Design, Analysis, and Pitfalls of Clinical Trials Using Ex Situ Liver Machine Perfusion: The International Liver Transplantation Society Consensus Guidelines

Abstract

Grade of recommendation b (wording associated with the grade of recommendation) Strong"Must," "should," or "ILTS recommends" Weak Can," "may," or "ILTS suggestsAccording to Guyatt GH et al. 32 a Level was downgraded if there was poor quality, strong bias or inconsistency between studies; level was upgraded if there was a large effect size.bRecommendations were reached by consensus of the panel and included the quality of evidence, presumed patient-important outcomes and costs.

A Call for Randomization in Clinical Trials of Liver Machine Perfusion Preservation

“…Although such studies are important and welcome, it is necessary to point out the limitations: (1) lack of randomization; (2) lack of objective, universally reproducible inclusion and exclusion criteria (e.g., liver biopsy); and (3) inappropriate control group. We must disagree with the authors’ statement: “… the study design had to be non‐randomized because to conduct a similar study using previously declined livers in a randomized way would be ethically unacceptable.” NMP is not considered experimental practice in LT anymore, given that its safety and feasibility have been already shown ( 4 ) ; however, its clinical superiority to SCS is not available yet, ( 5,6 ) and a large randomized trial did not show differences in relevant clinical outcomes like patient and graft survival, biliary complications, use of blood products, overall complication rate, and hospital or intensive care unit (ICU) stay. ( 3 ) A randomized comparison to SCS would have been unethical only if NMP was undisputedly associated with significantly better transplant outcomes.…”

“…Recommendations privileged randomized trials using clinically relevant endpoints, such as 1‐year graft/patient survival, ischemic cholangiopathy, or other relevant complications (https://ilts.org/education/lectures/machine-perfusion-and-clinical-trials-session-special-considerations-and-pitfalls-in-clinical-trials-using-machine-perfusion/). ( 6 )…”

Ischemia-free liver transplantation. Is this the right answer to overpass organ shortage and post-liver transplant complications?

“…Even if several clinical trials evaluating the efficacy of machine perfusion (MP) in LT used EAD as primary end-point [6] , Olthoff's criteria [7] are often used for their simplicity rather than sensitivity, as other scores proved to be more accurate in predicting post-LT graft loss [ 8 , 9 ]. EAD, as defined by Olthoff, is highly dependent on transaminases levels.…”

“…Still their correlation with a poor outcome has never been confirmed in the context of MP technology [10] . Primary endpoint should better be conventional “hard” endpoints such as graft loss, patient death or clinically relevant complications (e.g., ischemic cholangiopathy) until a validated biomarker able to predict clinical outcomes is identified [6] .…”

Liver viability using normothermic regional perfusion in uncontrolled donation after circulatory death deserves a multi‐parametric assessment

“…While this can be easily done during ex-situ MP, it is far more challenging during NRP where fluid administration, blood losses, and third space fluid shifting might complicate the scenario. 8 Monitoring of transaminases during NRP should not prevent eventual ex-situ graft perfusion since the liver has a unique regenerative potential and no consensus has so far been reached about when to proceed to NMP.…”