The Combined Effect of Delirium and Falls on Length of Stay and Discharge.

INTRODUCTION: Delirium or a fall are associated with many negative outcomes including increased length of stay (LOS) and discharge to a facility; however, this relationship is incompletely understood. METHODS: A cross-sectional study of all hospitalizations in a large, tertiary care hospital evaluated the effect of delirium and a fall on the outcomes of LOS and risk of being discharged to a facility. RESULTS: The study included 29,655 hospital admissions. A total of 3,707 (12.5%) patients screened positive for delirium and 286 (0.96%) had a reported fall. After adjustment for covariates, relative to patients without delirium or a fall, patients with delirium only had a 1.64-fold longer LOS; patients with fall only had a 1.96-fold longer LOS; and patients who had delirium and fall had a 2.84-fold longer LOS. The adjusted odds of discharge to a facility, relative to those without delirium or a fall, was 8.98 times higher in those with delirium and a fall. CONCLUSIONS: Delirium and falls influence LOS and likelihood of being discharged to a facility. The joint impact of falls and delirium on LOS and facility discharge was more than additive. Hospitals should consider the integrated management of delirium and falls.

The Association between Delirium and In-Hospital Falls: A Cross-Sectional Analysis of a Delirium Screening Program.

Methods: A cross-sectional study using delirium screening and falls reports was used to measure the association between delirium and falls. All inpatient data from August, 2018, to January, 2020, at a large academic medical center were analyzed. A multivariable logistic regression of 29,655 hospital admissions was used to understand the association between in-hospital delirium and falls. Results: Analysis revealed a delirium rate of 12.5% (n = 3,707) of all admissions and 286 (0.9%) admissions with falls; of the falls studied, 37.6% of these patients screened positive for delirium during their admission. Relative to those who screened negative for delirium, admissions that screened positive for delirium had a 2.81 increased odds of falling. Conclusions: Delirium and falls are related. This strong association should motivate health systems to look closely at both problems. Falls and delirium can both have immense impacts on the patient and the health system. The powerful association between them provides a window to reduce these additional patient harms. More specifically, a modern delirium screening tool should be used as part of routine risk assessment focused on reducing in-hospital falls.

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.

Assessment of Pancreas Safety in the Development Program of Once-Weekly GLP-1 Receptor Agonist Dulaglutide.

OBJECTIVE: To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials. RESEARCH DESIGN AND METHODS: A total of 6,005 patients with type 2 diabetes participated (dulaglutide group N = 4,006 [dose range 0.1-3.0 mg]; active comparator group [metformin, sitagliptin, exenatide twice daily, insulin glargine] N = 1,541; placebo group N = 703; 245 placebo-treated patients subsequently received dulaglutide or sitagliptin and were also included in these groups) for up to 104 weeks. The following events were adjudicated: investigator-reported pancreatitis, adverse events (AEs) of severe or serious abdominal pain of unknown etiology, and confirmed asymptomatic increases in pancreatic enzymes ≥3× the upper limit of normal range. RESULTS: Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient-years, placebo group 3.52 patients/1,000 patient-years, sitagliptin group 4.71 patients/1,000 patient-years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with AEs. CONCLUSIONS: The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.

Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.

Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2 , P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2 , P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2 , P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1-Q3] values were: dulaglutide vs placebo: 8.0 [4.4-20.4] vs 8.0 [4.4-23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4-21.2] vs 8.9 [4.4-27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4-29.2] vs 12.4 [5.3-50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient-years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.

Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates.

OBJECTIVE: Estimate the proportion of phosphodiesterase type-5 inhibitor (PDE5-I) patients who co-possess nitrates and compare the proportion of tadalafil patients dispensed nitrates to a matched control group. Secondarily, examine the percentage of co-possession of PDE5-Is and nitrates where the products were dispensed on the same day or written by the same prescriber. METHODS: Male patients aged 18+ years filling PDE5-I prescriptions between December 2003 and March 2006 were identified using a U.S. longitudinal prescription database (IMS Health LRx). Similar patients not dispensed a PDE5-I during this period were matched to the tadalafil-dispensed cohort using a propensity score approach. Co-possession, as a proxy for concurrent use, was defined as an overlap in time on therapy for a PDE5-I and nitrate and was compared for the three PDE5-Is and for tadalafil to the matched control group. RESULTS: Among 601,063 tadalafil patients, 3.31% were dispensed a nitrate during the study period, compared to 6.18% in control patients (n = 601,063). When co-possessed prescriptions were defined by overlapping exposure periods, the proportion of PDE5-I patients with co-possessed nitrates ranged from 1.44% (tadalafil) to 1.72% (vardenafil) and 2.13% (sildenafil). Co-possession percentages of PDE5-I prescriptions were 0.83% for tadalafil and 1.07% for sildenafil and vardenafil. The majority (54.29%) of co-possessed PDE5-I and nitrate prescriptions had the nitrate dispensed prior to the PDE5-I prescription identified in the study cohort. CONCLUSIONS: Keeping in mind the limitations of observational studies, these results suggest that co-dispensing of nitrates and PDE5-Is is low. Compared to control patients, the proportion of nitrate co-possession was lowest for patients filling tadalafil. Tadalafil patients also had the lowest co-possessed proportion among the three PDE5-I cohorts. While the majority of co-possessed drug pairs were prescribed by different providers, the highest percentage of co-prescribing from the same physician was among cardiologists. These results suggest that physicians adhere to contraindications and are careful about co-prescribing of nitrates with PDE-5Is.

Climate control: United States weather modification in the cold war and beyond.

Rainmaking, hail busting, fog lifting, snowpack enhancing, lightning suppressing, hurricane snuffing...weather control. At the lunatic fringe of scientific discussion in the early twentieth century--and the subject of newspaper articles with tones ranging from skeptical titters to awestruck wonder--weather modification research became more serious after World War II. In the United States, the 'seeds' of silver iodide and dry ice purported to enhance rainfall and bust hailstorms soon became seeds of controversy from which sprouted attempts by federal, state and local government to control the controllers and exploit 'designer weather' for their own purposes.

Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women.

OBJECTIVE: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160 mg/dL or reduce elevated LDL-C levels to below lipid-lowering goals in postmenopausal women. PATIENTS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60 mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective. This post-hoc analysis included the 2413 women who did not take lipid-lowering medications at any time during the trial and for whom LDL-C measurements were available. The threshold for high LDL-C (> or = 160 mg/dL) and LDL-C lipid-lowering goals were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines. RESULTS: The percent of women with LDL-C < 160 mg/dL was comparable between treatment groups at baseline (placebo, 57.5%; raloxifene 60 mg, 56.4%; raloxifene 120 mg, 56.8%). At 3 years, the percent of these women whose LDL-C had increased to above 160 mg/dL was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 65% (95% CI, 44%-78%) and 64% (95% CI, 43%-77%), respectively. Among women with elevated (defined for these analyses as > or = 160 mg/dL) LDL-C at baseline, the proportion having elevated LDL-C at 3 years was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 32% (95% CI, 24%-40%) and 40% (95% CI, 32%-48%), respectively. Fifty percent and 13% of these women achieved LDL-C goals of < 160 mg/dL and < 130 mg/dL, respectively (P < 0.001 vs. placebo for both) in the raloxifene 60 mg group, with similar results for the raloxifene 120 mg group. CONCLUSIONS: In postmenopausal women with osteoporosis not taking concurrent lipid-lowering therapy, raloxifene significantly reduced the incidence of LDL-C > or = 160 mg/dL and significantly increased the proportion achieving LDL-C goals for lipid-lowering compared with placebo. Whether these and other effects of raloxifene on cardiovascular risk markers will improve cardiovascular outcomes requires further study.

Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial.

BACKGROUND: Raloxifene has been approved for prevention and treatment of postmenopausal osteoporosis in Caucasian women. It also has some positive effects on serum lipids in Caucasians. The objective of this study was to determine the effect of raloxifene hydrochloride on lumbar spine and total hip bone mineral density (BMD), bone metabolism, and serum lipids in Chinese postmenopausal women with osteoporosis. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled clinical trial in which 204 postmenopausal Chinese women with osteoporosis were assigned to receive raloxifene (60 mg) or placebo treatment daily for 12 months. BMD, serum bone metabolism markers, and serum lipids were measured before and after drug administration. BMD was measured by Dual-Energy X-Ray Absorptiometry (DEXA) and bone metabolism markers were analyzed by one-step enzyme-linked immunosorbent assay. Serum lipids were measured by enzymatic analysis. RESULTS: At the end of the 12-month study, lumbar spine BMD increased in both groups with a mean increase of (3.3 +/- 4.8)% in the raloxifene group and (1.0 +/- 4.9)% in the placebo group (P < 0.001). There was a mean increase in total hip BMD of (1.4 +/- 4.8)% in the raloxifene group and a mean decrease of (0.9 +/- 5.0)% in the placebo group (P < 0.001). No subject in the raloxifene group had a new vertebral fracture and 5 placebo subjects had new fractures (P > 0.05). In the raloxifene group, the median decreases in the biochemical markers of bone metabolism serum osteocalcin and C-telopeptide were 41.7% and 61.5%, respectively. These changes were statistically significant compared with those in the placebo group (10.6% and 35.6%, P < 0.001, respectively). Both total cholesterol and low-density lipoprotein cholesterol decreased significantly in the raloxifene group compared with those in the placebo group (P < 0.001, respectively) and there was no significant effect of raloxifene on high-density lipoprotein cholesterol and triglycerides compared with placebo. CONCLUSIONS: Raloxifene 60 mg/d for 12 months significantly increases lumbar spine and total hip BMD, significantly decreases bone turnover, and has favourable effects on serum lipids in Chinese postmenopausal women with osteoporosis.

Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in postmenopausal women: a randomized clinical trial in Beijing.

OBJECTIVE: To determine the effects of raloxifene hydrochloride (RLX) on bone mineral density (BMD), bone metabolism markers and serum lipids in healthy postmenopausal women in Beijing. METHODS: A multicenter, randomized, double-blind, placebo-controlled study was conducted in a total of 204 healthy postmenopausal women (age 59.5 +/- 5.0 years and weight 62.8 +/- 8.7 kg) treated with either RLX 60 mg (n = 102) or placebo (n = 102) daily for 12 months. BMD, serum lipids, and bone markers were measured before and after drug administration. RESULTS: Compared with placebo, RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine, percentage increase in total BMD was 2.3% with RLX compared with a decrease of 0.1% with placebo (P < 0.001). Corresponding values for total hip BMD were a 2.5% increase for RLX and a 1.1% increase for placebo (P = 0.011). For biochemical markers of bone metabolism, serum osteocalcin and C-telopeptide, percentage decreases were 27.65% and 24.02% in RLX-treated subjects. Corresponding values in placebo were a 10.64% decrease and a 15.75% increase (RLX compared with placebo, both P < 0.001). For total cholesterol and low-density lipoprotein cholesterol levels, percentage decreases were 6.44% and 34.58% in the RLX-treated group. Corresponding values in placebo-treated patients were a 1.44% increase and a 19.07% decrease (RLX compared with placebo, both P < 0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early owing to an adverse event (3 in the RLX group and 2 in the placebo group). CONCLUSIONS: This study confirms that RLX exerts positive effects on the skeleton, increasing BMD and decreasing biochemical markers of bone metabolism, and has a positive effect on the overall serum lipid profile in postmenopausal women in China.

[A randomised clinical trial to study the effects of raloxifene hydrochloride on bone mineral density, biochemical markers of bone metabolism and serum lipids in postmenopausal women].

OBJECTIVE: To determine the effect of raloxifene hydrochloride (RLX) on bone mineral density (BMD), biochemical markers of bone metabolism and lipid metabolism in Chinese postmenopausal women. METHODS: This was a multicenter, randomized, double blind placebo controlled study in China with a total of 204 postmenopausal women [mean age (60 +/- 5) years (x +/- s) and weight (63 +/- 9) kg (x +/- s)] treated with either RLX 60 mg (n = 102) or placebo (n = 102) daily for 12 months. BMD, serum lipid and bone markers were determined before and after drug administration. RESULTS: Compared to placebo, RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine, percentage increase in total BMD was 2.30% with RLX compared to a decrease of 0.08% with placebo (P < 0.001). Corresponding values for total hip BMD were 2.46% increase for RLX and 1.07% for placebo (P < 0.05). For biochemical markers of bone metabolism, serum osteocalcin and C-telopeptide, percentage decrease were 27.6% and 24.0% in raloxifene-treated subjects. Corresponding values in placebo were 10.6% decrease and 15.8% increase (RLX compared to placebo, both P < 0.001). For total cholesterol and low-density lipoprotein cholesterol, percentage decrease were 6.4% and 34.6% in the raloxifene-treated group. Corresponding values in placebo were 1.4% increase and 19.1% decrease (RLX compared to placebo, both P < 0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early due to an adverse event (3 in the RLX group and 2 in the placebo group). CONCLUSIONS: This study confirms that RLX exerts positive effects on the skeleton, increasing BMD and decreasing biochemical markers of bone metabolism, and decreased total cholesterol and low-density lipoprotein cholesterol in postmenopausal women in China.

Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes.

BACKGROUND: The long-term effects of the selective estrogen-receptor modulator raloxifene hydrochloride on glycemic control and markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes mellitus are unknown. OBJECTIVE: The aim of this analysis was to compare the effects of 3-year treatment with raloxifene 60 mg/d versus placebo on glycemic control and markers of cardiovascular disease risk in osteoporotic postmenopausal women with and without type 2 diabetes. METHODS: In this analysis, we included women from the Multiple Outcomes of Raloxifene Evaluation trial (a multicenter, double-masked trial) who were randomized to receive raloxifene 60 mg/d (n = 2557) or placebo (n = 2576). Baseline and 36-month fasting plasma glucose (FPG) and total cholesterol (TC) were measured for all participants. Glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein (apo) A-I, apo B, and fibrinogen were assessed in approximately 1800 participants from selected larger sites. RESULTS: At baseline, 202 of all 5133 women (3.9%) had type 2 diabetes. Of the approximately 1800 women who were assessed for HbA1c, LDL-C, TGs, apo A-I, apo B, and fibrinogen, 70 (3.9%) had type 2 diabetes at baseline. Compared with placebo, raloxifene did not significantly affect HbA1c, FPG, HDL-C, or TGs in women with or without diabetes. Raloxifene produced statistically significant reductions in TC, LDL-C, and fibrinogen both in women with diabetes (all P < or = 0.004) and without diabetes (all P < 0.001). Raloxifene significantly increased apo A-I (P < 0.001) and reduced apo B (P < 0.001) in women without diabetes. In the raloxifene-treated group, body weight increased by a mean 0.31 kg (P < 0.001) in women without diabetes. CONCLUSIONS: In osteoporotic postmenopausal women with or without type 2 diabetes, raloxifene 60 mg/d did not affect glycemic control and had favorable effects on TC, LDL-C, and fibrinogen levels.

Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.

The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.

Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis.

BACKGROUND: Raloxifene hydrochloride therapy reduces the risk for vertebral fractures at 3 years, but the effects on clinical vertebral fractures in the first year are not known. METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled 7705 women with osteoporosis, defined by prevalent vertebral fractures and/or a bone mineral density (BMD) T score at or below -2.5, who were treated with placebo or raloxifene at a dosage of 60 or 120 mg/d for 3 years. New clinical vertebral fractures were defined as incident vertebral fractures associated with signs and symptoms suggestive of vertebral fractures, such as back pain, and were diagnosed by means of postbaseline adjudicated spinal radiographs. Scheduled spinal radiographs were obtained at baseline and at 2 and 3 years. In addition, unscheduled spinal radiographs were obtained in women who reported signs or symptoms suggestive of vertebral fracture, and these radiographs subsequently underwent adjudication. If an adjudicated fracture was identified, this was also considered a clinical fracture. RESULTS: At 1 year, raloxifene, 60 mg/d, decreased the risk for new clinical vertebral fractures by 68% (95% confidence interval [CI], 20%-87%) compared with placebo in the overall study population, and by 66% (95% CI, 23%-89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene, 60 mg/d, group was decreased by 46% (95% CI, 14%-66%) at 2 years and by 41% (95% CI, 17%-59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene, 60 mg/d, compared with placebo (P<.001). We found no significant differences in the risk reductions for clinical vertebral fractures between the raloxifene groups at 1, 2, or 3 years. CONCLUSION: The early risk reduction for new clinical vertebral fractures with 1 year of raloxifene treatment was similar to that reported with other antiresorptive agents.

Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.

CONTEXT: Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown. OBJECTIVE: To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women. DESIGN: Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999. SETTING: Outpatient and community settings at 180 sites in 25 countries. PARTICIPANTS: A total of 7705 osteoporotic postmenopausal women (mean age, 67 years). INTERVENTION: Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years. MAIN OUTCOME MEASURES: Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure. RESULTS: In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P =.94), or among women at increased cardiovascular risk (P =.86) or with evidence of established coronary heart disease (P =.60). CONCLUSIONS: Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.

Bone histomorphometric and biochemical marker results of a 2-year placebo-controlled trial of raloxifene in postmenopausal women.

Raloxifene is a selective estrogen receptor modulator that has been shown to increase bone density. The purpose of this study was to examine the effects of raloxifene on bone tissue by studying bone biopsy specimens before and after 2 years of raloxifene or placebo therapy. The women in this study were participants of the double-blind, placebo-controlled, multicenter study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Subjects from two U.S. sites and two European sites were included if they consented to a bone biopsy. Iliac crest bone biopsies were performed at baseline and after 2 years. Tetracycline labeling preceded each biopsy. A total of 65 paired biopsy specimens were evaluated with 25, 22, and 18 patients in the placebo, raloxifene HCl (60 mg) and raloxifene HCl (120 mg) treatment groups, respectively. They were analyzed using standard histomorphometry. None of the biopsy specimens showed evidence of toxic effects on bone or bone cells or met criteria for osteomalacia. Biopsy specimens in the placebo and raloxifene groups had the appearance of normal bone, with no evidence of marrow fibrosis or increases in the amount of woven bone or numbers of empty osteocyte lacunae. Compared with the baseline, the bone formation rate (BFR) decreased significantly in both raloxifene groups. The change in BFR in the group treated with 120 mg of raloxifene was -62.3%, which was significantly lower than the change in the placebo group of -21.0% (p = 0.03). No change in resorption parameters could be measured by histomorphometry, but there was a decrease in urinary type I collagen excretion. The results from this study suggest that raloxifene has actions on bone tissue that are similar to those observed with estrogen. The depressive effects on bone remodeling are less marked than the effects seen with alendronate.

Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.