Rebecca J. Mullan

Adverse Effects of Testosterone Therapy in Adult Men: A Systematic Review and Meta-Analysis

CONTEXT The risks of testosterone therapy in men remain poorly understood. OBJECTIVE The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. DATA SOURCES We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. STUDY SELECTION Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. DATA EXTRACTION Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. DATA SYNTHESIS The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. CONCLUSIONS The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.

Vitamin D and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

CONTEXT Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. OBJECTIVE The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. DESIGN AND METHODS We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. RESULTS We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. CONCLUSIONS Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.

The Effect of Vitamin D on Falls: A Systematic Review and Meta-Analysis

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

Hormonal therapy and sex reassignment: a systematic review and meta‐analysis of quality of life and psychosocial outcomes

Objective  To assess the prognosis of individuals with gender identity disorder (GID) receiving hormonal therapy as a part of sex reassignment in terms of quality of life and other self‐reported psychosocial outcomes.

The effect of vitamin D on falls

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

The Diabetes Mellitus Medication Choice Decision Aid: A Randomized Trial

BACKGROUND Patient involvement in the choice of antihyperglycemic agents could improve adherence and optimize glycemic control in patients with type 2 diabetes mellitus. METHODS We conducted a pilot, cluster randomized trial of Diabetes Medication Choice, a decision aid that describes 5 antihyperglycemic drugs, their treatment burden (adverse effects, administration, and self-monitoring demands), and impact on hemoglobin A(1c) (HbA(1c)) levels. Twenty-one clinicians were randomized to use the decision aid during the clinical encounter and 19 to dispense usual care and an educational pamphlet. We used surveys and video analysis to assess postvisit decisional outcomes, and medical and pharmacy records to assess 6-month medication adherence and HbA(1c) levels. RESULTS Compared with usual care patients (n = 37), patients receiving the decision aid (n = 48) found the tool more helpful (clustered-adjusted mean difference [AMD] in a 7-point scale, 0.38; 95% confidence interval [CI], 0.04-0.72); had improved knowledge (AMD, 1.10 of 10 questions; 95% CI, 0.11-2.09); and had more involvement in making decisions about diabetes medications (AMD, 21.8 of 100; 95% CI, 13.0-30.5). At 6-month follow-up, both groups had nearly perfect medication use (median, 100% of days covered), with better adherence (AMD, 9% more days covered; 95% CI, 4%-14%) and persistence (AMD, 12 more days covered; 95% CI, 3-21 days) in the usual care group, and no significant impact on HbA(1c) levels (AMD, 0.01; 95% CI, -0.49 to 0.50). CONCLUSION An innovative decision aid effectively involved patients with type 2 diabetes mellitus in decisions about their medications but did not improve adherence or HbA(1c) levels. Trial Registration clinicaltrials.gov Identifier: NCT00388050.

Accuracy of Diagnostic Tests for Cushing’s Syndrome: A Systematic Review and Metaanalyses

CONTEXT The diagnosis of Cushings syndrome (CS) requires the use of tests of unregulated hypercortisolism that have unclear accuracy. OBJECTIVE Our objective was to summarize evidence on the accuracy of common tests for diagnosing CS. DATA SOURCES We searched electronic databases (MEDLINE, EMBASE, Web of Science, Scopus, and citation search for key articles) from 1975 through September 2007 and sought additional references from experts. STUDY SELECTION Eligible studies reported on the accuracy of urinary free cortisol (UFC), dexamethasone suppression test (DST), and midnight cortisol assays vs. reference standard in patients suspected of CS. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics and quality and data to estimate the likelihood ratio (LR) and the 95% confidence interval (CI) for each result. DATA SYNTHESIS We found 27 eligible studies, with a high prevalence [794 (9.2%) of 8631 patients had CS] and severity of CS. The tests had similar accuracy: UFC (n = 14 studies; LR+ 10.6, CI 5.5-20.5; LR- 0.16, CI 0.08-0.33), salivary midnight cortisol (n = 4; LR+ 8.8, CI 3.5-21.8; LR- 0.07, CI 0-1.2), and the 1-mg overnight DST (n = 14; LR+ 16.4, CI 9.3-28.8; LR- 0.06, CI 0.03-0.14). Combined testing strategies (e.g. a positive result in both UFC and 1-mg overnight DST) had similar diagnostic accuracy (n = 3; LR+ 15.4, CI 0.7-358; LR- 0.11, CI 0.007-1.57). CONCLUSIONS Commonly used tests to diagnose CS appear highly accurate in referral practices with samples enriched with patients with CS. Their performance in usual clinical practice remains unclear.

Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis

CONTEXT Osteoporosis and osteopenia are associated with increased fracture incidence. OBJECTIVE The aim of this study was to determine the comparative effectiveness of different pharmacological agents in reducing the risk of fragility fractures. DATA SOURCES We searched multiple databases through 12/9/2011. STUDY SELECTION Eligible studies were randomized controlled trials enrolling individuals at risk of developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selective estrogen receptor modulators, denosumab, or calcium and vitamin D. DATA EXTRACTION Reviewers working independently and in duplicate determined study eligibility and collected descriptive, methodological quality, and outcome data. DATA SYNTHESIS This network meta-analysis included 116 trials (139,647 patients; median age, 64 yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to moderate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30, and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandronate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely less effective, although these data were limited. Calcium and vitamin D were ineffective given separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95% confidence interval, 0.68–0.96). CONCLUSIONS Teriparatide, bisphosphonates, and denosumab are most effective in reducing the risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and clinicians need to consider their associated harms and costs.

Patient-Important Outcomes in Registered Diabetes Trials

CONTEXT Concerns about the safety and efficacy of diabetes interventions persist, in part because randomized clinical trials (RCTs) have not measured their effect on patient-important outcomes, ie, death and quality of life (morbidity, pain, function). OBJECTIVE To systematically determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes. DATA SOURCES On November 10, 2007, we searched primary RCT registries ClinicalTrials.gov (http://www.clinicaltrials.gov), International Standard Randomized Controlled Trial Number Register (http://isrctn.org), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). STUDY SELECTION We identified phase 2 through 4 RCTs enrolling patients with diabetes. Of 2019 RCTs, 1054 proved eligible. We randomly sampled 50% of the eligible RCTs (527 of 1054) and selected 436 registered since registration became mandatory (2004). DATA EXTRACTION Pairs of reviewers working independently collected study characteristics and determined the outcomes measured and their type (physiological outcomes, surrogate outcomes thought to reflect an increased risk for patient-important outcomes, and patient-important outcomes). RESULTS Of the 436 registered RCTs included in this analysis, 24 (6%) had not started enrollment, 109 (25%) were actively enrolling, and 303 (69%) had completed enrollment. Primary outcomes were patient-important outcomes in only 78 of 436 RCTs (18%; 95% confidence interval [CI], 14%-22%), physiological and laboratory outcomes in 69 of 436 (16%; 95% CI, 13%-20%), and surrogate outcomes in 268 of 436 (61%; 95% CI, 57%-66%). Patient-important outcomes were reported as primary or secondary outcomes in 201 of 436 (46%; 95% CI, 41%-51%). In multivariate analysis, large trials (odds ratio [OR], 1.10; 95% CI, 1.02-1.19 for every additional 100 patients) and trials of longer duration (OR, 1.03; 95% CI, 1.01-1.06 for every additional 30 days) were more likely while parallel design RCTs (OR, 0.15; 95% CI, 0.05-0.44) and type 2 diabetes trials (OR, 0.23; 95% CI, 0.09-0.61) were less likely to assess patient-important outcomes as a primary outcome. CONCLUSION In this sample of registered ongoing RCTs in diabetes, only 18% included patient-important outcomes as primary outcomes.

Antiandrogens for the Treatment of Hirsutism: A Systematic Review and Metaanalyses of Randomized Controlled Trials

CONTEXT The relative efficacy of antiandrogens for the treatment of hirsutism remains unclear. OBJECTIVE We performed a systematic review and metaanalyses of randomized controlled trials (RCTs) evaluating the effect of antiandrogens on hirsutism. DATA SOURCES We used librarian-designed search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006), review of reference lists, and contact with hirsutism experts to identify eligible RCTs. STUDY SELECTION Eligible studies were RCTs of at least 6 months of antiandrogen use in women with hirsutism. Reviewers, with acceptable chance-adjusted agreement (kappa = 0.72), independently assessed eligibility. DATA EXTRACTION Reviewers used structured forms to assess and collect methodological quality (allocation concealment, blinding, and loss to follow-up) and study data. DATA SYNTHESIS Of 348 candidate studies, 12 were eligible (18 comparisons). Their methodological quality was low. Random-effects metaanalyses showed that compared with placebo, antiandrogens reduce Ferriman-Gallwey scores by 3.9 [95% confidence interval (CI), 2.3-5.4; inconsistency (I(2)) = 0%]. When compared with metformin, spironolactone reduced hirsutism scores by 1.3 (CI, 0.03-2.6) and flutamide by 5.0 (CI, 3.0-7.0; I(2) = 0%). For these interventions, two to five women need to receive treatment for one to notice improvement. Spironolactone or finasteride in combination with contraceptives (1.7; CI, 0.1-3.3; I(2) = 0%) or flutamide with metformin (4.6; CI, 1.3-7.9; I(2) = 40%) appear superior to monotherapy with contraceptives and metformin, respectively. Only three RCTs reported patient self-assessments of hirsutism. CONCLUSIONS Weak evidence suggests antiandrogens are mildly effective agents for the treatment of hirsutism.