Lars G. Hemkens

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 Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P 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.

HIV infection and cardiovascular disease

AIMS With the success of antiretroviral therapy (ART), non-human immunodeficiency virus (HIV)-related comorbidities like cardiovascular diseases (CVDs) are of increasing concern. We describe important recent research developments on the epidemiology of CVD in HIV infection, ART-related metabolic changes, and cardioprotective anti-inflammatory mechanisms, and summarize management strategies for CVD risk reduction. METHODS AND RESULTS We systematically identified and analysed systematic reviews and most cited literature published in the last 3 years and supplemented findings with selected evidence based on clinical expertise. Among HIV-infected individuals, the prevalence of CVD risk factors and the risk for CVD is higher compared with HIV negatives. Antiretroviral drugs may induce dyslipidaemia, reduce insulin sensitivity, and promote body fat redistribution that additionally contributes to CVD risk. Some antiretroviral drugs may increase risk for CVD events, but the absolute risk increase is moderate and has to be put into perspective with the massive HIV-related benefits. Sustained HIV suppression reduces systemic inflammatory markers and is associated with a moderate reduction in CVD events. Regular CVD risk assessment and counselling to stop smoking must be regularly done in all HIV-infected individuals. Statins are effective for the treatment of dyslipidaemia in HIV infection, but drug interactions with ART need to be considered. CONCLUSION Human immunodeficiency virus-infected individuals are at increased risk for CVD. Timely initiation of ART with consequent viral suppression is likely to reduce CVD events and to offset potential side effects from ART-induced metabolic changes. Reduction in smoking in HIV-infected individuals is a public health priority.

Association between ambient air pollution and diabetes mellitus in Europe and North America: systematic review and meta-analysis.

Background Air pollution is hypothesized to be a risk factor for diabetes. Epidemiological evidence is inconsistent and has not been systematically evaluated. Objectives We systematically reviewed epidemiological evidence on the association between air pollution and diabetes, and synthesized results of studies on type 2 diabetes mellitus (T2DM). Methods We systematically searched electronic literature databases (last search, 29 April 2014) for studies reporting the association between air pollution (particle concentration or traffic exposure) and diabetes (type 1, type 2, or gestational). We systematically evaluated risk of bias and role of potential confounders in all studies. We synthesized reported associations with T2DM in meta-analyses using random-effects models and conducted various sensitivity analyses. Results We included 13 studies (8 on T2DM, 2 on type 1, 3 on gestational diabetes), all conducted in Europe or North America. Five studies were longitudinal, 5 cross-sectional, 2 case–control, and 1 ecologic. Risk of bias, air pollution assessment, and confounder control varied across studies. Dose–response effects were not reported. Meta-analyses of 3 studies on PM2.5 (particulate matter ≤ 2.5 μm in diameter) and 4 studies on NO2 (nitrogen dioxide) showed increased risk of T2DM by 8–10% per 10-μg/m3 increase in exposure [PM2.5: 1.10 (95% CI: 1.02, 1.18); NO2: 1.08 (95% CI: 1.00, 1.17)]. Associations were stronger in females. Sensitivity analyses showed similar results. Conclusion Existing evidence indicates a positive association of air pollution and T2DM risk, albeit there is high risk of bias. High-quality studies assessing dose–response effects are needed. Research should be expanded to developing countries where outdoor and indoor air pollution are high. Citation Eze IC, Hemkens LG, Bucher HC, Hoffmann B, Schindler C, Künzli N, Schilowski T, Probst-Hensch NM. 2015. Association between ambient air pollution and diabetes mellitus in Europe and North America: systematic review and meta-analysis. Environ Health Perspect 123:381–389; http://dx.doi.org/10.1289/ehp.1307823

Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey

Objective To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. Design Meta-epidemiological survey. Data sources PubMed searched up to November 2014. Methods Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results. Results The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17 275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I2=0%)). Conclusions Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

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.

Benefit assessment of salt reduction in patients with hypertension: systematic overview.

Objective We assessed the benefits and harm of reduced salt intake in patients with essential hypertension focusing on patient-relevant outcomes and blood pressure. Methods A systematic search of five electronic databases was performed to identify high-quality secondary literature based on randomized controlled trials (RCTs). An update primary literature search (RCTs) was performed for the time period up to 2010 that was not covered by secondary literature. Major outcomes were death, cardiovascular morbidity/mortality, hospital stays, terminal renal failure, quality of life, and adverse events. Change in blood pressure was defined as surrogate parameter. Results Four different systematic reviews and two RCTs met the inclusion criteria. Only one review reported limited data on patient-relevant outcomes. Over an intervention period of up to 12 months, mean SBP was reduced by 3.6–8.0 mmHg in all reviews. For the same intervention period, a statistically significant advantage with regard to mean DBP reduction ranging from 1.9 to 2.8 mmHg was found in three reviews. The fourth publication reported a nonsignificant reduction (DBP reduction of 4.7 mmHg). None of the RCTs identified in the primary literature search update reported data on patient-relevant outcomes. However, both RCTs found blood pressure improvements with salt reduction. Conclusion A benefit from a salt-reduced diet in patients with high blood pressure is not proven with regard to patient-relevant outcomes based on systematic reviews and RCTs published up to 2010. The results indicate a blood pressure-lowering effect through reduced salt intake in hypertensive patients.

Completion and publication rates of randomized controlled trials in surgery: an empirical study

OBJECTIVE To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. BACKGROUND Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown. METHODS All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. RESULTS In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008). CONCLUSIONS Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.

Routinely collected data and comparative effectiveness evidence: promises and limitations

Routinely collected data (RCD) are increasingly used for biomedical research. Extensive resources have been invested in this field: they include the set-up of disease registries and clinical databases at regional, national or international levels; the promotion of the use of electronic health

Clinical effectiveness of stress-reduction techniques in patients with hypertension: systematic review and meta-analysis.

Objective: A systematic review and meta-analysis focusing on patient-relevant outcomes and blood pressure was conducted to assess the clinical effectiveness of stress-reduction techniques in adults with essential hypertension. Methods: Systematic reviews and randomized controlled trials (RCTs) were identified as part of a systematic search in six electronic databases ending September 2012. RCTs comparing stress-reduction techniques versus no such techniques with a follow-up of at least 24 weeks and published in English or German were included. Outcomes of interest were death, cardiovascular morbidity/mortality, end-stage renal disease, health-related quality of life, adverse events, changes in blood pressure, and changes in antihypertensive medication. When appropriate, meta-analyses were used to combine data. Results: Seventeen RCTs analyzing different stress-reduction techniques such as biofeedback, relaxation or combined interventions were identified. Data were not reported for most of the patient-relevant outcomes, and meta-analyses could only be used to evaluate effects on blood pressure. The data indicated a blood pressure-lowering effect, but the studies had methodological shortcomings and heterogeneity between them was high. Mean group differences for DBP ranged from −10 to 1 mmHg and for SBP from −12 to 10 mmHg. In terms of antihypertensive medication, no favorable effects of stress-reduction techniques could be identified. Conclusions: The available RCTs on stress-reduction techniques used for at least 24 weeks appeared to indicate a blood pressure-lowering effect in patients with essential hypertension, but this should be interpreted with caution because of major methodological limitations. A benefit of specific stress-reduction techniques in hypertensive patients remains unproven.

The reporting of studies using routinely collected health data was often insufficient

Objectives To assess reporting quality of studies using routinely collected health data (RCD) to inform the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) guideline development. Study Design and Setting PubMed search for observational studies using RCD on any epidemiologic or clinical topic. Sample of studies published in 2012. Evaluation of five items based on the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guideline and eight newly developed items for RCD studies. Results Of 124 included studies, 39 (31.5%) clearly described its design in title or abstract. Complete information to frame a focused research question, that is, on the population, intervention/exposure, and outcome, was provided for 51 studies (41.1%). In 44 studies where definitions of codes or classification algorithms would be necessary to operationalize such a research question, only nine (20.5%) reported all items adequately. In 81 studies describing multivariable analyses, 54 (66.7%) reported all variables used for modeling and 34 (42.0%) reported basic details required for replication. Database linkage was reported adequately in 12 of 41 studies (29.3%). Statements about data sharing/availability were rare (5/124; 4%). Conclusion Most RCD studies are insufficiently reported. Specific reporting guidelines and more awareness and education on their use are urgently needed.