Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW. Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women. JAMA. 1998;279(18):1445-1451. doi:10.1001/jama.279.18.1445
From the Brigham and Women's Hospital, Boston, Mass (Dr Walsh); University of Pittsburgh, Pittsburgh, Pa (Dr Kuller); University of Oklahoma Health Sciences Center, Oklahoma City (Dr Wild); Lilly Research Laboratories, Indianapolis, Ind (Drs Paul, Lawrence, Shah, and Anderson); and Clinical Studies, St Petersburg, Fla (Dr Farmer).
Context.— Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic
effects on bone and estrogen-antagonistic effects on breast and uterus.
Objective.— To identify the effects of raloxifene on markers of cardiovascular risk
in postmenopausal women, and to compare them with those induced by hormone
replacement therapy (HRT).
Design.— Double-blind, randomized, parallel trial.
Setting.— Eight sites in the United States.
Participants.— 390 healthy postmenopausal women recruited by advertisement.
Intervention.— Participants were randomized to receive 1 of 4 treatments: raloxifene,
60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d,
and medroxyprogesterone acetate, 2.5 mg/d); or placebo.
Main Outcome Measures.— Change and percent change from baseline of lipid levels and coagulation
parameters after 3 months and 6 months of treatment.
Results.— At the last visit completed, compared with placebo, both dosages of
raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C)
by 12% (P<.001), similar to the 14% reduction
with HRT (P<.001). Both dosages of raloxifene
significantly lowered lipoprotein(a) by 7% to 8% (P<.001),
less than the 19% decrease with HRT (P<.001).
Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C)
by 15% to 17% (P<.05), less than the 33% increase
with HRT (P<.001). Raloxifene did not significantly
change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen
activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides
by 20%, and decreased PAI-1 by 29% (for all, P<
.001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P<.001), unlike HRT, which had no effect. Neither treatment changed
fibrinopeptide A or prothrombin fragment 1 and 2.
Conclusions.— Raloxifene favorably alters biochemical markers of cardiovascular risk
by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had
no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and
lipoprotein(a). Further clinical trials are necessary to determine whether
these favorable biochemical effects are associated with protection against
MILLIONS OF postmenopausal women currently face a difficult dilemma:
whether they should or should not take estrogen replacement. Estrogen use
may protect against osteoporosis and heart disease, but may increase the risks
of breast and endometrial cancers.1 Thus, there
could be serious consequences in choosing to take estrogen, or in choosing
not to take estrogen. Nearly half of postmenopausal women who begin hormone
treatment discontinue use within 1 year.2 This
is believed to be because of lingering concerns they may have about the long-term
hazards of this treatment or unacceptable adverse effects such as vaginal
bleeding and breast tenderness.
Since estrogen is clearly not an ideal treatment, drugs have been sought
that have an estrogenic effect in some tissues, such as bone and cardiovascular
system, but not in others, such as breast and endometrium. This tissue selectivity
is biologically possible because the conformation of a drug-estradiol receptor
complex determines the particular DNA response elements to which it can bind.
Drugs that have these tissue-specific effects have been termed selective estrogen
receptor modulators. Potentially, with these agents the benefits of estrogen
could be derived without the accompanying risks. One such drug, tamoxifen,
used initially to prevent the recurrence of breast cancer, caused considerable
excitement when it was found to protect against osteoporosis3
and cardiovascular disease.4,5
Unfortunately, it was later found to increase the incidence of endometrial
Raloxifene, a benzothiophene derivative that binds to the estrogen receptor,7 is likewise a selective estrogen receptor modulator.
The raloxifene-estrogen receptor complex does not bind to the estrogen-response
element. Instead, it binds to a unique area of DNA called the raloxifene-response
element, to produce estrogen-agonistic effects in some tissues and estrogen-antagonistic
effects in others.8 Raloxifene appears to have
an estrogen-antagonistic effect on breast tissue. Raloxifene inhibits estrogen-dependent
proliferation of human MCF-7 breast cancer cells in vitro9
and inhibits the development of carcinogen-induced mammary tumors in rats.10 Raloxifene also has an estrogen-antagonistic effect
on the uterus, producing minimal endometrial stimulation11
in ovariectomized rats. In contrast, raloxifene has estrogen-agonistic effects
on bone and cholesterol. Raloxifene treatment lowered serum cholesterol levels
of ovariectomized rats11,12 and
rabbits,13 and preserved bone density of ovariectomized
rats.11,12 The hypolipidemic effect
required binding to the estrogen receptor.14
Short-term clinical studies in humans have demonstrated that raloxifene,
at high dosages of 200 mg/d and 600 mg/d for 2 months, significantly decreased
low-density lipoprotein cholesterol (LDL-C) by approximately 9% to 12%. This
was comparable to the 11% decline seen with conjugated equine estrogen, 0.625
mg/d.15,16 Therefore, raloxifene,
like estrogen, has the potential to reduce cardiovascular risk in postmenopausal
women. If this potential is realized, it will be an important finding. Raloxifene
may be widely used in the future, since it has been recently shown to increase
the bone mineral density of healthy postmenopausal women.17
The present study was performed to identify the effects of lower dosages
of raloxifene, 60 mg/d and 120 mg/d, on important cardiovascular intermediate
end points. These include LDL-C, high-density lipoprotein cholesterol (HDL-C),
triglycerides, and fibrinogen. In addition, potentially important cardiovascular
risk markers such as high-density lipoprotein-2 cholesterol (HDL2-C),
lipoprotein(a) (Lp[a]), apolipoproteins A-I and B, prothrombin fragment 1
and 2 (F1+2), fibrinopeptide A (FPA), and plasminogen activator
inhibitor-1 (PAI-1) were also measured.
Healthy postmenopausal women with an intact uterus were eligible if
they were aged 45 to 72 years and had had amenorrhea for at least 12 months.
Women who had undergone hysterectomy were also eligible if they were aged
50 to 72 years. Postmenopausal status in all subjects was verified by a follicle-stimulating
hormone level of at least 30 mIU/mL (30 IU/L) and a serum estradiol level
of at most 40 pg/mL (147 pmol/L). Body mass index was required to be between
18 and 31 kg/m2 and stable within 15% for the
previous 2 years. Subjects were excluded if they did not qualify for therapy
according to the prescribing information for conjugated equine estrogen and
medroxyprogesterone acetate; had a history of breast cancer or any estrogen-dependent
neoplasia; had any other cancer within the previous 5 years (except for excised
superficial skin lesions); had any history of deep venous thrombosis, thromboembolic
disorders, or cerebral vascular accident; or had acute coronary disease or
unstable angina in the previous year. In addition, women treated with hypolipidemic
drugs, warfarin, androgen, systemic corticosteroids, estrogen, or progestin
within 3 months of entry were excluded. Women were also excluded if they had
intolerable postmenopausal symptoms, uterine bleeding, diabetes mellitus,
or other endocrinopathy requiring drug therapy (except if biochemically euthyroid
while receiving thyroid hormone replacement); if they had impaired liver or
kidney function; if they abused alcohol or other drugs; if they had ever participated
in another raloxifene trial; or if they had participated in any investigational
trial within the previous month.
This prospective, double-blind, placebo-controlled, randomized, parallel
study was conducted at 8 sites in the United States. The study was approved
by the ethical review boards at each site and all subjects gave written informed
consent. Subjects were recruited by advertisement, and typically were reimbursed
for their expenses. We chose a sample size that had 80% power to detect the
smallest change in the mean LDL-C level that we considered to be clinically
significant, which was a 6% change vs placebo, using a 2-sided significance
level of .05. We used an SD of 0.48 mmol/L (19 mg/dL) for LDL-C, based on
prior placebo-controlled trials evaluating estrogen in healthy postmenopausal
women.18 This indicated that we would need
76 subjects to complete each treatment arm. Assuming a 15% dropout rate seen
with similar studies, we calculated that we would need to enroll approximately
90 subjects per treatment arm (a total of at least 360).
Three hundred ninety subjects were found to be eligible and were randomly
assigned using a random number table generated by a computer program (Clinpro/LBL;
Clinical Systems Inc, Garden City, NY) and a block size of 8, to 1 of 4 therapy
groups: (1) raloxifene hydrochloride, 60 mg/d; (2) raloxifene hydrochloride,
120 mg/d; (3) hormone replacement therapy (HRT), 0.625 mg of conjugated equine
estrogen and 2.5 mg of medroxyprogesterone acetate given in a continuous combined
fashion; or (4) placebo. All treatments were given for 6 months, taken as
2 tablets and 2 capsules of blinded study medication each morning. The study
medication and placebo were formulated in identical tablets and capsules.
Compliance was ascertained by pill counts performed at every visit, and expressed
as the ratio of (number of pills dispensed − number of pills returned)/total
days of therapy. Subjects were considered compliant if they took more than
70% of their expected study medication and did not miss more than 6 days of
treatment in any 2-week period. Subjects were instructed not to significantly
change their diet during the study. This was assessed by dietary questionnaires19 completed at baseline and end point. Subjects fasted
for at least 12 hours prior to each of 10 visits: 1 visit for screening, 3
visits in the week prior to randomization to obtain baseline measurements,
3 visits during the 12th week of treatment, and 3 visits during the 24th week
of treatment. Three visits were scheduled at each time point to provide multiple
measures. This was done to minimize the effects of day-to-day variation in
lipid levels. Serum lipids were measured on all 3 days during each 7-day interval,
and coagulation markers were measured on 2 of those 3 days.
Fasting serum for lipid analyses was obtained on 3 different days within
a 7-day time period at baseline, 12 weeks, and 24 weeks. Blood was centrifuged
within 30 minutes of collection at 3000g for 10 minutes
at 4°C and the plasma was frozen. Samples were then shipped to a central
laboratory (Covance, Indianapolis, Ind) where they were stored at -70°C
for up to 1 year. Two analytical runs of each assay were performed, with all
the samples for a given subject contained in the same batch. All serum samples
drawn in the same week that were free of hemolysis and not visibly lipemic
were pooled prior to lipid analysis.
High-density lipoprotein and high-density lipoprotein-3 (HDL3)
were sequentially separated by precipitation with dextran sulfate and magnesium
chloride.20 Cholesterol and triglycerides were
measured with enzymatic reagents (Boehringer-Mannheim, Indianapolis). LDL-C
was calculated using the Friedewald equation: LDL-C = (total cholesterol −
HDL-C) − (triglycerides × 0.20). Eight subjects were excluded
from the LDL-C analysis because of triglyceride values greater than 4.4 mmol/L
(389 mg/dL). Lipoprotein(a) was quantified21
by an automated immunoprecipitin analysis (IncStar Corp, Stillwater, Minn).
Apolipoproteins A-I and B were quantified using rate nephelometry.22 The intra-assay and interassay coefficients of variation,
respectively, for these assays were 1.4% and 4.3% for HDL-C, 1.2% and 9.6%
for HDL3-C, 1.1% and 2.6% for triglycerides, 2.6% and 5.6% for
Lp(a), 2.5% and 4.8% for apolipoprotein A-I, and 1.7% and 3.7% for apolipoprotein
Fasting serum for measurement of coagulation factors was obtained on
2 different days within a 7-day time period at baseline, 12 weeks, and 24
weeks. Blood was drawn by technicians extensively trained in nontraumatic
phlebotomy technique to minimize ex vivo coagulation activation. To assess
the quality of phlebotomy, blood samples obtained at screening were assayed
on a continuing basis for FPA, the coagulation activation marker most sensitive
to traumatic phlebotomy. Specimens with FPA levels greater than 50 ng/mL were
believed to result from traumatic phlebotomy (9 [3.6%] of 258 screening samples),
based on the values previously reported in postmenopausal women.23
Results were reported back to each site to facilitate improvements in phlebotomy
Following phlebotomy, blood was transferred to tubes (SCAT-1; Hematologic
Technologies Inc, Burlington, Vt), containing anticoagulants with final concentrations
of EDTA, 4.5 mmol/L; aprotinin, 0.15 kallikrein inhibition units per liter
(KIU/L); and D-Phe-Pro-Arg chloromethyl ketone, 20 µmol/L, a potent
serine protease inhibitor. Blood was centrifuged within 30 minutes of collection
at 3000g for 10 minutes at 4°C, and the plasma
was frozen. Samples were shipped to a central laboratory (Covance, Indianapolis)
where they were stored at −70°C for up to 1 year. As for lipids,
2 analytical runs of each assay were performed during the course of the study.
All the samples for a given patient were assayed in the same run. All coagulation
assays were performed in duplicate. If the difference between the 2 results
was within the coefficient of variation of the assay, their average was reported.
If not, repeat duplicate analyses were performed until agreement was achieved
or the results were rejected.
Prior to the study, it was decided to exclude FPA and F1+2
values obtained from samples that had FPA levels greater than 50 ng/mL, since
in all likelihood such samples represent phlebotomy artifact. PAI-1 activity
and fibrinogen levels were not excluded, since these analytes are less subject
to traumatic phlebotomy. To examine the impact of this exclusionary rule on
the results of the study, the data were reanalyzed without any exclusions.
The differences among treatments were unaltered.
Fibrinogen was measured by the Clauss clotting technique with an automated
coagulation analyzer (MLA Electra 1600C; Medical Laboratory Automation, Pleasantville,
NY) that uses a photometric clot detection technique. Plasminogen activator
inhibitor-1 activity in plasma was determined using an amidolytic assay kit
(Spectrolyse PL; Biopool, Umea, Sweden).24
Prothrombin fragment 1 and 2 was measured by enzyme immunoassay (Enzygnost
F1+2; Behringwerke AG, Marburg, Germany).25
Fibrinopeptide A was assayed by a competitive enzyme immunoassay in plasma
extracted with bentonite to remove fibrinogen (Asserachrome FPA; Diagnostica
Stago, Asnieres, France).26 The intra-assay
and interassay coefficients of variation, respectively, for these assays were
0.7% to 1.7% and 1.9% to 2.5% for fibrinogen; 4.1% to 18.3% and 7.1% to 23.7%
for PAI-1; 4.8% to 5.2% and 6.7% to 12.6% for F1+2; and 8.6% to
12.3% and 14.3% to 20% for FPA.
The primary analysis was change and percent change from baseline to
end point for all lipid and coagulation markers using a 2-way analysis of
variance (ANOVA) with treatment and investigators as fixed effects in the
model, since no treatment-by-investigator interaction (for all 8 investigators)
was found in any of the variables. End point refers
to the last visit completed, which was either a 3-month or 6-month visit.
All analyses were performed using data from all randomly assigned subjects
according to the intent-to-treat principle27
of last-observation-carried-forward, in which subjects were assigned to the
therapy actually received. Thus, analyses were performed in all subjects who
had a baseline and at least 1 postbaseline result. Most of the lipid and coagulation
data were skewed and in some cases heterogeneity of variances was observed.
Therefore, ANOVA was performed on appropriate power-transformed or rank-transformed
data. For absolute changes from baseline, two-thirds power transformations
were used for HDL-C, LDL-C, triglycerides, Lp(a), apolipoprotein A-I, and
F1+2; and rank transformations were used for apolipoprotein B,
HDL2-C, FPA, fibrinogen, and PAI-1. For percent changes from baseline,
two-thirds power transformations were used for HDL-C, triglycerides, apolipoprotein
A-I, and F1+2; rank transformations were used for LDL-C, HDL2-C, Lp(a), apolipoprotein B, FPA, and PAI-1; and no transformations
were used for fibrinogen. Medians are presented as descriptive statistics
of the variable. The SEs for the medians were calculated using the d-delete
To determine if differences in the years after menopause among the groups
could account for any of the treatment differences, an analysis of covariance
was performed using years after menopause as a covariate. To determine if
differences in the proportions of hysterectomies among the groups could account
for any of the treatment differences, hysterectomy status was used as an effect
in the ANOVA.
Adverse events were analyzed using the Cochran-Mantel-Haenszel technique,
stratified by investigators. All dietary variables were analyzed for changes
from baseline to end point using rank-transformed ANOVA.
Of 541 women who underwent screening procedures, 390 were found to be
eligible and were randomized (98 to placebo; 95 to raloxifene, 60 mg daily;
101 to raloxifene, 120 mg daily; and 96 to HRT). Three hundred forty-nine
patients were seen at 3 months (90, 84, 92, and 83 patients for the 4 groups,
respectively), and 326 completed the study (85, 81, 90, and 70 patients for
the 4 groups, respectively). As shown in Table 1, the 4 therapy groups did not significantly differ regarding
age, race, body mass index, current tobacco use, alcohol consumption, and
blood pressure. The HRT group was the greatest number of years after menopause,
possibly related to the higher proportion of hysterectomies in this group.
These differences in years after menopause and in the proportion of hysterectomies
among the treatment groups did not account for the differences in any of the
efficacy measurements observed. At baseline, the mean daily dietary intakes
of total joules (7531 J [1800 cal]), protein (81 g), fat (58 g), carbohydrates
(243 g), sucrose (10 g), cholesterol (232 mg), and dietary fiber (22 g) were
not significantly different among the groups. There were no significant differences
among the groups in any of the dietary variables over the course of the study.
Systolic and diastolic blood pressure, weight, and heart rate did not significantly
change in any of the 4 treatment groups. Study drug compliance was 84% at
3 months and 94% at 6 months, which did not significantly differ among therapy
At baseline, there were no significant differences in lipoprotein levels
among treatment groups. As shown in Figure
1 and Figure 2, the effect
of treatment was evident by 3 months, with little additional change at 6 months,
implying short-term stability of these changes. There were no significant
differences between the 2 dosages of raloxifene tested. The levels of all
measured lipids, except for Lp(a), did not change more than 1% during the
6-month treatment with placebo. This stability of the control group over time
may have been achieved by obtaining multiple blood specimens, as well as the
subjects' success in maintaining a constant diet. Both of these factors would
serve to minimize the effects of biological variation of lipid levels. At
end point (ie, the last visit completed), the following statistically significant comparisons with placebo were noted (Table 2), and were not different when the analysis was restricted
to only those subjects who completed this 6-month study: low-density lipoprotein
cholesterol levels were lowered by 12% with the 2 raloxifene dosages (P<.001 for both) and were lowered by 14% with HRT (P<.001). The difference between raloxifene and HRT was
High-density lipoprotein cholesterol levels were unchanged by raloxifene,
but were increased by 10% with HRT (P<.001). High-density
lipoprotein-2 cholesterol levels were increased by 15% and 17% for the 2 raloxifene
dosages (P=.009 and P=.005,
respectively), and were increased by 33% (P<.001)
for HRT. Hormone replacement therapy raised HDL2-C levels significantly
more (P<.001) than did either dosage of raloxifene.
High-density lipoprotein-3 cholesterol levels were not significantly changed
by any treatment.
Triglyceride levels were not changed by either raloxifene dosage, but
were increased by 20% with HRT (P<.001).
Apolipoprotein A-I levels were increased by 5% with raloxifene, 120
mg/d (P<.001) and were increased by 12% with HRT
(P<.001). Hormone replacement therapy raised apolipoprotein
A-I significantly more (P<.001) than did either
dosage of raloxifene. Apolipoprotein B levels were reduced by 9% with both
raloxifene dosages (P<.001 for both), but were
not changed by HRT.
Lipoprotein(a) levels were lowered by 7% and 8% for the 2 raloxifene
dosages (P=.04 and P=.02,
respectively) and were lowered by 19% with HRT (P<.001).
Hormone replacement therapy reduced Lp(a) levels significantly more (P<.001) than did either dosage of raloxifene. There
was a weak correlation (r=0.28, P<.001) between the percentage changes in Lp(a) and LDL-C.
At baseline, there were no significant differences in coagulation factor
levels between treatment groups. At end point, the following statistically
significant comparisons with placebo were noted (Table 3), and were not different when the
analysis was restricted to only those subjects who completed this 6-month
study: fibrinogen levels were lowered by 10% and 12% for the 2 raloxifene
dosages (P<.001 for both), but were unchanged
by HRT. There was no correlation between the percent change in fibrinogen
and any of the lipoproteins measured. Plasminogen activator inhibitor-1 levels
were not changed by either raloxifene dosage, but were reduced by 19% with
HRT (P<.001). Fibrinopeptide A and F1+2
levels were not significantly changed by raloxifene or HRT.
The most commonly noted adverse events were vaginal bleeding, breast
tenderness, and hot flashes (Table 4).
Hot flashes were the most common adverse event in the raloxifene groups, with
the highest incidence (22%) occurring at the 120-mg dosage. In contrast, vaginal
bleeding was the most common adverse event in the HRT group (45%), and occurred
significantly (P<.001) more often than in the
placebo or raloxifene groups. Significantly more patients in the HRT group
discontinued the study, primarily because of vaginal bleeding (P<.001). In contrast, there were few discontinuations because of
hot flashes in the raloxifene groups. There were no other adverse events that
had a statistically significant higher incidence in the raloxifene groups
compared with the placebo group.
This study demonstrates that raloxifene, a selective estrogen receptor
modulator, favorably alters several markers of cardiovascular risk in healthy
postmenopausal women. Specifically, raloxifene reduced the levels of LDL-C,
fibrinogen, and Lp(a); did not raise triglyceride levels; and raised HDL2-C levels. However, in contrast with HRT, raloxifene had no effect
on HDL-C and PAI-1 levels and a lesser effect on HDL2-C and Lp(a)
levels. There were no significant differences between the 2 dosages tested.
The changes seen with HRT are similar to those previously reported.29
The decrease in LDL-C by raloxifene would be expected to reduce the
risk of coronary artery disease. Epidemiological studies have found that the
levels of LDL-C are related to risk of coronary artery disease among both
men and women. Moreover, clinical trials that lowered LDL-C levels in women
have been found to reduce the incidence of a second cardiac event. One such
trial of a lipid-lowering agent found that a 30% reduction in LDL-C levels
in women was associated with a 46% reduction in cardiovascular events.30 This suggests that the 12% reduction in LDL-C levels
observed in this study, if sustained over time, might lower the incidence
of heart disease by as much as 18%. The 7% reduction in Lp(a) levels may reduce
this risk even more.
The decline in fibrinogen levels induced by raloxifene treatment may
also serve to lower cardiovascular risk. Fibrinogen levels have been found
to be an independent risk factor for heart disease, with a reduction of 0.5%
for every 0.01-g/L decrease in fibrinogen levels.31
We may hypothesize that the 0.42-g/L reduction in fibrinogen induced by raloxifene
in this study could therefore translate into an additional 21% reduction in
cardiovascular events. This is speculative, since, to our knowledge, there
is no evidence to date from a clinical trial that shows that lowering the
fibrinogen level of an individual will reduce her cardiovascular risk.
Although there are similarities between the effects of raloxifene and
estrogen on lipid and coagulation factors, there are differences as well.
This indicates that the serum levels of these factors are controlled by processes
that operate by independent mechanisms. Some of these processes appear to
be alterable by estrogen only, some by raloxifene only, and some by both.
This independence of mechanisms is consistent with the observation that the
magnitudes of the changes in LDL, HDL, and triglyceride levels induced by
estrogen treatment are not significantly correlated within individual subjects.18 One noteworthy difference between estrogen and raloxifene
is in their effect on HDL-C, HDL2-C, and apolipoprotein A-I levels,
which were only marginally increased by raloxifene. Therefore, raloxifene
does not appear to have full agonistic activity against the target(s) that
estrogen modulates to increase HDL. In contrast, the lowering of LDL-C represents
an estrogen-agonistic effect of raloxifene and is similar in magnitude to
the estrogen effect. This is consistent with the in vitro observation that
raloxifene lowers LDL-C by binding to the estrogen receptor.8
The effect of raloxifene on markers of cardiovascular risk bore a greater
resemblance to the pattern previously reported for tamoxifen32- 34
(Table 5). Since these data are
not derived from the same clinical trial, the percentage changes seen may
not be directly comparable among the different treatment groups. However,
these trials were all performed in similar groups of healthy postmenopausal
women, and illustrate that the raloxifene and tamoxifen effects on HDL-C,
HDL2-C, and apolipoprotein A-I are both distinctly smaller than
estrogen's effect. The overall similarity of the effects of raloxifene and
tamoxifen is noteworthy, since the changes induced by tamoxifen on cardiovascular
risk markers could be responsible for its apparent cardioprotective effect.
This cardioprotective effect is supported by the observation that postmenopausal
women with breast cancer who received tamoxifen in a randomized, controlled,
clinical trial4 were found to have a significantly
lower incidence of fatal myocardial infarction (odds ratio, 0.37; 95% confidence
interval, 0.18-0.77). In another such controlled clinical trial,5
women randomized to tamoxifen treatment had fewer hospital admissions for
cardiac disease (relative risk, 0.68; 95% confidence interval, 0.48-0.97).
A third such trial35 found a trend toward fewer
cardiovascular deaths in women given tamoxifen, but this did not reach statistical
significance (relative risk, 0.85; 95% confidence interval, 0.47-1.58).
With the exception of hot flashes, raloxifene was found to be free of
any significant adverse effects. Most important, raloxifene did not cause
vaginal bleeding or breast tenderness. In contrast, almost half of HRT subjects
experienced vaginal bleeding and approximately a third of HRT subjects experienced
breast tenderness. Both of those symptoms caused many participants randomized
to HRT to drop out of the study, and they also cause many women who have been
prescribed HRT to stop taking it. Although the incidence of hot flashes was
6% and 12% higher for the 2 dosages of raloxifene compared with placebo, it
did not cause subjects to discontinue their participation. It therefore appears
that long-term compliance could be greater for treatment with raloxifene than
is currently the case with HRT.
In summary, raloxifene at both dosages favorably altered a number of
lipid and coagulation markers of cardiovascular risk. For the most part, the
direction of the response paralleled that of HRT, although not necessarily
of the same magnitude. The pattern of response bore a greater similarity to
tamoxifen than to HRT. Because of these beneficial effects on biochemical
markers of cardiovascular risk, it can be speculated that raloxifene, used
at either 60 mg/d or 120 mg/d, might substantially reduce the risk of heart
disease in postmenopausal women. Conclusive proof would require a clinical
trial with cardiovascular events as the definitive end point.