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Stability of ARDS subphenotypes over time in two randomised controlled trials.

ABSTRACT: RATIONALE:Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time. OBJECTIVE:To determine the stability of ARDS subphenotypes over time. METHODS:Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes. MEASUREMENTS AND MAIN RESULTS:In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment. CONCLUSIONS:ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.

SUBMITTER: Delucchi K

PROVIDER: S-EPMC6497167 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Stability of ARDS subphenotypes over time in two randomised controlled trials.

Delucchi Kevin K Famous Katie R KR Ware Lorraine B LB Parsons Polly E PE Thompson B Taylor BT Calfee Carolyn S CS

Thorax 20180224 5

<h4>Rationale</h4>Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time.<h4>Objective</h4>To determine the stability of ARDS subphenotypes over time.<h4>Methods</h4>Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only ...[more]

PMID: 29477989

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Project description:Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder.We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort.We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days).We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials.National Institutes of Health.

Project description:AIMS/HYPOTHESIS:This study aimed to evaluate the effect of ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.gov NCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population. METHODS:Post hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks. RESULTS:Overall, mean (SD) baseline eGFR was 88.2 (18.8) ml min-1 (1.73 m)-2 and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were -2.3, -2.7 and -0.7 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were -0.2, 0.1 and -2.0 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was -29.5% (-44.8, -9.8; p?<?0.01) for ertugliflozin 5 mg and -37.6% (-51.8, -19.2; p?<?0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA1c (mmol/mol [95% CI]) at week 104 were similar between treatment groups: -6.84 (-7.64, -6.03), -7.74 (-8.54, -6.94) and -6.84 (-7.65, -6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c (% [95% CI]) at week 104 were: -0.63 (-0.70, -0.55), -0.71 (-0.78, -0.64) and -0.63 (-0.70, -0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. CONCLUSIONS/INTERPRETATION:Ertugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria. TRIAL REGISTRATION:clinicaltrials.gov NCT01999218 and NCT02033889.

Project description:Driving pressure (?Prs) across the respiratory system is suggested as the strongest predictor of hospital mortality in patients with acute respiratory distress syndrome (ARDS). We wonder whether this result is related to the range of tidal volume (VT). Therefore, we investigated ?Prs in two trials in which strict lung-protective mechanical ventilation was applied in ARDS. Our working hypothesis was that ?Prs is a risk factor for mortality just like compliance (Crs) or plateau pressure (Pplat,rs) of the respiratory system.We performed secondary analysis of data from 787 ARDS patients enrolled in two independent randomized controlled trials evaluating distinct adjunctive techniques while they were ventilated as in the low VT arm of the ARDSnet trial. For this study, we used VT, positive end-expiratory pressure (PEEP), Pplat,rs, Crs, ?Prs, and respiratory rate recorded 24 hours after randomization, and compared them between survivors and nonsurvivors at day 90. Patients were followed for 90 days after inclusion. Cox proportional hazard modeling was used for mortality at day 90. If colinearity between ?Prs, Crs, and Pplat,rs was verified, specific Cox models were used for each of them.Both trials enrolled 805 patients of whom 787 had day-1 data available, and 533 of these survived. In the univariate analysis, ?Prs averaged 13.7?±?3.7 and 12.8?±?3.7 cmH2O (P?=?0.002) in nonsurvivors and survivors, respectively. Colinearity between ?Prs, Crs and Pplat,rs, which was expected as these variables are mathematically coupled, was statistically significant. Hazard ratios from the Cox models for day-90 mortality were 1.05 (1.02-1.08) (P?=?0.005), 1.05 (1.01-1.08) (P?=?0.008) and 0.985 (0.972-0.985) (P?=?0.029) for ?Prs, Pplat,rs and Crs, respectively. PEEP and VT were not associated with death in any model.When ventilating patients with low VT, ?Prs is a risk factor for death in ARDS patients, as is Pplat,rs or Crs. As our data originated from trials from which most ARDS patients were excluded due to strict inclusion and exclusion criteria, these findings must be validated in independent observational studies in patients ventilated with a lung protective strategy.Clinicaltrials.gov NCT00299650 . Registered 6 March 2006 for the Acurasys trial. Clinicaltrials.gov NCT00527813 . Registered 10 September 2007 for the Proseva trial.

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Stability of ARDS subphenotypes over time in two randomised controlled trials.

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Stability of ARDS subphenotypes over time in two randomised controlled trials.

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