Dear Editor,

The effectiveness of polymyxin B hemoperfusion (PMX-HP) in septic shock is still controversial and has not been proven in randomized controlled trials (RCTs) with mortality as an endpoint. A recently published observational study, which analyzed a Japanese real-world big data, reported that the efficacy of PMX-HP depends on the baseline Sequential Organ Failure Assessment (SOFA) score and is effective in patients with moderate levels of organ damage. In the Surviving Sepsis Campaign guideline 2021, PMX-HP treatment is recommended as “suggested against” for sepsis and septic shock. The recommendation is mainly based on the results of a few RCTs and does not reflect the results of observational studies. Recently, there has been a growing consensus that large-scale observational studies are also important among clinical studies on sepsis. We believe that the combined approach, that is to identify appropriate patients through the analysis of real-world data and to validate them by a well-designed prospective trial, is crucial in the development and evaluation of sepsis therapies including PMX-HP.

There have been increasing reports on the effectiveness of various blood purification therapies on sepsis. However, the benefits of these treatments remain controversial. Regarding PMX-HP, although several RCTs have been conducted, clear survival benefits have not been evidenced so far. The EUPHAS Study [1] showed improved survival in the PMX-HP group, while the ABDO-MIX study [2] and the EUPHRATES Trial [3] failed to provide evidence on the mortality reduction.

I read with great interest the paper by Fujimori et al. [4] that examined the relationship between the efficacy of PMX-HP and the baseline SOFA score using a large Japanese inpatient database. The authors found a significant survival benefit of PMX-HP in patients with SOFA scores in the range of 7–12 but not in those with lower severity (SOFA ≤ 6) or very high severity (SOFA ≥ 13). We think this result agrees well with the results of the subgroup analysis of the EUPHRATES trial, which reported that patients with Endotoxin Activity Assay (EAA) levels of 0.6–0.9, excluding those with EAA > 0.9 who are a particularly severe population, showed a significant survival benefit of PMX-HP [5]. In addition, in the analysis of the multicenter EUPHAS 2 registry data of PMX-HP treated patients, the European cohort with the mean baseline SOFA score of 11.8 showed a significantly better survival rate compared to the Asian cohort with the mean baseline SOFA score of 15.6 [6]. These results suggest that the efficacy of PMX-HP is prominent in patients with a medium severity of organ damage.

The TIGRIS trial, a second Phase III trial targeting the highly effective patient group found in the sub-analysis of the EUPHRATES trial, has been approved by the FDA and is currently underway [7]. A protocol amendment to use SOFA scores in addition to MODS as patient enrollment criteria has also been approved by the FDA.

The Surviving Sepsis Campaign guideline 2021 states that PMX-HP treatment is “suggested against” in cases of sepsis or septic shock [8]. However, we believe that some caution should be exercised in interpreting this recommendation. The recommendations in the guideline are mainly based on the results of RCTs and do not reflect the results of observational studies. Recently, there has been a growing consensus that observational studies are also important among clinical studies on sepsis [9]. Using Japanese sepsis patient registry data, we reported that PMX-HP contributes to improved survival and shorter intensive care unit stays in patients with septic shock [10].

Another point to consider is how to define endpoints for clinical studies on sepsis. When establishing guideline recommendations, mortality is evaluated as the main outcome. Although mortality is objective and directly related to patient benefit, there is a growing consensus that it is not always appropriate as the primary endpoint of studies on sepsis [11‒13]. The causes of death are diverse, and short-term treatment targeting a single pathogenic process of sepsis is unlikely to result in improved survival. Intermediate endpoints such as change in organ dysfunction score, time to shock reversal or organ-support free days should also be considered as endpoints.

In summary, clinical studies on sepsis should be conducted on appropriate patients and using appropriate evaluation indices. We believe that the combined approach, that is to identify candidate patient groups through the analysis of real-world big data and to validate them by well-designed prospective trials, is crucial in the evaluation of various treatments of sepsis, including blood purification therapies.

The author has no conflicts of interest to declare.

No external funding.

Horoyasu Ishikura has written the paper. The author read and approved the final manuscript.

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