Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial.
Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial.
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DOI：
10.1016/s2213-2600(18)30177-2
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Irish Critical Care Trials Group
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文献类型：
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作者：
Calfee CS;Delucchi KL;Sinha P;Matthay MA;Hackett J;Shankar-Hari M;McDowell C;Laffey JG;O'Kane CM;McAuley DF;Irish Critical Care Trials Group
基于疾病亚型针对患者的精准医学方法已经改变了癌症，哮喘和其他异质性综合征的方法。在三项美国临床试验中发现了两种不同的ARDS亚表型，它们对呼气末正压通气和液体管理的反应不同。目前尚不清楚这些亚表型是否存在于不同的人群中，并对药物治疗产生不同的反应。我们对539例参加英国辛伐他汀治疗ARDS多中心、安慰剂对照随机试验（HARP-2）的患者的数据进行了二次分析。对基线数据进行潜在类别分析，不考虑结果，以确定亚表型。比较各亚表型和治疗组的临床结局。两类（两个亚表型）模型比一类模型有所改善（p<0.0001），65%的受试者处于低炎症亚表型，35%的受试者处于高炎症亚表型。额外的类并没有改善模型拟合。两种亚表型的临床和生物学特征与先前的研究相似。虽然最初的试验发现安慰剂和辛伐他汀之间的28天生存率没有差异，但在按治疗和亚表型分层的患者中发现了显著不同的生存率（p<0.0001）。具体而言，在高炎症亚表型中，辛伐他汀治疗患者的28天生存率显著高于安慰剂（p = 0.008）。在90天生存期中观察到类似的模式。在HARP-2队列中确定了两种ARDS亚表型，具有不同的临床和生物学特征以及不同的临床结局;与安慰剂相比，辛伐他汀可改善高炎症亚表型的生存率。这些发现支持在重症监护临床试验中进一步追求预测富集策略。
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. 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. 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. 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.