Carolyn S Calfee1, Kevin L Delucchi2, Pratik Sinha3, Michael A Matthay4, Jonathan Hackett5, Manu Shankar-Hari6, Cliona McDowell7, John G Laffey8, Cecilia M O'Kane5, Daniel F McAuley9. 1. Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: carolyn.calfee@ucsf.edu. 2. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA. 3. Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA, USA. 4. Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. 5. Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. 6. Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, UK; School of Immunology and Microbial Sciences, Kings College London, London, UK. 7. Northern Ireland Clinical Trials Unit, The Royal Hospitals Belfast, Belfast, UK. 8. Anaesthesia, School of Medicine, and Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada; Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. 9. Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; Regional Intensive Care Unit, The Royal Hospitals Belfast, Belfast, UK.
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.
RCT Entities:
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.
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