‘Faith Healing’ and ‘Subtraction Anxiety’ in Unblinded Trials of Procedures

Rajkumar, Christopher; Nijjer, Sukhjinder; Cole, Graham; Al‐Lamee, Rasha; Francis, Dárrel P.

doi:10.1161/circoutcomes.118.004665

Cited by 46 publications

(21 citation statements)

References 9 publications

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“…n March 12, 2018, CQO published "Moving the Goal Posts Into Unblinded Territory: The Larger Lessons of DEFER and FAME 2 and Their Implications for Shifting End Points in ISCHEMIA" by Rajkumar et al 1 The article -now entitled "'Faith Healing' and 'Subtraction Anxiety' in Unblinded Trials of Procedures: Lessons from DEFER and FAME-2 for endpoints in the ISCHEMIA trial" -focused on biases that can be introduced when potentially subjective end points are used in unblinded studies of revascularization. The authors illustrated their key points in the context of DEFER (Deferral of PTCA Versus Performance of PTCA) and FAME 2 (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2), and the ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches).…”

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confidence: 99%

“…After publication of the article by Rajkumar et al, 1 the ISCHEMIA investigators pointed out factual errors in the description of their trial. We have published their response to us immediately as an online eLetter, the contents of which also will be published as a Letter to the Editor in this issue of CQO.…”

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confidence: 99%

“…In the past, we have not felt the need to share every critique of another study with authors of the study being examined. For example, the FAME and DEFER trials and several other articles were also discussed in the article by Rajkumar et al 1 It is not practical for us to reach out to every author who is mentioned by another.…”

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confidence: 99%

“…Second, I want to briefly address the subtle question of intent that relates to both the ISCHEMIA investigators and authors of the article by Rajkumar et al 1 I regret that there has been discussion on social media hinting that changes made in the ISCHEMIA trial were done haphazardly or, even worse, deceitfully. Nothing could be further from the truth.…”

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confidence: 99%

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Nallamothu

2018

Circ: Cardiovascular Quality and Outcomes

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Nallamothu

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“…Darrel Francis and colleagues at the National Heart and Lung Institute at Imperial College London noticed the change and wrote a critical article in Circulation: Cardiovascular Quality 1. They said that cardiovascular death and non-fatal myocardial infarction were objective events and that their measurement was resistant to bias, whereas hospital admission for unstable angina and heart failure was vulnerable to bias.…”

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confidence: 99%

Stent trial researchers are accused of changing endpoints to suit results

Wise¹

2018

BMJ

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Placebo Control and Blinding in Randomized Trials of Procedural Interventions

Rajkumar,

Thomas,

Foley

et al. 2024

JAMA Surg

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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 &lt; .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 &lt; .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.

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‘Faith Healing’ and ‘Subtraction Anxiety’ in Unblinded Trials of Procedures

Cited by 46 publications

References 9 publications

The Ultimate Goal Post

The Ultimate Goal Post

Stent trial researchers are accused of changing endpoints to suit results

Placebo Control and Blinding in Randomized Trials of Procedural Interventions

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