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EUPHRATES Trial Publication

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The post hoc analysis of the EUPHRATES trial has recently been published in Intensive Care Medicine (1). This analysis follows the results concerning the Overall Population, recently published in JAMA (2). Although the primary endpoint was not met in the Overall Population, important statistically significant clinical results were obtained in a specific septic shock population with endotoxemia treated with Polymyxin B hemoperfusion therapy.

In particular, in patients with septic shock, MOD score > 9 and EAA level from 0.6 to 0.89, it was demonstrated that:

181217-EUPHRATES-results-infographic_EN

Although these results come from a post hoc analysis it should be considered that to this date no other Blood Purification Therapy for the treatment of septic shock has demonstrated a signal of this order of magnitude in terms of mortality reduction and other clinical benefit.

The EUPHRATES double-blinded randomized clinical trial was carried out in 55 North American tertiary hospitals in the period from September 2010 to June 2016.

The primary endpoint of EUPHRATES was to test whether Polymyxin B Hemoperfusion (PMX-HP) in addition to standard therapy improves 28-day survival compared with standard therapy alone among patients with septic shock and high endotoxin activity (EAA ≥ 0.6 measured with the Endotoxin Activity Assay, EAA™).

The study enrolled 450 patients for randomization (n= 224 PMX-HP/ n= 226 SHAM). Following an interim analysis enrollment was restricted to patients with a MOD score above 9 (n= 295 patients, 147 PMX-HP/148 SHAM).

Although in the overall population mean arterial pressure (MAP) from baseline to day 3 was significantly improved in the PMX-HP group compared to the sham group (P < 0.005) and the PMX-HP group had significantly more ventilator-free days until day 28 compared to the sham group (P = 0.02), there was no significant difference in 28-day mortality between the two groups.

By considering the population with MOD score > 9, EAA > 0.6 and a complete scheme of two treatments received (Per Protocol Population n= 244), a signal of reduction in 28-day mortality in favor of PMX-HP therapy was registered, but not statistically significant (38/115 (33.0) 47/129 (36.4), −3.4% (−15.2 to 9.0) P=0.58).

Interestingly, the study showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). A subsequent in vitro study (3) found that EAA ≥ 0.9 seem to represent a critical threshold for the EAA and that the patient’s endotoxin burden might be immeasurable at this level.

A post hoc analysis was therefore undertaken to evaluate the impact of PMX-HP in the patient population with septic shock, MODS > 9 and EAA 0.6 to 0.89 who received the full two treatments of PMX-HP or sham.

 

Results

 

  • Significant absolute mortality reduction of 10.7%(adjusted for APACHE II score and MAP); 28-day mortality in the PMX-HP group was 26.1% (23/88) and in the SHAM group 36.8% (39/106), P = 0.047 [risk difference 10.7%, OR 0.52, 95% CI (0.27-0.99), P = 0.047].
  • The mortality improvement was consistent to 90 days: PMX-HP group 29.5% (26/88) and in the SHAM group 40.6% (43/106), P = 0.02 [risk difference 11.0%, OR 0.57, 95% CI (0.35-0.93), P = 0.02].
  • Patients treated with PMX-HP showed a significant improvement in MAP compared to the SHAM group [+ 8 mmHg median (IQR) (-0.5-19.5) vs. 4 mmHg (-4.0-11), P <0.05].
  • Patients treated with PMX-HP showed a significant improvement in ventilator-free days (VFD) to 28 days compared to the SHAM group [20 median (IQR) (0.5-23.5) vs. 6 median (IQR) (0-20), P = 0.004].
  • Patients treated with PMX-HP who had norepinephrine > 0.1 μg/kg/min at baseline demonstrated an even higher 28-day mortality reduction compared to the SHAM group [PMX-HP 17/69 (24.6%) vs. SHAM 34/85 (40.0%)].

 

Conclusion

The results of EUPHRATES and in particular the subsequent post hoc analysis highlight the importance of suggesting precision therapies for specific populations. In selected patients, in this case patients with septic shock, MODS > 0.9 and EAA of 0.6 to 0.89 Polymyxin B Hemoperfusion resulted in significant improvement in mean arterial pressure, ventilator-free days and mortality.

 

It is important to notice that these results are in line with previously published studies:

 

  • The EUPHAS RCT trial found a significant survival benefit of PMX-HP in post-surgical abdominal patients with septic shock not responding to conventional therapies (4).

 

  • A propensity-matched analysis of nearly 4000 patients with septic shock, and on CRRT due to AKI, showed a significant better survival in patients who were treated with PMX-HP compared to those who only received standard therapy (5).

 

  • A meta-analysis of 17 studies (5 RCTs and 12 non-RCTs) showed a significant beneficial effect of PMX-HP on mortality in patients with severe sepsis and septic shock, in particular in intermediate- and high-risk groups (6).

 

Until now Polymyxin B hemoperfusion is the only Blood Purification therapy described in International Surviving Sepsis Guidelines (2016) for the treatment of endotoxic septic shock (not recommended in favour – not recommmended against) (7). PMX-HP was recommended by the ADQI study group in 2016 (8). More than 150.00 patients have been treated with PMX-HP therapy and more than 300 peer-reviewed articles have been published.

 

References

  1. Klein, D. J., Foster, D., Walker, P. M., Bagshaw, S. M., Mekonnen, H., and Antonelli, M. (2018) Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive care medicine (Pubmed)
  2. Dellinger, R. P., Bagshaw, S. M., Antonelli, M., Foster, D. M., Klein, D. J., Marshall, J. C., Palevsky, P. M., Weisberg, L. S., Schorr, C. A., Trzeciak, S., and Walker, P. M. (2018) Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial. JAMA : the journal of the American Medical Association320, 1455-1463 (Pubmed)
  3. Romaschin, A. D., Obiezu-Forster, C. V., Shoji, H., and Klein, D. J. (2017) Novel Insights into the Direct Removal of Endotoxin by Polymyxin B Hemoperfusion. Blood purification44, 193-197 (Pubmed)
  4. Cruz, D. N., Antonelli, M., Fumagalli, R., Foltran, F., Brienza, N., Donati, A., Malcangi, V., Petrini, F., Volta, G., Bobbio Pallavicini, F. M., Rottoli, F., Giunta, F., and Ronco, C. (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA : the journal of the American Medical Association301, 2445-2452 (Pubmed)
  5. Iwagami, M., Yasunaga, H., Noiri, E., Horiguchi, H., Fushimi, K., Matsubara, T., Yahagi, N., Nangaku, M., and Doi, K. (2016) Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis. Blood purification42, 9-17 (Pubmed)
  6. Chang, T., Tu, Y. K., Lee, C. T., Chao, A., Huang, C. H., Wang, M. J., and Yeh, Y. C. (2017) Effects of Polymyxin B Hemoperfusion on Mortality in Patients With Severe Sepsis and Septic Shock: A Systemic Review, Meta-Analysis Update, and Disease Severity Subgroup Meta-Analysis. Critical care medicine45, e858-e864 (Pubmed)
  7. Rhodes, A., et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.Intensive Care Med, 2017 (Pubmed)
  8. Cerda, J., et al., Role of Technology for the Management of AKI in Critically Ill Patients: From Adoptive Technology to Precision Continuous Renal Replacement Therapy.Blood Purif, 2016. 42(3): p. 248-265 (Pubmed)