Heterogeneity of Effect of PEEP Strategy by Subphenotypes Derived From Clinical Data in ARDS
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Pulmonary, Research, 2022
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INTRODUCTION/HYPOTHESIS: Acute respiratory distress syndrome (ARDS) is a heterogeneous condition. Recently, two subphenotypes using widely available clinical data were identified. Subphenotype B exhibits clinical and laboratory signals consistent with higher inflammation and has higher mortality compared to subphenotype A. The presence of heterogeneity of treatment effect (HTE) between these subphenotypes has not been explored. The objective of this study was to assess the HTE of different positive end-expiratory pressure (PEEP) strategies on 28-day mortality according to these subphenotypes in adult patients with ARDS. METHODS: This is a retrospective evaluation of two prior ARDS trials (ALVEOLI and ART) that compared high vs. low PEEP strategies. Patients were classified in two subphenotypes using a K-means clustering algorithm on nine clinical elements collected at randomization (pH, PaO2, bicarbonate, bilirubin, creatinine, mean arterial pressure, heart rate, respiratory rate and FiO2). This model was constructed using data from the two large trials (EDEN and FACTT), and validated using data from four trials (ALVEOLI, ARMA, SAILS, and ART). Biological characteristics of the subphenotypes were validated by evaluating the levels of pro-inflammatory plasma biomarkers. The primary outcome was 28-day mortality. HTE of PEEP was assessed following a pre-planned Bayesian hierarchical logistic model and reported as odds ratio (OR), 95% credible interval (CrI) and probability of benefit (OR < 1.00) or harm (OR >1.00). Priors were weakly informative, and sensitivity analyses considering different priors were performed. RESULTS: Data from 1559 ARDS patients were analyzed. High PEEP resulted in higher risk for 28-day mortality compared to low PEEP in patients in subphenotype A (OR, 1.66 [95% CrI, 1.13 to 2.47]; probability of harm of 99.4%) but not in subphenotype B (OR, 0.94 [95% CrI, 0.65 to 1.34]; probability of benefit of 63.9%). These effects were not modified when patients were stratified by either PaO2/FiO2 ratio or driving pressure, when the trials were assessed separately or using different priors. CONCLUSIONS: Our study demonstrates HTE of PEEP strategies across two subphenotypes derived from common clinical variables. This work may allow predictive enrichment in future clinical trials.
Meta Tag
Content Type Presentation
Knowledge Area Pulmonary
Knowledge Area Research
Knowledge Area Procedures
Knowledge Level Advanced
Membership Level Select
Tag Acute Respiratory Distress Syndrome ARDS
Tag Positive End Expiratory Pressure PEEP
Tag Mechanical Ventilation
Tag Outcomes Research
Year 2022
clinical data
targeted therapies


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