Importance:
Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When blinded trials are eventually conducted, procedural interventions may be less effective than previously believed.
Objective:
We investigated the importance of blinding in trials of surgical and interventional procedures by comparing effect sizes from blinded and unblinded trials of the same procedure.
Data Sources:
Searches of Medline and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to 31st March 2019. A secondary search identified unblinded RCTs assessing the same intervention, condition, and endpoint, for paired comparison.

Study Selection:

Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion.

Data Extraction and Synthesis:

Random-effects meta-regression, with blinding as a fixed-effect and intervention and endpoint grouping as a random effect was used to calculate the impact of blinding for each endpoint.

Main outcomes and measures:
Endpoints were examined in pre-specified subgroups: patient reported or healthcare professional-assessed, quality of life, pain, blood pressure, exercise-related, recurrent bleeding, and all-cause mortality (PROSPERO:CRD4202020663).
Results:
Ninety-seven endpoints were matched from 72 blinded and 55 unblinded trials, including 111,500 individual-patient endpoints.
Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related (standardized mean difference (SMD) 0.59, 95%CI 0.29 to 0.89, p=0.0001), quality of life (SMD 0.32, 95%CI 0.11 to 0.53, p=0.003) and healthcare professional-assessed endpoints (SMD 0.40, 95%CI 0.18 to 0.61, p=0.0002). The placebo effect accounted for 88.1%, 55.2% and 61.3%, respectively, of the observed unblinded effect size for these endpoints.
There was no significant difference between unblinded and blinded trials for patient-reported endpoints (SMD 0.31, 95%CI -0.02 to 0.64, p=0.07), blood pressure (SMD 0.26, 95%CI -0.10 to 0.62, p=0.15), all-cause mortality (odds ratio (OR) 0.23, 95%CI -0.26 to 0.72, p 0.36), pain (SMD 0.03, 95%CI -0.52 to 0.57, p=0.91), and recurrent bleeding events (OR -0.12, 95%CI -1.11 to 0.88, p=0.88).
Conclusions and Relevance:
The magnitude of the placebo effect depends on the endpoint. Placebo-control in trials of procedural interventions has greatest impact on exercise-related, quality of life and healthcare professional-assessed endpoints.