Review on the Eolia trial - posted by Dr Ketan Kargirwar

Clinical Question ▪ In patients with severe ARDS, does the early initiation of Extracorporeal Membrane Oxygenation (ECMO), compared to standard care, improve mortality at day 60.

Highlight of Trial
 ▪ The trial was conducted with sequential design methodology according to the triangular test.
 ▪ Triangular test designs have the advantage of allowing a study to be stopped early either for efficacy or for futility.
 ▪ The stopping rules were defined prior to the commencement of the trial. The trial could be stopped due to: ▪ Safety ▪ Efficacy ▪ Futility (ie unlikely to reach a definitive result)
▪ The data safety monitoring board (DSMB) recommended stopping the trial after the 4th interim analysis 249/331 (75% of planned recruitment) when it met the predefined stopping rules for futility. ▪ A post hoc rank preserving structural failure time analysis was performed to adjust for high rate of crossover in the control group in the estimation of the “actual and unbiased” ECMO effect on survival.

Outcome
 ▪ Primary outcome: No statistical difference in mortality at day 60 ▪ ECMO group 44/124 (35%) vs Control group 57/125 (46%) ▪ Relative risk, 0.76; 95% confidence interval [CI], 0.55 to 1.04; P=0.09 ▪

▪ Secondary outcomes: ▪ Compared to control group, the ECMO group had:
▪ Lower relative risk of treatment failure 0.62 (95% CI, 0.47 to 0.82; P<0.001) ▪ Treatment failure was defined as death by day 60 in patients in the ECMO group, and as crossover to ECMO or death in patients in the control group
 ▪ Lower risk of Renal replacement therapy (RRT) at day 60 (50 vs. 32 days; median difference, 18 days; 95% CI, 0 to 51)
 ▪ Underwent less proning (59 vs. 46 days; median difference, 13 days; 95% CI, 5 to 59)
 ▪ Cross over to ECMO occurred in 35/125 (28%) of control patients ▪ Occurred at median 4 days (IQR 1 to 7) ▪ Median PaO2:FiO2 51 mmHg (IQR 46 to 61), median SaO2 77% (IQR 74 to 87), median lactate was 3.2 mmol/L (1.5-6.2) ▪ 9 patients had cardiac arrest, 7 had right heart failure, 11 received RRT ▪ 7 underwent venoarterial (VA) ECMO (and 6 had E-CPR)
▪ 60 day mortality was higher in cross over patients than rest of controls: 20/35 (57%) in cross over patients vs 90 (41%) in remaining cross over patients ▪ The hazard ratio for death within 60 days, for the ECMO group compared to controls after adjusting for selective crossover with the rank-preserving structural failure time analysis, was 0.51 (95% CI, 0.24 to 1.02; P=0.055) ▪

Weaknesses ▪ Underpowered to answer the trial question.
▪ Trial was stopped early at 249/331 (75% of recruitment) due to predefined futility rules (ie unlikely to get a definitive result.
▪ Initial power calculation was based on a 60% mortality in the control group, which became clear was inflated compared to the actual mortality rate in the controls of 46%.
 ▪ A 20% absolute risk reduction sets a very large requirement for a single ICU intervention, increasing the risk of a falsely negative trial (CESAR, published in 2009, had a ARR of 16%)
 ▪ High cross over rate of controls
▪ The 28% cross over rate resulted a reduction of separation between the two arms, and diluted the ECMO treatment effect. This potentially impacted the trial in the following ways:
 ▪ The cross over complicates the interpretation of the two arms in an intention to treat analysis.
▪ It also introduces a potential bias against the ECMO group in the secondary risk of treatment failure analysis, as ECMO was initiated much later and in sicker patients than the rest of the controls
▪ Despite the use of objective criteria, the decision to crossover controls to ECMO was ultimately at the discretion of unblinded treating clinicians
 ▪ Equipoise – high cross over rate raises the question whether some clinicians had clinical equipoise ▪ Lack of blinding of clinicians and patients/families (however difficult in such a trial)
 ▪ Slow recruitment of 249 patients over 6 years, leading to potential trial fatigue and/or change of practice.
 ▪ Expertise of ECMO centers not clearly defined ▪ Importance of VV ECMO configuration is uncertain (i.e. femoral-jugular versus femoral-femoral approach)
▪ Majority of ARDS patients in this trial were male and had pneumonia and septic shock. Extrapolation to other ARDS patient groups is uncertain
 ▪ The trial does not distinguish between the use of VV ECMO and VA ECMO. In particular, 7 cross over control patients underwent VA ECMO for cardiac arrest

Will EOLIA change my practise of ECMO in ARDS : There is no right or wrong answer !!! but, we should continue to use ECMO for clinical benefit in selected group of patients with the help of experts and dedicated ECMO centre as a rescue therapy in severe ARDS patients. The result of the trial produce equipoise among the clinicians due to crossover of patients. However until now there is very less data on this intervention in ARDS patients and it might be difficult to conduct another new large RCT in near future to rule out this uncertainty. Also with the diversity in practices of ECMO all over the world and with evolving technology of ECMO there is substantial consensus around use of early ECMO in ARDS.
Dr Ketan kargirwar