Failure to Improve the Oxygenation Index Is a Useful Predictor of Therapy Failure in Acute Respiratory Distress Syndrome Clinical Trials.

OBJECTIVE

Acute respiratory distress syndrome trials powered for mortality require significant resources, limiting the number of evaluable therapies. Validation of intermediate endpoints would enhance the feasibility of testing novel acute respiratory distress syndrome therapies in pilot studies and potentially reduce the frequency of failed large clinical trials. We sought to determine whether a change in the oxygenation index over the first 7 days of acute respiratory distress syndrome could discriminate between therapies likely or unlikely to show benefit in larger clinical trials.

DESIGN

A derivation cohort from three acute respiratory distress syndrome studies was used to estimate the 7-day change in oxygenation index. Receiver operating characteristic curves were used to calculate optimal thresholds and predictability of the change in oxygenation index for 28-day mortality and ventilator-free days. The thresholds were then validated in two cohorts. Then, for each individual acute respiratory distress syndrome study, the threshold 7-day oxygenation index change was tested as an outcome measure and compared with mortality and ventilator-free days as reported in the original study.

SETTING

Medical ICUs.

PATIENTS

Acute respiratory distress syndrome patients.

INTERVENTIONS

Various.

MEASUREMENTS AND MAIN RESULTS

Change in oxygenation index, 28-day mortality, and ventilator-free days. In the derivation cohort, the mean 7-day oxygenation index improved by 4.2 (± 11.7) in 28-day survivors compared with an increase of 2.4 (± 11.6) in 28-day nonsurvivors (p < 0.001). The mean 7-day oxygenation index decreased by 5.9 (± 8.4) in patients with more than 14 ventilator-free days, compared with a decrease of 1.9 (± 12.4) among those with less than 14 ventilator-free days (p = 0.001). The optimal 7-day oxygenation index threshold for predicting mortality was an increase of 1.71 and for predicting less than 14 ventilator-free days, a decrease of 2.34. When used as a surrogate endpoint, the optimal 7-day oxygenation index change closely approximated mortality and ventilator-free day outcomes in three Acute Respiratory Distress Syndrome Network studies used for the derivation cohort and a distinct study used for validation. The change in oxygenation index was a poor predictor of individual patient outcome.

CONCLUSIONS

Failure to meet a threshold improvement in the oxygenation index over the first 7 days of therapy can be used to identify therapies unlikely to succeed in subsequent trials powered for mortality and ventilator-free days. By reducing trial time and costs, use of the 7-day oxygenation index change as an intermediate endpoint could increase the number of clinical trials of promising therapies for acute respiratory distress syndrome and reduce the number of large-scale trials of therapies unlikely to be of benefit.