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[Lancet Respir Med发表述评]:ARDS临床试验的新前沿:随机分组前区分表型
2019年10月18日 研究点评, 进展交流 暂无评论

COMMENT| VOLUME 7, ISSUE 10, P830-831, OCTOBER 01, 2019

A new frontier in ARDS trials: phenotyping before randomisation

Carolyn M Hendrickson, Carolyn S Calfee

Lancet Respir Med 2019; 7: 830-831 DOI:https://doi.org/10.1016/S2213-2600(19)30175-4

Despite decades of progress in both the experimental understanding of acute respiratory distress syndrome (ARDS) and in preclinical studies identifying potentially effective new treatments, most clinical trials for ARDS have not shown a mortality benefit.1–3 Considerable clinical and biological heterogeneity within this syndrome are widely considered to be important barriers to identifying effective treatments for ARDS. Understanding the clinical, biological, and physiological properties that drive this heterogeneity has the potential to improve clinical outcomes through a shift in the paradigm of ARDS treatment from the current one-size-fits-all strategy to a more targeted approach, although the optimal approach to targeted therapy remains uncertain.

Radiographic heterogeneity on CT scans of patients withARDS was first described in the literature just before the turn of this century. As CT scans became more commonly available in patients with ARDS, researchers began to study how radiographic morphology relates to differences in biology, physiology, and clinical outcomes. Distinct lung morphologies in ARDS can be classified into focal and non-focal radiographic phenotypes, with corresponding differences in gas distribution patterns during mechanical ventilation, plasma biomarker profiles,4 and alveolar fluid clearance.5 The non-focal phenotype has been reported to show lower lung compliance and a higher likelihood of response to recruitment maneuvers.6 These findings have suggested that radiographic phenotypes might offer an effective and pragmatic approach to defining physiologically and biologically distinct groups of patients who might respond differently to mechanical ventilation.5–9 Personalising mechanical ventilation to patient-specific physiology for enhanced lung protection in ARDS is an exciting target for precision medicine research.10

In this issue of The Lancet Respiratory Medicine,Jean-Michel Constantin and colleagues11 present the Lung Imaging for Ventilator Setting in ARDS (LIVE) trial, the first randomised controlled trial that makes use of radiographic phenotypes to assign different mechanical ventilation strategies in 400 patients with moderate-to-severe ARDS. Patients were randomly assigned to either standard low-tidal volume mechanical ventilation (control group) or a so-called personalised mechanical ventilation strategy (intervention group) targeting either focal or non-focal ARDS, adjudicated before randomisation. The authors must be commended for developing this novel approach to ARDS clinical trials and for tackling the logistical challenges of quickly phenotyping study participants before randomisation. The trial showed no difference in 90-day mortality between the intervention and control groups in the intention-to-treat analysis. However, the authors highlight a substantial amount of misclassification of phenotypes that might have biased the study to the null. Compared with post-hoc classification of phenotypes by a core group of investigators masked to treatment allocation and outcome, 21% of the radiographic phenotypes assigned at the time of randomisation were misclassified. In a subsequent subgroup analysis, a significant interaction between misclassification and mortality was observed, with higher mortality among participants randomised to a misaligned ventilator strategy. When the 40 patients who were misclassified in the personalised group were excluded, the personalised strategy appeared to increase survival compared with the one-size-fits-all approach.

The results of this trial11 highlight both the promise and the potential pitfalls of personalised medicine in critically ill patients. On the one hand, the results of the subgroup analysis excluding patients who were misclassified raise the tantalising possibility that personalisation of ventilatory strategy might improve patient outcomes. At the same time, the challenges encountered in the protocol execution emphasise how the pursuit of matching therapy to phenotype might be compromised by the additional logistical burdens of both obtaining and interpreting diagnostic tests for phenotype classification. In the case of this trial,11 the study protocol called for radiographic phenotype to be classified by CT; however, only 34% of patients were actually classified using CT scans, with the remainder classified using chest x-ray. Moreover, accurate classification using either modality proved difficult, as illustrated by the discrepancies between local and real-time adjudication and central and posthoc adjudication. These issues emphasise that reliable identification of patient phenotypes will be a major hurdle for future precision medicine clinical trials in critically ill populations.

Setting aside the substantial challenges of accurately and efficiently assigning phenotypes, the interpretation of these results is further complicated by the bundled interventions that were studied. The comparison of two treatment bundles can either washout effects of the most impactful intervention, or it can create ambiguity about which part of the intervention drives any harm or benefit observed. In this study,11 the intervention groups for the patients with focal versus non-focal ARDS differed in many respects, including with respect to positive endexpiratory pressure, neuromuscular blockade, prone positioning, tidal volumes, and recruitment manoeuvres. As a result, it is difficult to establish whether any benefit of a personalised strategy in fact derives from personalisation or from one or more specific components of the intervention. Similarly, a negative study result does not rule out the possibility that some part of the intervention bundle was beneficial.

A major strength of this study is the choice to directly compare a precision medicine strategy to the current standard-of-care approach to mechanical ventilation in ARDS. To accurately establish whether to shift the evidence base supporting the current standard of care, we must first understand how a novel approach to treatment assignment stacks up against the well established approach of low tidal volume mechanical ventilation. The findings of the subgroup analysis excluding patients who were misclassified suggest potential promise for this more personalised approach, but it will require further prospective validation.

Identifying phenotypes prospectively before randomization in a clinical trial is a new frontier in ARDS clinical research, and this trial will move the field forward by highlighting many of the challenges ahead. Understanding how phenotypes defined by clinical features, biological markers, radiographic findings, and physiological profiles might or might not overlap, and how to design the optimal approach to selecting patients for a given therapeutic intervention, will be important goals for future precision studies in ARDS. Likewise, the research community must continue to develop robust preclinical evidence to guide rational interventions for specific biological and physiological subtypes and inform future trial design. Prospective pilot testing of pragmatic yet reliable methods of defining phenotypes for use in clinical trials will be crucial to moving forward. Although the findings from the LIVE study11 are unlikely to change current clinical practice, this study is an important milestone in the efforts to advance the principles of precision medicine in the care of patients with ARDS.

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