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ORIGINAL RESEARCH |
From the *University of California, San Francisco, California; Kaiser Permanente Medical Care Program, Oakland, California; and Lilly Research Laboratories, Indianapolis, Indiana.
Address reprint requests to: Deborah Grady, MD, MPH, University of California, San Francisco, 1635 Divisadero Street, Suite 600, San Francisco, CA. 94115; e-mail: dgrady{at}itsa.ucsf.edu.
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ABSTRACT |
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 ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer.
RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2–3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI –0.5–4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100–582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8–1.1), gallbladder disease (RR 1.0; 95% CI 0.7–1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4–5.1), or endometrial cancer (RR 0.9; 95% CI 0.3–2.7).
CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer.
LEVEL OF EVIDENCE: I
We aimed to assess the effect of raloxifene on major adverse events that have been documented to occur with postmenopausal hormone therapy (increased risk of breast cancer, coronary events, stroke, venous thromboembolic events, gallbladder disease, and endometrial cancer)4–6 or with tamoxifen (increased risk of venous thromboembolic events, stroke, cataracts, and endometrial cancer).7–10 Some of these potential adverse events have already been evaluated using data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a 4-year randomized, controlled trial with an average duration of follow-up of 3.3 years designed to evaluate the effect of raloxifene in 7,705 postmenopausal women with osteoporosis.2,3 Results of the MORE trial also indicate that there is no early or overall increase in risk of coronary events or stroke among women treated with raloxifene.11 We used data from the MORE trial to examine the effects of raloxifene on the risk for venous thromboembolic events, gallbladder disease, endometrial cancer, and cataracts.
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PATIENTS AND METHODS |
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ABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Participants in the MORE trial were at least 2 years postmenopausal, up to 80 years of age, and had osteoporosis (bone density at the lumbar spine or femoral neck at least 2.5 standard deviations below the mean for normal young women, or radiographic evidence of at least 1 moderate or 2 mild morphometric vertebral fractures on lateral spine radiography). Women were excluded if they had or were suspected of having breast cancer; invasive endometrial cancer; abnormal uterine bleeding; history of stroke, deep venous thrombosis within the prior 10 years unless due to an accident, or any other thromboembolic event within the past 10 years; any cancer (except nonmelanoma skin cancer) within the past 5 years; acute or chronic liver disease or a secondary cause of osteoporosis. Women were also excluded if they drank more than 4 alcoholic drinks per day or had recently taken systemic estrogens, progestins, androgens, systemic corticosteroids, or large doses of vitamin D.2,3 The protocol was approved by the institutional review board at each of the centers, and all participants provided written informed consent.
Participants were randomly assigned (stratified by low bone mineral density or prior morphometric vertebral fracture) with equal probability to 3 treatment groups: placebo, raloxifene 60 mg, or raloxifene 120 mg. The sponsor produced 2 sets of randomly numbered medication kits that were dispensed in numerical order by stratum at enrollment. Each woman was instructed to take 2 identical masked pills daily: 2 placebos, 1 placebo and 1 raloxifene 60 mg, or 2 raloxifene 60mg. Thus, twice as many women received raloxifene as placebo. Participants and investigators were blinded to treatment status. All women received 500 mg of elemental calcium and 400 to 600 IU of vitamin D daily.
At baseline, all participants had general physical and breast examinations and mammography or breast ultrasonography and provided information on age, ethnicity, cigarette smoking, alcohol consumption, age at menopause, prior hysterectomy, prior or current medical conditions, and current concomitant medications. Height, weight, blood pressure, and total cholesterol were measured.
At follow-up visits that occurred every 6 months, women were asked whether they had experienced any adverse event (any undesirable experience that was new or worsened since the last visit). Participants were also asked a series of questions to determine whether cardiovascular events, endometrial cancer, or breast cancer had occurred. Use of all medications was recorded.
Medical records, including reports of radiographs and scans, were requested whenever a participant reported a possible venous thromboembolic event during the course of the study. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. A panel of 3 physicians expert in the clinical management of venous thromboembolism and blinded to treatment assignment independently classified each event as definite, probable, or possible, following the guidelines of the World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception case definitions.12 The analyses were limited to events classified as definite or probable. One physician employee of the sponsor, knowledgeable in the diagnosis of venous thromboembolism and blinded to treatment assignment, classified each event as idiopathic or secondary. Idiopathic events occurred without antecedent surgery, trauma, injury, immobilization, use of medications known to increase risk of venous thromboembolism (oral or transdermal estrogen, tamoxifen, or cyclosporin), history of stroke, coagulopathy, cancer within 6 months, or history of venous thrombosis, myocardial infarction, or congestive heart failure.
Gallbladder disease, cataract, and cataract surgery were self-reported. No medical records were obtained to document these diagnoses. Eye examinations were not performed at baseline or during follow-up. Women were classified as having gallbladder disease if they reported gallbladder disease, gallbladder surgery, cholelithiasis, or cholecystitis. Gallbladder disease and cataract were classified as new if no disease was reported at baseline and worsening if a cataract or gallbladder disease had been reported at baseline but worsened at any time during follow-up.
Diagnostic transvaginal ultrasound was recommended for participants who reported vaginal bleeding or other complaints suggestive of uterine pathology. Endometrial thickness exceeding 5.0 mm triggered repeat ultrasound and endometrial sampling using either a standard biopsy instrument or hysteroscopy. At 17 of the 180 centers, the protocol required transvaginal ultrasound at baseline and annually in all participants with a uterus; some other centers elected to perform transvaginal ultrasound in a subset of participants. All endometrial pathology was read locally, and when possible, samples were also analyzed by a central pathology laboratory. The most serious diagnosis assigned to any biopsy by either the local or central laboratory is reported.
Primary analyses were performed by intention-to-treat, with participants allocated to assigned treatment regardless of compliance or other postrandomization factors. An as-treated analysis was also performed, where inclusion in the risk sets was limited to women whose average compliance with therapy during the trial (measured by pill count) was at least 80%. Participants who were lost to follow-up were censored at the last date at which they were known to be alive without the outcome of interest. All hypotheses were tested at the 0.05 (2-tailed) level of significance. No adjustments were made for multiple comparisons.
Baseline subject characteristics were compared using analysis of variance for continuous data and Pearson 
2 test for categorical data. In the primary analyses, Pearson 2 tests were used to compare the rate of venous thromboembolism, cataract, gallbladder disease, and uterine hyperplasia or cancer among women assigned to each raloxifene dose with the rate among those assigned to placebo. Fisher exact tests were used to compare rates when the number of events for any outcome was less than 5. Because results were similar for all outcomes for the 2 doses of raloxifene, we present only analyses comparing the pooled raloxifene treatment groups with placebo. Relative risk (RR) and 95% confidence intervals (CIs) are reported. For venous thromboembolic events, RR was also estimated by year since randomization. Differential treatment effect over time was tested using a logistic regression model with time by treatment interaction as a factor. For venous thromboembolic events, excess risk and its 95% confidence intervals (CIs) were calculated using an exposure-adjusted Poisson regression model.13 We repeated the analyses for idiopathic and nonidiopathic events and among women who were identified at baseline as being at high risk for cardiovascular events based on evidence of established coronary heart disease or the presence of cardiovascular risk factors.11
The number needed to treat for 3.3 years to cause 1 additional case of venous thromboembolism and its 95% CI were calculated based on the absolute risk difference between raloxifene and placebo using the adjusted Wald method.14 Statistical analyses were performed using SAS 6.12 software (SAS Institute, Inc., Cary, NC).
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RESULTS |
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ABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The mean duration of follow-up was 3.3 years, with a maximum treatment duration of 4 years. After 1 year of treatment, 7.3% of women in the raloxifene group and 6.0% of those in the placebo group were lost to follow-up. By 4 years, these proportions had risen to 25.0% and 28.3%, respectively. By the end of the first year of treatment, 94.1% of the women remaining in follow-up in both the raloxifene and placebo groups were taking more than 80% of assigned study medication. By 4 years, these proportions were 95.0% and 95.1%, respectively.
During 25,703 woman-years of observation, 82 venous thromboembolic events were reported. Of these, 73 were confirmed as definite or probable and are included in the analysis: 44 women suffered deep vein thrombosis, 14 pulmonary embolism, 6 both deep vein thrombosis and pulmonary embolism, and 9 retinal vein thrombosis. Among women with a deep vein thrombosis or pulmonary embolism, 50% had recent major surgery or prolonged immobilization, 8% had a history of venous thrombosis more than 10 years before enrolling in the trial and 3% had both risk factors.
One or more venous thromboembolic event(s) occurred in 59 women (3.5 per 1,000 woman-years at risk) assigned to raloxifene and in 14 (1.7 per 1,000 woman-years) assigned to placebo (RR, 2.1; 95% CI, 1.2–3.8) (Table 2). The excess event rate associated with raloxifene therapy was 1.8 per 1,000 woman-years (95% CI –0.5–4.1), and the number needed to treat with raloxifene for 3.3 years to cause 1 additional venous thromboembolic event was 170 (95% CI 100–582). Among women in the raloxifene group, risk was similarly elevated for deep venous thrombosis (RR 3.1; 95% CI 1.4–6.9) and pulmonary embolism (RR 4.5; 95% CI 1.1–19.5). Incidence of retinal vein thrombosis was not different between women assigned to raloxifene and placebo (RR 0.4; 95% CI 0.1–1.5). Risk was increased more for idiopathic events (RR 7.5; 95% CI 1.0–57.0; P = .05) than for secondary events (RR 1.7; 95% CI 0.9– 3.2; P = .1), but the difference between these relative risks was not significant (P = .3). Risk in the raloxifene group was 6-fold higher than in the placebo group during the first 2 years of treatment, but decreased to about the same rate as in the placebo group thereafter (Table 2; P value for time-by-treatment interaction = .01; Fig. 1). Among those women in the MORE trial with increased cardiovascular risk, the RR of developing venous thromboembolic events with raloxifene compared with placebo was 1.5 (95% CI 0.5–4.7). There was no significant difference between the relative risks for venous thromboembolic events comparing each of the 2 doses of raloxifene with placebo (raloxifene 60 mg/day, RR = 1.9 [95% CI 1.0–3.6]; raloxifene 120 mg/day, RR = 2.4 [95% CI 1.3–4.4]; P = .4). There was also no difference in the results when the analysis was restricted to women who had taken 80% or more of assigned study medication during the trial (RR for any venous thromboembolic event 2.0; 95% CI 1.1–3.5).
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One woman in the raloxifene group died from pulmonary embolism 1 year after discontinuing study drug due to breast cancer. Four women with deep vein thrombosis subsequently died from other causes (all assigned to raloxifene), 2 from gastrointestinal carcinoma, 1 from myocardial infarction, and 1 from lung cancer. Six women had a pulmonary embolism concomitant with a deep vein thrombosis; all were in the raloxifene group.
At baseline, there were no differences in the reported prevalence of cataract or gallbladder disease in the raloxifene and placebo groups (Table 1). There was no significant increased risk for cataract or gallbladder disease for either of the 2 doses of raloxifene or for the pooled raloxifene groups compared with placebo (Table 3). There was also no difference in the results when these analyses were restricted to women who had taken 80% or more of assigned study medication during the trial.
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There was no difference in the incidence of uterine bleeding reported by women in the placebo and raloxifene groups (3.7% in each group, P = 1.0). There were also no differences between placebo and raloxifene-treated women in risk of any type of endometrial hyperplasia or endometrial cancer (Table 3). The majority of uterine cancer cases were reported to be adenocarcinoma (n = 12), with 1 case of sarcoma (raloxifene) and 1 case of homologous mixed Mullerian tumor (placebo). There was no significant difference in risk for endometrial hyperplasia or cancer for women assigned to either of the 2 doses of raloxifene compared with placebo and no change in the results when the analyses were restricted to women who had taken 80% or more of assigned study medication during the trial.
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DISCUSSION |
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ABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A marked increase in risk of venous thromboembolism was observed in the first 2 years of raloxifene treatment, but no apparent increase in risk was identified thereafter. Increased risk for venous thromboembolism also seems to decline over time with prolonged use of hormone therapy, but remains elevated for 3 to 4 years.4,5,15,18,20 There is no evidence concerning the effect of duration of use on risk for venous thromboembolism among tamoxifen users. The finding that risk of thromboembolism associated with raloxifene is elevated for only 2 years may be due to chance or might be related to the arbitrary annual cut points that we used to calculate risk. For example, if 1 placebo event is reclassified from year 3 to year 2, the RR in year 2 would be reduced from 6.6 to 3.3 and in year 3 would be increased from 0.9 to 1.1. Currently, it is generally recommended that women taking postmenopausal hormone therapy, raloxifene, or tamoxifen stop therapy during periods of high risk for venous thromboembolism, such as prolonged immobilization. Given the concern that a chance maldistribution of events in the placebo group may have contributed to an exaggerated risk estimate early on and a lack of risk thereafter, we believe that women should discontinue raloxifene during periods of high risk for venous thromboembolic events regardless of the duration of treatment.
Although the number of idiopathic events was small, the RR seems to be substantially higher, although not significantly different, for idiopathic than for secondary venous thromboembolic events among women in MORE assigned to raloxifene. In contrast, the Heart and Estrogen/progestin Replacement Study found that the RR for both types of events was increased to the same degree among women using estrogen plus progestin.20 It is possible that hormone therapy and raloxifene have different effects on risk for secondary venous thromboembolic events, but it is more likely that differences in the definition of idiopathic events between these trials led to the discrepant findings. The definition of idiopathic venous thromboembolic events in the MORE trial was very stringent, resulting in only 1 of 14 events in the placebo group being classified as idiopathic. Recategorizing just 2 events in the placebo group from the secondary to the idiopathic category would eliminate the difference between the relative risks for these 2 categories of venous thromboembolic events in women taking raloxifene.
In the population studied, for every 170 women treated with raloxifene for 3 years, 1 woman would experience a venous thromboembolic event that she would not have had if she had not received such treatment. Of note, the number needed to treat to cause 1 venous thromboembolic event depends primarily on the underlying risk of venous thromboembolism in the population and will be lower in women who are at higher risk (ie, those with known hypercoagulable states, prior venous thromboembolism, cancer, prolonged immobilization, or advanced age). Raloxifene is contraindicated in women with prior venous thromboembolism. Others at risk for venous thromboembolism should carefully weigh the increased risk against potential benefits.
Treatment with raloxifene was not associated with an increased risk of cataract. The effect of estrogen on cataracts has not been well-studied, but observational data suggest that use of oral estrogen might be associated with a reduction in the incidence of cataracts or lens opacities.21,22 In contrast, tamoxifen treatment has been associated with an increased risk of cataract.10,19 We found no increased risk for gallbladder disease or surgery associated with raloxifene use. Some observational studies suggest that postmenopausal estrogen use increases risk for gallbladder disease as much as 2-fold to 4-fold,23 but increased risk is not consistently observed.24 The only randomized trial that reported gallbladder outcomes found a 40% increase in risk of gallbladder disease among women taking estrogen plus progestin compared with placebo; treatment of 46 women over 4 years resulted in 1 excess gallbladder surgery.5,25 We know of no evidence on risk for gallbladder disease among women taking tamoxifen.
Unopposed estrogen is associated with a 2-fold to 9-fold increased risk of endometrial cancer that increases with duration of use.6 Estrogens stimulate mitosis in endometrial cells, leading to endometrial hyperplasia and cancer.26 Addition of sufficient progestin to the estrogen regimen reduces mitotic activity, stimulates differentiation of endometrial cells to the secretory state, and obviates the increase in risk of endometrial cancer.6,26,27 Like estrogen, treatment with tamoxifen increases endometrial cancer risk 2-fold to 7-fold.7,8,28–30 The mechanism of the increased risk for endometrial cancer associated with tamoxifen is presumed to be estrogenic, but estrogen and tamoxifen have different effects on the uterus. Unlike estrogen, tamoxifen use is not associated with an orderly progression from endometrial hyperplasia to cancer. Most importantly, there is no evidence that added progestin therapy prevents this increased risk.31–33 In contrast, we found no evidence of an increased risk for endometrial hyperplasia or cancer associated with 3 years of raloxifene use. Thus, addition of another medication or routine endometrial surveillance is not required in women taking raloxifene.
In choosing preventive interventions, clinicians should weigh the risks as well as the benefits associated with therapy. Estrogen, tamoxifen, and raloxifene are associated with an equivalent 2-fold to 4-fold increased risk of venous thromboembolic events. Unlike estrogen, however, raloxifene does not increase risk for gallbladder disease or endometrial cancer, and in contrast to tamoxifen, raloxifene does not increase risk for cataracts or uterine cancer.
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Footnotes |
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Financial Disclosure Eli Lilly and Company funded the Multiple Outcomes of Raloxifene Evaluation trial and provided study medications.
Received February 12, 2004. Received in revised form June 11, 2004. Accepted June 17, 2004.
10.1097/01.AOG.0000137349.79204.b8
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S. Martino, J. A. Cauley, E. Barrett-Connor, T. J. Powles, J. Mershon, D. Disch, R. J. Secrest, S. R. Cummings, and For the CORE Investigators Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene J Natl Cancer Inst, December 1, 2004; 96(23): 1751 - 1761. [Abstract] [Full Text] [PDF]
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 Raloxifene Increases Risk for Venous Thromboembolism Journal Watch Gastroenterology, November 30, 2004; 2004(1130): 7 - 7. [Full Text]
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