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ORIGINAL RESEARCH |
From the Women’s Health and Internal Medicine, Comprehensive NeuroScience, Inc, Atlanta, Georgia; Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts; Lilly Research Laboratories, Indianapolis, Indiana.
Address reprint requests to: Stephen Gordon, MD, Comprehensive NeuroScience, Inc, Women’s Health and Internal Medicine, 6065 Roswell, Suite 820, Atlanta, GA 30328; e-mail: flashmd_4919{at}msn.com.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Postmenopausal women currently taking continuous combined estrogen–progestin therapy (conjugated equine estrogen, 0.625 mg/medroxyprogesterone acetate, 2.5 or 5 mg) daily for 5 or more months were enrolled. Women were randomized to 1 of 4 blinded regimens: 1) 12 weeks estrogen–progestin; 2) 12 weeks placebo; 3) 4 weeks placebo, then 8 weeks raloxifene; or 4) 12 weeks raloxifene. For the final 36 weeks, all subjects received raloxifene. Vasomotor symptoms were assessed by patient diaries.
RESULTS: A total of 266 women (mean age 57.5) were enrolled. Mean hot flush frequency at baseline was approximately 1 per week in the entire population, with 16% of women reporting hot flushes. Mean frequency and severity of hot flushes during the first 12 weeks of the study were statistically greater in the 3 groups transitioned off estrogen–progestin (range of hot flushes per week: 4 weeks, 11–12; 8 weeks, 18–24; 12 weeks, 13–16), as compared with those continuing estrogen–progestin, with no difference between these 3 groups (P
.1). Approximately 50–70% of these women reported hot flushes, generally rated as mild to moderate by participants, after estrogen–progestin discontinuation.
CONCLUSION: A large proportion of women discontinuing estrogen–progestin experience hot flushes. Raloxifene does not appear to increase the frequency or severity of vasomotor symptoms in women discontinuing estrogen–progestin more than that observed with placebo treatment after estrogen–progestin discontinuation. Transition from estrogen–progestin to raloxifene with no washout period therefore may be acceptable.
LEVEL OF EVIDENCE: I
Raloxifene is a selective estrogen receptor modulator used for the prevention and treatment of postmenopausal osteoporosis.3,4 Randomized controlled clinical trials have demonstrated that raloxifene preserves bone mineral density in healthy postmenopausal women and decreases the risk of vertebral fracture by up to 55% in postmenopausal women with osteoporosis treated for up to 3 years.3–5 Raloxifene therapy is associated with an increased risk for venous thromboembolism similar in magnitude to estrogen–progestin therapy but does not cause endometrial bleeding or breast tenderness.6–8 Raloxifene also has a neutral effect on the incidence of endometrial hyperplasia and endometrial cancer, in contrast to other selective estrogen receptor modulators, such as tamoxifen.6,9 Raloxifene has been reported to increase the incidence of hot flushes (eg, 28% versus 21% for raloxifene and placebo, respectively).10
Women who discontinue estrogen–progestin therapy may experience symptoms of estrogen withdrawal (vasodilatation, sweats, sleep disturbance). For those women who chose to then initiate raloxifene for the prevention or treatment of osteoporosis, transition from estrogen–progestin to raloxifene may be associated with a further exacerbation of these symptoms. The objective of the current study was to compare different strategies to transition women from continuous combined estrogen–progestin therapy to raloxifene to identify the best-tolerated protocol. The current report focuses on the vasomotor diary results from the 12-week transitioning phase of the trial. It is anticipated that this knowledge will promote compliance with drug therapy.
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MATERIALS AND METHODS |
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). Postmenopausal women who were already taking estrogen–progestin were eligible to enter the study. Inclusion criteria included age less than 75 years, last menstrual period at least 12 months before having entered the study or laboratory evidence of menopause, current usage of estrogen–progestin in the form of either Premarin (Wyeth Pharmaceuticals, Philadelphia, PA; 0.625 mg) along with medroxyprogesterone acetate (2.5 or 5 mg) or Prempro (Upjohn Company, Kalamazoo, MI) on a daily basis for at least 5 months. Women were excluded if they had a previous history of hysterectomy; history of breast cancer or estrogen-dependent neoplasia; abnormal uterine bleeding; current osteoporosis; history of deep venous thrombosis, thromboembolic disorders, cerebral vascular accident, or myocardial infarction; treatment with bisphosphonate or fluoride therapy within 3 months of enrollment; diabetes or other endocrine disorders requiring pharmacologic therapy; or clinically significant postmenopausal symptoms.
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5 years) and then randomized within each stratum at the site level (block size 8) to a 12-week course of one of following 4 treatment sequences: 1) continued estrogen–progestin for 12 weeks (Estrogen–Progestin); 2) placebo for 12 weeks (Placebo); 3) placebo for 4 weeks followed by raloxifene 60 mg/d for 8 weeks (Placebo-Raloxifene); and 4) raloxifene 60 mg/d for 12 weeks (Raloxifene). For the final 36 weeks of the study, all subjects received raloxifene 60 mg/d in a single-blind fashion. Raloxifene 60 mg/d (Evista; Eli Lilly and Company, Indianapolis, IN) was provided as an oral tablet and conjugated equine estrogens 0.625 mg/d (Premarin) was provided as an encapsulated tablet. Medroxyprogesterone acetate (2.5 mg; Provera) was provided as an encapsulated tablet identical in appearance to the Premarin capsule. Women took 1 or 2 medroxyprogesterone acetate capsules depending on whether their usual dosage had been 2.5 or 5 mg/d, respectively. Placebo was provided in tablets identical in appearance to those of raloxifene or those of encapsulated conjugated equine estrogens or medroxyprogesterone acetate. Compliance to study medication was determined by pill counts. A subject was regarded as severely noncompliant if she missed more than 30% of study drug between 2 separate visit intervals. The protocol was approved by the institutional review board at each study site. Women signed a written informed consent document before entering the study.
The primary objective of the study was to determine the effect of the transition from estrogen–progestin to raloxifene on overall quality of life. The results presented herein focus on vasomotor symptom results from patient diaries. Study visits occurred at 4-week intervals for the first 24 weeks of the study and then at the 52-week study completion. Subject diaries were used to quantify the number and severity of hot flushes and night sweats experienced daily for the 7 days before the baseline visit (ie, after the 4-week lead-in period) and at every visit thereafter. Subjects rated the maximum severity of vasomotor symptoms on an ordinal scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. At each study visit, women were questioned about the occurrence and nature of adverse events. All adverse events reported at each postbaseline visit were recorded.
All analyses were performed using an intent-to-treat approach. Because the number and severity of hot flushes and night sweats were not normally distributed as determined by Shapiro-Wilk tests, ranked analysis of variance procedures were used for the analyses. Specifically, the independent variables were investigator and therapy, and the dependent variable was the ranked change from baseline to each postbaseline time point. One-way analysis of variance was used to analyze continuous baseline characteristics. For categorical variables (incidence of hot flushes or night sweats, adverse events, discontinuation from the study, compliance), either 
2 or Fisher exact test was used. All tests were 2-sided with significance level of .05.
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RESULTS |
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). A total of 16.5% of women discontinued the study during the 12-week double-blind phase, with no significant differences between treatment groups (P = .24). There were no significant differences in reporting of adverse events among the treatment groups during the 12-week period (P = .19). There were no reports of venous thromboembolic events during the study. There were also no significant differences in the number of women who were severely noncompliant among the treatment groups during this time period (P = .8).
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). Although not statistically significant, there was a small increase from baseline in the mean number of hot flushes and night sweats, as well as an increase in the percentage of women with these symptoms (Table 2). Some subjects reported a decrease in the number of hot flushes (8 fewer per week) whereas others reported a marked increase in numbers (up to 36/wk at the 4-week period, 24/wk at the 8-week period, and 24/wk at the 12-week time period in 3 different subjects). Similar results were observed for night sweats. No woman in this treatment arm discontinued from this phase of the protocol because of vasomotor symptoms. A total of 13.2% of subjects reported vaginal bleeding during this period (Figure 2).
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). Mean hot flush frequency ranged from 11 to 12 per week at 4 weeks, 18 to 24 per week at 8 weeks, and 13 to 16 per week at 12 weeks (Figure 3).
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.64). The range in standard deviations was large, with a minimum of 2.8 per week at baseline (Placebo-Raloxifene group) and a maximum of 37.8 per week (Placebo group) at week 8. Results on night sweats were similar to those observed for hot flushes. Frequency and severity of night sweats increased significantly within all 3 treatment groups over the 12-week period (P < .001), but there was no significant difference among the 3 groups (P > .1) (Figure 3
). The vast majority of vasomotor events reported were rated as mild or moderate, with only occasional severe events reported (data not shown). The rate of discontinuation because of intolerable vasodilatation was low (Placebo, 9%; Placebo-Raloxifene, 11%; Raloxifene, 12%) and not significantly different among the 3 groups (P = .88). Reports of vaginal bleeding were no different among the 3 transitioned groups, ranging from 1.5% to 4.6% (P = .62) (Figure 2).
When comparing the 3 transitioned treatment groups to the Estrogen–Progestin group during the 12-week transitioning period, there were statistically significant differences for vasomotor symptoms. All 3 transitioned arms had marked increases in the frequency and severity of hot flushes and night sweats, which was significantly different from the Estrogen–Progestin arm (P < .001). There was also a significant difference in discontinuations because of intolerable vasomotor symptoms when comparing the 3 transitioned groups to the Estrogen–Progestin group (P = .005). However, the continued Estrogen–Progestin arm had a higher incidence of vaginal bleeding when compared with the other arms (P = .004) (Figure 2).
The study design (Figure 1) provides an opportunity to compare the effect of direct transition from estrogen–progestin to raloxifene compared with an intervening washout period before initiating raloxifene in a larger sample of patients. Data were pooled from the 2 treatment arms where transition from estrogen–progestin to raloxifene was performed directly (direct transition, n = 135) and from the 2 treatment arms with a placebo washout period (placebo washout, n = 131) and compared at the 4-week post-transition time point. There was no significant difference in the baseline characteristics between the 2 combined groups.
The results for these 2 combined groups are analogous to those observed with the individual treatment arms, with no significant difference in vasomotor symptoms between the 2 groups (P > .5). At baseline, the percent of subjects reporting hot flushes and the mean number of hot flushes were 15% and 1 per week for the placebo washout group and 18% and 1 per week for the direct transition group, respectively. At 4 weeks after transition, both the group with an intervening washout period and the group transitioned directly to raloxifene showed an increase in hot flushes, with 54% of subjects in each group reporting hot flushes and an overall mean of 11 per week for both groups (P > .5). Similar results were observed for night sweats (P > .5).
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DISCUSSION |
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Our results indicate that discontinuation of estrogen–progestin is associated with an increase in frequency and severity of hot flushes and night sweats irrespective of whether women were transitioned to raloxifene. During the 12-week transition period, vasomotor symptoms were similar in the group of women transitioned immediately to raloxifene as compared with those that had a 4-week course of placebo followed by 8 weeks of raloxifene and those with 12 weeks of placebo. On average, the frequency of vasomotor symptoms after the discontinuation of estrogen–progestin was between 2–3 per day. The vast majority of vasomotor events were rated as mild or moderate, and the rate of discontinuation from vasodilatation was low. These results are interesting in that they suggest that raloxifene does not contribute further to vasomotor symptoms in women discontinuing estrogen–progestin. Thus, direct transition form estrogen–progestin to raloxifene with no washout period may be clinically acceptable.
Peak incidence of vasomotor symptoms after discontinuation of estrogen–progestin occurs about 8 weeks from the last dose of estrogen–progestin. This observation is new, and to our knowledge, has not been documented previously on the basis of a randomized, controlled trial. Current clinical practice regarding the transitioning of patients from estrogen–progestin to raloxifene consists of a minimum period of 4-week wash-out from estrogen–progestin followed by initiation of raloxifene 60 mg/d. However, our data suggest that a 4-week washout period may actually constitute one of the least conducive approaches to transitioning women from estrogen–progestin to raloxifene. Nearly half of women who did not have vasomotor symptoms 4 weeks after discontinuing estrogen–progestin will develop new onset vasomotor symptoms over the next 4 weeks. Although this appears to be purely related to the discontinuation of estrogen–progestin and not to be influenced by treatment with raloxifene, physicians may have a difficult time convincing individual women who do not experience vasomotor symptoms until they initiate raloxifene 4 weeks after discontinuing estrogen–progestin. Thus, if a washout period is used in transitioning women from estrogen to raloxifene, we recommend that this period be for at least 8 weeks.
The findings among women who continued in a blinded fashion on estrogen–progestin reveal the highly subjective and unpredictable nature of vasomotor symptoms. Clearly, some women reported the onset of a high frequency of vasomotor symptoms despite the fact that their estrogen–progestin regimen had not been modified. This provides an interesting paradox to the high favorable placebo response rate seen in hot flush treatment trials.11,12 Thus, the development of hot flushes is highly subjective, and any clinical conclusion around the course and behavior of vasomotor symptoms needs to based on accurate data from double-blind randomized controlled trials.
There are a number of limitations to this study. The reasons for initially starting or continuing on estrogen–progestin before entry into the trial were not captured during the randomization process. The population in our study most likely consisted of both women who initiated estrogen–progestin for control of vasomotor symptoms and those taking it for other known or perceived benefits. Whether discontinuation of estrogen–progestin in women with or without underlying menopausal symptoms at baseline results in similar trends in ensuing vasomotor symptoms both in the absence and presence of raloxifene is not known. In addition, this study was conducted in the period before the Women’s Health Initiative findings that have resulted in recent changes to clinical recommendations and in a wider awareness among the general population of the risks and benefits of estrogen progestin therapy.13 Women’s attitudes regarding the transition from estrogen–progestin to raloxifene may have evolved since the trial has concluded. Finally, the current study examined only several of many potential ways in which to transition women from estrogen–progestin to raloxifene. Other proposed approaches include the progressive tapering down of estrogen–progestin over periods ranging from weeks to months, with an intermediate period of no treatment, and progressive tapering up of raloxifene treatment over a period of days to weeks. Despite these limitations, the trial provides valuable insights into the natural course of vasomotor symptoms after discontinuation of estrogen–progestin, as well as during the transition onto raloxifene.
Many patients discontinuing estrogen–progestin are in need of treatment for the prevention or treatment of osteoporosis. Recommended therapeutic options consist of bisphosphonates or raloxifene.1,2 For women who choose raloxifene, the current data suggest that initiation of raloxifene immediately upon discontinuation of estrogen–progestin, in a manner analogous to the initiation of bisphosphonates, is a clinically acceptable approach. With either treatment, women may suffer from comparable vasomotor symptoms. The vasomotor symptoms will improve over time and may be managed through a variety of nonhormonal means.14 Alternatively, clinicians may wish to discontinue their patients from estrogen–progestin, monitor them for at least 8 weeks, until the vasomotor symptoms stabilize or start improving, and then initiate raloxifene treatment.
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Footnotes |
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Financial Disclosure
This study was supported by Eli Lilly and Company. Authors Ciaccia, Plouffe Jr, Rosen, and Siddhanti are employees of and hold stock in Eli Lilly and Co. Author Gordon has received honoraria from and is a stockholder of Eli Lilly. Author Walsh is on the Speakers Bureau of Eli Lilly, and Wyeth and has received honoraria from Eli Lilly.
doi: 10.1097/01.AOG.0000110247.98588.ff
Received July 10, 2003. Received in revised form October 28, 2003. Accepted November 6, 2003.
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REFERENCES |
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2. North American Menopause Society. Amended report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy [review]. Menopause 2003;10:6–12.[Medline]
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6. Cummings S, Eckert S, Krueger K, Grady D, Powles T, Cauley J, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999;281:2189–97.
7. Davies GC, Huster WJ, Shen W, Mitlak B, Plouffe LJr, Shah A, Cohen FJ, et al. Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause 1999;6:188–95.[Medline]
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13. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, et al, for the Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
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