Background: Rosiglitazone and pioglitazone may increase the incidence of fractures. We aimed to determine systematically the risk of fractures associated with thiazolidinedione therapy and to evaluate the effect of the therapy on bone density. Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), other trial registries and product information sheets through June 2008. We selected long-term (≥ 1 year) randomized controlled trials involving patients with type 2 diabetes and controlled observational studies that described the risk of fractures or changes in bone density with thiazolidinediones. We calculated pooled odds ratios (ORs) for fractures and the weighted mean difference in bone density. Results: We analyzed data from 10 randomized controlled trials involving 13 715 participants and from 2 observational studies involving 31 679 participants. Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% confidence interval [CI] 1.18–1.79; p < 0.001). Five randomized controlled trials showed a significantly increased risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; p < 0.001) but not among men (OR 1.00, 95% CI 0.73–1.39; p = 0.98). The 2 observational studies demonstrated an increased risk of fractures associated with rosiglitazone and pioglitazone. Bone mineral density in women exposed to thiazolidinediones was significantly reduced at the lumbar spine (weighted mean difference –1.11%, 95% CI –2.08% to –0.14%; p = 0.02) and hip (weighted mean difference –1.24%, 95%CI –2.34% to –0.67%; p < 0.001) in 2 randomized controlled trials. Interpretation: Long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.

Background—: The relationship between obstructive sleep apnea (OSA) and cardiovascular events remains unclear. We conducted a systematic review to determine the incident risk of cardiovascular events among patients with OSA. Methods and Results—: We searched MEDLINE and EMBASE in January 2011 for prospective studies that followed up patients with OSA for incident ischemic heart disease, stroke, and cardiovascular mortality. Outcomes data were pooled using random effects meta-analysis and heterogeneity assessed with the I ² statistic. Regression analysis was performed to evaluate the effects of different gradations of OSA severity based on apnea-hypopnea index. We identified 9 relevant studies from 1731 citations. OSA was associated with incident stroke in a meta-analysis of 5 studies (8435 participants), odds ratio (OR) 2.24; 95% confidence interval (CI), 1.57–3.19; I ² =7%. A significant association was seen in studies that were predominantly on men; OR, 2.87; 95% CI, 1.91–4.31, whereas data on women were sparse. In the overall analysis of 6 studies (8785 participants), OSA was nonsignificantly associated with ischemic heart disease (OR, 1.56; 95% CI, 0.83–2.91), with significant findings in the 5 studies that recruited mainly men (OR, 1.92; 95% CI, 1.06–3.48). Substantial heterogeneity was noted (I ² =74%). OSA was linked to cardiovascular death in 2 studies involving 2446 participants (OR, 2.09; 95% CI, 1.20–3.65, I ² =0%). Regression analysis showed greater likelihood of stroke or cardiovascular events with increasing apnea-hypopnea index values. Conclusions—: OSA appears to be associated with stroke, but the relationship with ischemic heart disease and cardiovascular mortality needs further research.

We set out to determine the effects of pharmacist‐led medication review in older people by means of a systematic review and meta‐analysis covering 11 electronic databases. Randomized controlled trials in any setting, concerning older people (mean age > 60 years), were considered, aimed at optimizing drug regimens and improving patient outcomes. Our primary outcome was emergency hospital admission (all cause). Secondary outcomes were mortality and numbers of drugs prescribed. We also recorded data on drug knowledge, adherence and adverse drug reactions. We retrieved 32 studies which fitted the inclusion criteria. Meta‐analysis of 17 trials revealed no significant effect on all‐cause admission, relative risk (RR) of 0.99 [95% confidence interval (CI) 0.87, 1.14, P = 0.92], with moderate heterogeneity (I² = 49.5, P = 0.01). Meta‐analysis of mortality data from 22 trials found no significant benefit, with a RR of mortality of 0.96 (95% CI 0.82, 1.13, P = 0.62), with no heterogeneity (I² = 0%). Pharmacist‐led medication review may slightly decrease numbers of drugs prescribed (weighted mean difference = −0.48, 95% CI −0.89, −0.07), but significant heterogeneity was found (I² = 85.9%, P < 0.001). Results for additional outcomes could not be pooled, but suggested that interventions could improve knowledge and adherence. Pharmacist‐led medication review interventions do not have any effect on reducing mortality or hospital admission in older people, and can not be assumed to provide substantial clinical benefit. Such interventions may improve drug knowledge and adherence, but there are insufficient data to know whether quality of life is improved.

We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events. Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published. There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events.

Background The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD. Methods MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose–response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I² statistic. Results Sixteen RCTs (14 fluticasone, 2 budesonide) with 17 513 participants, and seven observational studies (n=69 000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I²=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I²=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001). Conclusion Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.

Background: As every healthcare intervention carries some risk of harm, clinical decision making needs to be supported by a systematic assessment of the balance of benefit to harm. A systematic review that considers only the favourable outcomes of an intervention, without also assessing the adverse effects, can mislead by introducing a bias favouring the intervention. Much of the current guidance on systematic reviews is directed towards the evaluation of effectiveness; but this differs in important ways from the methods used in assessing the safety and tolerability of an intervention. A detailed discussion of why, how and when to include adverse effects in a systematic review, is required. Methods: This discussion paper, which presupposes a basic knowledge of systematic review methodology, was developed by consensus among experienced reviewers, members of the Adverse Effects Subgroup of The Cochrane Collaboration, and supplemented by a consultation of content experts in reviews methodology, as well as those working in drug safety. Results: A logical framework for making decisions in reviews that incorporate adverse effects is provided. We explore situations where a comprehensive investigation of adverse effects is warranted and suggest strategies to identify practicable and clinically useful outcomes. The advantages and disadvantages of including observational and experimental study designs are reviewed. The consequences of including separate studies for intended and unintended effects are explained. Detailed advice is given on designing electronic searches for studies with adverse effects data. Reviewers of adverse effects are given general guidance on the assessment of study bias, data collection, analysis, presentation and the interpretation of harms in a systematic review. Conclusion: Readers need to be able to recognize how strategic choices made in the review process determine what harms are found, and how the findings may affect clinical decisions. Researchers undertaking a systematic review that incorporates adverse effect data should understand the rationale for the suggested methods and be able to implement them in their review.