| | Raloxifene and Risk for Stroke Based on the Framingham Stroke Risk Score published online 19 June 2009. Abstract PurposeRaloxifene reduces vertebral fracture and invasive breast cancer risks, but increases fatal strokes in postmenopausal women at increased coronary risk. We assessed whether this risk is concentrated in postmenopausal women already at high stroke risk. MethodsRaloxifene Use for The Heart (RUTH) enrolled 10,101 postmenopausal women (mean age 67 years) with or at increased coronary heart disease risk; Multiple Outcomes of Raloxifene Evaluation (MORE) enrolled 7705 osteoporotic postmenopausal women (mean age 66 years). A Framingham Stroke Risk Score (FSRS) was calculated for all women with no prior cerebrovascular events (n =16,858). The validity of the FSRS was assessed in the placebo groups, and then raloxifene-associated stroke risk was analyzed by FSRS subgroups. ResultsFSRS predicted an increased stroke risk in the placebo group of both clinical trials. There was no difference in the incidence of nonfatal strokes between the raloxifene and placebo groups in MORE or RUTH, regardless of baseline Framingham stroke risk. In RUTH, women with FSRS <13 showed no increase in raloxifene-associated fatal stroke risk (hazard ratio [HR] 1.08; 95% confidence interval [CI], 0.49-2.37). Those with FSRS ≥13 had a 75% increased risk of raloxifene-associated fatal stroke (HR 1.75; 95% CI, 1.01-3.02; interaction P=.33). In MORE, where 80% of women had a FSRS <13, no increase in fatal (HR 0.57; 95% CI, 0.19-1.68) stroke risk was observed. DiscussionRisk of fatal stroke associated with raloxifene was greater in women at high stroke risk. These results might be useful for identifying postmenopausal women at high risk of first stroke who should avoid raloxifene therapy. Treatment with raloxifene reduces the risk of vertebral fractures1 and of invasive breast cancer2, 3, 4 and has no effect on risk for coronary disease events.3, 5 In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene had no effect on risk for nonfatal or fatal stroke in postmenopausal women with osteoporosis.5 In the Raloxifene Use for The Heart (RUTH) trial, which enrolled postmenopausal women with or at high risk for coronary events, risk for fatal stroke was increased among women randomized to raloxifene, despite no increase in risk for nonfatal stroke.3, 6 Clinical Significance•Raloxifene increased the risk of fatal stroke in postmenopausal women at increased coronary risk, but not in postmenopausal women with osteoporosis who were at low risk for coronary events. •The excess risk of fatal stroke associated with raloxifene treatment was almost entirely in women with a high risk of stroke before beginning raloxifene treatment. •Assessing stroke risk using the Framingham stroke risk profile can be useful for identifying postmenopausal women who should avoid raloxifene therapy because of high risk of stroke. Despite the potential benefits of treatment with raloxifene in women who would like to reduce risk of vertebral fractures and invasive breast cancer, those with a history of stroke or transient ischemic attack are at very high risk of subsequent stroke7, 8, 9 and should not take raloxifene. For women without a history of cerebrovascular events, we asked if an assessment of stroke risk could help identify women at increased risk for raloxifene-associated fatal stroke who should avoid treatment and those who are not at increased risk for raloxifene-associated fatal stroke, improving the benefit to risk profile. Previous analyses have demonstrated that no single risk factor was predictive of raloxifene-associated fatal stroke in RUTH.6 We hypothesized that a cluster of risk factors might better predict raloxifene-associated stroke risk. The most commonly used tool is the Framingham stroke risk score, which estimates risk for first stroke based on age, blood pressure, presence of diabetes and noncerebrovascular cardiovascular disease, cigarette smoking, atrial fibrillation, and left ventricular hypertrophy.10, 11 Although the Framingham stroke risk score is used in current guidelines for prevention of stroke,12 it has been validated in few cohorts other than Framingham13, 14 and has not been evaluated in large cohorts of women. We hypothesized that the increased risk for fatal stroke associated with raloxifene treatment might be concentrated in women at high risk for stroke. To test this hypothesis, we aimed first to validate the Framingham stroke risk score among women in MORE and RUTH without a history of cerebrovascular events, and then to determine if the increased risk for fatal stroke associated with raloxifene is concentrated among the women with high baseline stroke risk defined by the Framingham stroke risk score. Methods  Study Design MORE (ClinicalTrials.gov number, NCT00670319) was a 4-year clinical trial among 7705 postmenopausal women with osteoporosis (mean age, 66 years) who were randomly assigned to placebo or 1 of 2 doses of raloxifene (60 mg or 120 mg daily) at 180 investigative sites in 25 countries.1, 2 The MORE study began in 1994 and was completed (last clinic visit) in 1999. Median follow-up was 47.4 months.15 Women with a history of stroke or venous thromboembolic events within 10 years of randomization were excluded. There was no increase in the risk of nonfatal or fatal stroke with raloxifene treatment in the overall cohort or in a subset of women (n=1035) who were at increased risk for cardiovascular events at baseline.5 RUTH (ClinicalTrials.gov number, NCT00190593) was initially designed to determine the effect of raloxifene 60 mg daily versus placebo on coronary events, and enrolled 10,101 postmenopausal women (mean age, 67 years) at 177 investigative sites in 26 countries, who had either established coronary disease or multiple risk factors for coronary events.3, 16 The RUTH study began in 1998 and was completed (last clinic visit) in 2005. Median follow-up was 67.2 months.3 Women without established coronary artery disease were eligible for enrollment in RUTH if they had a cardiovascular risk score ≥4 based on the presence of the following risk factors: lower extremity arterial disease (4 points), diabetes mellitus (3 points), age ≥70 years (2 points), cigarette smoking (1 point), hypertension (1 point), or hyperlipidemia (1 point).16 Women with a history of cerebrovascular events were eligible, but those with a known or suspected history of venous thromboembolic events were excluded. In the MORE trial, 88 women had a history of stroke or transient ischemic attack (TIA) (at least 10 years before randomization); in RUTH, 860 women had a history of stroke or TIA. These women were not included in the calculation of Framingham stroke risk scores because the model was designed to predict risk of first stroke. The protocols for both trials were approved by the ethics review board at each investigative site. All women gave written informed consent for participation in accordance with the principles of the Declaration of Helsinki. Analyses were performed by the sponsor statistician (JS) with input from coauthors. The academic authors had unrestricted request-based access to data from both trials. Copies of the trial database were retained by both the sponsor and an academic institution (University of California, San Francisco) for the MORE trial, and by the sponsor only for the RUTH trial. All authors were involved in interpreting the data and in drafting and revising the manuscript and can attest to the accuracy and completeness of the reported data. Assessment of Stroke Details of the assessment and adjudication of stroke events in the MORE and RUTH trials have been published.3, 5 In MORE, cardiovascular (including cerebrovascular) events were collected as a secondary endpoint and adjudicated after completion of the trial by one board-certified cardiologist who was blinded to treatment assignment and compensated by the sponsor but not otherwise associated with the trial.5 Events were adjudicated as stroke if a computed tomography scan was read by a physician as consistent with recent stroke, the hospital discharge diagnosis was stroke, a physician's notes diagnosed stroke, or there was documentation of sudden-onset persistent focal neurological deficit for more than 24 hours. All adjudicated strokes and deaths due to stroke are included in the present analyses. Because the incidence of stroke did not differ between the raloxifene 60 mg/day and 120 mg/day dose groups in MORE,5 data from both dose groups were combined for these analyses. In RUTH, stroke and all-cause mortality were secondary endpoints adjudicated during the trial by a committee comprised of clinicians with therapeutic expertise in neurology, gerontology, vascular disease, and thrombosis who were blinded to treatment assignment and not employed by the sponsor.3, 6 Stroke was defined as the rapid onset of a persistent neurologic deficit lasting more than 24 hours, in most cases supported by findings on imaging studies. Noncoronary deaths (including noncoronary cardiovascular and noncardiovascular deaths) were adjudicated by the Chair of the committee, who assigned a cause of death based on available clinical information, death certificate or autopsy information, and temporal relationship between the date of death and occurrence of adverse events. All deaths adjudicated as cerebrovascular were included in the current analyses. Nonfatal stroke was defined to have occurred in women having at least one adjudicated stroke who were either alive at end of study or died of a cause other than stroke. Framingham Stroke Risk Score Calculation The Framingham stroke risk score was calculated retrospectively for each woman in MORE (n=7617) and RUTH (n=9241) who had not experienced a prior stroke or TIA.11 Information on variables included in calculation of the risk score were obtained from data collected at baseline in each trial, as summarized in Table 1. Blood pressure was measured at baseline in both MORE and RUTH. In MORE, diabetes was defined as a baseline fasting blood glucose >7.8 mmol/L or use of hypoglycemic medication, current cigarette smoking was self-reported, and established cardiovascular disease was assessed by asking subjects at baseline whether they had ever experienced a myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty, whereas peripheral vascular disease or congestive heart failure was identified by self-reported historical diagnoses or investigator-reported pre-existing condition. In RUTH, diabetes was defined as self-reported diabetes and taking an oral hypoglycemic agent, or a baseline fasting plasma glucose >7.8 mmol/L. Current cigarette smoking was self-reported and defined as smoking an average of at least 10 cigarettes per day for the 6 months before enrollment. In RUTH, established cardiovascular disease (myocardial infarction, coronary artery bypass grafting, catheter-based coronary revascularization, or a history of angina pectoris with documented coronary heart disease, or lower extremity arterial disease) was assessed by self-report with supporting information such as a hospital discharge summary, physician's report, or other appropriate documentation, whereas congestive heart failure was reported either as a historical diagnosis or pre-existing condition. In both MORE and RUTH, atrial fibrillation was self-reported as an historical diagnosis or noted on baseline electrocardiogram as a pre-existing condition. Left ventricular hypertrophy was based on an electrocardiogram obtained at baseline. Because the upper age limit for the Framingham risk score is 85 years, women who were older than 85 years were assigned age 85 years for the risk score calculation. Similarly, women who had a systolic blood pressure above 216 mm Hg, the upper limit for the Framingham risk score, were assigned a systolic blood pressure of 216 mm Hg.11 | | |  | Framingham Stroke Risk Factor | MORE | RUTH | |
|---|
| Age | Self-reported | Self-reported | | | Systolic blood pressure | Measured in seated subjects | Measured in seated subjects | | | Antihypertensive use | Self-reported medication use | Self-reported medication use | | | Smoking | Self reported current smoking status | Self-reported current smoking status | | | Diabetes | Baseline fasting plasma glucose value >7.8 mM or taking hypoglycemic medication at baseline | Baseline fasting plasma glucose value >7.8 mM or self-reported medical history and taking hypoglycemic medication | | | Cardiovascular disease | Self-reported medical history of CHD (prior MI, CABG, or PTCA) by direct subject query OR PVD or CHF self-reported medical history or reported by investigator as a pre-existing condition. | CHD (prior MI, CABG, or PTCA) by direct subject query and documented by hospital discharge summary, physician report, or other appropriate documentation, OR PVD by direct subject query and documented with symptoms, hospital discharge summary, or other appropriate documentation, OR CHF self-reported or reported by investigator as a pre-existing condition. | | | Atrial fibrillation | Self-reported medical history or reported by investigator as a pre-existing condition. | Self-reported medical history or reported by investigator as a pre-existing condition. | | | Left ventricular hypertrophy | Based on baseline ECG | Based on baseline ECG | | | | |
Statistical Methods To validate the Framingham stroke risk score in predicting incident stroke, separate analyses were conducted among women with no history of stroke or transient ischemic attack in the placebo groups in the MORE and RUTH trials. First, the association between Framingham stroke risk score and incident stroke was assessed using a Cox proportional hazards regression model with time to first stroke as the outcome, and Framingham stroke risk score as the predictor. Second, the predictive ability of the Framingham stroke risk model in the 2 placebo groups was assessed by calculating the number of strokes that would be expected to occur11 and the ratio of expected-to-observed strokes with 95% confidence interval (CI).17 To determine if the increased risk for fatal stroke associated with raloxifene use was concentrated among women with high baseline stroke risk, women enrolled in RUTH were categorized by quartile of baseline Framingham stroke risk score. Given the small number of strokes among women in the placebo group in MORE (n=31), we did not perform analyses by quartiles. We used Cox proportional hazards regression models to determine if the hazard ratio for nonfatal and fatal stroke comparing the raloxifene and placebo groups was associated with the baseline Framingham stroke risk score. The interaction between treatment effect and baseline Framingham stroke risk score was tested at a .10 significance level. The absolute risk difference in the incidence of stroke events comparing the raloxifene and placebo groups and its 95% CI were calculated assuming a normal distribution of the incidence rate. Kaplan-Meier curves for fatal stroke were generated for women in RUTH with baseline Framingham stroke risk scores equal to or below the median compared with those above the median. Results Baseline Characteristics The median Framingham stroke risk score at baseline was 9 in MORE6, 7, 8, 9, 10, 11, 12 and 13 in RUTH11, 12, 13, 14, 15, 16 among women without a history of cerebrovascular disease (Table 2). Approximately 80% of the women enrolled in MORE had a score less than the median score in RUTH, corresponding to an estimated 10-year probability of stroke of 10%. In contrast, women in the upper half of risk in RUTH (median, 16 points) had an estimated 10-year probability of 19%, and those in the highest quartile of risk (median, 19 points) had an estimated 32% 10-year probability of stroke. | | | | | MORE (N=7617⁎) | RUTH (N=9241⁎) | |
|---|
| | Quartile 1 (n=2877) | Quartile 2 (n=1791) | Quartile 3 (n=2627) | Quartile 4 (n=1946) | Overall | |
|---|
| Framingham stroke risk score, median (interquartile range) | 9(6-12) | 9(8-11) | 13(12-13) | 15(14-16) | 19(17-20) | 13(11-16) | | | Age, mean (SD), years | 66(7) | 63(5) | 66(6) | 69(5) | 72(6) | 67(7) | | | SBP, mean (SD), mm Hg | 136(20) | 131(15) | 144(16) | 152(18) | 159(19) | 145(20) | | | Antihypertensive use, % | 26 | 82 | 88 | 93 | 97 | 89 | | | Smoking, % | 17 | 14 | 16 | 17 | 18 | 16 | | | Diabetes, % | 3.2 | 30 | 45 | 49 | 65 | 46 | | | Cardiovascular disease, % | 2.9 | 71 | 54 | 50 | 52 | 58 | | | Atrial fibrillation, % | 1.0 | 0.1 | 0.5 | 1.5 | 18 | 4.4 | | | Left ventricular hypertrophy, % | 2.5 | 1.8 | 4.0 | 10 | 41 | 13 | | | | |
| ⁎ Excludes participants with a history of stroke or TIA at baseline. |
Except for smoking, the prevalence of all of the Framingham stroke risk factors was higher among women in RUTH compared with that in MORE (Table 2). Because eligibility for RUTH required cardiac risk factors, even women in the lowest quartile of Framingham risk score in RUTH (Table 2) had a higher prevalence of antihypertensive medication use (82%), diabetes (30%), and established cardiovascular disease (71%) compared with women in the MORE trial (26% antihypertensive medication, 3% diabetes, and 3% established cardiovascular disease). In RUTH, women in the highest quartile of stroke risk had a much higher baseline prevalence of atrial fibrillation (18%) and left ventricular hypertrophy (41%) compared with women in the lowest quartile (0.1% and 1.8%, respectively). Performance of Framingham Stroke Risk Score in Predicting Incident Stroke For each 1-point increase in Framingham stroke risk score in women assigned to placebo, the risk of any stroke increased 26% (hazard ratio [HR] 1.26; 95% CI, 1.17-1.36) in MORE and 13% (HR 1.13; 95% CI, 1.10-1.17) in RUTH. Among women assigned to placebo in RUTH, risk of stroke increased by quartile of Framingham stroke risk score. Compared with the first quartile, the risk of stroke increased by 58% (HR 1.58; 95% CI, 0.97-2.56), 94% (HR 1.94; 95% CI, 1.26-2.99), and 274% (HR 3.74; 95% CI, 2.48-5.63) in the second, third, and fourth quartiles, respectively. Based on the Framingham stroke risk model in MORE, 34 incident strokes would be expected in women assigned to placebo, and 31 were observed (ratio of expected/observed=1.09; 95% CI, 0.76-1.54). In women assigned to placebo in RUTH, 288 incident strokes would be expected, and 190 were observed (ratio of expected/observed=1.51; 95% CI, 1.31-1.74). Effect of Raloxifene on Stroke Risk by Baseline Framingham Stroke Risk Score There was no difference in the incidence of nonfatal strokes between the raloxifene and placebo groups in MORE or RUTH, regardless of baseline Framingham stroke risk (Figure 1A). There was no difference in the incidence of fatal strokes between the raloxifene and placebo groups in MORE, based on only 13 events (Figure 1B). In RUTH, the incidence of fatal stroke was similar between the raloxifene and placebo groups in each of the lower 2 quartiles of Framingham stroke risk score (quartile 1: HR 1.00, 95% CI, 0.32-3.08; quartile 2: HR 1.17, 95% CI, 0.39-3.49), but risk for fatal stroke was higher among women in the upper 2 quartiles who were assigned to raloxifene compared with placebo (quartile 3: HR 2.05, 95% CI, 0.78-5.39; quartile 4: HR 1.65, 95% CI, 0.85-3.21) (Figure 1B). However, these differences in risk of fatal stroke across quartiles of baseline stroke risk in RUTH were not statistically different (P-value for interaction of hazard ratios=.76). Similar to the relative hazards, there was no difference in absolute risk of nonfatal stroke between the raloxifene and placebo groups in MORE or in any quartile of Framingham stroke risk in RUTH. The difference in absolute risk of fatal stroke in MORE and in the lower 2 quartiles of Framingham stroke risk score in RUTH was very close to 0, but the absolute difference was increased at 1 to 2 fatal strokes per 1000 person-years of treatment with raloxifene in the upper 2 quartiles of Framingham stroke score in RUTH (Figure 2). An absolute excess of 17 fatal strokes was observed in the raloxifene group compared with placebo in RUTH, 16 of which occurred in women with Framingham stroke risk scores in the upper 2 quartiles (Figure 1B). Based on the findings described above and because of the small number of fatal strokes in each quartile of Framingham stroke risk, we also evaluated the effect of raloxifene on risk for fatal stroke after dichotomizing the RUTH population at the median Framingham stroke risk score (13 points). The incidence of fatal stroke was higher in the raloxifene group compared with placebo in women with a Framingham stroke risk score >13 (HR 1.75, 95% CI, 1.01-3.02; Figure 3A), but not in those with scores below 13 (HR 1.08, 95% CI, 0.49-2.37; Figure 3B); however, these differences in hazard ratios were not statistically different (P-value for interaction=.33). The absolute excess in risk of fatal stroke in women assigned to raloxifene was 1.3 (95% CI, 0.05-2.5) events per 1000 woman-years in participants with a Framingham stroke risk score above the median, compared with 0.07 (95% CI, −0.8-0.8) events per 1000 woman-years in those at or below the median. Discussion These analyses demonstrate that the Framingham stroke risk score was predictive of incident stroke among women assigned to the placebo group in 2 large, randomized trials, and suggest that the increased risk of fatal stroke associated with raloxifene treatment was concentrated among women at high risk for stroke based on the Framingham stroke risk score. The Framingham stroke risk score is an established tool for assessing the risk of stroke,12 but its validity has not been well studied across geographic regions or in large populations of women. We confirmed that higher Framingham stroke risk score predicted an increased risk of stroke in postmenopausal women who were overall at lower (MORE) or higher (RUTH) stroke risk. The model performed well in predicting expected numbers of strokes in a population of postmenopausal women at lower risk for stroke (MORE), but overestimated the number of strokes that occurred in a high-risk cohort (RUTH) by approximately 50%. Overestimation of the expected number of strokes based on the Framingham stroke risk score has been reported previously.13, 14, 18 In RUTH, overestimation could be due to the high proportion of women using lipid-lowering and other risk-reducing medications relative to the original Framingham cohort and to women in the MORE trial. For example, baseline use of statin drugs, which reduce the risk of incident stroke,19 was reported by 47% of women in RUTH,3 compared with about 14% of women in the MORE trial. Overall, these findings suggest that the Framingham stroke risk score predicts stroke risk in individual women and can discriminate populations of postmenopausal women at higher or lower risk of incident stroke, but may require calibration for accurate prediction of absolute stroke risk in populations where use of medications that reduce cardiovascular risk is prevalent. The distribution of Framingham stroke risk scores across the MORE and RUTH trials was broad, reflecting the enrollment criteria of the 2 trials, and provided an opportunity to assess the effect of raloxifene on stroke across a range of baseline stroke risk. Several observations from these analyses support the hypothesis that the increased risk for fatal stroke associated with raloxifene treatment in the RUTH trial might be concentrated in women at high risk for stroke. First, there was no evidence for an increased relative or absolute risk of fatal stroke among postmenopausal women with a low baseline risk of stroke, either in the MORE study overall or among women in RUTH who were below the median of Framingham stroke risk. Based on their Framingham stroke risk score, women in these groups had an estimated 10-year probability of stroke below 10%. Second, of 17 excess fatal strokes among women assigned to raloxifene compared with placebo in RUTH, all but one occurred among those with Framingham stroke risk scores above 13, the median in RUTH. Thus, the excess risk of fatal stroke appeared to be almost entirely among postmenopausal women with a higher baseline risk of stroke (Framingham 10-year probability >10%). Statistical tests for interaction of baseline stroke risk and increased risk for raloxifene-associated fatal stroke were not statistically significant, but this test is not very powerful given the low number of fatal strokes in RUTH. The Framingham stroke risk score is a composite of stroke risk factors that gives different weights to different factors based on data from the Framingham cohort. For example, atrial fibrillation receives more weight than either smoking or diabetes. It would be easier to classify stroke risk based on one risk factor than to calculate the Framingham stroke risk score. As reported previously,6 current smokers in RUTH had a higher risk of raloxifene-associated stroke than nonsmokers, but smoking status alone did not account for the association between Framingham stroke risk score and risk for fatal stroke associated with raloxifene. When assessed in individual subgroup analyses,6 other individual Framingham stroke risk factors, including age, blood pressure, atrial fibrillation, and established cardiovascular disease, also did not identify women at high risk of raloxifene-associated fatal stroke as well as the composite Framingham stroke risk score. While single risk factors do not seem to predict the risk of raloxifene-associated fatal stroke as well as the Framingham stroke risk score, we have not evaluated other stroke risk models. Thus, the benefits and risks of raloxifene should be carefully considered in postmenopausal women with any combination of multiple risk factors that would place them at a high risk of stroke similar to the upper 2 quartiles of Framingham stroke risk score in RUTH. There are several limitations inherent in both the analyses for this study and their interpretation. The MORE and RUTH trials were not designed to prospectively collect information to calculate the Framingham stroke risk profile, and calculation of the score was done retrospectively. As a result, ascertainment of some of the variables was dependent on subject or investigator reporting, and the variables were collected in a similar but not identical manner in the 2 studies. For example, the presence of atrial fibrillation was not assessed specifically by electrocardiogram in either study, and clinically apparent cardiovascular disease at baseline required supporting documentation in RUTH but was based on self-report in MORE. Although some misclassification of Framingham stroke risk score based on self-reported diagnoses may have occurred, such misclassification would likely have made it more difficult to find a difference in raloxifene-associated risk for fatal stroke. None of these analyses were prespecified, but we selected the Framingham stroke risk score as a composite estimate of stroke risk before the analyses were begun. The difference in relative risk for stroke death in women with estimated baseline 10-year stroke risk <10% (HR 1.08) and those with baseline 10-year risk >10% (HR 1.75) was not statistically different. This might be because the number of fatal strokes was small and the test for interaction was underpowered, or because these relative risks differ by chance. This suggests caution in interpreting these results, and an increase in fatal stroke with raloxifene among women with a lower Framingham stroke risk score cannot be completely excluded based on these results. However, additional data on raloxifene and stroke risk to either confirm or refute these findings are not expected because no future large trials of raloxifene in postmenopausal women at increased cardiovascular or stroke risk are planned. In conclusion, data from the MORE and RUTH trials suggest that the risk of fatal stroke associated with raloxifene treatment may be greater in women already at high risk of stroke. Excess risk of fatal stroke was observed only in the RUTH trial, and all but one of the excess cases of fatal stroke in RUTH occurred in women with Framingham stroke risk scores above the median. These findings may provide a framework to assist physicians in counseling postmenopausal women who are considering taking raloxifene to reduce risk of vertebral fractures or invasive breast cancer. For postmenopausal women without a history of cerebrovascular events, assessing their stroke risk using the Framingham stroke risk profile or similar instruments may be useful for identifying postmenopausal women at high risk of first stroke who should avoid raloxifene therapy. Acknowledgments The RUTH and MORE trials were both supported by Eli Lilly and Company (Indianapolis, IN). We thank the investigators, staff, and the 17,806 women who participated in the RUTH and MORE trials. Complete lists of the investigators and sub-investigators of both trials have been published previously.1, 3 We also are indebted to Steve Zheng for statistical programming. References 1. 1Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637–645. MEDLINE |
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a Departments of Family and Preventive Medicine, University of California, San Diego, La Jolla, Calif b Lilly Research Laboratories, Indianapolis, Ind c Preventive Cardiology, Columbia University Medical Center, New York, NY d University of California, San Francisco and the San Francisco VA Medical Center, Calif  Requests for reprints should be addressed to Elizabeth Barrett-Connor, MD, Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive 0607, La Jolla, CA 92093-0607
Funding: Studies funded by Lilly Research Laboratories. Conflict of Interest: Elizabeth Barrett-Connor and Deborah Grady were paid external investigators for the Raloxifene MORE and RUTH studies by Lilly Research Laboratories. Lori Mosca was a paid external investigator for the Raloxifene RUTH study by Lilly Research Laboratories. David A. Cox, Jingli Song, and Bruce Mitlak are employees of Lilly Research Laboratories and have financial interest in the company. Authorship: All authors had access to the data and a role in writing the manuscript. PII: S0002-9343(09)00333-7 doi:10.1016/j.amjmed.2009.01.033 © 2009 Elsevier Inc. All rights reserved. | |
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