Study Results

DPC data analysis(2)Observational Study

Study design
Propensity-matched analysis of a Japanese nationwide registry data.
Patients
Patients aged 20 years or older who met the following criteria: (1) whose primary diagnosis was sepsis based on the ICD-10 codes and (2) administered noradrenaline during the hospitalization. Patients who died within 3 days after the start of noradrenaline or transferred to other hospitals within 28 were excluded.
Primary endpoint
The 28-day mortality, counting from the day of shock onset (the day of first noradrenaline administration).
Secondary endpoint
Noradrenaline-, CHDF-, and ventilator-free days at day 28.
Main results
  • A total of 30,731 patients (4,766 with PMX and 25,965 without) met the selection criteria and were included in the analysis. As a result of propensity score (PS) matching, 4,141 pairs of patients in each group were created.
  • The survival rate at 28 days after the onset of shock was 77.9% in the PMX group and 71.1% in the control group, which was significantly higher in the PMX group (p＜0.0001).
  • Noradrenaline-, CHDF-, and ventilator-free days at day 28 (median, interquartile range) were 24 (11-26) days in the PMX group and 22 (0-25) days in the control group (p＜0.0001), 24 (9-28) days in the PMX group and 22 (0-28) days in the control group (p＜0.0001), and 20 (1-28) days in the PMX group and 14 (0-28) days in the control group (p＜0.0001), respectively, all of which were significantly longer in the PMX group.
  • The odds ratio of survival with and without PMX was examined in four subgroups stratified by the maximum noradrenaline dose per day. The survival rate of the PMX group was significantly higher in the three groups with doses of less than 20 mg/day, but there was no significant difference in the group with dose of 20 mg/day or higher.
Reference
  • “Effects of Polymyxin B Hemoperfusion on Septic Shock Patients Requiring Noradrenaline: Analysis of a Nationwide Administrative Database in Japan.”
    Fujimori K et al. Blood Purif(Feb 12, 2021 online) PubMed

EUPHRATES TrialRCT

Study sites
55 ICUs in US and Canada
Study design

Multi-centered, double blind, randomized controlled study

  • Control arm：standard medical care
  • PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion
Patients

Septic shock patients with age >= 18, who meets all of the following criteria

  • Septic shock requiring vasopressor support
  • At least 1 new onset organ dysfunction
  • Endotoxemia (≥ 0.60 Endotoxin Activity Assay)
  • Multiple Organ Dysfunction Score (MODS) > 9 (Criteria added after interim analysis)
Primary endpoint
Mortality at day 28
Secondary endpoint
Survival time from baseline to death within 28 days, Improvement of organ function from baseline to day 3, Change in MAP from baseline to day 3, Change in CVI (cardiovascular index) from baseline to day 3, Mechanical ventilation and RRT alive and free days etc.
Main results
  • 450 patients met the inclusion criteria and randomized (ITT population). Among them, 294 patients were MODS > 9. 375 patients completed the planned two sessions of treatment (Per Protocol population). Among them, 245 were MODS > 9.
  • Mortality at 28 day in ITT population was 37.7% for PMX arm and 34.5% for control arm.
  • Mortality at 28 day in ITT population with MODS > 9 was 44.5% for PMX arm and 43.9% for control arm.
  • Mortality at 28 day in Per Protocol population was 28.9% for PMX arm and 29.2% for control arm.
  • Mortality at 28 day in Per Protocol population with MODS > 9 was 33.0% for PMX arm and 36.4% for control arm.
  • Increase in mean arterial pressure (from baseline to 72h) was significantly higher in PMX arm compared to control arm (in ITT population, PMX arm:9.4mmHg vs control arm：4.1mmHg, p<0.005, in MODS>9 population, PMX arm:8.1mmHg vs control arm：3.9mmHg, p=0.02）. In addition, the ventilator free days in the patient group of MODS> 9 was significantly longer in PMX group (PMX arm: 12.7 days vs. sham arm: 9.8 days, p = 0.02).
  • There were a total of 264 serious adverse events, with a frequency of 65.1% in the PMX arm and 57.3% in the control arm. Common serious adverse events were worsening of sepsis (PMX arm: 10.8% vs. control arm: 9.1%) and septic shock (PMX arm: 6.6% vs. control arm: 7.7%).
  • As a result of subgroup analysis, a high effect of PMX was found in the group of 194 patients in the range of EAA value 0.6-0.89. In this group of patients, the mortality after 28 days was 26.8% for PMX arm and 36.8% for control arm. Logistic regression analysis adjusted with baseline mean arterial pressure and APACHE II score showed significant differences between groups.
Reference
  • “The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial.”
    Klein DJ et al. Trials (2016) 15:218 PubMed
  • “Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.”
    Dellinger RP et al. JAMA (2018) 320:1455-63 PubMed
  • “Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial.”
    Klein DJ et al. Intensive Care Med (2018) 44:2205-12 PubMed

JSEPTIC DIC StudyObservational Study

Study design
Retrospective observational study conducted in 42 ICUs in Japan.
Database of sepsis regstry (Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study Database) was analyzed by propensity score matching analysis.
Patients
Septic shock patients, age >= 16, who received vasopressor at the day of ICU admission with cardiovascular SOFA score >= 3.
Primary endpoint
All-cause hospital mortality
Secondary endpoint
ICU mortality, number of ICU-free days (ICUFDs) in the first 28 days.
Main results
  • Of 1,723 eligible patients, 522 had received PMX-HP. Propensity score matching created 262 matched pairs (i.e., 262 patients in each of the non-PMX-HP and PMX-HP groups).
  • The proportion of all-cause hospital mortality was significantly lower in the PMX-HP group than in the non-PMX-HP group (32.8% vs. 41.2%; odds ratio (OR): 0.681; 95% confidence interval (CI): 0.470–0.987; P = 0.042).
  • The number of ICUFD in the first 28 days was significantly higher in the PMX-HP group than in the non-PMX-HP group (18 (0-22) vs. 14 (0-22) days, respectively; P = 0.045).
  • there was no significant difference in ICU mortality between the two groups (21.8% vs. 24.4%; OR:0.844; CI: 0.548–1.300; P = 0.443).
Reference
  • “Potential survival benefit of polymyxin B hemoperfusion in patients with septic shock: a propensity-matched cohort study.”
    Nakamura Y et al. Crit Care (2017) 21:134 PubMed

EUPHAS2 StudyRegistry

Study design
Multi-centered registry
Patients
Severe sepsis or septic shock patients who received PMX treatment
Main results
  • Data between 2010 and 2014 were analyzed. Registry is ongoing.
  • 357 cases were registered from 57 centers (Europe: 46, Asia (India): 11).
  • Of the 357 cases, 305 were septic shock. Main infection sites were the abdomen (44%) and the lungs (17.6%).
  • Adverse events were recorded in 26 out of a total of 576 sessions, which includes tachycardia: 2, blood pressure reduction: 10, hemorrhage: 1, and column coagulation: 13. None of these adverse events caused clinical worsening or death of the patients.
  • After 72 h from the first cycle of PMX-HP, SOFA score improved significantly (before treatment:12.4±4.2, 72h:10.5±5.3, P<0.001). Also, cardiovascular, respiratory and renal SOFA score significantly improved. Inotropic score and lactate levels decreased significantly. Coagulation SOFA significantly increased, reflecting the reduction of platelet counts.
  • Overall 28-day survival rate was 54.5 %. Patients with abdominal infection treated with PMX-HP within 24 h from the diagnosis of septic shock had a 28-day survival rate of 64.5 %. Patients showing a significantly cardiovascular improvement after PMX-HP had a 28-survival rate of 75 % in comparison to the 39 % of patients who did not (p < 0.001).
Reference
  • “Polymyxin‑B hemoperfusion in septic patients: analysis of a multicenter registry.” Cutuli SL et al. Ann Intensive Care (2016) 6:77 PubMed
Study Web Site
https://www.euphas2.eu/

DPC data analysis(1)Observational Study

Study design
Propensity-matched analysis of a Japanese nationwide database
Patients
Adult patients in the Japanese diagnosis procedure combination (DPC) database satisfying the following criteria: hospitalized in 2007–2012; diagnosed as having sepsis; required noradrenaline and/or dopamine; and started CRRT in intensive care unit
Primary endpoint
28-day in-hospital mortality
Secondary endpoint
Duration of CRRT and vasopressors (noradrenaline or dopamine) among survivors.
Main results
  • Of 3,759 eligible patients, 1,068 received PMX. Propensity-score matching produced a matched cohort of 978 pairs.
  • The 28-day mortality was 40.2% (393/978) in the PMX group and 46.8% (458/978) in the control group (p = 0.003).
  • Logistic regression analysis revealed a significant association between the use of PMX and decreased 28-day mortality　(adjusted OR 0.75; 95% CI 0.62–0.91).
  • When differentiating the number of PMX sessions (1 or 2) incorporated in the multivariable logistic regression model, the adjusted OR of 28-day mortality was 0.83 (95% CI 0.67–1.02) for the one PMX session group and 0.64 (95% CI 0.49–0.83) for the 2 PMX session group as compared with the no PMX group.
Reference
  • “Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis.”
    Iwagami M et al. Blood Purif (2016) 42:9-17 PubMed

ABDO-MIX StudyRCT

Study sites
18 ICUs in France
Study design

Multi-centered randomized, open-label study

  • Control arm：standard medical care
  • PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion
Patients
Septic shock adult patients who underwent emergency surgery to treat visually confirmed peritonitis.
Primary endpoint
Mortality on day 28
Secondary endpoint
Mortality on day 90, reduction in the severity of organ failures based on Sequential Organ Failure Assessment (SOFA) scores.
Main results
  • Among the 938 screened patients, 243 patients were randomly assigned to the study. Eleven patients were excluded due to refusal to participate and 232 patients (113 in the PMX group and 119 in the control group) were followed up to 90 days.
  • Day 28 mortality in the PMX HP group (n = 119) was 27.7 versus 19.5 % in the conventional group (n = 113), p = 0.14 (OR 1.5872, 95 % CI 0.8583–2.935).
  • Mortality rate at day 90 was 33.6 % in PMX-HP versus 24 % in conventional groups, p = 0.10 (OR 1.6128, 95 % CI 0.9067–2.8685); reduction in SOFA score from day 0 to day 7 was -5 (-11 to 6) in PMX-HP versus -5 (-11 to 9), p = 0.78. There were no significant differences of frequency of Adverse Events between the two groups.
  • Among the 220 PMX sessions performed, premature interruption was observed in 25 cases (11 %) mainly during the first session and especially due to circuit clotting. In total, 2 PMX sessions were completed in only 81 of 119 patients (69.8 %).
Reference
  • “Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial.”
    Payen DM et al. Intensive Care Med (2015) 41:975-84 PubMed
  • “Polymyxin B hemoperfusion in septic shock: just look at the evidence!”
    Antonelli M et al. Intensive Care Med (2015) 41:1731-2 PubMed

EUPHAS StudyRCT

Study sites
10 ICUs in Italy
Study design

Multi-centered randomized, open-label study

  • Control arm：standard medical care
  • PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion
Patients
Severe sepsis or septic shock due to intra-abdominal cavity infection requiring emergency surgery
Primary endpoint
Change in MAP and vasopressor requirement
Secondary endpoint
PaO2/FIO2 (fraction of inspired oxygen) ratio, change in organ dysfunction measured using Sequential Organ Failure Assessment (SOFA) scores, and 28-day mortality
Main results
  • 64 patients (34 in the PMX group and 30 in the control group) entered the study
  • MAP increased (76 to 84 mm Hg; P=0.001) and vasopressor requirement decreased (inotropic score, 29.9 to 6.8; P=0.001) at 72 hours in the PMX group but not in the control group (MAP, 74 to 77 mm Hg; P=.37; inotropic score, 28.6 to 22.4; P=.14). The PaO2/FIO2 ratio increased (235 to 264; P=0.049) in the polymyxin B group but not in the conventional therapy group (217 to 228; P=0.79).
  • SOFA scores improved in the polymyxin B group but not in the conventional therapy group (change in SOFA, −3.4 vs −0.1; P=0.001).
  • 28-day mortality was 32% (11/34 patients) in the polymyxin B group and 53% (16/30 patients) in the conventional therapy group (unadjusted hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20-0.94; adjusted HR, 0.36; 95% CI, 0.16-0.80).
Reference
  • “Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock.”
    Cruz DN et al. JAMA (2009) 301:2445-52 PubMed