Placebo Control and Blinding in Randomized Trials of Procedural Interventions: A Systematic Review and Meta-Regression.

Importance: Unlike 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. Objective: To 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 Sources: Searches 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 Selection: Placebo-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 Synthesis: Random-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 Measures: End 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. Results: Ninety-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 Relevance: The 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.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Revascularization in stable coronary artery disease.

Management of stable coronary artery disease (CAD) centers on medication to prevent myocardial infarction and death. Many anti-anginal medications also have benefit for reducing symptoms, and have been proven to be effective against placebo control. Before effective preventive medications were available, patients with stable CAD often underwent revascularization with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), on the plausible assumption that these procedures would prevent adverse events and reduce symptoms. However, recent randomized controlled trials have cast doubt on these assumptions.Considering results from the recent ISCHEMIA trial, we discuss the evidence base that underpins revascularization for stable CAD in contemporary practice. We also focus on patient groups at high risk of myocardial infarction and death, for whom revascularization is often recommended. We outline the areas of uncertainty, unanswered research questions, and key areas of potential miscommunication in doctor-patient consultations.

Adenosine induced ventricular fibrillation in a structurally normal heart: a case report.

BACKGROUND: Adenosine is the first-line pharmacotherapy for termination of supraventricular tachycardia through its action on the atrioventricular node. However, pro-arrhythmic effects of adenosine are also recognised, most notably in the presence of pre-excited atrial fibrillation. In this case report, we describe the induction of ventricular fibrillation in a patient with no demonstrable accessory pathway, nor any other structural heart disease. This rare, idiosyncratic reaction has never previously been reported and is of relevance given the widespread and routine use of adenosine in clinical practice. CASE PRESENTATION: A 26-year-old woman of Cypriot origin presented to our emergency department with a sudden onset of palpitations and chest discomfort. She was healthy, with no previous medical history and no regular medications. An electrocardiogram demonstrated a narrow complex tachycardia with a rate of 194 beats per minute. Following failure of vagal maneuvers to terminate the tachycardia, the assessing physician administered a single intravenous dose of 6 mg adenosine. Our patient instantaneously developed coarse ventricular fibrillation and circulatory collapse. Cardiopulmonary resuscitation was initiated and our patient was rapidly defibrillated to sinus rhythm with a single 150 J direct current shock. A 900-mg loading dose of intravenous amiodarone was commenced and our patient was managed in the cardiac high dependency unit. No further arrhythmias were identified on continuous cardiac monitoring. On review, her presenting electrocardiogram had demonstrated rapidly conducted atrial fibrillation with no evidence of ventricular pre-excitation. Concordantly, her resting electrocardiogram was not suggestive of any accessory pathway. This was conclusively excluded on invasive electrophysiology study, with negative programmed ventricular stimulation up to three extrastimuli. Extensive laboratory investigations were unremarkable and failed to identify an underlying cause for her episode of atrial fibrillation. Furthermore, cardiac magnetic resonance imaging demonstrated a structurally normal heart, with no edema, fibrosis or infarction as well as normal coronary artery anatomy. CONCLUSIONS: Adenosine remains a safe and highly efficacious therapy for supraventricular tachycardia. However, this unusual case demonstrates the ability of adenosine to induce circulatory collapse and reminds the clinician that prompt access to resuscitation, defibrillation, and transcutaneous pacing equipment is mandatory with every administration of this drug.