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ORIGINAL RESEARCH |
From the Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
Address reprint requests to: Mark Lakshmanan, MD, Lilly Research Laboratories, Lilly Corporate Center, Indianopolis, IN 46285
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Abstract |
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Methods: Common treatment groups were pooled across eight randomized, parallel clinical trials (6–30 months’ duration) of raloxifene to create the following three databases: placebo-controlled, HRT-controlled, and estrogen-controlled databases. Incidence and severity of all treatment-emergent adverse events, defined as events that first occurred or worsened during treatment, were compared among groups in each of the databases.
Results: Discontinuation rates overall, and those related to adverse events, were not significantly different between treatment groups in any database. There was no significant difference in incidence of vaginal bleeding or breast discomfort between women treated with raloxifene (60 mg/d) or placebo. Both of these events were reported more frequently in women receiving HRT or estrogen. Vaginal bleeding was responsible for significantly more discontinuations from the HRT groups compared with the raloxifene group. Hot flashes was the only event common to all three databases that was significantly increased in the raloxifene group, but this event did not increase the discontinuation rates. The incidence of leg cramps was greater in raloxifene-treated women compared with placebo-treated women in the placebo-controlled database, but did not cause any discontinuations of therapy. Raloxifene had no effect on the incidence of vaginal symptoms or central nervous system events.
Conclusion: Raloxifene had an adverse event profile distinct from HRT and unopposed estrogen and was well tolerated by postmenopausal women.
Continuous, long-term (5–10 years or more) hormonal therapy regimens (unopposed estrogen or estrogen plus progestin combinations) can protect postmenopausal women from developing osteoporosis.1 Other potential benefits of estrogen therapies were suggested by observational studies2,3 but were not found in randomized, clinical trials.4,5 A minority of postmenopausal women currently take estrogen or hormone replacement therapy (HRT) long enough for maximal benefit, because of side effects such as vaginal bleeding and breast pain, and fear of uterine and breast cancers.6,7 A major challenge for any intervention is to optimize long-term adherence to therapy. New therapies with improved tolerability might improve compliance by women to long-term intervention.
Raloxifene (Evista, Eli Lilly and Company, Indianapolis, IN) is a selective estrogen receptor modulator and can act as a tissue-specific estrogen receptor agonist or antagonist.8 Raloxifene is a benzothiophene compound and is distinguished from compounds of the triphenyl-ethylene class, including tamoxifen and toremifene,9 by its lack of endometrial stimulation.10,11 Raloxifene was shown recently to be effective in preventing10 and treating11 osteoporotic bone loss in postmenopausal women. Raloxifene lowers serum low-density lipoprotein (LDL) cholesterol, favorably affects other biochemical risk factors for cardiovascular disease, and has no adverse effects on these risk factors.12 Raloxifene (60 mg per day) was approved for prevention of postmenopausal osteoporosis in the United States and several other countries.
Few adverse events have been observed in clinical trials with raloxifene.10–13 Despite large sample sizes, there was variability between adverse events detected in the various trials. For example, an increased incidence of hot flashes was reported with raloxifene compared with placebo in two clinical trials,12,13 but there were no treatment-specific differences in hot flashes in two others,10,11 which might relate to subject characteristics. An analysis that encompasses a broader sample of women would increase the power to detect adverse events associated with raloxifene treatment and improve clinical relevance of these findings. We conducted a primary analysis of data combined from eight randomized clinical trials of raloxifene that included 2789 postmenopausal women. We present the adverse event profile of raloxifene 60 mg per day, the target dose for prevention of postmenopausal osteoporosis, compared with placebo, HRT, and unopposed estrogen.
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Materials and Methods |
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). Details of the study designs and primary endpoint results for three of these trials have been published: they include an osteoporosis prevention study,10 an osteoporosis treatment study,11 and a cardiovascular risk factor study.12 The other five trials either have been accepted for publication with regard to their primary endpoints or are continuing. The trials included in each database and the resulting treatment groups are summarized in Table 2. Note that trial 3 had both placebo and estrogen comparison groups, and is represented in the placebo-controlled and estrogen-controlled databases. Trial 5 had both placebo and HRT comparison groups and is represented in the placebo-controlled and HRT-controlled databases. The demographics of the database populations are summarized in Table 3.
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Exclusion criteria common to all trials included a history of estrogen-dependent neoplasia, cancer in the previous 5 years excluding excised superficial lesions, treatment with androgens, calcitonin or glucocorticoids within 6 months of enrollment, previous treatment with bisphosphonates or fluoride (except for dental prophylaxis), current treatment with hypolipidemic agents or pharmacologic doses of vitamin D, and abnormal kidney or liver function. Also excluded were women with clinically significant menopausal symptoms, including hot flashes and vaginal dryness. Systemic estrogen treatment within 6 months of enrollment was exclusionary in all studies except for trial 6, which excluded estrogen treatment within the last month.
Adverse Event Reporting
In clinical trials for registration of new compounds, recording all treatment-emergent adverse events is important for their earliest detection. "Treatment-emergent adverse events" (subsequently referred to as adverse events) included any experience that subjects found undesirable and were defined as events that first occurred or worsened during treatment. Adverse events were collected and recorded without inference to causality and were elicited by open-ended, nondirected questioning of the women, clinical observation, and source document review. For some studies, adverse events were first classified using the World Health Organization Adverse Reaction Terminology dictionary, then classified using the Coding Symbol and Thesaurus for Adverse Reaction Terminology dictionary. In other studies, events were initially classified using the Coding Symbol and Thesaurus for Adverse Reaction Terminology dictionary. Each adverse event was recorded according to the subjects’ perceived severity of the event (mild, moderate, or severe), defined as follows: mild, change in subject’s condition that did not affect usual activities; moderate, mild disruption in subject’s usual activity; severe, major disruption in subject’s usual activity. Reasons stated for discontinuing were monitored and recorded.
Adverse events were analyzed by treatment group and incidences were calculated as percentages of sample sizes for each treatment group. For calculating uterine-related events, including vaginal hemorrhage, menorrhagia, metrorrhagia, uterine hemorrhage, withdrawal bleeding, menstrual disorder, and uterine disorder, the sample size of each treatment group was adjusted to exclude women who had hysterectomies.
Statistical Analyses
Statistical Analysis Software (SAS Inc, Cary, NC) version 6.08 was used for all statistical analyses. All of the analyses were based on an intent-to-treat principle. Incidence rates for adverse events, overall discontinuation rates, and discontinuations due to adverse events were compared among treatment groups by using the Cochran-Mantel-Haenszel general association test, adjusting for protocol.14 Analysis of adverse events during cyclic HRT regimens found that norgestrel-treated women were similar to those treated with medroxyprogesterone acetate in terms of adverse events. Data from subjects treated with those two regimens were pooled in all subsequent analyses.
Adverse events were first analyzed for significant differences in incidence among all the treatment groups in each database (Table 2
). Events with significantly different incidences across all treatment groups were then tested in pairwise comparisons between the raloxifene (60 mg per day) group10 and the corresponding placebo, HRT, or estrogen group in each database. Only events that were significantly different in both the overall comparison and the pairwise comparison are presented, and the significance levels presented throughout are those corresponding to the pairwise comparisons. All treatment differences were tested at a two-sided significance level of .05. Statistical significance levels are reported as nominal P values; no attempt was made to correct for the analysis of multiple endpoints. This was a conservative approach to avoid missing adverse events marginally associated with use of a drug. In analysis of multiple endpoints, attempts to correct for multiple comparisons might require extremely low P values for acceptance of differences.15
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Urogenital Events
Incidence of vaginal bleeding in women treated with raloxifene was low in all of the databases (less than 7%) and was not significantly different from that observed in placebo-treated women (Figure 1). In contrast, bleeding was experienced on at least one occasion by 89% and 64% of women receiving cyclic HRT and continuous combined HRT, respectively, in the HRT-controlled database, and by almost half of women receiving unopposed estrogen in the estrogen-controlled database. The incidence of vaginal bleeding was significantly greater in women receiving hormonal therapies than in raloxifene-treated women in both databases (Figure 1). No women assigned to raloxifene reported moderate or severe bleeding. The percentages of vaginal bleeding episodes reported as moderate or severe were 15.1%, 13.4%, and 14.3% in the cyclic HRT group, continuous combined HRT group, and estrogen group, respectively. Compared with raloxifene-treated subjects, the incidence of discontinuations due to vaginal bleeding was significantly higher in women treated with cyclic HRT (raloxifene, 0.5%; cyclic HRT, 4.6%; P = .006) and continuous combined HRT (raloxifene, 0%; continuous combined HRT, 13.4%; P < .001). There were no discontinuations due to vaginal bleeding in any treatment group of the estrogen-controlled trials.
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Breast Events
In the placebo-controlled database, there was no significant difference between groups in incidence of breast pain (Figure 2). Breast pain was reported significantly more frequently by women receiving HRT or unopposed estrogen than by those receiving raloxifene in the HRT- and estrogen-controlled databases, respectively (Figure 2). The percentage of breast pain episodes reported as moderate or severe was identical (0.9%) for the raloxifene and placebo groups in the placebo-controlled database, and similar in the raloxifene and estrogen groups in the estrogen-controlled database (raloxifene, 1.7%; estrogen, 3.8%; P = .223). In the HRT-controlled database, incidence of breast pain reported as moderate or severe was significantly greater among women assigned to HRT than those assigned to raloxifene (HRT, 7.6%; raloxifene, 0%; P < .001). Breast pain was not a significant cause of discontinuation in any of the databases.
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summarizes the other adverse events reported, with significantly different incidence in at least one of the three databases. The incidence of hot flashes was significantly higher in women treated with raloxifene than in those assigned to placebo in the placebo-controlled database (Table 4). The incidence of hot flashes in women treated with raloxifene was similar across the three databases; however, the incidence of hot flashes was predictably lower in women receiving HRT or unopposed estrogen than in those receiving either placebo or raloxifene (Table 4). The incidence of hot flashes and events believed to be associated with them are analyzed further.
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). Of 32 occurrences of leg cramps in the raloxifene group, all were reported as mild or moderate (19 and 13, respectively). The incidence of leg cramps was comparable between the raloxifene and HRT groups in the HRT-controlled database (Table 4). Leg cramps tended to occur more frequently in the raloxifene group compared with the unopposed estrogen group in the estrogen-controlled database (Table 4), but this difference was not statistically significant (P = .075). There were no discontinuations due to leg cramps in either the raloxifene group or the respective comparison groups in any of the three databases.
The incidence of abdominal pain, which includes cramping associated with menses, was not significantly different between treatment groups in the placebo-controlled and estrogen-controlled databases. However, abdominal pain was reported significantly more frequently in women receiving HRT than in those receiving raloxifene in the HRT-controlled database (Table 4). The severity of abdominal pain did not differ significantly between treatment groups. The number of women who discontinued due to abdominal pain (zero in the raloxifene group and two in the HRT group) was too small for statistical comparison.
The incidence of flatulence was not significantly different between treatment groups in the placebo-controlled database. This event was reported significantly more frequently by women assigned to HRT or estrogen compared with raloxifene in the HRT-controlled and estrogen-controlled databases, respectively (Table 4).
In the HRT-controlled database, there was a small but significant increase in the following adverse events reported among women treated with raloxifene compared with those treated with HRT: infection, chest pain, dyspnea, and herpes zoster (Table 4). However, the incidence of these events was not significantly different between the raloxifene group and the comparison groups in the placebo-controlled or estrogen-controlled databases (Table 4).
There was no evidence that raloxifene was associated with adverse events of the central nervous system. The incidences of the following self-reported central nervous system events were not significantly different between groups in the three databases: depressive symptoms, emotional lability, insomnia, anxiety, dizziness, malaise, and amnesia.
Hot Flashes and Events Related to Vasomotor Instability
The increased incidence of new hot flashes among raloxifene-treated women in the placebo-controlled studies was observed during the first 6 months of therapy; after 6 months, incidence of new hot flashes in the raloxifene-treated group was not different from that in the placebo-treated group (Table 5). Compared with the placebo group this increase was small (about 7 of 100 women treated), and hot flashes in women treated with raloxifene were mild to moderate (Table 5). The number of women with severe hot flashes and the number who cited hot flashes as a reason for discontinuing did not differ significantly between treatment groups in placebo-controlled studies (Table 5).
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Discussion |
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The women in the present study were at risk for or had osteoporosis and were not being treated for hot flashes, vaginal dryness, or other clinically significant menopause symptoms. Postmenopausal women, the primary target population for preventive therapy, generally do not seek therapy for menopausal symptoms after the initial perimenopausal phase, making it important to compare raloxifene to placebo.
Overall discontinuation rates and those related to adverse events were comparable between the raloxifene and placebo groups. Raloxifene was not different from placebo in the incidence of vaginal bleeding or other vaginal complaints. The lack of vaginal bleeding with raloxifene is consistent with its reported lack of proliferative effect on endometrium.10,11 The incidence of breast pain also was not different between the raloxifene and placebo groups. No improvements were reported in adverse events in the raloxifene group compared with the placebo group, an expected finding in placebo-controlled trials that do not target the treatment of specific symptoms. In the placebo-controlled database, two events were reported significantly more often among women assigned to raloxifene, hot flashes and leg cramps.
The increased incidence of new or worsened hot flashes in the raloxifene group compared with the placebo group occurred during the first 6 months of therapy. The incidence of hot flashes attributable to raloxifene was 7%. The incidence of events that accompany hot flashes (sweating and sleep disturbance) was not different between the raloxifene group and other groups.
More leg cramps were reported in the raloxifene group than in the placebo group. The incidence of leg cramps attributable to raloxifene was 4%. They were generally mild and did not result in any discontinuations of raloxifene.
Most postmenopausal women do not seek therapy to prevent osteoporosis and other postmenopausal conditions.6,7 Estrogen and HRT are still the most common therapies; therefore, it is important to compare adverse event profiles of raloxifene, estrogen, and HRT. There are relatively few large, prospective, randomized controlled trials of estrogen or HRT, and even fewer that directly compared various types and routes of administration of these therapies. The current trials were limited to one dose of daily oral conjugated equine estrogen, and the progestin was medroxyprogesterone acetate or norgestrel, taken sequentially or continuously. These combinations are the most common in the United States and many other countries, and represent a reasonable basis for comparison.
The overall discontinuation rates and those related to adverse events were comparable between the raloxifene, unopposed estrogen, and HRT groups. In contrast to the placebo-controlled database, there were differences in the specific adverse event profiles for raloxifene, estrogen, and HRT. There were more hot flashes with raloxifene, and more vaginal bleeding and breast pain with HRT and estrogen.
In the estrogen-controlled and HRT-controlled databases, hot flashes and sweating were less frequent among women taking unopposed estrogen or HRT compared with those taking raloxifene. These results were expected, because of the known efficacy of estrogen and HRT for alleviating hot flashes.16 There was no effect of hot flashes on sleep patterns of women taking raloxifene compared with estrogen or HRT. It is unlikely that women seeking medical relief of hot flashes would respond to raloxifene therapy for these complaints.
In the estrogen-controlled and HRT-controlled databases, vaginal bleeding and breast pain were reported less with raloxifene than with estrogen or HRT. Hormone-controlled studies ranged from 6 to 12 months and included cyclic and continuous HRT. Estrogen and HRT were associated with increased incidences of vaginal bleeding and breast pain. Raloxifene was associated with rates of vaginal bleeding and breast pain comparable to those of placebo and significantly less than those of estrogen or HRT. Because vaginal bleeding and breast tenderness are among the most frequent reasons for discontinuation of estrogen and HRT,6,7 those differences might be desirable to postmenopausal women considering preventive therapy for osteoporosis.
Although a small number of women reported infection, chest pain, dyspnea, and herpes varicellazoster with raloxifene in the HRT-controlled database, none of the events were reported as serious or led to discontinuation. These conditions are expected in postmenopausal women regardless of therapy and no association between those events and estrogen or tamoxifen has been reported. Because similar differences were not detected in the placebo-controlled or estrogen-controlled databases, these events were not likely a result of raloxifene. Likewise, because estrogen might improve urinary incontinence and has been used to treat that condition in postmenopausal women,17 the increased incidence of urinary incontinence in the unopposed estrogen group compared with the raloxifene group in the estrogen-controlled database was probably not a clinically significant effect attributable to estrogen therapy. The same might be true for findings of abdominal pain and flatulence. Those results likely resulted from the large number (more than 600) of comparisons made in this study, and that some comparisons would appear statistically significant by chance.
The potential effects of raloxifene on adverse effects of the central nervous system are important because studies suggested that estrogen might improve18,19 or have a neutral effect20,21 on cognitive function in postmenopausal women. Raloxifene had no significant effect on the incidence of any central nervous system-related adverse event. Cognitive function and mood, assessed with established psychometric test batteries as secondary safety endpoints, were not significantly different between postmenopausal women treated with raloxifene or placebo in an osteoporosis treatment trial.22 A very rare but significant adverse event associated with postmenopausal hormone therapy is an approximately threefold increase in the incidence of venous thromboembolism.4,23 A similar risk was observed for raloxifene in an ongoing, large-scale osteoporosis treatment trial of over 7000 postmenopausal women (unpublished data), and raloxifene is contraindicated in women with current or previous venous thromboembolic events. That difference was not statistically demonstrable in the present analysis, probably because of the low incidence of venous thromboembolism. Nevertheless, that risk should be considered in selecting postmenopausal women appropriate for these therapies.
The specific profiles of raloxifene, estrogen, and HRT must be considered and discussed with each woman when selecting a regimen preventing osteoporosis and other postmenopausal conditions. Because few women currently take preventive therapy compared with the large number of women at risk for osteoporosis, new alternatives are needed. Raloxifene represents an option as a first-line therapy for preventing postmenopausal osteoporosis10 and continues to be studied for the treatment of other postmenopausal conditions.12,24
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Footnotes |
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Financial Disclosure
Each of the authors is a full-time employee of Eli Lilly and Company, which markets raloxifene under the trade name Evista. Mark Lakshmanan and William Huster own stock and stock options, and Yili Lu, Graham Davies, and Leo Plouffe hold stock options in Eli Lilly and Company.
Received June 9, 1998. Received in revised form September 11, 1998. Accepted October 1, 1998.
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B. S. KOMM and C. R. LYTTLE Developing a SERM: Stringent Preclinical Selection Criteria Leading to an Acceptable Candidate (WAY-140424) for Clinical Evaluation Ann. N.Y. Acad. Sci., December 1, 2001; 949(1): 317 - 326. [Abstract] [Full Text] [PDF]
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S. R. Goldstein, P. Neven, L. Zhou, Y. L. Taylor, A. V. Ciaccia, and L. Plouffe Jr Raloxifene Effect on Frequency of Surgery for Pelvic Floor Relaxation Obstet. Gynecol., July 1, 2001; 98(1): 91 - 96. [Abstract] [Full Text] [PDF]
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M. E. Lippman, K. A. Krueger, S. Eckert, A. Sashegyi, E. L. Walls, S. Jamal, J. A. Cauley, and S. R. Cummings Indicators of Lifetime Estrogen Exposure: Effect on Breast Cancer Incidence and Interaction With Raloxifene Therapy in the Multiple Outcomes of Raloxifene Evaluation Study Participants J. Clin. Oncol., June 15, 2001; 19(12): 3111 - 3116. [Abstract] [Full Text] [PDF]
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 R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]
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 L. louffe Jr. Selective Estrogen Receptor Modulators (SERMs) in Clinical Practice Reproductive Sciences, January 1, 2000; 7(1_suppl): S38 - S46. [Abstract] [PDF]
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A. L. Franks and K. K. Steinberg Encouraging News From the SERM Frontier JAMA, June 16, 1999; 281(23): 2243 - 2244. [Full Text] [PDF]
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 J. An, C. Tzagarakis-Foster, T. C. Scharschmidt, N. Lomri, and D. C. Leitman Estrogen Receptor beta -Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens J. Biol. Chem., May 18, 2001; 276(21): 17808 - 17814. [Abstract] [Full Text] [PDF]
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