Rollin Brant

Subcutaneous Low-Molecular-Weight Heparin Compared with Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis

Abstract Background. Low-molecular-weight heparin has a high bioavailability and a prolonged half-life in comparison with conventional unfractionated heparin. Limited data are available for low-molecular-weight heparin as compared with unfractionated heparin for the treatment of deep-vein thrombosis. Methods. In a multicenter, double-blind clinical trial, we compared fixed-dose subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion for the initial treatment of patients with proximal-vein thrombosis, using objective documentation of clinical outcomes. Results. Six of 213 patients who received low-molecular-weight heparin (2.8 percent) and 15 of 219 patients who received intravenous heparin (6.9 percent) had new episodes of venous thromboembolism (P = 0.07; 95 percent confidence interval for the difference, 0.02 percent to 8.1 percent). Major bleeding associated with initial therapy occurred in 1 patient receiving low-molecular-weight h...

D-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism: A Systematic Review

Context Clinicians may not know which d-dimer assay is best for diagnosing deep venous thrombosis (DVT) or pulmonary embolism (PE). Contribution This meta-analysis summarizes data from 78 prospective studies that compared results of different d-dimer assays with findings of objective tests (for example, compression ultrasonography, venography, lung scanning) in patients with suspected DVT or PE. Enzyme-linked immunosorbent assays (ELISAs) had the best sensitivity (about 95%) and negative likelihood ratios (about 0.1) for excluding DVT and PE. None of the assays had positive likelihood values that greatly increased the certainty of diagnosis. Implications Negative ELISA results are strong evidence against DVT or PE. The Editors Tests for d-dimer to exclude venous thromboembolic disease have been available since the 1980s (1). Hundreds of original studies, reviews, commentaries, and technical notes related to d-dimer as a diagnostic aid have been published. Even with this extensive literature, the role of d-dimer in the diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) remains unclear. This lack of clarity is due in part to the multiple d-dimer assays that are available (Appendix Table 1), availability of central laboratory and point-of-care testing, and concerns about differing sensitivities and variability of the assays (1). In 1998, the American College of Chest Physicians Consensus Panel on Pulmonary Embolism called for more evaluation of the utility of d-dimer (2). In 1999, a Clinical Practice Guideline of the American Thoracic Society also called for additional outcome studies to further define the role of rapid bedside assays of d-dimer (3). As recently as 2000, investigators argued that the whole-blood agglutination test with d-dimer is not validated for clinical use for the exclusion of DVT (4). Although several useful reviews of the topic exist (1, 3, 5), none in recent years have comprehensively reviewed the world literature in an effort to summarize the accumulated published experience with d-dimer testing. Given continuing uncertainty about d-dimer testing, we performed a systematic review of the literature to assess the sensitivity and specificity of the d-dimer assays and the variability of those measures among studies for diagnosing DVT and PE. The comparative findings among the differing d-dimer assays provide both the laboratory pathologist and clinician with a practical pathway for translating clinical research into practice. Methods We used several sources to guide our review processes, including recommendations by Lijmer and colleagues concerning avoidance of bias in studies of diagnostic tests (6), the Standards for Reporting Diagnostic Accuracy (STARD) statement (7, 8), and guidelines for meta-analyses of observational studies in epidemiology (9). Study Identification We attempted to identify all published trials in all languages that used d-dimer to exclude PE or DVT on the basis of objective diagnostic tests. Studies were identified by searching PubMed from 1983 to January 2003 and EMBASE from 1988 to January 2003. All searches used the key words d -dimer, PE, and DVT. We augmented our searches by manually reviewing the reference lists of all original articles and all review articles. This was done by 2 of the authors working together. Abstracts were excluded. Study Eligibility At least 2 authors evaluated each study for inclusion. Any disagreements were resolved by discussion. Authors were not blinded to journal, author, or institution. Studies were included if they met all of the following criteria: 1) A specific statement was made about whether PE or DVT (not the inclusive term thromboembolic disease) was being diagnosed; 2) the diagnosis of PE or DVT was based on objective tests; 3) studies were performed prospectively; 4) participants were recruited consecutively; 5) the population studied included a broad spectrum of patients; 6) results of d-dimer and the diagnostic tests for PE and DVT were interpreted independently; 7) the participants studied were suspected of having PE or DVT, and all studies included patients with and without disease; 8) the decision to perform the reference diagnostic test was made independently of the d-dimer result; 9) test descriptions were sufficiently detailed to permit replication; 10) the cutoff value for a negative d-dimer test result was stated unless qualitative tests were used; and 11) sensitivity and specificity or the raw data for these calculations were presented. We labeled studies that did not meet the third, fourth, or tenth inclusion criteria as tier 3 studies and included them in sensitivity analyses. We categorized studies that met all inclusion criteria into 2 tiers. Tier 1 included studies that compared an enzyme-linked immunosorbent assay (ELISA) and at least one other d-dimer assay. Tier 2 included the tier 1 studies and all other studies that met all inclusion criteria. Data Extraction Two authors collected data on the following study-level factors: 1) the d-dimer assay used in the study, 2) the cutoff value below which disease was considered to be absent, and 3) whether d-dimer was used to exclude PE or DVT. At least 2 authors confirmed the values for sensitivity and specificity. Statistical Analysis Sensitivities reflect the proportion of patients with disease who had a positive d-dimer result, while specificities reflect the proportion of patients without disease who had a negative d-dimer result, depending on cutoff level. Values for the likelihood ratio (the multiplicative factor for converting pretest to post-test disease probabilities) associated with positive test results were obtained by the following formula: sensitivity/(1 corresponding specificity). This formula provided likelihood ratios arising from negative test results. Primary analysis was restricted to the 500-ng/mL cutoff because that was the most commonly used value. On the basis of the varying array of assays examined in individual studies and our anticipation of important between-study heterogeneity, we applied a linear mixed-model approach (10) to jointly analyze the proportions of positive test results in the disease and nondisease samples (that is, true-positive and false-positive rates). Similar models have been applied to Bayesian meta-analysis of receiver-operating characteristic curves (11). The main explanatory term in the model was a fixed effect reflecting distinct positive response rates for each combination of assay and population. To allow for variability in assay performance that might arise from idiosyncratic features of patient samples, such as spectrum of disease severity, and other aspects of study context, such as laboratory procedure, we incorporated 3 random-effects terms corresponding to assay nested within patient group (disease/nondisease) nested within study. Residual variances were assumed to follow the standard binomial form depending on underlying proportion and sample size. Applying restricted maximum likelihood, we obtained population average estimates for sensitivity and specificity, which were later combined to provided estimated likelihood ratios. Overall, the estimates did not differ substantially from conventional sample-size weighted averages, although the associated standard errors were increased, reflecting underlying between-study heterogeneity. The joint statistical significance of overall differences was assessed by using likelihood-based Wald tests. Pairwise differences between estimates were assessed on the basis of the model-based standard errors without adjustment for multiple comparisons. Significant pairwise differences should be interpreted with caution when the Wald test is not significant. Confidence limits are derived from asymptotic standard errors; asymmetric intervals for likelihood ratios reflect the application of likelihood theory to logarithmically transformed estimates. Values for the sensitivity and specificity for the different studies and test types were examined graphically by use of boxplots. The range between the upper and lower quartiles of the values for each assay provides a measure of between-study variability associated with the assay. Sensitivity analyses were conducted by adding the 30 studies that did not meet one or more of the 3 inclusion criteria previously mentioned (tier 3 analysis) and by analyzing sensitivity and specificity at the 250-ng/mL and 1000-ng/mL cutoffs. All analyses were conducted by using S-PLUS, version 6.1.2, 2002 (Insightful Corp., Seattle, Washington) (12). Data Synthesis Figure 1 summarizes our search. We initially identified 513 potentially relevant reports. Thirty-one studies (13-43) were included; they met a priori inclusion criteria and compared 2 or more assays, including an ELISA (tier 1 analysis). An additional 47 studies (44-90) were also included; they did not have a comparative ELISA but met the a priori inclusion criteria evaluating a d-dimer assay. The 47 studies combined with the 31 studies provided a study sample of 78 studies (tier 2 analysis). Thirty additional studies (91-120) that did not meet one or more inclusion criteria were included in the sensitivity, or tier 3, analysis, which also included the 78 studies in the tier 2 analysis. Figure 1. Reports evaluated for inclusion in the review. Appendix Tables 2 and 3 list the d-dimer assays that were evaluated, patient characteristics, and the objective diagnostic reference test that was used for patients with clinically suspected DVT (49 studies) and clinically suspected PE (31 studies). All studies met the 11 criteria for inclusion listed in the Methods section. There was a total of 78 studies (2 studies [60, 71] gave data for patients with PE and DVT separately in the same article). In the various studies, prevalence of DVT ranged from 20% to 78% (overall prevalence, 36%), and the prevalence of PE ranged from 8% to 62% (overall prevalence, 25%). Sixteen studies of DVT used comp

A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.

BACKGROUND Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. METHODS We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). RESULTS Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular-weight heparin as compared with warfarin was 16 percent, and the absolute difference in the incidence of venous thrombosis was 6 percent in favor of low-molecular-weight heparin (95 percent confidence interval, 0.8 to 11.4 percent). The incidence of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (P = 0.04), and the absolute difference was 1.5 percent in favor of warfarin (95 percent confidence interval, 0.1 to 3.0 percent). CONCLUSIONS Our data demonstrate that the small reduction in the incidence of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, was offset by an increase in bleeding complications. Although the use of low-molecular-weight heparin is simpler, because it is administered subcutaneously without the need for monitoring, it may be more costly than warfarin. Warfarin is inexpensive, but the overall cost of its use is increased by the need to monitor the intensity of anticoagulation. At this time it is unclear which of these approaches is the most cost effective.

Procedural pain and brain development in premature newborns.

Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.

Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis in Patients after Elective Hip Arthroplasty: A Systematic Review

The use of accurate, objective venographic testing to detect deep venous thrombosis in patients who undergo hip arthroplasty has led to randomized trials of various prophylactic regimens against venous thromboembolism (123). The need for in-hospital prophylaxis has been firmly established (24, 25) and accepted in clinical practice. Evidence-based medicine guidelines (26) based on venographic end points recommend low-molecular-weight heparin (LMWH) prophylaxis or warfarin prophylaxis for 7 to 10 days in patients who undergo elective hip surgery (25). These guidelines are considered a grade 1A recommendation, which indicates a strong recommendation for a therapy that has a clear benefit; the recommendation is based on randomized clinical trials that do not have important limitations and that can apply to most patients in most circumstances without reservation (26). Recent surveys indicate that more than 90% of patients who have undergone elective hip surgery have received thromboprophylaxis (27, 28). The results of randomized trials in Europe indicate the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty (2934). In contrast, on the basis of relatively low rates of symptomatic venous thromboembolism observed in descriptive studies in North America with long-term follow-up, investigators have inferred that extended prophylaxis is not required (3539). For these reasons, the reports of the Fifth (24) and Sixth (25) American College of Chest Physicians Consensus Conferences stated that extended out-of-hospital prophylaxis by using LMWH may offer additional protection. This is a 2A recommendation because of uncertainty regarding the riskbenefit ratio (24) and cost-effectiveness (25). A grade 2A recommendation indicates unclear benefit based on randomized clinical trials without important limitations and is an intermediate-strength recommendation (26). A possible interpretation of the North American data (3539) is that extended prophylaxis is unnecessary for patients in the United States and Canada because of differences in clinical practice, a shorter length of hospital stay, and earlier patient ambulation compared with Europe. A recent epidemiologic study (27) used a linked hospital discharge database provided by the State of California to report the outcomes in 19 586 patients undergoing total-hip arthroplasty and 24 059 patients undergoing knee arthroplasty. Of the patients having elective hip surgery who had symptomatic venous thromboembolism, the median time of the event was postoperative day 17, whereas the median time in patients having knee surgery was postoperative day 7; most patients (>90%) received in-hospital prophylaxis. These findings strongly suggest a need for extended out-of-hospital prophylaxis in patients undergoing total-hip replacement but not for patients undergoing total-knee replacement. Given the uncertainty about the need for extended prophylaxis, we performed a systematic review to provide clinicians with a practical pathway for translating clinical research into practice. Methods To ensure high methodologic quality, we adhered to the 15 criteria for systematic review outlined by McAlister and colleagues (40, 41). The first 10 criteria assess methodologic rigor, and the last 5 criteria assess the scientific basis of treatment recommendations (40). We also adhered to the QUOROM (Quality of Reporting of Meta-analyses) guidelines (42) for the reporting of meta-analyses of randomized trials. We systematically identified published and unpublished articles for inclusion in this analysis, described variations in study design and execution, evaluated study quality (43), and quantified the relative benefits of extended prophylaxis with LMWH (44). We excluded studies that did not use venography to assess the presence or absence of deep venous thrombosis because previous studies have shown that noninvasive tests, including duplex ultrasonography, are relatively insensitive for detecting thrombosis in patients who have undergone hip replacement (25). Study Identification We attempted to identify all published and unpublished randomized trials that compared extended prophylaxis with LMWH versus out-of-hospital placebo in patients undergoing hip arthroplasty. A strategy was developed for locating all studies in the PubMed and MEDLINE databases that were published between January 1976 and May 2001; the search was not restricted to English-language journals. We augmented our MEDLINE search by manually reviewing the reference lists of original articles and review articles. We also reviewed abstracts in conference proceedings and through the Cochrane Library Database and contacted investigators and pharmaceutical companies. Study Eligibility Two investigators independently evaluated studies for inclusion in the systematic review, and any disagreements were resolved by discussion between these two investigators. Investigators were not blinded to journal titles, author names, or institutional affiliations. Studies were included if they 1) enrolled patients undergoing elective hip arthroplasty, 2) randomly assigned participants to treatment groups, 3) investigated the extended posthospital discharge efficacy of once-daily subcutaneous LMWH compared with out-of-hospital placebo for prevention of deep venous thrombosis, 4) objectively documented the presence or absence of all episodes of deep venous thrombosis and proximal venous thrombosis by using bilateral ascending contrast venography, and 5) used objective methods for assessing bleeding complications (2932, 45, 46). Abstracts that reported full methods and results were eligible for inclusion. Deep venous thrombosis was defined as constant intraluminal filling defects in the deep veins; proximal venous thrombosis was defined as constant intraluminal filling defects in the popliteal deep veins or in the more proximal deep veins. Data Extraction One study investigator collected data on the following study-level factors: 1) the type of LMWH prophylaxis used, 2) whether a high-risk dose, approved by a regulatory affairs authority, was used, 3) the frequency of administration of LMWH, 4) the length of in-hospital stay, 5) the time interval after surgery when venography was performed [in days], and 6) venographic findings. For the last factor, we noted new out-of-hospital findings on venography or combined in-hospital and out-of-hospital findings on venography; where both findings were reported, we analyzed new out-of-hospital findings, which were more conservative and more recent. Two investigators independently extracted data on the major outcomes, which were the frequency of 1) all episodes of deep venous thrombosis, 2) proximal venous thrombosis, 3) symptomatic deep venous thrombosis and pulmonary embolism, and 4) major-bleeding complications. They also recorded data on other variables, including death, minor bleeding, wound hematomas, and thrombocytopenia. After the two investigators made their respective independent selection of studies for inclusion in the analysis, we compared their selections and calculated the percentage of agreement between them and the coefficient (47). Investigator disagreements were resolved by discussion. Assessment of Study Quality We assessed the quality and strength of each study by examining four key issues: 1) true randomization by using a random-numbers table or a computer program; 2) the masking of the allocation sequences from the investigators, staff, and patients involved in the study; 3) double-blinding [45]; and 4) the proportion of patients with successful (adequate) venography. One investigator extracted these data from the primary studies. When details were not reported, we requested additional information from the authors. Data Synthesis and Statistical Analysis For each of the major outcomes, we calculated summary treatment effects as the relative risk and the number needed to treat for benefit (NNTB) to prevent one thromboembolic event. The relative risk was used as the primary measure of treatment effect. We considered a P value less than 0.05 to be statistically significant for all statistical tests. Analyses were performed by using the metan procedure (48) of Stata software, release 6.0 (Stata Corp., College Station, Texas). To assess the validity of combining results from individual studies, we used the MantelHaenszel test for statistical heterogeneity (49). The outcome values were combined in both fixed-effects and random-effects models to estimate treatment effects on outcomes for all the studies. The relative risk ratios were consistent among studies for the treatment effect of preventing venographically documented deep venous thrombosis (all episodes and cases of proximal deep venous thrombosis); however, the 95% CIs for the relative risk ratios within studies were relatively wide. Therefore, we combined the data to provide more precise estimates of relative risk and NNTB. Results for NNTB were based on random-effects analysis of risk. Sensitivity Analysis We performed a sensitivity analysis for each of the three major outcomes. To uncover possible publication bias, we created inverted funnel plots for the major outcomes by plotting odds ratios against the sample size for each study (50). Moreover, to identify any studies that exerted a disproportionate influence on the summary treatment effect, we performed repeated calculations in which the data from each individual study were deleted, one at a time. Trials that met all inclusion criteria except for onethe use of bilateral ascending venography to assess end points at the end of the out-of-hospital study intervalwere included in a secondary meta-analysis of symptomatic venous thromboembolism and major bleeding end points. Results Study Identification and Selection Our search strategies identified 206 potentially relevant studies. After an initial scanning of titles and abstracts, we excluded 184 studies: 160 studies did

Choroid plexus tumours

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966–1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a ‘wait and see’ approach in choroid plexus-papilloma.

Automated analysis of digital oximetry in the diagnosis of obstructive sleep apnoea

BACKGROUND The gold standard diagnostic test for obstructive sleep apnoea (OSA) is overnight polysomnography (PSG) which is costly in terms of time and money. Consequently, a number of alternatives to PSG have been proposed. Oximetry is appealing because of its widespread availability and ease of application. The diagnostic performance of an automated analysis algorithm based on falls and recovery of digitally recorded oxygen saturation was compared with PSG. METHODS Two hundred and forty six patients with suspected OSA were randomly selected for PSG and automated off line analysis of the digitally recorded oximeter signal. RESULTS The PSG derived apnoea hypopnoea index (AHI) and oximeter derived respiratory disturbance index (RDI) were highly correlated (R = 0.97). The mean (2SD) of the differences between AHI and RDI was 2.18 (12.34)/h. The sensitivity and specificity of the algorithm depended on the AHI and RDI criteria selected for OSA case designation. Using case designation criteria of 15/h for AHI and RDI, the sensitivity and specificity were 98% and 88%, respectively. If the PSG derived AHI included EEG based arousals as part of the hypopnoea definition, the mean (2SD) of the differences between RDI and AHI was –0.12 (15.62)/h and the sensitivity and specificity profile did not change significantly. CONCLUSIONS In a population of patients suspected of having OSA, off line automated analysis of the oximetry signal provides a close estimate of AHI as well as excellent diagnostic sensitivity and specificity for OSA.

Mortality and Institutionalization Following Hip Fracture

OBJECTIVES: To identify determinants of mortality and institutionalization after hip fracture and to identify those older hip fracture patients at high risk of death or institutionalization after hip fracture.

Epinephrine and Dexamethasone in Children with Bronchiolitis

BACKGROUND Although numerous studies have explored the benefit of using nebulized epinephrine or corticosteroids alone to treat infants with bronchiolitis, the effectiveness of combining these medications is not well established. METHODS We conducted a multicenter, double-blind, placebo-controlled trial in which 800 infants (6 weeks to 12 months of age) with bronchiolitis who were seen in the pediatric emergency department were randomly assigned to one of four study groups. One group received two treatments of nebulized epinephrine (3 ml of epinephrine in a 1:1000 solution per treatment) and a total of six oral doses of dexamethasone (1.0 mg per kilogram of body weight in the emergency department and 0.6 mg per kilogram for an additional 5 days) (the epinephrine-dexamethasone group), the second group received nebulized epinephrine and oral placebo (the epinephrine group), the third received nebulized placebo and oral dexamethasone (the dexamethasone group), and the fourth received nebulized placebo and oral placebo (the placebo group). The primary outcome was hospital admission within 7 days after the day of enrollment (the initial visit to the emergency department). RESULTS Baseline clinical characteristics were similar among the four groups. By the seventh day, 34 infants (17.1%) in the epinephrine-dexamethasone group, 47 (23.7%) in the epinephrine group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group had been admitted to the hospital. In the unadjusted analysis, only the infants in the epinephrine-dexamethasone group were significantly less likely than those in the placebo group to be admitted by day 7 (relative risk, 0.65; 95% confidence interval, 0.45 to 0.95, P=0.02). However, with adjustment for multiple comparisons, this result was rendered insignificant (P=0.07). There were no serious adverse events. CONCLUSIONS Among infants with bronchiolitis treated in the emergency department, combined therapy with dexamethasone and epinephrine may significantly reduce hospital admissions. (Current Controlled Trials number, ISRCTN56745572.)

Alberta Physical Activity and Breast Cancer Prevention Trial: Sex Hormone Changes in a Year-Long Exercise Intervention Among Postmenopausal Women

PURPOSE We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone-binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk. METHODS A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12-month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models. RESULTS Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months. CONCLUSION This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous-intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer.