Calfee CS, et al. - This study was undertaken to determine if subphenotypes of acute respiratory distress syndrome (ARDS) exist in non-US patient populations and respond differently to pharmacotherapies. Researchers identified two subphenotypes of ARDS in the HARP-2 cohort, with distinct clinical and biological features and disparate clinical outcomes. It was noted that the hyperinflammatory subphenotype had improved survival with simvastatin vs placebo and supported further pursuit of predictive enrichment strategies in critical care clinical trials.

Methods

• HARP-2 was a multicentre, randomised controlled trial.
• For this trial, simvastatin (80 mg) vs placebo done in general intensive care units (ICUs) at 40 hospitals in the UK and Ireland within 48 h of onset of ARDS.
• The primary outcome was ventilator-free days.
• Secondary outcomes included non-pulmonary organ failure-free days and mortality.
• In a secondary analysis of HARP-2, researchers applied latent class analysis to baseline data without consideration of outcomes to identify subphenotypes, and they compared clinical outcomes across subphenotypes and treatment groups.

Results

• Five hundred forty subjects were selected to HARP-2.
• One patient withdrew consent for the use of their data, so data from 539 subjects were studied.
• A two-class (two subphenotype) model was an improvement over a one-class model (p < 0·0001), with 353 (65%) patients in the hypoinflammatory subphenotype group and 186 (35%) in the hyperinflammatory subphenotype group in the secondary analysis.
• Findings revealed that additional classes did not improve model fit.
• It was noted that clinical and biological characteristics of the two subphenotypes were similar to previous studies.
• Researchers found that patients with the hyperinflammatory subphenotype had fewer ventilator-free days (median 2 days [IQR 0–17] vs 18 [IQR 0–23]; p < 0·0001), fewer non-pulmonary organ failure-free days (15 [0–25] vs 27 [21–28]; p < 0·0001), and higher 28-day mortality (73 [39%] vs 59 [17%]; p < 0·0001) than did those with the hypoinflammatory subphenotype.
• Significantly different survival was identified across patients stratified by treatment and subphenotype (p < 0·0001) although HARP-2 found no difference in 28-day survival between placebo and simvastatin.
• Patients treated with simvastatin had significantly higher 28-day survival than did those given placebo (p=0·008) within the hyperinflammatory subphenotype.
• For 90-day survival, a similar pattern was noted.