Adverse effects of the common treatments for polycystic ovary syndrome: a systematic review and meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is common among women of childbearing age and the available pharmacological therapies have different side-effect profiles. OBJECTIVE: We summarized the evidence about the side effects of oral contraceptive pills, metformin, and anti-androgens in women with PCOS. DATA SOURCE: Sources included Ovid Medline, OVID EMBASE, OVID Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL from inception through April 2011. STUDY SELECTION: We included comparative observational studies enrolling women with PCOS who received the agents of choice for at least 6 months and reported adverse effects. DATA EXTRACTION: Using a standardized, piloted, and Web-based data extraction form and working in duplicate, we abstracted data from each study and performed meta-analysis when possible. DATA SYNTHESIS: We found 22 eligible studies of which 20 were randomized. No study reported severe side effects (eg, lactic acidosis, thromboembolic episodes, liver toxicity, cancer incidence, or pregnancy loss). Meta-analysis demonstrated no significant change in weight in oral contraceptive pills or flutamide users. Indirect evidence from populations without PCOS demonstrated no increased risk of lactic acidosis with metformin, only case reports of liver toxicity with flutamide (no comparative evidence), and increased relative risk difference of venous thromboembolism with oral contraceptive pills but very low absolute risk. Evidence on mortality, cardiovascular mortality, and cancer was inconclusive. CONCLUSIONS: Drugs commonly used to treat PCOS appear to be associated with very low risk of severe adverse effects although data are extrapolated from other populations.

Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent disorder that affects women of childbearing age and may be related to obesity and insulin resistance. OBJECTIVE: The purpose of this systematic review was to appraise the evidence of the impact of lifestyle modification (LSM) interventions on outcomes of women with PCOS. DATA SOURCES: Sources included Ovid Medline, OVID Embase, OVID Cochrane Library, Web of Science, Scopus, PsycINFO, and CINAHL (up to January 2011). STUDY SELECTION: We included randomized controlled trials that enrolled woman of any age with PCOS who received LSM and compared them against women who received no intervention, minimal intervention, or metformin. DATA EXTRACTION: Two authors performed the data extraction independently. DATA SYNTHESIS: We included 9 trials enrolling 583 women with a high loss to follow-up rate, lack of blinding, and short follow-up. Compared with minimal intervention, LSM significantly reduced fasting blood glucose (weighted mean difference, -2.3 mg/dL; 95% confidence interval, -4.5 to -0.1, I² = 72%, P = .04) and fasting blood insulin (weighted mean difference, -2.1 µU/mL, 95% confidence interval, -3.3 to -1.0, I² = 0%, P < .001). Changes in body mass index were associated with changes in fasting blood glucose (P < .001). Metformin was not significantly better than LSM in improving blood glucose or insulin levels. We found no significant effect of LSM on pregnancy rate, and the effect on hirsutism was unclear. CONCLUSIONS: The available evidence suggests that LSM reduces fasting blood glucose and insulin levels in women with PCOS. Metformin has similar effects. Translation of these short-term effects to patient-important outcomes, beyond diabetes prevention, remains uncertain.

Lessons learned from the conduct of a multisite cluster randomized practical trial of decision aids in rural and suburban primary care practices.

BACKGROUND: The decision aids for diabetes (DAD) trial explored the feasibility of testing the effectiveness of decision aids (DAs) about coronary prevention and diabetes medications in community-based primary care practices, including rural clinics that care for patients with type 2 diabetes. METHODS: As originally designed, we invited clinicians in eight practices to participate in the trial, reviewed the patient panel of clinicians who accepted our invitation for potentially eligible patients, and contacted these patients by phone, enrolling those who accepted our invitation. As enrollment failed to meet targets, we recruited four new practices. After discussing the study with the clinicians and receiving their support, we reviewed all clinic panels for potentially eligible patients. Clinicians were approached to confirm participation and patient eligibility, and patients were approached before their visit to provide written informed consent. This in-clinic approach required study coordinators to travel and stay longer at the clinics as well as to screen more patient records for eligibility. The in-clinic approach was associated with better recruitment rates, lower patient retention and outcome completion rates, and a better intervention effect. RESULTS: We drew four lessons: 1) difficulties identifying potentially eligible patients threaten the viability of practical trials of DAs; 2) to improve the recruitment yield, recruit clinicians and patients for the study at the clinic, just before their visit; 3) approaches that improve recruitment may be associated with reduced retention and survey response; and 4) procedures that involve working closely with the practice may improve recruitment and may also affect the quality of the implementation of the interventions. CONCLUSION: Success in practice-based trials in usual primary care including rural clinics may require the smallest possible research footprint on the practice while implementing a streamlined protocol favoring in-clinic, in-person interactions with clinicians and patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01029288.

A systematic review of patient-reported measures of burden of treatment in three chronic diseases.

BACKGROUND: Burden of treatment refers to the workload of health care and its impact on patient functioning and well-being. There are a number of patient-reported measures that assess burden of treatment in single diseases or in specific treatment contexts. A review of such measures could help identify content for a general measure of treatment burden that could be used with patients dealing with multiple chronic conditions. We reviewed the content and psychometric properties of patient-reported measures that assess aspects of treatment burden in three chronic diseases, ie, diabetes, chronic kidney disease, and heart failure. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, and EBSCO CINAHL through November 2011. Abstracts were independently reviewed by two people, with disagreements adjudicated by a third person. Retrieved articles were reviewed to confirm relevance, with patient-reported measures scrutinized to determine consistency with the definition of burden of treatment. Descriptive information and psychometric properties were extracted. RESULTS: A total of 5686 abstracts were identified from the database searches. After abstract review, 359 full-text articles were retrieved, of which 76 met our inclusion criteria. An additional 22 articles were identified from the references of included articles. From the 98 studies, 57 patient-reported measures of treatment burden (full measures or components within measures) were identified. Most were multi-item scales (89%) and assessed treatment burden in diabetes (82%). Only 15 measures were developed using direct patient input and had demonstrable evidence of reliability, scale structure, and multiple forms of validity; six of these demonstrated evidence of sensitivity to change. We identified 12 content domains common across measures and disease types. CONCLUSION: Available measures of treatment burden in single diseases can inform derivation of a patient-centered measure of the construct in patients with multiple chronic conditions. Patients should take part in developing the measure to ensure salience and relevance.

Treatment of hyperprolactinemia: a systematic review and meta-analysis.

BACKGROUND: Hyperprolactinemia is a common endocrine disorder that can be associated with significant morbidity. We conducted a systematic review and meta-analyses of outcomes of hyperprolactinemic patients, including microadenomas and macroadenomas, to provide evidence-based recommendations for practitioners. Through this review, we aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinemia. METHODS: We searched electronic databases, reviewed bibliographies of included articles, and contacted experts in the field. Eligible studies provided longitudinal follow-up of patients with hyperprolactinemia and evaluated outcomes of interest. We collected descriptive, quality and outcome data (tumor growth, visual field defects, infertility, sexual dysfunction, amenorrhea/oligomenorrhea and prolactin levels). RESULTS: After review, 8 randomized and 178 nonrandomized studies (over 3,000 patients) met inclusion criteria. Compared to no treatment, dopamine agonists significantly reduced prolactin level (weighted mean difference, -45; 95% confidence interval, -77 to -11) and the likelihood of persistent hyperprolactinemia (relative risk, 0.90; 95% confidence interval, 0.81 to 0.99). Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinemia, amenorrhea/oligomenorrhea, and galactorrhea. A large body of noncomparative literature showed dopamine agonists improved other patient-important outcomes. Low-to-moderate quality evidence supports improved outcomes with surgery and radiotherapy compared to no treatment in patients who were resistant to or intolerant of dopamine agonists. CONCLUSION: Our results provide evidence to support the use of dopamine agonists in reducing prolactin levels and persistent hyperprolactinemia, with cabergoline proving more efficacious than bromocriptine. Radiotherapy and surgery are useful in patients with resistance or intolerance to dopamine agonists.

Clinical review. 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, 0.68­0.96). 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.

Clinical review. Risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis.

CONTEXT: Testing men at increased risk for osteoporotic fractures has been recommended. OBJECTIVE: The aim of this study was to estimate the magnitude of association and quality of supporting evidence linking multiple risk factors with low bone mass-related fractures in men. DATA SOURCES: We searched MEDLINE, EMBASE, Web of Science, SCOPUS and Cochrane CENTRAL through February 2010. We identified further studies by reviewing reference lists from selected studies and reviews. STUDY SELECTION: Eligible studies had to enroll men and quantitatively evaluate the association of risk factors with low bone density-related fractures. DATA EXTRACTION: Reviewers working independently and in duplicate determined study eligibility and extracted study description, quality, and outcome data. DATA SYNTHESIS: Fifty-five studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate with fair levels of multivariable adjustment and adequate exposure and outcome ascertainment. Statistically significant associations were established for age, low body mass index, current smoking, excessive alcohol use, chronic corticosteroid use, history of prior fractures, history of falls, history of hypogonadism, history of stroke, and history of diabetes. Statistical heterogeneity of the meta-analytic estimates of all associations was significant except for chronic corticosteroid use. None of these associations were of large magnitude (i.e. adjusted odds ratios were generally <2). No evidence supporting a particular effective testing or screening strategy was identified. CONCLUSIONS: Multiple risk factors for fractures in men were identified, but their usefulness for stratifying and selecting men for bone density testing remains uncertain.

Adherence to preventive recommendations: experience of a cohort presenting for executive health care.

Adherence to recommended preventive services and immunizations in adults is suboptimal and often associated with socioeconomic status, race, and access to care. The aim of this study is to evaluate adherence in a cohort without these barriers to ascertain realistically optimal adherence rates and to examine remaining barriers among relatively advantaged individuals. Specifically, it employed a sample of 6889 patients presenting for executive health care from 2005 to 2009. Adherence varied across colorectal cancer screening (79%), mammography (89%), cervical cancer screening (91%), tetanus immunization (82%), and pneumococcal vaccination (62%). Multivariate logistic regressions revealed that age, education, alcohol use concerns, and being married were positively associated with adherence to certain services. Individuals without the usual barriers to care have variable, less-than-ideal rates of adherence to preventive services, which correlate with some health behaviors and demographics. Understanding the predictors of adherence may inform quality improvement processes aimed at optimizing disease prevention.

Clinical review: 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.

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.

Clinical review 1: 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.

Translating comparative effectiveness into practice: the case of diabetes medications.

BACKGROUND: In recent years, there has been significant interest and investment in conducting comparative effectiveness research (CER) of medical treatments to improve the quality of care and reduce costs. The Agency for Healthcare Research and Quality (AHRQ) has been leading this effort and has invested a significant amount of resources to advance CER. However, little is known about translating the findings from CER into routine practice such that it provides value to the patients, clinicians, and the healthcare system. METHODS: We present the role of shared decision making for patient-centered CER translation and its application to diabetes medications. CER of oral diabetes medications suggests that all medications are similar in their effects on glycemic control, but there is variability in side-effects, which may affect medication adherence and treatment intensification. Shared decision making, facilitated by tools such as decision aids, may enhance the quality of diabetes care by activating patients, enhancing the patient-clinician communication, and improving uptake and adherence to the medication that is determined to be consistent with patients' goals, values, and preferences. We describe the iterative, multidisciplinary process for developing and testing a diabetes medication decision aid, and examine the implications for CER translation. RESULTS: In our pilot study we found the decision aid to be acceptable to patients and providers and effective for knowledge translation; however, it did not impact short-term outcomes. DISCUSSION: Our pilot trial found that decision aids enhanced the discussion about diabetes medications without any adverse effects on the outcomes. Further issues related to the use of decision aids to translate CER need to be addressed in larger trials to understand the effectiveness and efficiency of translating evidence into routine practice in unique contexts of patients, providers, and healthcare systems.

Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.

CONTEXT: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. OBJECTIVE: To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. DATA SOURCES: Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. STUDY SELECTION: Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. DATA EXTRACTION: Reviewers with methodological expertise conducted data extraction independently. RESULTS: The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit. CONCLUSIONS: Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.

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. METHODS: We searched electronic databases, bibliography of included studies and expert files. All study designs were included with no language restrictions. Reviewers working independently and in pairs selected studies using predetermined inclusion and exclusion criteria, extracted outcome and quality data. We used a random-effects meta-analysis to pool proportions and estimate the 95% confidence intervals (CIs). We estimated the proportion of between-study heterogeneity not attributable to chance using the I(2) statistic. RESULTS: We identified 28 eligible studies. These studies enrolled 1833 participants with GID (1093 male-to-female, 801 female-to-male) who underwent sex reassignment that included hormonal therapies. All the studies were observational and most lacked controls. Pooling across studies shows that after sex reassignment, 80% of individuals with GID reported significant improvement in gender dysphoria (95% CI = 68-89%; 8 studies; I(2) = 82%); 78% reported significant improvement in psychological symptoms (95% CI = 56-94%; 7 studies; I(2) = 86%); 80% reported significant improvement in quality of life (95% CI = 72-88%; 16 studies; I(2) = 78%); and 72% reported significant improvement in sexual function (95% CI = 60-81%; 15 studies; I(2) = 78%). CONCLUSIONS: Very low quality evidence suggests that sex reassignment that includes hormonal interventions in individuals with GID likely improves gender dysphoria, psychological functioning and comorbidities, sexual function and overall quality of life.

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

BACKGROUND: Bisphosphonates 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/DESIGN: This 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. DISCUSSION: This 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 REGISTRATION: Clinical Trials.gov Identifier: NCT00578981.

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.

Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

BACKGROUND: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. METHODS/DESIGN: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. DISCUSSION: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.

A treatment decision aid may increase patient trust in the diabetes specialist. The Statin Choice randomized trial.

AIMS: Decision aids in practice may affect patient trust in the clinician, a requirement for optimal diabetes care. We sought to determine the impact of a decision aid to help patients with diabetes decide about statins (Statin Choice) on patients' trust in the clinician. METHODS: We randomized 16 diabetologists and 98 patients with type 2 diabetes referred to a subspecialty diabetes clinic to use the Statin Choice decision aid or a patient pamphlet about dyslipidaemia, and then to receive these materials from either the clinician during the visit or a researcher prior to the visit. Providers and patients were blinded to the study hypothesis. Immediately after the clinical encounter, patients completed a survey including questions on trust (range 0 to total trust = 100), knowledge, and decisional conflict. Researchers reviewed videotaped encounters and assessed patient participation (using the OPTION scale) and visit length. RESULTS: Overall mean trust score was 91 (median 97.2, IQR 86, 100). After adjustment for patient characteristics, results suggested greater total trust (trust = 100) with the decision aid [odds ratio (OR) 1.77, 95% CI 0.94, 3.35]. Total trust was associated with knowledge (for each additional knowledge point, OR 1.3, 95% CI 1.1, 1.6), patient participation (for each additional point in the OPTION scale, OR 1.1, 95% CI 1.1, 1.2), and decisional conflict (for every 5-point decrease in conflict, OR 1.5, 95% CI 1.2, 1.9). Total trust was not associated with visit length, which the decision aid did not significantly affect. There was no significant effect interaction across the trial factors. CONCLUSIONS: Preliminary evidence suggests that decision aids do not have a large negative impact on trust in the physician and may increase trust through improvements in the decision-making process.

Systematic reviewers commonly contact study authors but do so with limited rigor.

OBJECTIVES: Author contact can enhance the quality of systematic reviews. We conducted a systematic review of the practice of author contact in recently published systematic reviews to characterize its prevalence, quality, and results. STUDY DESIGN AND SETTING: Eligible studies were systematic reviews of efficacy published in 2005-2006 in the 25 journals with the highest impact factor publishing systematic reviews in clinical medicine and the Cochrane Library, identified by searching MEDLINE, EMBASE, and the Cochrane Library. Two researchers determined whether and why reviewers contacted authors. To assess the accuracy of the abstracted data, we surveyed reviewers by e-mail. RESULTS: Forty-six (50%) of the 93 eligible systematic reviews published in top journals and 46 (85%) of the 54 eligible Cochrane reviews reported contacting authors of eligible studies. Requests were made most commonly for missing information: 40 (76%) clinical medicine reviews and 45 (98%) Cochrane reviews. One hundred and nine of 147 (74%) reviewers responded to the survey, and reported a higher rate of author contact than apparent from the published record. CONCLUSION: Although common, author contact is not a universal feature of systematic reviews published in top journals and the Cochrane Library. The conduct and reporting of author contact purpose, procedures, and results require improvement.

Clinical review: Drug-induced hypoglycemia: a systematic review.

CONTEXT: Drug-induced hypoglycemia is a significant adverse effect that may cause important morbidity. OBJECTIVE: The aim of the study was to systematically review the literature for drugs reported to cause hypoglycemia and assess the quality of evidence and strength of association supporting this causal link. DATA SOURCES: We searched electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) and the drug information system Micromedex through November 2007 and sought additional references from experts. STUDY SELECTION: Studies were eligible if they reported hypoglycemia as a side effect of a drug not used to treat hyperglycemia, regardless of their design, language, size, or follow-up duration. We excluded hypoglycemia caused by industrial exposures, nonpharmacological chemical exposures, alcohol, herbs, nutritional supplements, and in vitro and animal studies. DATA EXTRACTION: Reviewers extracted study characteristics and methodological quality and, when possible, data to estimate the odds of developing hypoglycemia when exposed to the offending agent. DATA SYNTHESIS: We found 448 eligible studies that described 2696 cases of hypoglycemia associated with 164 different drugs. The quality of evidence supporting associations between drugs and hypoglycemia was mostly very low due to methodological limitations and imprecision. The most commonly reported offending drugs were quinolones, pentamidine, quinine, beta blockers, angiotensin-converting enzyme agents, and IGF. CONCLUSIONS: Very low quality evidence substantiates the association between hypoglycemia and the use of numerous nondiabetic drugs.