>> So, I'm going to discuss the design and results of the effect
of targeted polymyxin B hemoperfusion on 28-day mortality in patients
with septic shock and elevated endotoxin level.
The endotoxin activity, the EUPHRATES randomized clinical trial.
I want to thank my co-authors.
That includes Massimo.
This was literally a cast of thousands to get this trial done.
It was a device trial.
It ran for over 5 years.
There were 2 primary investigators at each site.
One nephrologist and 1 intensivist and research coordinators.
All need to be thanked.
Endotoxemia and septic shock comes both from gram-negative infection but also from the gut
and is well documented to occur in gram-positive septic shock.
This was a theragnostic approach in this clinical trial combining a diagnostic test,
in this case the endotoxin activity assay, which is a rapid turnaround test
to identify significant endotoxin activity.
And followed by a polymyxin B hemoperfusion run.
This therapy targets the removal of endotoxin and is approved for use
in a number of countries around the world.
There had been conflicting multi-center randomized clinical trial results.
The EUPHAS trial suggesting benefit, and the ABDOMIX trial not showing any benefit.
Neither trial used endotoxin activity for decision on inclusion.
And neither trial was blinded, as this one was.
Fifty-five hospitals in US/Canada enrollment between 2010 and 2016.
Adults, septic shock patients
with high endotoxin assay activity, defined as 0.6 or greater.
Inclusion criteria included vasopressor therapy for at least 2 consecutive hours
at a significant dose and no more than 30 intravenous antibiotics
for known or suspected infection.
Minimum fluid therapy and 1 additional organ dysfunction.
Exclusion criteria.
There were quite a few.
The ones that I wanted to mention is you had to have achieved a blood pressure target.
You could not still be hypotensive despite vasopressors.
Patients with end stage renal disease on chronic dialysis were excluded,
because there had been some previous data
that perhaps this would be a kidney-sparing treatment.
Platelet count less than 30,000 because the active treatment arm required a femoral
hemodialysis catheter.
Known hypersensitivity to polymyxin B. Sensitivity or allergy to heparin.
And after the interim analysis, the DSMB recommended that only patients
that were more severely ill be continued to be enrolled in the trial.
Following that interim analysis, patients with MODS equal to
or less than 9 were excluded from enrollment.
Patients got initially a 2-hour hemoperfusion treatment with the polymyxin B chamber.
This was repeated in 24 hours.
This was the first hemoperfusion or hemodialysis trial
that was blinded by FDA requirement in the US.
The principal investigator, co-investigators, and clinical team were blinded.
Unblinded were the research coordinator and the nephrologist that oversaw the hemoperfusion.
There were fake catheters put on the groin in the sham group.
And curtains or doors were closed,
and the dialysis machine was run to simulate hemoperfusion.
Blinding was successful in 97% of the patients enrolled in the study.
As to the results, first let me say that there was no difference at baseline
between the 2 groups as to any demographic or preexisting condition
that would be associated with clinical outcome.
About half of the patients qualified of the patients screened that met all
of the inclusion criteria did not meet the endotoxin activity assay threshold
for enrollment.
There were 450 patients randomized into the study, 224 to the polymyxin B, 226 to the sham.
There was 1 patient lost to follow up in the polymyxin B group.
You'll see that after the amendment, there were 147 patients that completed the study
with a MODS greater than 9 in the PMX group, 148 in the sham group.
One patient again lost to follow up in the PMX group.
This shows the primary results in all participants in the study
and in the MODS greater than 9 group.
You can see there was no difference in outcome, no difference in mortality.
Very flat between the 2 treatment groups,
both in the all participants and the MODS greater than 9.
There was a per protocol analysis per the statistical analysis plan that was
to be triggered if there was a 5% difference between patients that were randomized
and patients that received 2 treatments.
Either sham or PMX.
It was triggered.
Again, the per protocol analysis including only patients that got 2 sham
or PMX treatments again did not show any difference between the groups.
These are secondary and exploratory endpoints.
This trial used what's called a hierarchical design.
Meaning that if the primary endpoint was not achieved
that all secondary endpoints were deemphasized.
That's why they're not in the main paper, which was published the week before last in JAMA.
I'm showing you these deemphasized endpoints only to point out that there was a difference
in change in mean arterial pressure in both all participants and MODS greater
than 9 that favored the PMS group.
And this had been reported in previous studies.
And there was also a difference in mechanical ventilation-free days
that favored the PMX group.
Nothing else in all of these secondary and exploratory endpoints.
It took about an hour longer to get patients started on the PMX versus the sham.
Obviously, it's a little quicker because you don't require a hemodialysis catheter.
Although we did simulate hemodialysis catheter insertion in the sham group.
There was no difference in serious adverse events between the group.
There was no difference in adverse events related
to device except 1 lower deep vein thrombosis in the device group,
1 hemorrhage in the device group, and 1 inferior vena cava thrombosis in the sham.
Surprisingly, we were not able to demonstrate reduction in endotoxin activity
between the sham and the PMX group.
We have 2-day values that were within 10 hours of the second treatment.
And we had a day-3 value that was 24 hours later.
This analysis was only done in patients that received 2 treatments,
either sham or PMX, for obvious reasons.
The MODS greater than 9 group had the same result as the all participants.
Again, failure to show reduction in endotoxin activity.
So, to finish, why did PMX hemoperfusion fail to alter clinical outcome in septic shock patients
with measured high levels of endotoxin activity?
Certainly, endotoxin removal after onset of septic shock may have no affect
on the trajectory of septic shock in these patients.
Was it underpowered for a small effect of endotoxin removal?
That is less likely, since there actually was a greater mortality in the PMX group.
Inadequate dosing of PMX column.
There is data published to indicate that enrolling patients
with very high endotoxin activity assay, as we had in this study.
Patients with 0.9 or 1, that that tremendous burden of endotoxin may not be capable
of removal to any significant degree with two 2-hour treatments.
So, in conclusion, among patients with septic shock and high endotoxin activity,
polymyxin B hemoperfusion treatment plus conventional medical therapy compared
with sham treatment plus conventional medical therapy did not reduce mortality at 28 days.
Thank you.