Cytokine hemoadsorption during cardiac surgery versus standard surgical care for infective

endocarditis (REMOVE): results from a multicenter, randomized, controlled trial

Diab M, Lehmann T, Bothe W, Akhyari P, Platzer S, Wendt D, Deppe AC, Strauch J, Hagel S, Günther
A, Faerber G, Sponholz C, Franz M, Scherag A, Velichkov I, Silaschi M, Fassl J, Hofmann B, Lehmann S,
Schramm R, Fritz S, Szabo G, Wahlers T, Matschke K, Lichtenberg A, Pletz MW, Gummert JF,
Beyersdorf F, Hagl C, Borger MA, Bauer M, Brunkhorst FM, Doenst T on behalf of the REMOVE Trial
Investigators
Circulation 2022; epub

Multi-Center RCT / 138 pts vs 144 pts / Infective Endocarditis

Medical Notes
From the medical perspective, please note the following:

1) REMOVE is the first multi-center, randomized, control trial investigating the efficacy of CytoSorb in
reducing the severity of postoperative organ dysfunction in an adequately powered population of
patients undergoing surgery for infective endocarditis (IE).
2) 282 all-comer IE patients undergoing cardiac surgery from 14 German heart centers were randomly
assigned to either CytoSorb (138 pts) or Control group (144 pts). Eligible subjects needed to have
EuroSCORE II > 3 (EuroSCORE ≥ 7 is considered indicative for high operative risk). Both groups were
well balanced in regards to baseline characteristics. The overall distribution of patients according to
the timing of surgery was around 28% elective, 9% emergency (≤ 24 hrs), and 63% urgent (< 7 days).
3) Since the pilot study1 to REMOVE showed that levels of cytokines were much more
prominent in IE patients on cardiopulmonary bypass (CPB), and that there was a significant
correlation between the plasma levels of interleukin (IL)-6, procalcitonin (PCT), and
midregional pro-Adrenomedullin (MR-proADM) during CPB and the severity of
postoperative organ dysfunction, the authors decided to investigate hemoadsorption in
patients undergoing cardiac surgery for IE and its ability to reduce the severity of
postoperative organ dysfunction, as measured by changes in the sequential organ failure
assessment (SOFA) score.
4) The primary outcome (∆SOFA) was defined as the difference between the mean total
postoperative SOFA score, calculated maximally to the 9th postoperative day, and the base
SOFA score. ΔSOFA was slightly lower in the hemoadsorption group, but the difference was
not statistically significant compared to the control group (1.79 ± 3.75 and 1.93 ± 3.53,
respectively, 95% CI:-1.30 to 0.83, p=0.6766).
5) Considered only as exploratory (i.e., being used to frame future research or explore new
hypotheses) the secondary outcomes were also analyzed. No significant difference was
observed between the groups in clinically relevant secondary outcomes such as 30-day
mortality, duration of postoperative hemodialysis, ventilation, and vasopressor therapy, or
the lengths of ICU and hospital stay.
6) Furthermore, almost 1/3 of enrolled patients were elective. This fact may have “diluted”
the intervention group with respect to their severity status, especially concerning their acute
hyperinflammatory state and levels of respective biomarkers. Despite quite a high median
pre-operative EuroSCORE II of around 19, if only urgent and emergent patients were
included in this trial, it is possible that the difference in outcomes could have been
substantially larger.

1Diab M et al. Changes in inflammatory and vasoactive mediator profiles during valvular surgery with or without infective
endocarditis: A case control pilot study. PLoS One 2020; 15(2): e0228286
7) The efficacy of hemoadsorption in reducing plasma levels of inflammatory mediators was
documented in a run-in phase of this trial (the first 25 patients in each study arm). Out of
11 inflammatory mediators measured (at skin incision, 30 and 60 min after starting CPB, at
the end of CPB, and 24 hours after surgery), plasma levels of 4 of them (IL-6, IL-1ß, IL-18, and
CT-proET-1) were significantly lower in the CytoSorb group at various time points. This trial
therefore additionally verified the efficacy of CytoSorb in reducing cytokines and other
inflammatory mediators in the first 50 patients enrolled, as declared by the authors.
8) The total duration of hemoadsorption in this treatment group was 2.31 ± 1.45 hours.
Authors offer the “short” time of treatment as a potential limitation of their study, together
with the lack of blinding. However, they argue then that the available evidence does not
support the speculation that longer durations of hemoadsorption may exert additional
effects and that the lack of blinding is unlikely to create a relevant bias because the primary
outcome (∆SOFA) is calculated based on the objective clinical and laboratory parameters
routinely collected in the ICU.
9) Whether ∆SOFA is the proper tool to assess the level of organ dysfunction in surgical IE
patients is not proven in this, or any other trial up to now. The authors stated that it served
as a clinically relevant outcome in several sepsis trials only, but not in IE and other post-CPB
patient cohorts. Moreover, REMOVE did not sufficiently address one of the most extensively
used outcomes as a surrogate endpoint for mortality or organ dysfunction – requirement for
vasopressor/inotropic support.
10) Another observation points to the quite low potential for the dysregulated inflammatory
response in the intervention cohort of patients. The median IL-6 level prior to surgery was
only 18.36 in the CytoSorb group (Supplementary material). It is highly possible that
patients in this trial were in fact not “sick enough” for CytoSorb therapy to demonstrate its
benefit, considering its concentration-dependent mode of action.
11) The distribution of adverse events between groups was equal, undoubtedly confirming an
excellent safety profile of the CytoSorb device and disproving a couple of previous
controversial single-center studies (see Santer et al. and Asch et al.).
12) Interestingly, CytoSorb was applied against protocol in the ICU in 9 patients (in 5 pts of the
hemoadsorption and 4 of the control group). This fact may have not influenced the final
results significantly, but a comparative analysis of outcomes of these patients and their
matched pairs from both groups may shed some light on the importance of post-surgical
continuation of CytoSorb therapy in IE patients.
13) Our medical team is closely collaborating with the authors of the REMOVE trial with the
intention of performing further subgroup analysis of this very valuable dataset. All involved
are convinced there is a benefit of CytoSorb use in selected IE surgical patients and we are
dedicated to proving it.