Acute respiratory distress syndrome subphenotypes and differential response to simvastatin:Secondary Analysis of a Randomized Controlled Trial

Background: Precision medicine approaches targeting patients based on disease subtype have transformed approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of ARDS have been identified in three US-based clinical trials and respond differently to positive end-expiratory pressure and fluid management. It remains unknown if these subphenotypes exist in different populations and respond differently to pharmacotherapies. Methods: We conducted a secondary analysis using data from 539 patients enrolled in a UK multicenter, placebo-controlled randomized trial of simvastatin for ARDS (HARP-2). Latent class analysis was applied to baseline data without consideration of outcomes to identify subphenotypes. Clinical outcomes were compared across subphenotypes and treatment groups. Findings: A two class (two-subphenotype) model was an improvement over a one class model (p<0.0001), with 65% of subjects in the hypo-inflammatory subphenotype and 35% in the hyper-inflammatory subphenotype. Additional classes did not improve model fit. The clinical and biological characteristics of the two subphenotypes were similar to prior studies. While the original trial found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0.0001). Specifically, within the hyper-inflammatory subphenotype, patients treated with simvastatin had significantly higher 28-day survival compared to placebo (p = 0.008). A similar pattern was observed for 90- day survival. Interpretation: Two subphenotypes of ARDS were identified in the HARP-2 cohort, with distinct clinical and biological features and disparate clinical outcomes; the hyper-inflammatory subphenotype had improved survival with simvastatin compared to placebo. These findings support further pursuit of predictive enrichment strategies in critical care clinical trials