Raloxifene and Cardiovascular
Events in Osteoporotic Postmenopausal Women
Four-Year Results From the MORE (Multiple
Outcomes of Raloxifene Evaluation) Randomized Trial
JAMA.
2002;287:847-857
Elizabeth Barrett-Connor, MD; Deborah Grady, MD; Andreas Sashegyi, PhD;
Pamela W. Anderson, MD; David A. Cox, PhD; Krzysztof Hoszowski, MD; Pentti
Rautaharju, MD; Kristine D. Harper, MD; for the MORE Investigators
Context Raloxifene, a selective estrogen receptor modulator, improves
cardiovascular risk factors, but its effect on cardiovascular events is
unknown.
Objective To determine the effect of raloxifene on cardiovascular events in
osteoporotic postmenopausal women.
Design Secondary analysis of data from the Multiple Outcomes of
Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled
trial conducted between November 1994 and September 1999.
Setting Outpatient and community settings at 180 sites in 25 countries.
Participants A total of 7705 osteoporotic postmenopausal women (mean age, 67
years).
Intervention Patients were randomly assigned to receive raloxifene, 60 mg/d (n
= 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.
Main Outcome
Measures Cardiovascular events,
including coronary events (myocardial infarction, unstable angina, or coronary
ischemia) and cerebrovascular events (stroke or transient ischemic attack),
collected as safety end points and subsequently adjudicated by a cardiologist
blinded to therapy. Cardiovascular risk at study entry was determined by the
presence of multiple cardiovascular risk factors or prior coronary events or
revascularization procedure.
Results In the overall cohort, there were no significant differences between
treatment groups in the number of combined coronary and cerebrovascular events:
96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%)
with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence
interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d
of raloxifene, respectively. Similar results were obtained when coronary and
cerebrovascular events were analyzed separately. Among the subset of 1035 women
with increased cardiovascular risk at baseline, those assigned to raloxifene
had a significantly lower risk of cardiovascular events compared with placebo
(RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of
cardiovascular events during the first year was not significantly different
across groups in the overall cohort (P
= .94), or among women at increased cardiovascular risk (P = .86) or with evidence of established
coronary heart disease (P = .60).
Conclusions Raloxifene therapy for 4 years did not significantly affect the
risk of cardiovascular events in the overall cohort but did significantly
reduce the risk of cardiovascular events in the subset of women with increased
cardiovascular risk. There was no evidence that raloxifene caused an early
increase in risk of cardiovascular events. Before raloxifene is used for
prevention of cardiovascular events, these findings require confirmation in
trials with evaluation of cardiovascular outcomes as the primary objective.
JAMA. 2002;287:847-857
Coronary heart disease (CHD) is the leading
cause of death among postmenopausal women in the United States and most of the
Western world.1 In
observational studies, postmenopausal women who take hormone replacement
therapy (HRT), alone or with a progestin, have approximately 30% less risk of
CHD compared with untreated postmenopausal women.2 Randomized clinical
trials have not confirmed a beneficial effect of HRT on either the progression
of coronary atherosclerosis or the risk of cardiovascular (CV) events in
postmenopausal women with existing CHD.3, 4 In the Heart and
Estrogen/progestin Replacement Study (HERS),3 and in preliminary
information from the Women's Health Initiative (WHI),5, 6 women assigned to
receive HRT experienced an early increased risk of acute coronary events. In
the Women's Estrogen for Stroke Trial (WEST),7 women assigned to
estradiol had an increased risk of stroke compared with placebo during the
first 6 months of treatment. Pooled analyses of smaller, short-term trials8, 9 and recent reports
from observational studies10-12 also suggest a
transient increase in risk of recurrent CV events after initiation of HRT in
postmenopausal women.
The Multiple Outcomes of Raloxifene Evaluation
(MORE) trial was a double blind, placebo-controlled trial designed to determine
the effect of raloxifene, a selective estrogen receptor modulator, on bone
mineral density and vertebral fractures in 7705 postmenopausal women with osteoporosis.13, 14 Raloxifene reduced
the risk of osteoporotic vertebral fractures and newly diagnosed breast cancer
without increasing the risk of endometrial cancer but increased the risk of
venous thromboembolic events to an extent similar to that of HRT and tamoxifen.13-17
Although raloxifene has favorable effects on
low-density lipoprotein cholesterol (LDL-C) and other risk factors for CHD18, 19 and improves vascular
endothelial function in postmenopausal women,20 the effect of
raloxifene on the risk of arterial CV events is unknown. Whether raloxifene
affects the risk of CV events in postmenopausal women is currently being tested
prospectively in the Raloxifene Use for The Heart (RUTH) trial, which enrolled
10 101 postmenopausal women with established CHD or with multiple risk
factors for acute CHD events; however, results will not be available for
several years.21
In the MORE trial, CV events and mortality were
reported as adverse events and serum lipid concentrations were measured. We
used these data to determine the early and overall effects of 4 years of
raloxifene therapy on the occurrence of major arterial CV events, including
coronary and cerebrovascular events. Since the MORE cohort was at relatively
low risk for CV events overall, we also determined the effect of raloxifene on
coronary and cerebrovascular events among women at increased risk for these
events as defined by the presence of multiple CV risk factors or evidence of
established CHD at baseline.
Study Design and Participants
Study participants were enrolled in the MORE study at 180 sites in 25
countries. Details of the study design, eligibility criteria, and flow of
participants through the trial have been published.13-15 Patients were at
least 2 years postmenopausal and had osteoporosis documented either by prior
vertebral fracture or bone mineral density T score of less than -2.5. Women
were excluded if they had a history of stroke or venous thromboembolic disease
during the past 10 years. Women with coronary artery disease, hypertension,
hypercholesterolemia, type 2 diabetes mellitus, or other risk factors for CV
disease were not excluded. The primary outcomes of MORE were bone mineral
density and vertebral fractures. Measurement of serum lipid concentrations was
a secondary objective of the trial, and assessment of major CV events
(including CV death) was a safety objective of the trial. The protocol was
approved by the ethical review board at each site. All women gave written
informed consent to participate in the study in accordance with the ethical
principles stated in the Declaration of Helsinki.
Randomization and Blinding
Details of the randomization and blinding procedures have been published.13-15 Briefly, women
were stratified by site and randomly assigned to receive raloxifene 60 mg/d or
120 mg/d or placebo (Figure 1).
The sponsor supplied randomly numbered kits containing identically appearing
raloxifene and placebo tablets. The women received 2 tablets daily: 2 placebo,
1 placebo and 1 tablet of 60-mg raloxifene, or 2 tablets of 60-mg raloxifene.
In addition, all women were provided with 500 mg of calcium and 400 to 600 IU
of cholecalciferol per day, beginning at study entry. Participants,
investigators, laboratory staff, and those who adjudicated the CV outcomes were
blinded to treatment assignment.
Baseline Assessments and
Follow-up
At baseline, information on age, ethnicity, years of education, reproductive
history, prior postmenopausal hormone use, cigarette smoking, alcohol
consumption, and health conditions was reported (Table 1).
In addition, women were asked whether they had previously experienced any of
the following CV events or procedures: myocardial infarction (MI), coronary
artery bypass graft (CABG) surgery, percutaneous coronary intervention, or
stroke. Other baseline clinical assessments included height, weight, blood
pressure, pulse, a standard 12-lead electrocardiogram (ECG), and measurement of
serum lipid concentrations (total cholesterol, high-density lipoprotein
cholesterol [HDL-C], and triglycerides) and fasting blood glucose. Use of all
prescription and over-the-counter medications was recorded at baseline.
Follow-up visits were scheduled at 3 and 6 months after enrollment and every 6
months thereafter.
CV Risk Assessment
We assessed CV risk for each woman by assigning a risk score based on evidence
of established CHD or the presence of CV risk factors, adapted from criteria
established previously for enrollment of women in the RUTH trial.21 Women with a prior
MI, percutaneous coronary intervention, or CABG surgery received a score of 4
points, regardless of the timing of the event or procedure relative to
enrollment. Women with diabetes mellitus (fasting blood glucose >140 mg/dL
[>7.8 mmol/L]) or taking hypoglycemic medication) received 3 points. Women
70 years or older received 2 points; those between age 65 and 70 years received
1 point. Women who were current smokers (10 or more cigarettes per day for 6
months before enrollment), had hypertension (systolic blood pressure >160 mm
Hg, diastolic blood pressure >95 mm Hg, or taking antihypertensive
medication), or had hyperlipidemia (LDL-C >160 mg/dL ([4.14 mmol/L] or HDL-C
<45 mg/dL [1.17 mmol/L] with triglycerides >250 mg/dL [2.82 mmol/L], or
receiving hypolipidemic therapy) received 1 point for each condition. The combination
of current smoking, hypertension, and hyperlipidemia was scored 4 points. Women
with 4 or more risk points were considered to be at increased risk for CV
events.21 Based on these
criteria, 1035 (13.4%) were defined as being at high risk for CV events, 202
with a prior acute coronary event or procedure and the remainder with no prior
history of acute coronary events but with multiple CV risk factors.
Ascertainment and Adjudication
of CV Events
Cardiovascular events were collected by asking women at each visit if they had
an MI, CABG surgery, percutaneous coronary intervention, or a stroke since the
previous visit and by recording unsolicited reports of adverse CV events. For
each reported event, the investigator reviewed available documentation,
including ECG reports, cardiac enzyme results, procedure reports,
hospitalization records, discharge summaries, or letters from physicians and
provided a written summary of these findings to the sponsor. All summaries of
reported CV events through 4 years of follow-up were reviewed and adjudicated
by a board-certified cardiologist, who was contracted by the sponsor, was not
associated with the trial, and was blinded to treatment assignment. No original
source documents were available to the adjudicator.
All reported deaths were adjudicated to be due
to either CV or non-CV causes. Cardiovascular deaths included coronary death
(fatal MI, sudden death, unwitnessed death in the absence of other likely
noncoronary causes, and death related to a coronary artery procedure) and
cerebrovascular death (fatal stroke). Nonfatal CV outcomes included coronary
events (MI, unstable angina, or coronary ischemia) and cerebrovascular events
(stroke or transient ischemic attack). Based on review of the case summaries,
the adjudicator determined that MI was present in women with symptoms
compatible with MI (ie, chest pain or anginal equivalent) who had documentation
of either elevated cardiac enzyme levels (ie, cardiac enzymes >2-fold above
the upper limit of normal or deemed consistent with MI by the local laboratory)
or positive ECG findings compatible with MI (ie, pathological Q waves, ST
depression or elevation or T-wave inversion); in hospitalized patients with a
discharge diagnosis of MI; or in patients who had an MI according to a
physician's statement in the medical record. Unstable angina was deemed to be
present in hospitalized patients with anginal symptoms (ie, chest pain or
anginal equivalent) with a primary diagnosis of this condition. A diagnosis of
coronary ischemia was made for women hospitalized with chest symptoms
consistent with angina but without additional supporting evidence of unstable
angina or other acute coronary syndromes.
Cerebrovascular events included stroke and
transient ischemic attack. Stroke was deemed to be present in patients with
symptoms compatible with stroke who had documentation of either positive
computed tomographic scan result (read by a physician as consistent with recent
stroke) or with persistent neurological deficit (>24 hours); in hospitalized
patients with a discharge diagnosis of stroke; or in patients who had a stroke
according to a physician's statement. Transient ischemic attack was deemed to
have occurred in hospitalized patients with symptoms compatible with stroke but
for whom a diagnosis of stroke was not established or for patients with a
primary diagnosis of transient ischemic attack.
Serial ECGs
A standard 12-lead ECG was obtained at baseline and at 24 and 48 months or at
early discontinuation. The ECG results were coded by the Epidemiological
Cardiology Research Center (EPICARE) at Wake Forest University, using the
NOVACODE serial classification system.22 Persons interpreting
the ECGs had no knowledge of treatment assignment, clinical symptoms, or
cardiac enzymes. Incident MI and myocardial ischemia based on ECG changes were
defined by changes in Q wave and ST-T wave scores. Incident MI required an
increase in Q wave score of at least 25 points (grade 2), or at least 15 points
(grade 1) with clinically significant ST-T wave evolution from the baseline ECG
(change in ST-T score of at least 10). Myocardial ischemia was defined as
borderline isolated Q-wave evolution without evolving ST-T waves or ischemic
evolution of ST-T waves without a significant Q wave.23 Serial ECGs were
obtained independent of the reporting of clinical CV events and were not used
in the adjudication of the clinical CV events because of the lack of temporal
association between them. Cardiovascular events identified from serial ECGs
were not included in the analysis of clinically reported events.
Measurement of Serum Lipids
Total cholesterol, HDL-C, and triglyceride concentrations were measured in all
women at baseline. Follow-up measurements were performed in serum obtained at
6, 12, 24, 36, and 48 months using previously described methods.18 Total cholesterol was
measured at follow-up visits in all women, whereas only samples from the 2738
women enrolled at the 14 study sites that had at least 100 enrolled patients
were assayed for HDL-C and triglyceride concentrations. Low-density lipoprotein
cholesterol levels were calculated using the Friedewald equation.24
Statistical Analyses
Procedures in SAS Version 6.09 were used to perform all statistical analyses
(SAS Institute Inc, Cary, NC). Analyses were performed using the
intention-to-treat principle with patients allocated to assigned treatment
regardless of compliance or other postbaseline factors. Unless otherwise
stated, all hypotheses were tested at the .05 (2-sided) level of significance.
No adjustments were made for multiple comparisons.
Baseline patient characteristics were compared
using analysis of variance for continuous data and Pearson 2 test for categorical data. Kaplan-Meier
curves were generated to assess the cumulative incidence of all CV events
(coronary and cerebrovascular events combined), and coronary and
cerebrovascular events separately. To examine early and longer-term effects of
raloxifene on CV risk, we compared across treatment groups the number of women
with a CV event (coronary and cerebrovascular events combined and analyzed
individually) after 1 and 4 years of treatment using Pearson 2 test, and calculated relative risks (RRs) and
95% confidence intervals (CIs) for each raloxifene treatment group compared
with placebo. Post hoc power calculations, performed using a 1-sided,
continuity-corrected Pearson 2
test, suggested that the data provided 80% power to detect a 1.9-fold increase
in risk of CV events in the first year with raloxifene 60 mg/d (1.8-fold when
raloxifene dose groups were pooled) over placebo in the total cohort and a
2.5-fold increase in risk in the first year with raloxifene 60 mg/d (2.3-fold
when the raloxifene dose groups were pooled) over placebo in the high-risk
subset. Through 4 years, the data provided 80% power to observe a 29% and 41%
RR reduction in the total cohort and high-risk subset, respectively.
We assessed whether treatment group imbalances
in baseline characteristics confounded the observed results by performing
multivariate regression analysis, including factors for treatment, baseline
characteristics, and the interaction between treatment and baseline characteristics
in the model.
For analysis of serum lipid concentrations,
percentage changes in these markers were compared between treatment groups
using an analysis of variance on rank transformed data from all women with a
baseline and at least 1 postbaseline measurement. Missing end point
observations were imputed by carrying forward the last available postbaseline
observation.
Baseline Characteristics
In the overall study cohort, women in the placebo and raloxifene groups were
generally similar at baseline with regard to demographics, CHD risk factors,
and prior evidence of CHD (Table 1).
The only exception was a greater proportion of women in the raloxifene groups
compared with placebo with evidence of diabetes at baseline (P = .02). Use of CV medications also was
balanced across treatment groups except for lipid-lowering therapy, which was
greater at baseline among women assigned to receive raloxifene compared with
placebo (Table 1).
On average, women were 67 years old, 19 years postmenopausal, primarily white
(96%), and had a mean body mass index of 25 kg/m2. Women had a
borderline-high mean serum concentration of total cholesterol (238 mg/dL [6.15
mmol/L] and LDL-C (155 mg/dL [4.01 mmol/L]). Most women were normotensive and
without established coronary artery disease, with less than 3% reporting a
prior coronary event or procedure (Table 1).
There was no significant difference across treatment groups among women in the
high-CV risk subset in age, other demographics, or in most CHD risk factors (Table 1).
As in the overall cohort, there were more women in the high-risk group with
evidence of diabetes in the raloxifene 60 mg/d compared with the other groups,
although the difference was not statistically significant (P = .10) in this subset. There also tended
to be fewer women with a prior history of MI (P
= .08) or CABG (P = .07) in the
raloxifene 60 mg/d group compared with the other groups. Use of lipid-lowering
therapy and most other CV medications was balanced across treatment groups at
baseline except for calcium channel blockers, which was less (P = .04) in the raloxifene 60 mg/d group.
Data were analyzed through 48 months of
follow-up, during which time 1996 participants (25.9%) discontinued from the
study before its completion: 679 in the placebo group, 670 in the raloxifene 60
mg/d group, and 647 in the raloxifene 120 mg/d group. At 4 years, vital status
was known for 5709 (74%) of the 7705 women originally enrolled in the trial.
Women for whom vital status could not be confirmed included those who
discontinued the trial early, primarily due to an adverse event (n = 910, 46%
of discontinuations) or personal decision (n = 696, 35% of discontinuations).
Compared with women who remained in the trial at 4 years, those who
discontinued early were slightly older (67.2 vs 66.2 years; P<.001), were more years past menopause
(19.9 vs 18.3 years; P<.001),
and had slightly higher serum triglyceride levels (115.9 mg/dL [1.31 mmol/L]
and 111.5 mg/dL [1.26 mmol/L]; P
= .004). Among the women who discontinued early, there were no significant
differences across the treatment groups in baseline characteristics or most
risk factors for CV disease (P.30), with the exceptions
of total cholesterol (placebo, 238.2 [6.17]; 60-mg/d raloxifene, 240.5 [6.23];
120-mg/d raloxifene, 234.7 mg/dL [6.08 mmol/L]; P = .03) and LDL-C (placebo, 154.8 [4.01]; 60-mg/d
raloxifene, 157.5 [4.08]; 120 mg/d raloxifene, 151.7 mg/dL [3.93 mmol/L]; P = .01).
Ninety-two percent of participants took at least
80% of the study medication, and 83% took at least 90% of the study medication.
Compliance did not differ significantly across treatment groups (P = .99 for 80%; P = .55 for 90% compliance).
CV Events
Placebo Event Rates
Figure 2
summarizes the incidence of CV events among women assigned to receive placebo
in the overall cohort and among subsets of women with increasing CV risk
scores. Among all participants, the placebo rate of CV events was 3.7% for all
CV events, 2.1% for coronary events, and 1.6% for cerebrovascular events. The
rate of coronary and cerebrovascular events increased progressively as the CV
risk score increased from 3 to 6 (Figure 2).
The placebo event rate for women with a CV risk score of 4 or more was
approximately 3.5-fold higher than in the overall cohort: 12.9% for all CV
events, 7.6% for coronary events, and 5.4% for cerebrovascular events.
Treatment Comparisons Overall
and in Subsets at Higher CV Risk
A total of 272 women experienced at least 1 major CV event during the trial:
156 experienced at least 1 coronary event (31 fatal; 125 nonfatal) and 117
experienced at least 1 cerebrovascular event (14 fatal,102 nonfatal, and 1
nonfatal event that was subsequently fatal) (Table 2).
Overall, coronary events included MI or coronary death (44%), unstable angina
(39%), and coronary ischemia (17%); cerebrovascular events included nonfatal or
fatal strokes (68%) and transient ischemic attacks (32%). The distribution of
events was similar among women in the high-risk subset (data not shown).
Kaplan-Meier survival curves show the cumulative
incidence of coronary and cerebrovascular events together and coronary and
cerebrovascular events alone over time (Figure 3).
For the total study population, there was no evidence for a time trend of an
early increase or a later decrease in risk of CV events with raloxifene (Figure 3).
During the first year of the trial, there were no significant differences
across treatment groups in the number of women with CV events (placebo, 23
[0.8%]; raloxifene 60 mg/d, 25 [0.9%]; raloxifene 120 mg/d, 23 [0.8%]; P = .94); coronary events (placebo, 15
[0.5%]; raloxifene 60 mg/d, 18 [0.7%]; raloxifene 120 mg/d, 13 [0.5%]; P = .65), or cerebrovascular events
(placebo, 8 [0.3%]; raloxifene 60 mg/d, 7 [0.2%]; raloxifene 120 mg/d, 10
[0.3%]; P = .76). Similar results
were obtained when nonfatal and fatal events were analyzed separately (P.17).
Pooling raloxifene dose groups, the RR of experiencing any CV event during the
first year in the overall study population was 1.05 (95% CI, 0.64-1.72).
In the subset of 1035 women with increased CV
risk, there also was no evidence for an early increase in risk of CV events
with raloxifene (Figure 3).
The number of CV events during the first year among women in the high-risk
subset was not significantly different across the treatment groups: 10 (3.1%),
placebo; 11 (3.0%), raloxifene 60 mg/d; and 9 (2.5%), raloxifene 120 mg/d (P = .86). Pooling the raloxifene dose
groups, the RR of experiencing any CV event during the first year among women
in the high-risk subset was 0.88 (95% CI, 0.42-1.87). The Kaplan-Meier curves
in the high-risk subset diverged beginning after approximately the first year,
which continued through 4 years with fewer events in the raloxifene groups
compared with placebo (Figure 3).
At 4 years, the incidence of CV events (coronary
and cerebrovascular events combined or analyzed individually) among all 7705
participants did not differ significantly across the treatment groups (Table 2).
Similar results were observed when nonfatal and fatal events were analyzed
separately and for the combined outcomes of coronary death/MI/unstable angina,
and all (fatal plus nonfatal) strokes (Table 2).
Among the 1035 women in the high-risk subset, there were significantly fewer CV
events among women assigned to raloxifene (RR, 0.60; 95% CI, 0.38-0.95 for both
raloxifene groups; Table 2).
The number of nonfatal CV events also was significantly less in the raloxifene
groups (RR, 0.61; 95% CI, 0.37-0.99 for the 60-mg/d group and RR, 0.50; 95% CI,
0.30-0.85 for the 120-mg/d group) in this subset, but the number of fatal CV
events was small and not significantly different. Similar trends were observed
when coronary and cerebrovascular events were analyzed individually; however,
most of the differences were not statistically significant and most of the 95%
CIs included 1.0 (Table 2).
The exception was the combined outcome of all strokes, for which there were
significantly fewer strokes among women receiving raloxifene compared with
those receiving placebo (RR, 0.38; 95% CI, 0.15-0.94). The proportion of women
in the high-risk subset with a prior MI or evidence of diabetes at baseline,
both important risk factors for CV events, was relatively high (approximately
17% for each), and was slightly imbalanced across treatment groups. However,
adjusting the analyses for these baseline variables did not change the
inference.
To determine whether the significant reduction
in CV events observed with raloxifene among those with 4 or more risk points
also was detectable in subsets of women at lower or higher CV risk, we analyzed
the RR of CV events in the raloxifene groups compared with placebo across the
range of CV risk scores from 3 or more points through 6 or more points (Figure 4).
For the raloxifene 60-mg/d group, the risk of CV events among women with a risk
score of at least 3 was similar to that in the overall cohort and not reduced
significantly compared with placebo. However, as observed for women with at
least 4 CV risk points, raloxifene 60 mg/d was associated with significantly
lower risk of CV events among subsets of women with risk scores of at least 5
(RR, 0.35; 95% CI, 0.18-0.70) and at least 6 (RR, 0.40; 95% CI, 0.18-0.87). The
reduction in risk of CV events with raloxifene 60 mg/d tended to be greater as
the CV risk score increased from at least 3 through at least 6 points (Figure 4).
Although the risk of CV events tended to be lower in the raloxifene 120-mg/d
group compared with placebo among women with a risk score at least 5 or at
least 6, the CIs were wide and none were significantly different from placebo (Figure 4).
Only 202 women who were enrolled in the MORE
trial had established CHD (prior MI, CABG surgery, or percutaneous coronary
intervention): 66, placebo; 56, raloxifene 60 mg/d; and 80, raloxifene 120
mg/d. Among these women, 4 (7.1%) in the raloxifene 60-mg/d group vs 15 (22.7%)
in the placebo group experienced a coronary or cerebrovascular event during the
trial (RR, 0.31; 95% CI, 0.12-0.82) compared with 12 (15%) in the raloxifene
120-mg/d group (RR, 0.66; 95% CI, 0.33-1.31). Similar results were obtained
when coronary events were analyzed separately, but the differences were not
statistically significant (RR, 0.39; 95% CI, 0.12-1.31 for raloxifene 60 mg/d;
RR, 0.92; 95% CI, 0.39-2.13 for raloxifene 120 mg/d). There were 9 cerebrovascular
events among women with established CHD: 6 (9%) in the placebo, 1 (1.7%) in the
raloxifene 60-mg/d (RR, 0.20; 95% CI, 0.03-1.25), and 2 (2.5%) in the
raloxifene 120-mg/d (RR, 0.28; 95% CI, 0.06-1.18) groups. There were 11 CV
events among women with established CHD during the first year of the trial: 5
(7.5%) in the placebo, 3 (5.3%) in the raloxifene 60-mg/d, and 3 (3.7%) in the
raloxifene 120-mg/d groups (RR, 0.71; 95% CI, 0.18-2.82 for raloxifene 60 mg/d
and RR, 0.50; 95% CI, 0.13-1.94 for raloxifene 120 mg/d; P = .60).
CV Events Identified From
Serial ECGs
Serial ECGs obtained at baseline and at 2 and 4 years were analyzed for changes
consistent with incident Q wave, MI, or myocardial ischemia. The number of
women with incident MI (placebo, 9 [0.4%]; raloxifene 60 mg/d, 8 [0.4%];
raloxifene 120 mg/d, 5 [0.2%]; P
= .22) or either incident MI or myocardial ischemia (placebo, 110 [4.8%],
raloxifene 60 mg/d, 89 [3.9%]; raloxifene 120 mg/d, 89 [3.9%]; P = .56) identified from ECG changes from
baseline to 4 years was not significantly different between treatment groups.
Serum Lipids
Compared with placebo, raloxifene treatment for 4 years resulted in significant
reductions in total and LDL-C but not HDL-C levels (Figure 5).
Reductions in total cholesterol and LDL-C levels were observed in the
raloxifene 60-mg/d and 120-mg/d groups as early as 6 months (median percentage
change: total cholesterol, -5% and -6%; LDL-C, -8% and –9%; both P<.001 vs placebo), and those levels
were maintained throughout the 4 years of the study (Figure 5).
The median 2.4% decrease in serum triglyceride levels in the placebo group was
significantly different from the median 1.1% and 1.5% increase in serum
triglyceride levels in the raloxifene 60-mg/d and 120-mg/d groups, respectively
(P = .004 for overall treatment
group difference). The absolute median increase in serum triglyceride levels in
both raloxifene groups was 0.89 mg/dL (0.01 mmol/L) over 4 years. Relative to
placebo, the effects of raloxifene on total, LDL-C, and HDL-C levels among
women in the high-risk subset were comparable to those observed in the whole
cohort although no significant change in triglyceride levels was observed in
this subset (Figure 5).
Overall, 1069 women (13.9%) reported taking
lipid-lowering therapy at baseline or at any time during the trial. Excluding
these women from the analyses, raloxifene decreased total cholesterol and LDL-C
levels by an amount comparable to that observed in the overall cohort (data not
shown). Significantly fewer women treated with raloxifene initiated new
lipid-lowering therapy during the course of the study both in the entire study
cohort (placebo, 232 [9.7%]; raloxifene 60 mg/d, 137 [5.9%]; raloxifene 120
mg/d, 122 [5.1%]; P<.001) and
among women in the high-risk subset (placebo, 37 [14.5%]; raloxifene 60 mg/d,
28 [9.8%]; raloxifene 120 mg/d, 22 [7.5%]; P
= .03).
In this secondary analysis of data from this
large study of osteoporotic postmenopausal women, raloxifene did not
significantly reduce the risk of CV events in the overall study population,
which was at relatively low risk for CV events, but it did significantly lower
the risk of CV events in a subset of women at high risk for acute coronary
events and in those with established CHD. The number of CV events was small,
but there was no evidence that raloxifene treatment was associated with an
early increase in CV morbidity or mortality in the overall cohort, among women
at high risk for or among women with established CHD.
Women enrolled in the MORE trial were selected
for increased risk for osteoporotic fracture rather than for an increased risk
of CV disease13; thus, the
overall study cohort was predominantly women without established CHD and was at
relatively low risk for CV events. Overall, CV mortality in MORE (1.5 per 1000
women-years) was less than that reported for women in the general US population
(2.95 per 1000 women-years).25 That MORE enrolled
women worldwide rather than only in the United States may have contributed to
this difference. However, the rate of acute coronary events and mortality in
MORE was in the range of those reported previously for postmenopausal women in
primary CV prevention studies such as the Women's Health Study26 and the Air
Force/Texas Coronary Atherosclerosis Prevention Study27 and is comparable to
that observed in the Nurses Health Study.28 We adapted criteria
established previously for identification of postmenopausal women at high risk
for acute coronary events for enrollment in the RUTH trial21 in order to identify
1035 women at increased CV risk in the MORE trial, 202 having experienced a
prior coronary event or undergone a procedure and 833 with no prior coronary
events but with multiple risk factors. The annual coronary event rate in this
subset was about 3.5-fold higher than in the overall cohort, and the
progressive increase in coronary and cerebrovascular event rates as the CV risk
score increased further supports the validity of the method used to identify
women at increased risk. As expected, the incidence of CV events was highest
(23%) among the 202 women who entered the MORE trial with established CHD and
is comparable with the combined incidence of 28% for coronary and
cerebrovascular events observed in HERS.3
During the first year of the trial, the number
of fatal or nonfatal events due to coronary artery or cerebrovascular disease
did not differ significantly across treatment groups in the overall study
population, among the 1035 women at high risk or among the 202 women who
entered the study with established CHD. This provides no evidence of an early
increase in risk for CV events although there were too few events during the
first year to draw more definitive conclusions. Hypotheses suggested to explain
the early increase in risk of CV events with HRT observed in HERS,3 WEST,7 and other studies5, 6, 9 include a prothrombotic
effect on the arterial system similar to the effect of HRT to increase the risk
of venous thrombolic events or a proinflammatory effect at the vessel wall that
could promote plaque destabilization in women with susceptible lesions.29 The former seems
unlikely given the preliminary evidence that neither raloxifene nor tamoxifen30 cause an early
increase in CV risk, and yet both increase the risk of venous thromboembolism
by a magnitude comparable to that of HRT.13, 16, 17 The finding that, in
contrast to HRT,31 neither
raloxifene19 nor tamoxifen32 increase C-reactive
protein levels in postmenopausal women together with studies showing that HRT
increases circulating levels of matrix metalloproteinase-9 (MMP-9)33 lend support to a
proinflammatory hypothesis related to plaque destabilization. However, direct
evidence to support a role for C-reactive protein, MMP-9, or other markers of
inflammation in early CV risk associated with HRT is lacking.
Although raloxifene did not significantly affect
the overall risk of CV events in the total study population, it was associated
with a significant 40% reduction in risk of coronary and cerebrovascular events
in the 13% of women at high risk. Because of the post hoc nature of these
analyses and the relatively small number of events involved, the possibility
that the significant risk reduction with raloxifene observed in the high-risk
subset was a chance finding cannot be discounted. However, the reduction in
risk for CV events was statistically significant for raloxifene 60 mg/d across
several subsets of women with increasing risk for CV, was consistent over time,
and was significant in the small subset of women with established CHD. The
separate incidences of coronary and cerebrovascular events were fewer in the
raloxifene 60 mg/d group compared with placebo in the high-risk subset although
these differences did not reach statistical significance. The effects observed
with raloxifene 120 mg/d were less consistent, but whether this represents a
true difference in effect between the doses is unknown.
Overall, raloxifene improved total cholesterol
and LDL-C levels with no effect on HDL-C levels, effects comparable to those
previously reported in a 6-month trial of 390 healthy postmenopausal women.18 The effects of
raloxifene on serum lipid concentrations in the high-risk subset were
comparable to those observed for the total cohort. Thus, the effect of
raloxifene to lower the risk of CV events in this subset, if real, is not
likely explained by a greater improvement in serum lipid concentrations among
these women.
There are several limitations to our study. The
MORE trial was not designed to test the effect of raloxifene on CV outcomes,
and larger trials with greater numbers of events are needed to confirm these
findings. Cardiovascular events were assessed by self-report and complete
supporting evidence for adjudication of events was not available in many cases.
The study was not designed to confirm vital status or to obtain information on
CV events occurring in women who discontinued the trial early. The overall
incidence and total number of CV events in this trial were small, providing
limited power to detect treatment group differences, especially in the number
of events through the first year of the trial. Finally, all of the women in
MORE had osteoporosis defined by bone mineral density or previous vertebral
fracture, so whether these findings can be generalized to nonosteoporotic women
is uncertain.
In summary, there was no evidence that
raloxifene caused an early increase in risk of CV events, either overall or
among postmenopausal women at high risk for or with CHD. Raloxifene therapy for
4 years did not significantly affect the overall risk of CV events in the total
MORE cohort but did significantly reduce the risk of CV events among women at
high risk for and among those with established CHD. Before raloxifene is used
for prevention of CV events, these findings must be confirmed by an adequately
powered, randomized trial with CV events as predefined outcomes.
Author/Article Information
Author Affiliations: Division of
Epidemiology, Department of Family and Preventive Medicine, University of
California, San Diego, La Jolla (Dr Barrett-Connor); Department of Epidemiology
and Biostatistics, University of California, San Francisco (Dr Grady); Lilly
Research Laboratories, Indianapolis, Ind (Drs Sashegyi, Anderson, Cox, and
Harper); Medical Center, Railway Hospital, Warsaw, Poland (Dr Hoszowski); and
Department of Public Health Services, Wake Forest University, Winston-Salem, NC
(Dr Rautaharju).
Corresponding Author and Reprints:
Elizabeth Barrett-Connor, MD, Division of Epidemiology, Department of Family
and Preventive Medicine, University of California, San Diego School of Medicine,
9500 Gilman Dr, No. 0607, La Jolla, CA 92093-0607 (e-mail: [log in to unmask]).
Financial Disclosures: Dr Barrett-Connor has served as a consultant for and has received
research support from Eli Lilly & Co. Dr Grady receives or has received
salary support via contracts with the University of California, San Francisco,
from Berlex Laboratories, Eli Lilly, Pfizer, and Wyeth-Ayerst Research. Drs Sashegi,
Anderson, Cox, and Harper are full-time employees of and own stock in Eli Lilly
& Co.
Author Contributions: Dr Barrett-Connor had full access to all the data in this study
and takes responsibility for the integrity of the data and accuracy of the data
analysis.
Study concept and design: Grady, Anderson, Cox, Harper.
Acquisition of data: Barrett-Connor, Sashegyi, Hoszowski, Rautaharju.
Analysis and interpretation of
data: Barrett-Connor, Grady,
Anderson, Cox, Rautaharju, Harper.
Drafting of the manuscript: Barrett-Connor, Anderson, Cox.
Critical revision of the
manuscript for important intellectual content: Barrett-Connor, Grady, Sashegyi, Anderson, Cox, Hoszowski,
Rautaharju, Harper.
Statistical expertise: Grady, Sashegyi.
Obtained funding: Hoszowski.
Administrative, technical, or
material support: Anderson, Cox,
Rautaharju, Harper.
Study supervision: Barrett-Connor, Harper.
Medical expertise: Anderson.
Principal investigator of ECG
laboratory: Rautaharju.
Funding/Support: This study was funded by Eli Lilly & Co.
Role of the Sponsor: The MORE trial protocol was designed by the sponsor in
consultation with the coordinating center at the University of California, San
Francisco. Study medication and randomization codes were provided by the
sponsor. Data on cardiovascular events, on which the present study is based,
were by investigators at their respective sites without regard to causality or
treatment group assignment. The cardiologists who adjudicated the
cardiovascular events were compensated for their time but were not otherwise
involved in the trial or associated with the sponsor. Data analyses were
performed by the statistical group of the sponsor (Dr Sashegyi) with review by
and input from the corresponding author (Dr Barrett-Connor). The manuscript was
written by Drs Barrett-Connor and Cox and was reviewed by each of the
coauthors. The manuscript also was reviewed before submission both by a study
publications committee consisting of a majority of nonsponsor investigators and
by sponsor staff.
Acknowledgment: We are indebted to Kathryn Krueger, MD, for implementation of the
study and contributions to the data analysis plan, Somnath Sarkar, PhD, for
contributions to the statistical analysis plans and for his guidance and
consultancy during the statistical analyses, and to Yiyong Fu, MS, for
extensive statistical programming support. We also thank Imre Pavo, MD, for
critically reviewing the manuscript, William Groh, MD, and Chamoun Chamoun, MD
(Krannert Institute of Cardiology, Indiana University School of Medicine) for
adjudication of the cardiovascular events, and all of the MORE trial
investigators who made this study possible.
A list of the MORE
Investigators has been published
previously (JAMA.
1999;282:637-656).
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.