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

Calfee, Carolyn S.; Delucchi, Kevin; Sinha, Pratik; Matthay, Michael A.; Hackett, Jonathan E.; Shankar-Hari, Manu; McDowell, Clíona; O’Kane, Cecilia; Paikray, Archana; Yates, C. J.; Polgarova, Petra; Price, Esther; McInerney, Amy; Zamoscik, Katarzyna; Dempsey, Ged; Seasman, Colette; Gilfeather, Lynn; Hemmings, Noel; O’Kane, Sinéad; Johnston, Paul; Pokorny, Lukas; Nutt, Chris; O'Neill, Orla; Prashast, Prashast; Smalley, Chris; Jacob, Reni; O’Rourke, James; Sultan, Syed Farjad; Schilling, Carole; Perkins, Gavin D.; Melody, Teresa; Couper, Keith; Daniels, Ron; Gao, Fang; Hull, Julian; Gould, T; Thomas, Matthew; Sweet, Katie; Breen, Dorothy; Neau, Emer; Peel, Willis J; Jardine, Catherine; Jefferson, P.; Wright, Stephen E.; Harris, Kayla; Hierons, Sarah; Laffey, John G.; McInerney, Veronica; Camporota, Luigi; Lei, Katie; Kaul, Sundeep; Chibvuri, Molly; Gratrix, Andrew; Bennett, Rachael E.; Martinson, Victoria; Sleight, Lisa; Smith, Neil; Hopkins, Philip; Hadfield, Daniel; Casboult, Sarah; Wade-Smith, Fiona; Dawson, Julie Ann; Mellis, Clare; Harris, Clair; Parsons, Georgina; Helyar, Sinead; Bodenham, Andrew; Elliot, S.; Beardow, Z.; Birch, Sian; Marsh, Brian; Martin, Teresa; Dhrampal, Akesh; Rosbergen, Melissa; Webb, Stephen T.; Bottrill, Fiona; Reschreiter, Henrik; Barcraft-Barnes, Helena; Camsooksai, Julie; Johnston, Andrew James; Clarkson, Aisling; Bentley, Conor; Cooper, Lauren B.; Qui, Yongyan; Mitchell, Natalie; Carrera, Ronald; Whitehouse, Arlo; Danbury, Chris; Jacques, Nicola; Brown, Abby; Rogerson, David; Morris, C.; Walsh, Timothy; Gillies, M. A.; Price, Grant; Kefala, Kallirroi; Young, Neil; Hope, David; McCulloch, Corrienne; Antonelli, Jean; Ramsay, Pam; Everingham, Kirsty; Boardman, Louise; Dawson, Heidi; Pollock, F. Edward; Thompson, Joanne; Welters, Ingeborg; Poole, Lee; Hampshire, Peter; Hall, Alison; Williams, Karen; Walker, Anna; Youds, Laura; Hendry, Samantha; Waugh, Victoria; Patrick-Heselton, Julie; Shaw, David M.; Chaudry, Irfan; Baldwin, Jacqueline; Drage, Stephen; Gordoa, Laura Ortiz-Ruiz de; McAuley, Daniel F.; Bannon, Leona; Quinn, Vanessa; McNamee, Lia; White, Griania; Cecconi, Maurizio; Mellinghoff, Johannes; Ryan, Donal; Nichol, Alistair; Agarwal, Banwari; Meale, Paula; James, Sarah Aissi; Dhadwal, Kulwant; Martı́n, Daniel; Walecka, Agnieszka; Ward, Stephen; Trinder, John; Hagan, Samantha; Montgomery, J; Léonard, Catherine; Lemon, Elizabeth; Trinick, Tom; Buddhavarapu, Murthy; Ward, Geraldine; Bassford, Christopher; Davidson, Alan; McGuigan, Kate; Benchiheub, Anissa; Hickey, Naomi; Binning, A.; Henderson, Steven; Wood, Jessica; Burtenshaw, Andrew; Kelly, Dawn; Martin, T. R. P.; Thrush, Jessica; Wollaston, Julie; Graystone, Stephen; Nicol, Gavin; Sellors, Gareth P

doi:10.1016/s2213-2600(18)30177-2

Cited by 512 publications

(511 citation statements)

References 24 publications

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“…A distinctive feature of the current study consistent with our previously presented work in ARDS subphenotypes[9, 12, 13] is that respiratory variables, including the PaO 2 /FiO 2 ratio (PF ratio) perform poorly at differentiating class (Figure 1). A recent study suggests stratification of patients by severity of ARDS using a cut-off of PaO 2 /FiO 2 ratio of 150 may lead to identification of more homogeneous patients in ARDS with differing anatomy and physiology and would serve as a better threshold than the Berlin classification.…”

Section: Discussionsupporting

confidence: 88%

“…In addition, these data demonstrate that expanding the number of clinical variables in the LCA models did not alter the number of classes in the population, further illustrating the stability of the 2 observed ARDS subphenotypes. Unlike the LCA in the HARP-2 trial,[13] no treatment effect with rosuvastatin was observed in either subphenotype in this study.…”

Section: Discussioncontrasting

confidence: 71%

“…Furthermore, replication of these findings in a fifth ARDS cohort from the UK and Ireland (HARP-2) albeit using a limited set of variables substantiate the robustness and generalizability of the two subphenotype model. [13]…”

Section: Discussionmentioning

confidence: 99%

“…[8–10] The subgroups are clinically and biologically distinct from one another and remain stable over the first three days of enrollment. [11] The hyper-inflammatory subphenotype was associated with increased inflammatory biomarkers, a higher prevalence of shock, and worse clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…[9, 12] Most recently, in the HARP-2 study, we observed a survival benefit in the hyper-inflammatory subphenotype with simvastatin therapy. [13]…”

Section: Introductionmentioning

confidence: 99%

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Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

et al. 2018

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Purpose: Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within 3 negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes. Methods: LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n=745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin. Results: The 2-class LCA model best fit the population. 40% of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at Day 60 and Day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo. Conclusions: Using LCA, a 2-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in 4 other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrates their utility for patient stratification in ARDS.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…[9, 12] Most recently, in the HARP-2 study, we observed a survival benefit in the hyper-inflammatory subphenotype with simvastatin therapy. [13]…”

Section: Introductionmentioning

confidence: 99%

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Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

et al. 2018

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Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies

et al. 2023

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ImportanceIt is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies.ObjectiveTo derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies.Design, Setting, and ParticipantsThis was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022.ExposuresTEs identified by K-means clustering of plasma biomarkers collected at hospital arrival.Main Outcomes and MeasuresAn association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS.ResultsA total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001).Conclusions and RelevanceResults of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

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Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

Patel

Martin

2023

JAMA Surg

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

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

Cited by 512 publications

References 24 publications

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies

Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

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