Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study

Moustgaard, Helene; Clayton, Gemma; Jones, Hayley E; Boutron, Isabelle; Jørgensen, Lars Nannestad; Laursen, David Ruben Teindl; Olsen, Mette Frahm; Paludan-Müller, Asger Sand; Ravaud, Philippe; Savović, Jelena; Sterne, Jonathan A C; Higgins, Julian P T; Hróbjartsson, Asbjørn

doi:10.1136/bmj.l6802

Cited by 192 publications

(204 citation statements)

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“…14 The point estimates from all MetaBLIND main analyses showed little evidence of an impact of lack of blinding (see Appendix), except for lack of blinding of patients in trials with patient reported outcomes (ROR 0.91 [0.61-1.34]). 3 In all analyses, the 95% credible intervals were wide, consistent with no bias as well as some degree of bias in either direction. 3 Variation between results of different metaepidemiological studies is also a challenge for other aspects of trial methodology, notably the impact of inadequate concealment of allocation.…”

Section: Meta-epidemiological Studies: Rationale and Variation In Rmentioning

confidence: 56%

“…3 In all analyses, the 95% credible intervals were wide, consistent with no bias as well as some degree of bias in either direction. 3 Variation between results of different metaepidemiological studies is also a challenge for other aspects of trial methodology, notably the impact of inadequate concealment of allocation. 7 Although such variation partly reflects imprecision, it may also imply varying degrees of systematic error or heterogeneity caused by differences of approach.…”

Section: Meta-epidemiological Studies: Rationale and Variation In Rmentioning

confidence: 56%

“…For instance, we studied the impact of lack of blinding of patients in trials with patient-reported outcomes, and the impact of lack of blinding of healthcare providers in trials where outcomes were reported by blinded outcome assessors. 3 We were surprised by the largely neutral results of MetaBLIND, and this, in conjunction with our observations of variability among other meta-epidemiological results, provided the impetus for writing this paper.…”

Section: Introductionmentioning

confidence: 85%

“…17,18 In MetaBLIND, the blinding status of patients, healthcare providers, and outcome assessors was determined specifically and analyses aimed to estimate the effect of lack of blinding of the three groups separately. 3…”

Section: Q2: How Was the Trial Characteristic Of Interest Defined?mentioning

confidence: 99%

“…In an attempt to address the variability of previous study results (described below), the ambiguity of the term "double-blind," and the inadequate reporting of blinding in trial reports, we designed the MetaBLIND study, a large meta-epidemiological study of blinding in randomized clinical trials. 3 In MetaBLIND, we sampled 142 meta-analyses (1153 trials) on any topic from Cochrane reviews. Data on the blinding status of patients, healthcare providers, and outcome assessors were extracted from trial publications and, when necessary, by contacting trial authors.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Ten questions to consider when interpreting results of a meta‐epidemiological study—the MetaBLIND study as a case

Moustgaard

Jones

Savović

et al. 2020

Research Synthesis Methods

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Randomized clinical trials underpin evidence‐based clinical practice, but flaws in their conduct may lead to biased estimates of intervention effects and hence invalid treatment recommendations. The main approach to the empirical study of bias is to collate a number of meta‐analyses and, within each, compare the results of trials with and without a methodological characteristic such as blinding of participants and health professionals. Estimated within‐meta‐analysis differences are combined across meta‐analyses, leading to an estimate of mean bias. Such “meta‐epidemiological” studies are published in increasing numbers and have the potential to inform trial design, assessment of risk of bias, and reporting guidelines. However, their interpretation is complicated by issues of confounding, imprecision, and applicability. We developed a guide for interpreting meta‐epidemiological studies, illustrated using MetaBLIND, a large study on the impact of blinding. Applying generally accepted principles of research methodology to meta‐epidemiology, we framed 10 questions covering the main issues to consider when interpreting results of such studies, including risk of systematic error, risk of random error, issues related to heterogeneity, and theoretical plausibility. We suggest that readers of a meta‐epidemiological study reflect comprehensively on the research question posed in the study, whether an experimental intervention was unequivocally identified for all included trials, the risk of misclassification of the trial characteristic, and the risk of confounding, i.e the adequacy of any adjustment for the likely confounders. We hope that our guide to interpretation of results of meta‐epidemiological studies is helpful for readers of such studies.

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Section: Meta-epidemiological Studies: Rationale and Variation In Rmentioning

confidence: 56%

Section: Meta-epidemiological Studies: Rationale and Variation In Rmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 85%

Section: Q2: How Was the Trial Characteristic Of Interest Defined?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Ten questions to consider when interpreting results of a meta‐epidemiological study—the MetaBLIND study as a case

Moustgaard

Jones

Savović

et al. 2020

Research Synthesis Methods

Self Cite

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Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy

D’Angelica

Ellis

Liu

et al. 2023

JAMA

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ImportanceDespite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood.ObjectiveTo define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics.Design, Setting, and ParticipantsPragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment.InterventionThe intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care).Main Outcomes and MeasuresThe primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program.ResultsThe trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, −13.0% [95% CI, −19.1% to −6.9%]; P &lt; .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, −3.3% [95% CI, −6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, −6.3% [95% CI, −11.4% to −1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, −1.2% [95% CI, −3.1% to 0.7%]; P = .32).Conclusions and RelevanceIn participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy.Trial RegistrationClinicalTrials.gov Identifier: NCT03269994

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Use of Placebo and Nonoperative Control Groups in Surgical Trials

et al. 2022

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IMPORTANCENonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. OBJECTIVE To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect). DATA SOURCES Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019. STUDY SELECTION Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program). DATA EXTRACTION AND SYNTHESIS Pairs of authors independently screened the search results,assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome. MAIN OUTCOMES AND MEASURESBetween-and within-group effect sizes expressed as Hedges g. RESULTSIn this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, −0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, −0.09 [95% CI, −0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, −0.11 [95% CI, −0.37 to 0.15]).

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Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study

Cited by 192 publications

References 33 publications

Ten questions to consider when interpreting results of a meta‐epidemiological study—the MetaBLIND study as a case

Ten questions to consider when interpreting results of a meta‐epidemiological study—the MetaBLIND study as a case

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy

Use of Placebo and Nonoperative Control Groups in Surgical Trials

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