction in the incidence of coronary events and a 58.5% relative
reduction in the incidence of invasive breast cancer (the other
primary outcome in RUTH).
For all analyses, unadjusted Cox proportional-hazards regression
models were used to estimate hazard ratios (HRs) and their 95%
confidence intervals (CIs) for the primary and secondary coronary
outcomes. Time to event was defined as the number of days between
randomization and the first diagnosis of a coronary event. Participants not experiencing the event were censored at the last date, at
which time study information was collected, or their date of death.
Secondary analyses compared the rate of coronary events between
treatment groups in an “as-treated” population defined as women
who were at least 70% adherent to the study treatment on the basis
of the pill count. Coronary and revascularization outcomes were
assessed separately for women with CHD risk factors and those with
established CHD through the use of Cox proportional-hazards
models.
Prespecified (n⫽17; race, body mass index, prior MI, prior angina
with documented CHD, prior coronary artery bypass graft, lowerextremity arterial disease, cardiovascular risk score, current smoker,
diabetes mellitus, hypertension, hyperlipidemia, statin use, aspirin
use, ␤-blocker use, calcium channel blocker use, angiotensinconverting enzyme inhibitor or angiotensin receptor blocker use,
diuretic use) and post hoc (n⫽7; Women’s Health Initiative–
specified age, total cholesterol, LDL cholesterol, HDL cholesterol,
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Circulation
Table 1.
February 24, 2009
Baseline Characteristics of All Women Randomized in RUTH With CHD Risk Factors or With Established CHD
With CHD Risk Factors (n⫽5067)
Established CHD (n⫽5034)
Characteristic
Placebo (n⫽2561)
Raloxifene (n⫽2506)
Placebo (n⫽2496)
Raloxifene (n⫽2538)
Mean age, y
67.50⫾6.81
67.27⫾6.76
67.47⫾6.54
67.65⫾6.48
⬍60
17.26
18.52
16.11
14.26
···
60–69
42.09
42.62
46.79
48.07
···
ⱖ70
40.65
38.87
37.10
37.67
···
29.26⫾5.41
29.40⫾5.49
28.16⫾4.71
28.27⫾4.78
⬍0.001
17.18
17.72
8.37†
6.42
⬍0.001
19.29⫾8.08
18.93⫾8.86
19.69⫾8.51
19.70⫾8.76
⬍0.001
Diabetes mellitus, %
64.65
64.38
26.39
27.11
⬍0.001
Hypertension, %
85.04
85.08
70.42
70.79
⬍0.001
Hyperlipidemia, %
66.38
65.84
80.93
80.58
⬍0.001
Age range, y, %
P*
0.181
0.013
2
Mean body mass index, kg/m
Current smoker, %
Mean time postmenopausal, y
Prior MI, %
0
0
58.81
58.39
Prior CABG, %
0
0
31.37†
34.32
0
43.78
43.94
Prior PCI, %
0
Lower-extremity arterial disease, %
13.39
Prior angina pectoris with documented CHD
Mean CV risk score
0
5.3⫾1.49
13.57
⬍0.001
7.90
8.00
65.63
67.10
5.28⫾1.44
10.26⫾3.70†
10.52⫾3.93
⬍0.001
0
Baseline medication use, %
Statins
30.93
30.29
62.86
63.95
⬍0.001
Antihypertensive
85.63
86.11
93.31
92.95
⬍0.001
Nitrates
18.20
17.76
49.84
48.98
⬍0.001
Warfarin
2.54
2.71
5.21
6.07
⬍0.001
Aspirin
32.33
32.20
81.61
80.34
⬍0.001
1.64
2.23
4.01
3.94
⬍0.001
Oral hypoglycemic agent
49.28
49.28
17.99
18.95
⬍0.001
Insulin
19.45
18.99
9.13
8.59
⬍0.001
31.92
30.99
50.98
49.21
⬍0.001
Total cholesterol, mmol/L
5.82
5.79
5.52
5.48
⬍0.001
LDL cholesterol, mmol/L
3.24
3.24
3.07
3.05
⬍0.001
Nonaspirin antiplatelet agent
Abnormal ECG
HDL cholesterol, mmol/L
1.37
1.37
1.35
1.34
0.006
Non-HDL cholesterol, mmol/L
4.44
4.42
4.16
4.14
⬍0.001
Triglycerides, mmol/L
1.85
1.84
1.74
1.74
⬍0.001
Fibrinogen, mmol/L
1.05
1.03
1.04
1.06
0.441
CABG indicates coronary artery bypass graft; PCI, percutaneous coronary intervention; and CV, cardiovascular.
*P values refer to differences between subgroups (with CHD risk factors versus with established CHD), with treatment groups combined within each subgroup.
†Significant differences between placebo and raloxifene treatment groups.
and triglycerides groups; geographical region of the world; years
since menopause) exploratory subgroup analyses were performed to
assess the consistency of the effect of treatment with raloxifene on
CHD risk; interaction effects were tested at the 0.10 significance
level using 1- or 2-df tests for the interaction terms in Cox
proportional-hazards regression models. In the post hoc age subgroup analysis, the prespecified age cuts for the age subgroup
analysis (ⱕ65, ⬎65 and ⬍70, and ⱖ70 years of age) were changed
to match those in the Women’s Health Initiative randomized trials.24
No adjustments for multiple testing were made for these subgroup
analyses.
To further explore the effect of raloxifene on the incidence of
coronary events by age, a post hoc Cox proportional-hazards
regression model was fitted with age as a continuous variable. The
log (hazard) was modeled as a quadratic function of age, with age as
a continuous variable and terms for treatment and treatment interac-
tions with age and age.2 HRs and 95% CIs were calculated at discrete
ages (for each discrete year from 54 to 70 years of age and then every
2 years thereafter). Baseline laboratory values and percentage change
from baseline to 1 year were analyzed with the use of an unadjusted
ranked 1-way ANOVA. All statistical analyses were performed with
SAS software version 8.2 (SAS Institute, Inc, Cary, NC).
Results
Baseline Characteristics
Overall, treatment groups were similar with respect to baseline characteristics except for a slightly higher cardiovascular
risk score in the raloxifene group (placebo, 7.8; raloxifene,
7.9; P⫽0.03)4 and a higher proportion of women with
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180
160
Placebo
Raloxifene
140
HR 0.95 (95% CI 0.84 - 1.07)
Log-rank test p-value = 0.40
120
100
80
60
40
20
B
180
Cumulative incidence, per 1000 women
A
Cumulative incidence, per 1000 women
Collins et al
160
Raloxifene and Coronary Outcomes
Placebo
Raloxifene
140
HR 0.87 (95% CI 0.71 - 1.06)
Log-rank test p-value = 0.16
120
100
80
60
40
20
0
0
0
1
2
3
4
5
6
0
7
1
2
3
Cumulative incidence, per 1000 women
160
Placebo
Raloxifene
140
HR 0.90 (95% CI 0.73 - 1.11)
Log-rank test p-value = 0.34
120
100
80
60
40
20
D
180
Cumulative incidence, per 1000 women
180
160
0
1
2
3
4
5
6
6
7
4
5
6
7
4
5
6
7
Placebo
Raloxifene
140
HR 0.92 (95% CI 0.77 - 1.09)
Log-rank test p-value = 0.31
120
100
80
60
40
20
7
Year
180
F
Placebo
Raloxifene
160
140
0
Cumulative incidence, per 1000 women
Cumulative incidence, per 1000 women
5
0
0
E
4
Year
Year
C
925
HR 0.91 (95% CI 0.74 - 1.11)
Log-rank test p-value = 0.36
120
100
80
60
40
20
1
2
3
Year
180
Placebo
Raloxifene
160
140
HR 0.97 (95% CI 0.83 - 1.12)
Log-rank test p-value = 0.66
120
100
80
60
40
20
0
0
0
1
2
3
4
5
6
Year
7
0
1
2
3
Year
Figure 1. Cumulative incidence for (A) primary coronary outcome, (B) nonfatal MI (including silent MI), (C) hospitalized ACS (HACS)
other than MI for the entire cohort (n⫽10 101), and (D) coronary death. Cumulative incidence for the primary coronary outcome for (E)
women with CHD risk factors (n⫽5067) and (F) women with established CHD (n⫽5034).
coronary artery bypass surgery in the raloxifene group (placebo, 15.5%; raloxifene, 17.3%; P⫽0.015).
Of the 10 101 participants, 5067 women (50.2%) had CHD
risk factors (placebo, 2561; raloxifene, 2506), and 5034
women (49.8%) had established CHD (placebo, 2496; raloxifene, 2538). The baseline characteristics for women with
CHD risk factors and those with established CHD are
presented in Table 1. Within each subpopulation, the baseline
characteristics were similar between treatment groups except
that among women with CHD a higher prevalence of smoking
was found in women assigned placebo and a higher mean
cardiovascular risk score and reported history of coronary
artery bypass surgery in women assigned raloxifene (see
Table 1 footnote). Most baseline characteristics differed
significantly between women with CHD and those with CHD
risk factors; women with CHD risk factors had a higher body
mass index; reported a higher prevalence of smoking, diabetes mellitus, and hypertension; reported lower use of statins and
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Circulation
Table 2.
February 24, 2009
Incidence and HR for Coronary Events and Revascularizations for Women With Risk Factors for CHD or Established CHD
With CHD Risk Factors
With Established CHD
Events, n (Annualized Rate, %)
End Point
Events, n (Annualized Rate, %)
Placebo (n⫽2561)
Raloxifene (n⫽2506)
HR (95% CI)
Placebo (n⫽2496)
Raloxifene (n⫽2538)
HR (95% CI)
Primary coronary point*
200 (1.54)
182 (1.40)
0.91 (0.74–1.11)
353 (2.81)
351 (2.72)
0.97 (0.83–1.12)
Nonfatal MI or HACS
112 (0.86)
89 (0.68)
0.80 (0.60–1.05)
248 (1.98)
237 (1.84)
0.93 (0.78–1.11)
71 (0.54)
54 (0.41)
0.76 (0.53–1.09)
137 (1.06)
129 (0.97)
0.92 (0.72–1.17)
Nonfatal MI
HACS
53 (0.40)
40 (0.30)
0.76 (0.50–1.14)
132 (1.03)
129 (0.98)
0.95 (0.75–1.21)
Coronary death
112 (0.84)
104 (0.79)
0.93 (0.71–1.22)
162 (1.23)
151 (1.12)
0.91 (0.73–1.13)
Acute MI
15 (0.11)
12 (0.09)
0.81 (0.38–1.72)
30 (0.23)
21 (0.16)
0.68 (0.39–1.19)
Sudden death
62 (0.47)
54 (0.41)
0.87 (0.61–1.26)
75 (0.57)
74 (0.55)
0.96 (0.70–1.33)
Unwitnessed death
Heart failure⫹CAD history
3 (0.02)
2 (0.02)
0.67 (0.11–4.00)
1 (0.01)
1 (0.01)
NA
21 (0.16)
21 (0.16)
1.00 (0.55–1.83)
38 (0.29)
36 (0.27)
0.92 (0.59–1.46)
CAD procedure related
3 (0.02)
6 (0.05)
2.01 (0.50–8.03)
8 (0.06)
3 (0.02)
0.37 (0.10–1.38)
Coronary cause unavailable
8 (0.06)
9 (0.07)
1.12 (0.43–2.91)
10 (0.08)
16 (0.12)
1.56 (0.71–3.43)
199 (1.56)
189 (1.48)
0.95 (0.78–1.16)
416 (3.49)
422 (3.44)
0.99 (0.86–1.13)
133 (1.03)
121 (0.93)
0.91 (0.71–1.16)
334 (2.75)
338 (2.70)
0.98 (0.85–1.14)
PCI
77 (0.59)
77 (0.59)
1.00 (0.73–1.38)
244 (1.97)
243 (1.89)
0.96 (0.81–1.15)
CABG
60 (0.46)
45 (0.34)
0.75 (0.51–1.10)
104 (0.81)
104 (0.79)
0.98 (0.74–1.28)
Other
0 (0.00)
1 (0.01)
NA
3 (0.02)
2 (0.02)
0.65 (0.11–3.89)
All revascularizations†
Coronary revascularization
HACS indicates hospitalized ACS; CAD, coronary artery disease; PCI, percutaneous coronary intervention; and CABG, coronary artery bypass graft.
*Primary coronary point comprised coronary death, nonfatal MI, or hospitalized ACS other than MI. For any participant with multiple coronary events, each event
was counted in each subcategory separately, but participants were counted only once in the primary coronary point analysis.
†All revascularizations comprised coronary and noncoronary revascularizations.
aspirin; and had higher total cholesterol and LDL cholesterol
levels (Table 1) than women with established CHD.
The median duration of follow-up was 5.6 years for both
treatment groups. Overall, 71% of women in the placebo
group and 70% in the raloxifene group took at least 70% of
assigned medication and were classified as adherent to
treatment (P⫽0.62).
(interaction P⫽0.64). The results of as-treated analyses were
similar to those of the intention-to-treat analyses for the
primary coronary outcome (HR for the comparison of the
raloxifene group with the placebo group, 0.96; 95% CI, 0.83
to 1.12; P⫽0.61) and its individual components (P⬎0.05 for
each comparison).
Coronary Events by Subgroup
Coronary Events
No effect of raloxifene was found on incidence of all
coronary events (coronary death, nonfatal MI, or hospitalized
ACS other than MI) or coronary death, nonfatal MI, and
hospitalized ACS individually (Figure 1). No early increase
was observed in the incidence of coronary events with
raloxifene compared with placebo (Figure 1), and the incidence of coronary events was numerically lower than with
placebo in each individual year of follow-up. Women with a
history of CHD had a numerically higher incidence of
coronary events than those with CHD risk factors (annualized
incidence, 2.81% versus 1.54%), but treatment with raloxifene had no effect on the incidence of coronary events in
either population (Table 2).
Among both women with CHD risk factors and those with
established CHD, no difference was found between treatment
groups in the incidence of coronary events overall or nonfatal
MI, hospitalized ACS, coronary death, and revascularization
individually (Table 2). The effect of raloxifene on the
incidence of coronary events did not differ between women
with CHD risk factors and those with established CHD
The effect of raloxifene on the incidence of coronary events
among subgroups of participants is shown in Figure 2. The
effect of raloxifene on the incidence of coronary events was
similar across subgroups (interaction P⬎0.1), except in the
case of the age subgroup analysis (interaction P⫽0.0118).
In women ⬍60 years of age, the incidence of coronary
events was significantly lower in those assigned to raloxifene
compared with placebo (HR, 0.59; 95% CI, 0.41 to 0.83;
P⫽0.003). In women ⱖ60 and ⬍70 or ⱖ70 years of age, no
significant difference was found in the incidence of coronary
events between treatment groups (HR, 1.06; 95% CI, 0.88 to
1.28; and HR, 0.98; 95% CI, 0.82 to 1.17, respectively).
Using the predefined age subgroup cutoffs did not yield a
significant interaction (P⫽0.287), and the incidence of coronary events was similar across treatment groups in each age
cohort (ⱕ65 years of age: HR, 0.84; 95% CI, 0.68 to 1.04;
⬎65 and ⬍70 years of age: HR, 1.09; 95% CI, 0.85 to 1.40;
ⱖ70 years of age: HR, 0.97; 95% CI, 0.81 to 1.16).
To further explore the effect of raloxifene on the incidence
of coronary events by age, the incidence of coronary events
was compared between treatment groups, with age as a
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Collins et al
Raloxifene and Coronary Outcomes
927
Figure 2. Effect of raloxifene on the primary coronary events by subgroup. HRs and 95% CIs are shown. BMI indicates body mass index;
CABG, coronary artery bypass graft; CV, cardiovascular; ACE, angiotensin-converting enzyme; and ARB, angiotensin receptor blocker.
continuous variable in linear and quadratic terms, along with
their interactions with treatment in the model. The HR was
then estimated in 1-year increments from 54 to 70 years of
age and in 2-year increments from 70 to 92 years of age
(Figure 3). The incidence of coronary events in the raloxifene
group was significantly lower than in the placebo group only
for women ⬍60 years of age.
In a post hoc analysis of the Women’s Health Initiative
studies, a nonsignificant trend was found toward a benefit of
HT on CHD risk in women who initiated it closer to
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928
Circulation
February 24, 2009
2.0
Hazard Ratio
1.5
Figure 3. Effect of raloxifene on the incidence
of the primary coronary end point (coronary
death, nonfatal MI, or hospitalized ACS other
than MI, whichever occurred first) by age. The
vertical line at 60 years of age was based on
the post hoc analysis to match the Women’s
Health Initiative age categories.
1.0
0.5
0.0
55
60
65
70
75
80
A ge (years)
+++ 95 percent confidence interval
menopause. We therefore analyzed our RUTH data in a
similar way, by years since menopause, and found that
raloxifene had no significant effect on the incidence of
coronary events in any subgroup (⬍10 years postmenopausal:
HR, 0.94; 95% CI, 0.64 to 1.37; ⱖ10 and ⱕ20 years
postmenopausal: HR, 1.02; 95% CI, 0.84 to 1.25; ⬎20 years
postmenopausal: HR, 0.92; 95% CI, 0.78 to 1.08; interaction
P⫽0.68). In women ⬍60 years of age, the mean length of
time since menopause was 9.9 years compared with 19.4
years for the overall RUTH population.
shown; interaction P⫽0.78). Compared with placebo, women
assigned to raloxifene had greater increases in HDL cholesterol (1.4%), body mass index (0.4%), and weight (0.3%) and
greater reductions in LDL cholesterol (⫺8.1%), non-HDL
lipoprotein levels (⫺5.4%), the ratio of cholesterol to HDL
(⫺4.8%), and fibrinogen levels (⫺9.1%) (Figure 4). No
significant differences were observed between treatment
groups for systolic or diastolic blood pressure.
Coronary Events by Region and Changes in Levels
of Cardiometabolic Risk Factors and
Blood Pressure
In these analyses of the RUTH trial data, raloxifene did not
increase or decrease the incidence of coronary events overall
in postmenopausal women with CHD risk factors or in those
with established CHD and did not cause early CHD harm at
any age. The incidence of coronary events was significantly
Discussion
The effect of raloxifene on the incidence of coronary events
did not differ significantly by region of the world (data not
Mean percent Change
Raloxifene
1.0
-2.6
3.6
-4.4
-3.6
Total cholesterol (mmol/L)
-8.2
LDL cholesterol (mmol/L)
1.4
HDL cholesterol (mmol/L)
-5.4
Non-HDL cholesterol (mmol/L)
-4.8
Cholesterol/HDL ratio
1.8
Triglycerides (mmol/L)
-9.1
Fibrinogen (mmol/L)
Body mass index
Placebo
0.4
(Kg/m2)
0.3
Weight (Kg)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
-0.1
-0.3
-15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1
0
1
2
3
4
0.9
2.3
1.9
-3.5
2.5
-2.3
12.2
14.0
5.2
-3.9
0.7
1.1
0.4
0.8
-0.8
-0.9
-0.5
-0.8
5
Mean Percent Change from Baseline in the Raloxifene Group
minus Mean Percent Change in the Placebo Group
Figure 4. Differences in mean percentage change in cardiometabolic risk factors and blood pressure from baseline in the raloxifene vs
placebo group. Horizontal lines represent the 95% CIs. The differences between groups were significant (P⬍0.05) for total cholesterol,
LDL, HDL, non-HDL cholesterol, ratio of cholesterol to HDL, fibrinogen, body mass index, and weight. The data on the right indicate
the mean percent changes in the parameters for the placebo and raloxifene groups.
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Collins et al
lower in postmenopausal women ⬍60 years of age assigned
raloxifene compared with placebo. Raloxifene had no effect
on the incidence of coronary events in any other subgroup. Of
note, the annualized CHD event rate in RUTH was similar to
that in a large international study of subjects (men and
women) with established arterial disease or multiple risk
factors for atherothrombosis.25
At baseline, women with CHD risk factors had a higher
body mass index; reported a higher prevalence of smoking,
diabetes mellitus, and hypertension and a lower use of statins
and aspirin; and had higher total cholesterol and LDL cholesterol
levels (Table 1) than women with established CHD. This
difference was likely created by the eligibility criteria. Women
with CHD were automatically eligible, whereas those without
CHD were required to have a certain risk factor score to be
eligible.17
No evidence was found of an early increase in coronary
events with raloxifene in the RUTH trial. This finding is in
contrast to results of some studies of HT, which have shown
an early increased risk of CHD outcomes associated with HT
use.20,26 –28 One potential reason may be that treatment with
oral HT results in a proinflammatory response that could
result in destabilization of susceptible atherosclerotic
plaques.29 In contrast to oral HT, raloxifene does not increase
levels of proinflammatory markers such as C-reactive protein,30 perhaps partly explaining the lack of early CHD harm
with raloxifene.
In RUTH, raloxifene had a relatively minor effect on
lipids. Lack of a larger effect of raloxifene on lipid levels may
have occurred because 66% of women in the raloxifene group
and 68% in the placebo group in RUTH used statins during
the trial (unpublished data).
The age subgroup findings suggest a possible cardioprotective action of raloxifene in women ⱕ60 years of age
enrolled in RUTH. Although this was a post hoc analysis, it
has biological plausibility based on the results of the Women’s Health Initiative and Nurses’ Health Study with estrogen
therapy20 –22 and animal studies of HT.19 It is also of note that
the risk reductions with estrogen therapy in the Women’s
Health Initiative20 study and with raloxifene in RUTH in
women ⬍60 years of age are similar, namely 0.62 (95% CI,
0.33 to 1.16) and 0.59 (95% CI, 0.41 to 0.83), respectively.
Recent results from the observational Nurses’ Health Study
also support the possibility that timing of postmenopausal
estrogen use initiation in relation to age might influence its
effect on the incidence of coronary events.21,31 A nonsignificant trend toward a benefit of HT on coronary outcomes
depending on years since menopause has been reported.23 We
did not find that the effect of raloxifene was dependent on
years since menopause.
These coronary effects of raloxifene should not be considered in isolation of the recognized effects of raloxifene on
other body systems. Raloxifene reduces the risk of vertebral
fracture1 and invasive breast cancer.2–5 Raloxifene also is
associated with an increased risk for venous thromboembolism and, in RUTH, was associated with an increased incidence
of death from stroke but not overall stroke or mortality.4
Raloxifene and Coronary Outcomes
929
Conclusions
Treatment with raloxifene for a median of 5.6 years had no
overall effect on coronary risk among postmenopausal
women with established CHD or at increased risk for coronary disease and did not appear to cause early coronary harm.
This finding is at best hypothesis generating. Likewise,
similar to trends in trials of HT, raloxifene may decrease the
risk of coronary events in younger postmenopausal women.
Individual patient potential benefits and risks should be
considered in the final decision as to whether to prescribe
raloxifene to a postmenopausal woman.
Acknowledgments
We thank the RUTH investigators and the women who enrolled in
the study; Roberta Secrest, PhD, for scientific review; and Melinda
Rance for help preparing the tables and figures.
Source of Funding
This study was sponsored by Eli Lilly and Co, Indianapolis, Ind.
Disclosures
Drs Collins, Barrett-Connor, Mosca, Grady, Kornitzer, and Wenger
received fees from Eli Lilly as members of the Executive Committee
of the RUTH study. Drs Geiger, Dowsett, Effron, and AmewouAtisso are employees and stockholders of Eli Lilly.
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CLINICAL PERSPECTIVE
Raloxifene is a selective estrogen receptor modulator that reduces the risk of vertebral fracture and the incidence of invasive
breast cancer in postmenopausal women. The Raloxifene Use for The Heart (RUTH) trial of 10 101 women showed that
raloxifene had no overall effect on the incidence of coronary events in women with established coronary heart disease or
coronary heart disease risk factors. In this further analysis, we provide detailed results of the effect of raloxifene on
coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc). The effect of raloxifene was similar across
the prespecified subgroups. Therefore, we further analyzed the effect based on a post hoc age subgroup analysis using age
categories defined in the Women’s Health Initiative randomized trials in an attempt to test the “younger woman
hypothesis” for hormone therapy response. The effect of raloxifene on the incidence of coronary events significantly
differed by age (interaction P⫽0.0118). The incidence of coronary events in women ⬍60 years of age was significantly
lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence
interval, 0.41 to 0.83; P⫽0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found
in the incidence of coronary events in women ⱖ60 and ⬍70 or ⱖ70 years of age. Our hypothesis-generating data support
the view that the cardiovascular response to hormones and hormone-related drugs may vary, depending on the age of the
recipient.
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