Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial

Abstract

Background: Precision medicine approaches that target patients on the basis of disease subtype have transformed treatment approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of acute respiratory distress syndrome (ARDS) have been identified in three US-based clinical trials, and these subphenotypes respond differently to positive end-expiratory pressure and fluid management. We aimed to investigate whether these subphenotypes exist in non-US patient populations and respond differently to pharmacotherapies.

Methods: HARP-2 was a multicentre, randomised controlled trial of simvastatin (80 mg) versus 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, and secondary outcomes included non-pulmonary organ failure-free days and mortality. In a secondary analysis of HARP-2, we applied latent class analysis to baseline data without consideration of outcomes to identify subphenotypes, and we compared clinical outcomes across subphenotypes and treatment groups.

Findings: 540 patients were recruited to HARP-2. One patient withdrew consent for the use of their data, so data from 539 patients were analysed. In our secondary analysis, 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. Additional classes did not improve model fit. Clinical and biological characteristics of the two subphenotypes were similar to previous studies. 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. Although HARP-2 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 hyperinflammatory subphenotype, patients treated with simvastatin had significantly higher 28-day survival than did those given 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 hyperinflammatory subphenotype had improved survival with simvastatin compared with placebo. These findings support further pursuit of predictive enrichment strategies in critical care clinical trials.

Funding: UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health.

Figure 1:

Continuous Variables By Subphenotype. Differences in standardized values of each continuous variable by subphenotype in the HARP-2 Study. The variables are sorted on the basis of the degree of separation between the subphenotypes, from maximum positive separation on the left (ie, hyper-inflammatory subphenotype higher than hypo-inflammatory subphenotype) to maximum negative separation on the right (ie, hyper-inflammatory subphenotype lower than hypo-inflammatory subphenotype). The y-axis represents standardized variable values, in which all means are scaled to zero and SDs to one. A value of +1 for the standardized variable signifies that the mean value for a given subphenotype was one SD higher than the mean value in the cohort as a whole. Mean values are joined by lines to facilitate displaying subphenotype profiles. sTNFr1= soluble tumor necrosis factor receptor-1. IL-6 = interleukin-6.

Figure 2:

Kaplan-Meier survival curves to 28 days (Figure 3A) and 90 days (Figure 3B) for patients in HARP-2, stratified by ARDS subphenotype and treatment (simvastatin vs placebo). Comparison of curves using the log-rank test. Figure 3A: overall p<0.0001; comparison of hyper-inflammatory subphenotype patients treated with simvastatin vs placebo p= 0.008. Figure 3B: overall p<0.0001; comparison of hyper-inflammatory subphenotype patients treated with simvastatin vs placebo p=0.03.

Figure 3:

Time to unassisted breathing over 28 days, stratified by subphenotype and treatment condition, from Fine-Gray competing risks model. Overall p<0.0001; comparison of hyper-inflammatory subphenotype patients treated with simvastatin vs. placebo p=0.10.