The Placebo Effect in Chronic Thromboembolic Pulmonary Hypertension Trials: A Systematic Review and Meta-Analysis

Abstract

Introduction: Placebo-controlled studies are crucial in clinical trials, but the placebo effect can vary across conditions. We aimed to assess the placebo effect in chronic thromboembolic pulmonary hypertension (CTEPH) trials. Methods: We conducted a systematic review and included randomized placebo-controlled trials investigating CTEPH interventions. Primary outcomes were the pre-post changes in the 6 min walk test (6MWT) and quality of life in the placebo arms. Secondary outcomes included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, and NT-proBNP levels. Meta-analyses were performed using random-effects models. Results: Seven trials with 270 CTEPH patients in placebo arms were analyzed. The average 6MWT change was not significant (-1.31 m; 95%CI -12.49 to +9.79). Quality of life with EQ-5D was not significantly improved (-0.04; 95%CI -0.10 to +0.02). mPAP, PVR, cardiac index, and NT-proBNP also demonstrated non-significant changes with small magnitudes. Conclusions: The placebo effect in CTEPH trials was not statistically significant and had small magnitude but should not discourage the use of placebo-controlled trials where applicable and ethical.

Keywords: 6 min walk test (6MWT); EQ-5D; chronic thromboembolic pulmonary hypertension (CTEPH); clinical trials; meta-analysis; natriuretic peptide; placebo effect; pulmonary embolism; pulmonary vascular resistance (PVR); systematic review.

Figure 1

Flowchart of studies selection.

Figure 2

Forest plots of 6MWT and quality of life change in placebo arms. Blue squares with lines represent individual study effect sizes with 95% confidence intervals; square size reflects study weight. The green diamond indicates the pooled effect size and its 95% confidence interval. Studies included with their references: BENEFiT [14]; Suntharalingam et al. [15]; CHEST-1 [7]; MERIT-1 [8]; AMBER 1 [16]; Tanabe et al. [17]; Ogo et al. [18].

Figure 3

Forest plots of mPAP, PVR, cardiac index, and NT-proBNP change in placebo arms. Blue squares with lines represent individual study effect sizes with 95% confidence intervals; square size reflects study weight. The green diamond indicates the pooled effect size and its 95% confidence interval. Studies included with their references: BENEFiT [14]; Suntharalingam et al. [15]; CHEST-1 [7]; MERIT-1 [8]; AMBER 1 [16]; Tanabe et al. [17]; Ogo et al. [18].