Between-trial heterogeneity in ARDS research

Abstract

Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome.

Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity.

Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I² = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001).

Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics.

Keywords: ARDS; Critical Care Research; Heterogeneity.

Fig. 1

28-day control group mortality for individual trial characteristics. The diamond represents the mean mortality rate (peak) with the corresponding 95% confidence interval (length of diamond). The black line denotes the 95% prediction interval, which is the estimated between-trial variability in mortality rates after adjusting for random chance and sample size, i.e. the between-trial heterogeneity. I² represents the proportion of between-trial variability that cannot be explained by chance.

Fig. 2

Heatmap of control group outcomes and baseline characteristics. On the y-axis, all included trials are ordered from highest to lowest (estimated) 28-day mortality rate. The color of a tile represents whether, for a specific trial, a reported variable was lowest (blue) or highest (red) among all trials that reported the variable. A white tile represents a variable not reported by a specific trial. The X-axis depicts the most reported baseline characteristics. Some show a concordant pattern (e.g. age) with 28-day mortality while others do not (e.g. SAPS II score, SOFA score). Most importantly, the distribution of white tiles demonstrates the large variability in the reporting of baseline characteristics.

Fig. 3

Differences in 28-day control group and intervention group mortality between significant and indeterminate trials, and the corresponding probability of a significant treatment effect. a Mean 28-day control group mortality was 43.9% in trials with a beneficial outcome versus 27.5% in trials with an indeterminate outcome or significant harm (p = 0.001). b The higher control group mortality, the higher the probability to obtain a beneficial trial outcome for the intervention group (p = 0.012). c Mean 28-day intervention group mortality does not differ between trials with significant benefit and trials with the indeterminate outcome or significant harm. (27.1% vs. 30.1%; p = 0.697). d The probability to obtain a beneficial trial outcome was not affected by intervention group mortality (p = 0.410)