Alain Nordmann

Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials

Objective To quantify the overall effects of bariatric surgery compared with non-surgical treatment for obesity. Design Systematic review and meta-analysis based on a random effects model. Data sources Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status. Eligibility criteria Eligible studies were randomised controlled trials with ≥6 months of follow-up that included individuals with a body mass index ≥30, compared current bariatric surgery techniques with non-surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events. Results The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference −26 kg (95% confidence interval −31 to −21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference −0.7 mmol/L (−1.0 to −0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%). Conclusions Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. Systematic review registration PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO).

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. Design Systematic review and meta-regression analysis of randomised controlled trials. Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. Study selection In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. Data extraction and synthesis Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterol alone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2% (95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class. Conclusions Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.

Meta-Analysis Comparing Mediterranean to Low-Fat Diets for Modification of Cardiovascular Risk Factors

BACKGROUND Evidence from individual trials comparing Mediterranean to low-fat diets to modify cardiovascular risk factors remains preliminary. METHODS We systematically searched MEDLINE, EMBASE, Biosis, Web of Science, and the Cochrane Central Register of Controlled Trials from their inception until January 2011, as well as contacted experts in the field, to identify randomized controlled trials comparing Mediterranean to low-fat diets in overweight/obese individuals, with a minimum follow-up of 6 months, reporting intention-to-treat data on cardiovascular risk factors. Two authors independently assessed trial eligibility and quality. RESULTS We identified 6 trials, including 2650 individuals (50% women) fulfilling our inclusion criteria. Mean age of enrolled patients ranged from 35 to 68 years, mean body mass index from 29 to 35 kg/m(2). After 2 years of follow-up, individuals assigned to a Mediterranean diet had more favorable changes in weighted mean differences of body weight (-2.2 kg; 95% confidence interval [CI], -3.9 to -0.6), body mass index (-0.6 kg/m(2); 95% CI, -1 to -0.1), systolic blood pressure (-1.7 mm Hg; 95% CI, -3.3 to -0.05), diastolic blood pressure (-1.5 mm Hg; 95% CI, -2.1 to -0.8), fasting plasma glucose (-3.8 mg/dL, 95% CI, -7 to -0.6), total cholesterol (-7.4 mg/dL; 95% CI, -10.3 to -4.4), and high-sensitivity C-reactive protein (-1.0 mg/L; 95% CI, -1.5 to -0.5). The observed heterogeneity across individual trials could, by and large, be eliminated by restricting analyses to trials with balanced co-interventions or trials with restriction of daily calorie intake in both diet groups. CONCLUSION Mediterranean diets appear to be more effective than low-fat diets in inducing clinically relevant long-term changes in cardiovascular risk factors and inflammatory markers.

Prevalence, Characteristics, and Publication of Discontinued Randomized Trials

IMPORTANCE The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Reliability of patients measuring blood pressure at home: prospective observational study

Measuring blood pressure at home is recommended to distinguish sustained hypertension from white coat hypertension and to monitor treatment.12 Blood pressure measured at home is a better predictor of 24 hour ambulatory blood pressure monitoring, target organ damage, and cardiovascular mortality than that measured by a doctor.3–5 We aimed to assess the accuracy of patients measuring blood pressure at home, to identify predictors of poor accuracy, and to determine if poor accuracy impairs assessment of hypertension. We asked 54 consecutive patients with hypertension or suspected hypertension (aged 30-83 years), who had been referred for 24 hour ambulatory blood pressure monitoring, to measure their blood pressure at home twice daily between 0600 and 1000 for 30 days, and to record the time and readings. All agreed to participate. A nurse instructed each …

Meta-analyses: what they can and cannot do

Meta-analyses overcome the limitation of small sample sizes or rare outcomes by pooling results from a number of individual studies to generate a single best estimate. As long as a meta-analysis is not limited by poor quality of included trials, unexplainable heterogeneity and/or reporting bias of individual trials, meta-analyses can be instrumental in reliably demonstrating benefit or harm of an intervention when results of individual randomised controlled trials are conflicting or inconclusive. Therefore meta-analyses should be conducted as part of a systematic review, i.e., a systematic approach to answer a focused clinical question. Important features of a systematic review are a comprehensive, reproducible search for primary studies, selection of studies using clear and transparent eligibility criteria, standardised critical appraisal of studies for quality, and investigation of heterogeneity among included studies. Cumulative meta-analysis may prevent delays in the introduction of effective treatments and may allow for early detection of harmful effects of interventions. As opposed to meta-analysis based on aggregate study data, individual patient data meta-analyses offer the advantage to use standardised criteria across trials and reliably investigate subgroup effects of interventions. Network meta-analysis allows the integration of data from direct and indirect comparisons in order to compare multiple treatments in a comprehensive analysis and determine the best treatment among several options. We conclude that meta-analysis has become a popular, versatile, and powerful tool. If rigorously conducted as part of a systematic review, it is essential for evidence-based decision making in clinical practice as well as on the health policy level.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

Objective To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. Design Cohort of protocols of randomised controlled trial and subsequent full journal publications. Setting Six research ethics committees in Switzerland, Germany, and Canada. Data sources 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. Results Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. Conclusions Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Effectiveness of Distant Healing for Patients with Chronic Fatigue Syndrome : A Randomised Controlled Partially Blinded Trial (EUHEALS)

Background: Distant healing, a form of spiritual healing, is widely used for many conditions but little is known about its effectiveness. Methods: In order to evaluate distant healing in patients with a stable chronic condition, we randomised 409 patients with chronic fatigue syndrome (CFS) from 14 private practices for environmental medicine in Germany and Austria in a two by two factorial design to immediate versus deferred (waiting for 6 months) distant healing. Half the patients were blinded and half knew their treatment allocation. Patients were treated for 6 months and allocated to groups of 3 healers from a pool of 462 healers in 21 European countries with different healing traditions. Change in Mental Health Component Summary (MHCS) score (SF-36) was the primary outcome and Physical Health Component Summary score (PHCS) the secondary outcome. Results: This trial population had very low quality of life and symptom scores at entry. There were no differences over 6 months in post-treatment MHCS scores between the treated and untreated groups. There was a non-significant outcome (p = 0.11) for healing with PHCS (1.11; 95% CI –0.255 to 2.473 at 6 months) and a significant effect (p = 0.027) for blinding; patients who were unblinded became worse during the trial (–1.544; 95% CI –2.913 to –0.176). We found no relevant interaction for blinding among treated patients in MHCS and PHCS. Expectation of treatment and duration of CFS added significantly to the model. Conclusions: In patients with CFS, distant healing appears to have no statistically significant effect on mental and physical health but the expectation of improvement did improve outcome.

Meta-Analysis of Combined Therapy with Angiotensin Receptor Antagonists versus ACE Inhibitors Alone in Patients with Heart Failure

Background There is insufficient evidence whether the benefit of adding angiotensin II receptor blockers (ARBs) to angiotensin-converting enzyme (ACE) inhibitors outweighs the increased risk of adverse effects in patients with heart failure. Methodology/Principal Findings Two independent reviewers searched and abstracted randomized controlled trials of ARBs and ACE inhibitors compared to ACE inhibitor therapy alone in patients with heart failure reporting mortality and hospitalizations having a follow-up of at least 6 months identified by a systematic literature search. Eight trials including a total of 18,061 patients fulfilled our inclusion criteria. There was no difference between patients treated with combination therapy and ACE inhibitor therapy alone for overall mortality, hospitalization for any reason, fatal or nonfatal MI. Combination therapy was, however, associated with fewer hospital admissions for heart failure (RR 0.81, 95%CI 0.72–0.91), although there was significant heterogeneity across trials (p-value for heterogeneity = 0.04; I2 = 57% [95%CI 0–83%]). Patients treated with combination therapy had a higher risk of worsening renal function and symptomatic hypotension, and their trial medications were more often permanently discontinued. Lack of individual patient data precluded the analysis of time-to-event data and identification of subgroups which potentially benefit more from combination therapy such as younger patients with preserved renal function and thus at lower risk to experience worsening renal function or hyperkalemia. Conclusions/Significance Combination therapy with ARBs and ACE inhibitors reduces admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but does not reduce overall mortality or all-cause hospitalization and is associated with more adverse events. Thus, based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved for patients who remain symptomatic on therapy with ACE inhibitors under strict monitoring for any signs of worsening renal function and/or symptomatic hypotension.

Cost‐Effectiveness of Drug‐Eluting Stents in a US Medicare Setting: A Cost‐Utility Analysis with 3‐Year Clinical Follow‐Up Data

BACKGROUND There is only limited information about cost-effectiveness of drug-eluting compared with bare metal stents (BMS) over a time horizon of more than 1 year. METHODS AND RESULTS We developed a Markov model based on clinical outcome data from a meta-analysis including 17 randomized controlled trials comparing drug-eluting versus BMS with a minimum follow-up of 1 (n = 8221) and a maximum follow-up of 3 years (n = 4105) in patients with chronic coronary artery disease. Costs were obtained as reimbursement rates for diagnosis related groups from the US Centers for Medicare and Medicaid Services. All costs and effects were discounted at 3% annually. All costs are reported in US dollars of the financial year 2007. The incremental effects are 0.002 (95% confidence interval −0.039 to 0.041) quality-adjusted life-years (QALYs) for the sirolimus- and −0.001 (−0.040 to 0.038) QALYs for the paclitaxel-eluting stents (PES). The incremental costs are