Kamal R Mahtani

Cardiovascular disease risk in healthy children and its association with body mass index: systematic review and meta-analysis.

Objectives To describe the association and its magnitude between body mass index category, sex, and cardiovascular disease risk parameters in school aged children in highly developed countries. Design Systematic review and meta-analysis. Quality of included studies assessed by an adapted version of the Cochrane Collaboration’s risk of bias assessment tool. Results of included studies in meta-analysis were pooled and analysed by Review Manager version 5.1. Data sources Embase, PubMed, EBSCOHost’s cumulative index to nursing and allied health literature, and the Web of Science databases for papers published between January 2000 and December 2011. Review methods Healthy children aged 5 to 15 in highly developed countries enrolled in studies done after 1990 and using prospective or retrospective cohort, cross sectional, case-control, or randomised clinical trial designs in school, outpatient, or community settings. Included studies had to report an objective measure of weight and at least one prespecified risk parameter for cardiovascular disease. Results We included 63 studies of 49 220 children. Studies reported a worsening of risk parameters for cardiovascular disease in overweight and obese participants. Compared with normal weight children, systolic blood pressure was higher by 4.54 mm Hg (99% confidence interval 2.44 to 6.64; n=12 169, eight studies) in overweight children, and by 7.49 mm Hg (3.36 to 11.62; n=8074, 15 studies) in obese children. We found similar associations between groups in diastolic and 24 h ambulatory systolic blood pressure. Obesity adversely affected concentrations of all blood lipids; total cholesterol and triglycerides were 0.15 mmol/L (0.04 to 0.25, n=5072) and 0.26 mmol/L (0.13 to 0.39, n=5138) higher in obese children, respectively. Fasting insulin and insulin resistance were significantly higher in obese participants but not in overweight participants. Obese children had a significant increase in left ventricular mass of 19.12 g (12.66 to 25.59, n=223), compared with normal weight children. Conclusion Having a body mass index outside the normal range significantly worsens risk parameters for cardiovascular disease in school aged children. This effect, already substantial in overweight children, increases in obesity and could be larger than previously thought. There is a need to establish whether acceptable parameter cut-off levels not considering weight are a valid measure of risk in modern children and whether methods used in their study and reporting should be standardised.

Can the London 2012 Olympics ‘inspire a generation’ to do more physical or sporting activities? An overview of systematic reviews

Objective To examine if there is an increased participation in physical or sporting activities following an Olympic or Paralympic games. Design Overview of systematic reviews. Methods We searched the Medline, Embase, Cochrane, DARE, SportDISCUS and Web of Knowledge databases. In addition, we searched for ‘grey literature’ in Google, Google scholar and on the International Olympic Committee websites. We restricted our search to those reviews published in English. We used the AMSTAR tool to assess the methodological quality of those systematic reviews included. Primary and secondary outcome measures The primary outcome was evidence for an increased participation in physical or sporting activities. Secondary outcomes included public perceptions of sport during and after an Olympic games, barriers to increased sports participation and any other non-sporting health benefits. Results Our systematic search revealed 844 citations, of which only two matched our inclusion criteria. The quality of these two reviews was assessed by three independent reviewers as ‘good’ using the AMSTAR tool for quality appraisal. Both reviews reported little evidence of an increased uptake of sporting activity following an Olympic Games event. Other effects on health, for example, changes in hospital admissions, suicide rates and drug use, were cited although there was insufficient evidence to see an overall effect. Conclusion There is a paucity of evidence to support the notion that hosting an Olympic games leads to an increased participation in physical or sporting activities for host countries. We also found little evidence to suggest other health benefits. We conclude that the true success of these and future games should be evaluated by high-quality, evidence-based studies that have been commissioned before, during and following the completion of the event. Only then can the true success and legacy of the games be established.

Physical activity for the prevention and treatment of major chronic disease: an overview of systematic reviews

BackgroundThe evidence that higher levels of physical activity and/or lower levels of physical inactivity are associated with beneficial health-related outcomes stems mainly from observational studies. Findings from these studies often differ from randomised controlled trials and systematic reviews currently demonstrate mixed results, due partly to heterogeneity in physical activity interventions, methodologies used and populations studied. As a result, translation into clinical practice has been difficult. It is therefore essential that an overview is carried out to compare and contrast systematic reviews, and to identify those physical activity interventions that are the most effective in preventing and/or treating major chronic disease. This protocol has been registered on PROSPERO 2013: CRD42013003523.MethodsWe will carry out an overview of Cochrane systematic reviews. We will search the Cochrane Database of Systematic Reviews for systematic reviews of randomised controlled trials that have a primary focus on disease-related outcomes. We will restrict reviews to those in selected major chronic diseases. Two authors will independently screen search outputs, select studies, extract data and assess the quality of included reviews using the assessment of multiple systematic reviews tool; all discrepancies will be resolved by discussing and reaching a consensus, or by arbitration with a third author. The data extraction form will summarise key information from each review, including details of the population(s) (for example, disease condition), the context (for example, prevention, treatment or management), the participants, the intervention(s), the comparison(s) and the outcomes. The primary outcomes of interest are the prevention of chronic disease and/or improved outcomes, in the treatment or management of chronic disease. These outcomes will be summarised and presented for individual chronic diseases (for example, any change in blood pressure in hypertension or glucose control in diabetes). Secondary outcomes of interest are to describe the structure and delivery of physical activity interventions across chronic disease conditions and adverse events associated with physical activity.DiscussionWe anticipate that our results could inform researchers, guideline groups and policymakers of the most efficacious physical activity interventions in preventing and/or managing major chronic disease.

Device-guided breathing exercises in the control of human blood pressure: systematic review and meta-analysis.

Objective: To evaluate whether device-guided breathing (DGB) lowers blood pressure (BP) in adults. Design: Systematic review and meta-analysis. Data sources: We searched Medline (1950–2010), Embase (1980–2010), the Cochrane Library including the Cochrane Central register of Controlled Trials (CENTRAL), AMED (1985–2010), CINAHL (1980–2010) and the Current Controlled Trials registry (as of October 2010). Outcome measures: Primary outcomes included the mean change in SBP and DBP. Secondary outcomes included change in heart rate, quality of life, compliance with the device and any side effects of the device. Results: We included eight trials of the Resperate device (InterCure Ltd, Lod, Israel), consisting of 494 adult patients. Use of this device resulted in significantly reduced SBP by 3.67 mmHg [95% confidence interval (CI) = −5.99 to −1.39; P = 0.002] and decreased DBP by 2.51 mmHg (95% CI = −4.15 to −0.87; P = 0.003). However, sensitivity analysis was carried out excluding the five trials sponsored by or involving the manufacturers of the device, which revealed no overall effect on BP using the device. The maximum trial duration was 9 weeks and no overall effect was seen on heart rate or quality of life using the device. Conclusion: There is evidence that short-term use of DGB may reduce both DBP and DBP. However, five of the eight trials were sponsored by or involved the manufactures of the device. When these trials were excluded we found no overall effect. We conclude that longer term, independent trials are required to validate this intervention.

Why clinical trial outcomes fail to translate into benefits for patients

Clinical research should ultimately improve patient care. For this to be possible, trials must evaluate outcomes that genuinely reflect real-world settings and concerns. However, many trials continue to measure and report outcomes that fall short of this clear requirement. We highlight problems with trial outcomes that make evidence difficult or impossible to interpret and that undermine the translation of research into practice and policy. These complex issues include the use of surrogate, composite and subjective endpoints; a failure to take account of patients’ perspectives when designing research outcomes; publication and other outcome reporting biases, including the under-reporting of adverse events; the reporting of relative measures at the expense of more informative absolute outcomes; misleading reporting; multiplicity of outcomes; and a lack of core outcome sets. Trial outcomes can be developed with patients in mind, however, and can be reported completely, transparently and competently. Clinicians, patients, researchers and those who pay for health services are entitled to demand reliable evidence demonstrating whether interventions improve patient-relevant clinical outcomes.

Pharmaceutical companies’ policies on access to trial data, results, and methods: audit study

Objectives To identify the policies of major pharmaceutical companies on transparency of trials, to extract structured data detailing each companies’ commitments, and to assess concordance with ethical and professional guidance. Design Structured audit. Setting Pharmaceutical companies, worldwide. Participants 42 pharmaceutical companies. Main outcome measures Companies’ commitments on sharing summary results, clinical study reports (CSRs), individual patient data (IPD), and trial registration, for prospective and retrospective trials. Results Policies were highly variable. Of 23 companies eligible from the top 25 companies by revenue, 21 (91%) committed to register all trials and 22 (96%) committed to share summary results; however, policies commonly lacked timelines for disclosure, and trials on unlicensed medicines and off-label uses were only included in six (26%). 17 companies (74%) committed to share the summary results of past trials. The median start date for this commitment was 2005. 22 companies (96%) had a policy on sharing CSRs, mostly on request: two committed to share only synopses and only two policies included unlicensed treatments. 22 companies (96%) had a policy to share IPD; 14 included phase IV trials (one included trials on unlicensed medicines and off-label uses). Policies in the exploratory group of smaller companies made fewer transparency commitments. Two companies fell short of industry body commitments on registration, three on summary results. Examples of contradictory and ambiguous language were documented and summarised by theme. 23/42 companies (55%) responded to feedback; 7/1806 scored policy elements were revised in light of feedback from companies (0.4%). Several companies committed to changing policy; some made changes immediately. Conclusions The commitments made by companies to transparency of trials were highly variable. Other than journal submission for all trials within 12 months, all elements of best practice were met by at least one company, showing that these commitments are realistic targets.

Evidence based medicine manifesto for better healthcare

A response to systematic bias, wastage, error, and fraud in research underpinning patient care

Evidence for non-communicable diseases: analysis of Cochrane reviews and randomised trials by World Bank classification

Introduction Prevalence of non-communicable diseases (NCDs) is increasing globally, with the greatest projected increases in low-income and middle-income countries. We sought to quantify the proportion of Cochrane evidence relating to NCDs derived from such countries. Methods We searched the Cochrane database of systematic reviews for reviews relating to NCDs highlighted in the WHO NCD action plan (cardiovascular, cancers, diabetes and chronic respiratory diseases). We excluded reviews at the protocol stage and those that were repeated or had been withdrawn. For each review, two independent researchers extracted data relating to the country of the corresponding author and the number of trials and participants from countries, using the World Bank classification of gross national income per capita. Results 797 reviews were analysed, with a reported total number of 12 340 trials and 10 937 306 participants. Of the corresponding authors 90% were from high-income countries (41% from the UK). Of the 746 reviews in which at least one trial had met the inclusion criteria, only 55% provided a summary of the country of included trials. Analysis of the 633 reviews in which country of trials could be established revealed that almost 90% of trials and over 80% of participants were from high-income countries. 438 (5%) trials including 1 145 013 (11.7%) participants were undertaken in low-middle income countries. We found that only 13 (0.15%) trials with 982 (0.01%) participants were undertaken in low-income countries. Other than the five Cochrane NCD corresponding authors from South Africa, only one other corresponding author was from Africa (Gambia). Discussion The overwhelming body of evidence for NCDs pertains to high-income countries, with only a small number of review authors based in low-income settings. As a consequence, there is an urgent need for research infrastructure and funding for the undertaking of high-quality trials in this area.

Lack of evidence for interventions offered in UK fertility centres

Carl Heneghan and colleagues call for better quality evidence to help people seeking assisted reproduction make informed choices

Trials of transvaginal mesh devices for pelvic organ prolapse: a systematic database review of the US FDA approval process

Introduction Transvaginal mesh devices are approved in the USA by the Food and Drug Administration (FDA), through the 510(k) system. However, there is uncertainty about the benefit to harm balance of mesh approved for pelvic organ prolapse. We, therefore, assessed the evidence at the time of approval for transvaginal mesh products and the impact of safety studies the FDA mandated in 2012 because of emerging harms. Methods We used FDA databases to determine the evidence for approval of transvaginal mesh. To create a ‘family tree’ of device equivalence, we used the 510(k) regulatory approval of the 1985 Mersilene Mesh (Ethicon) and the 1996 ProteGen Sling (Boston Scientific), searched for all subsequently related device approvals, and for the first published randomised trial evidence. We assessed compliance with all FDA 522 orders issued in 2012 requiring postmarketing surveillance studies. Results We found 61 devices whose approval ultimately relied on claimed equivalence to the Mersilene Mesh and the ProteGen Sling. We found no clinical trials evidence for these 61 devices at the time of approval. Publication of randomised clinical trials occurred at a median of 5 years after device approval (range 1–14 years). Analysis of 119 FDA 522 orders revealed that in 79 (66%) the manufacturer ceased market distribution of the device, and in 26 (22%) the manufacturer had changed the indication. Only seven studies (six cohorts and new randomised controlled trial) covering 11 orders were recruiting participants (none had reported outcomes). Conclusions Transvaginal mesh products for pelvic organ prolapse have been approved on the basis of weak evidence over the last 20 years. Devices have inherited approval status from a few products. A publicly accessible registry of licensed invasive devices, with details of marketing status and linked evidence, should be created and maintained at the time of approval.