Brian A. Swiglo

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.

Insulin sensitizers for the treatment of hirsutism: A systematic review and metaanalyses of randomized controlled trials

CONTEXT Insulin sensitizers, including metformin and thiazolidinediones (TZDs), improve hyperinsulinemia and reproductive dysfunctions in some women with hyperandrogenism. The extent to which these agents improve hirsutism remains unclear. OBJECTIVE Our objective was to conduct a systematic review and metaanalyses of randomized controlled trials of metformin or TZDs for the treatment of hirsutism. DATA SOURCES We searched the following databases: MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006). Review of reference lists and contact with hirsutism experts further identified candidate trials. STUDY SELECTION Reviewers working independently and in duplicate, with acceptable chance-adjusted agreement (kappa = 0.72), determined trial eligibility. Eligible trials randomly assigned women with hirsutism to at least 6 months of insulin sensitizers or control and measured hirsutism outcomes. DATA EXTRACTION Reviewers working independently and in duplicate determined the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS Of 348 candidate studies, 16 trials (22 comparisons) were eligible. The methodological quality of these trials was low. Random-effects metaanalyses showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with placebo [pooled weighted mean difference (WMD) of -1.5; 95% confidence interval (CI), -2.8 to -0.2; inconsistency (I(2)) = 75%]. There was no significant difference between insulin sensitizers and oral contraceptives (WMD of -0.5; CI, -5.0, 3.9; I(2) = 79%). Metformin was inferior to both spironolactone (WMD of 1.3; CI, 0.03, 2.6) and flutamide (WMD of 5.0; CI, 3.0, 7.0; I(2) = 0%). CONCLUSIONS Imprecise and inconsistent evidence of low to very low quality suggests that insulin sensitizers provide limited or no important benefit for women with hirsutism.

A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials of DHEA Treatment Effects on Quality of Life in Women with Adrenal Insufficiency

CONTEXT Women with primary or secondary adrenal insufficiency report a decreased health-related quality of life (HRQOL) despite traditional adrenal replacement therapy. Dehydroepiandrosterone (DHEA) has been studied as an agent to improve HRQOL in these patients. OBJECTIVE We sought to conduct a systematic review and meta-analysis of randomized controlled trials of DHEA effects on HRQOL in women with adrenal insufficiency. DATA SOURCES We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, and PsycInfo) and reference lists of eligible studies through July 2008. STUDY SELECTION Eligible trials randomly assigned women with primary or secondary adrenal insufficiency to either DHEA or control and measured the effect of treatment on HRQOL. DATA EXTRACTION Reviewers working independently and in duplicate assessed the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS We found 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta-analysis showed a small improvement in HRQOL in women treated with DHEA compared with placebo [effect size of 0.21; 95% confidence interval, 0.08 to 0.33; inconsistency (I(2)) = 32%]. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant. CONCLUSIONS DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.

Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses.

OBJECTIVE Because estrogen therapies are widely prescribed for amenorrhea associated with anorexia nervosa (AN), we conducted a systematic review and meta-analyses to estimate the influence of estrogen preparations (EP) on bone mineral density in women with AN. METHOD Prospective cohort studies and randomized clinical trials (RCTs) comparing the effect of EP use to no treatment or placebo on bone mineral density and bone fractures were included. Independent reviewers selected studies for inclusion and extracted study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population. RESULTS Using random-effects meta-analyses and inconsistency across trials using the I(2) statistic, data were combined across two eligible prospective cohort studies and four RCTs; none reported effects on bone fractures. Compared with placebo or no treatment, low quality evidence found EPs have a moderate effect on bone mineral density in the lumbar spine [ES (effect size) 0.33, 95% CI (confidence interval) 0.09, 0.56; I(2) = 0%)], but no significant effect on the femoral neck (ES 0.13, 95% CI -0.16, 0.43; I(2) = 0%). There were no significant treatment-subgroup interactions. DISCUSSION In general, EPs have uncertain benefit and should be avoided by women with AN in whom the success of weight and nutritional rehabilitation is judged by menses resumption.

Protocol for the Osteoporosis Choice trial. A pilot randomized trial of a decision aid in primary care practice

BackgroundBisphosphonates can reduce fracture risk in patients with osteoporosis, but many at-risk patients do not start or adhere to these medications. The aims of this study are to: (1) preliminarily evaluate the effect of an individualized 10-year osteoporotic fracture risk calculator and decision aid (OSTEOPOROSIS CHOICE) for postmenopausal women at risk for osteoporotic fractures; and (2) assess the feasibility and validity (i.e., absence of contamination) of patient-level randomization (vs. cluster randomization) in pilot trials of decision aid efficacy.Methods/DesignThis is a protocol for a parallel, 2-arm, randomized trial to compare an intervention group receiving OSTEOPOROSIS CHOICE to a control group receiving usual primary care. Postmenopausal women with bone mineral density T-scores of <-1.0, not receiving bisphosphonate therapy, and receiving care at participating primary care practices in and around Rochester, Minnesota, USA will be eligible to participate in the trial. We will measure the effect of OSTEOPOROSIS CHOICE on five outcomes: (a) patient knowledge regarding osteoporosis risk factors and treatment; (b) quality of the decision-making process for both the patient and clinician; (c) patient and clinician acceptability and satisfaction with the decision aid; (d) rate of bisphosphonate use and adherence, and (e) trial processes (e.g., ability to recruit participants, collect patient outcomes). To capture these outcomes, we will use patient and clinician surveys following each visit and video recordings of the clinical encounters. These video recordings will also allow us to determine the extent to which clinicians previously exposed to the decision aid were able to recreate elements of the decision aid with control patients (i.e., contamination). Pharmacy prescription profiles and follow-up phone interviews will assess medication start and adherence at 6 months.DiscussionThis pilot trial will provide evidence of feasibility, validity of patient randomization, and preliminary efficacy of a novel approach -- decision aids -- to improving medication adherence for postmenopausal women at risk of osteoporotic fractures. The results will inform the design of a larger trial that could provide more precise estimates of the efficacy of the decision aid.Trial registrationClinical Trials.gov Identifier: NCT00578981

Rosiglitazone reduced type 2 diabetes but increased heart failure in patients with impaired glycemic control.

Source Citation Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised cont...