ImportanceUnlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed.ObjectiveTo investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm.Data SourcesSearches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison.Study SelectionPlacebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity.Data Extraction and SynthesisRandom-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020.Main Outcomes and MeasuresEnd points were examined in prespecified subgroups: patient-reported or health care professional–assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality.ResultsNinety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional–assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, −0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, −0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, −0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, −0.52 to 0.57; P = .91), or recurrent bleeding events (OR, −0.12; 95% CI, −1.11 to 0.88; P = .88).Conclusions and RelevanceThe magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional–assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

中文翻译：

---

程序干预随机试验中的安慰剂对照和盲法

重要性与药物不同，程序干预在被临床实践接受之前很少针对安慰剂进行试验。当安慰剂对照试验最终进行时，程序干预的效果可能不如之前认为的那么有效。 目的 通过比较进行和不进行相同手术的试验的效果大小，研究在外科手术和介入手术试验中纳入安慰剂组的重要性数据源 MEDLINE 和 Embase 的搜索确定了从成立到 2019 年 3 月 31 日期间任何医学和外科专业的程序干预的所有安慰剂对照试验。二次搜索确定了评估相同干预措施、病情和治疗的随机临床试验。研究选择需要皮肤切口或内窥镜技术的解剖部位特定手术的安慰剂对照试验符合纳入条件；然后将这些试验与没有安慰剂对照且处于预先指定的异质性限度内的试验相匹配。数据提取和合成随机效应元回归，其中安慰剂和盲法作为固定效应，干预和终点分组作为随机效应，用于计算安慰剂对照对每个终点的影响。数据分析时间为 2019 年 3 月至 2020 年 3 月。主要结果和测量在预先指定的亚组中检查终点：患者报告或医疗保健专业人员评估的结果、生活质量、疼痛、血压、运动相关结果、复发性出血和结果 72 项盲法安慰剂对照试验（以下简称“盲法”）和 55 项无安慰剂对照的非盲法试验（以下简称“非盲法”）中匹配了 97 个终点，其中包括 111 500 个个体患者终点。对于运动相关结果，非盲试验比盲试验具有更大的标准化效应量（标准化均数差 [SMD]，0.59；95% CI，0.29 至 0.89；磷< .001）和生活质量（SMD，0.32；95% CI，0.11 至 0.53；磷= .003）和医疗保健专业人员评估的终点（SMD，0.40；95% CI，0.18 至 0.61；磷< .001）。安慰剂效应分别占这些终点观察到的非盲效应大小的 88.1%、55.2% 和 61.3%。对于患者报告的终点，非盲试验和盲试验之间没有显着差异（SMD，0.31；95% CI，-0.02 至 0.64；磷= .07)、血压（SMD，0.26；95% CI，-0.10 至 0.62；磷= .15），全因死亡率（比值比 [OR]，0.23；95% CI，-0.26 至 0.72；磷= .36)，疼痛（SMD，0.03；95% CI，-0.52 至 0.57；磷= .91），或复发性出血事件（OR，-0.12；95% CI，-1.11 至 0.88；磷= .88）。结论和相关性本次系统评价和荟萃回归中发现的安慰剂效应的大小取决于终点。程序干预试验中的安慰剂对照对运动相关、生活质量和医疗保健专业评估的终点影响最大。程序干预的随机临床试验可以相应地考虑安慰剂对照。