A Prognostic Enrichment Strategy for Selection of Patients With Acute Respiratory Distress Syndrome in Clinical Trials

Objectives: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials. Design: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies. Setting: A network of multidisciplinary ICUs. Patients: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. Interventions: None. Measurements and Main Results: We evaluated different thresholds for patient’s age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age ( 70 yr), PaO2/FIO2 (≤ 100, 101–150, > 150 mm Hg), plateau pressure ( 30 cm H2O), and number of extrapulmonary organ failure ( 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84–0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model. Conclusions: Combined thresholds for patient’s age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials. Drs. Villar and Kacmarek designed and supervised the study. Ms. Rosa L. Fernández was the project manager and supervised the study. Drs. Ambrós, Mosteiro, Martínez, Lorena Fernández, Ferrando, Carriedo, Soler, Parrilla, Hernández, Andaluz-Ojeda, Añón, Vidal, González-Higueras, Martín-Rodríguez, Díaz-Lamas, Blanco, Belda, Díaz-Domínguez, Rico-Feijoó, Martín-Delgado, and Romera enrolled patients and collected the data. Dr. Villar obtained funding for the study. Dr. Villar, Ms. Rosa L. Fernández, Drs. Kacmarek, Ambrós, Mosteiro, Martínez, Lorena Fernández, Ferrando, Carriedo, Soler, Parrilla, Hernández, Andaluz-Ojeda, Añón, Vidal, González-Higueras, Martín-Rodríguez, Díaz-Lamas, Blanco, Belda, Díaz-Domínguez, Rico-Feijoó, Martín-Delgado, Romera, and González-Martín made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it for important intellectual content; and approved the final version. Dr. Villar, Ms. Rosa L. Fernández, and Dr. Kacmarek wrote the first draft. Dr. Villar, Ms. Rosa L. Fernández, and Dr. Kacmarek were involved in all stages of study development and delivery. Dr. Villar, Ms. Rosa L. Fernández, Dr. González-Martín, and Dr. Kacmarek performed and supervised data management and statistical analysis. Dr. Villar, Ms. Rosa L. Fernández, and Dr. González-Martín had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Villar, Ms. Rosa L. Fernández, and Dr. González-Martín had full access to all the data in the study and had final responsibility for the decision to submit for publication. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://bit.ly/29S62lw). Supported, in part, by Instituto de Salud Carlos III (CB06/06/1088, PI10/0393, PI13/0119, PI16/00049), Asociación Científica Pulmón y Ventilación Mecánica, and College of Physicians of Las Palmas, Spain (OA16/019). Dr. Villar has received a research grant from Maquet. Dr. Belda disclosed government work. Dr. Díaz-Dominguez disclosed work for hire. Dr. Rico-Feijoó received funding from Pfizer, Merck Sharp & Dohme Corp., and Astellas Pharma España. Dr. Kacmarek’s institution received funding from Medtronic and Venner Medical; and he received funding from consulting for Medtronic (airway care) and Orange Medical (mechanical ventilators and ventilation). The remaining authors have disclosed that they do not have any potential conflicts of interest. Current address for Dr. Carlos Ferrando, MD, PhD: Department of Anesthesiology & Critical Care, Hospital Clinic, Barcelona, Spain. Members of the SIESTA Network are listed in the Appendix. Registered at www.clinicaltrials.gov (NCT00435110, NCT00736892, NCT02288949, NCT02836444). For information regarding this article, E-mail: jesus.villar54@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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