Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial

Hepatology. 2024 May 1;79(5):1033-1047 doi: 10.1097/HEP.0000000000000715.
Abstract
BACKGROUND AND AIMS:

In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial.

APPROACH AND RESULTS:

The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4).

CONCLUSIONS:

HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This large open labelled multi-centre randomised control trial is an exciting development in the field of liver HMP. The key strength of this work is that 43% (n=27) of the HMP-O2 livers had continuous perfusion, having been placed on device at the donor. This is the first trial in liver HMP to do this and is an important development. Made possible by Organ Recovery Systems portable Lifeport Liver device, especially considering 81% travelled by air, a current limitation of the portable NMP devices. They demonstrated a nonsignificant reduction in EAD with 11% in HMP-O2 and 16% in SCS, while the finding is not significant it is in keeping with the 5 other published RCTs on HMP liver. The lack of significance may derive from the fact that within the intervention group only 24% were ECDs (including 5 DCD), upon sub-group analysis of these ECDs they find the reduction of EAD to be significant (20% in HMP-O2 and 33.3% in SCS p=0.004). This is in keeping with previous large RCTs that the beneficial effects of HMP-O2 are amplified in the ECD cohort, especially in DCDs seen in Rijn et al’s 2021 trial published in the New England Journal who perfused only DCD livers. None of their secondary outcomes reach significance, but with PNF only occurring in the SCS group with 3 patients and a further 2 (n=5 6.8%) went on to require re-transplant also due to ischaemic cholangiopathy. In HMP-O2 only 1 required retransplant, this was due to HAT. Biliary complications were nearly double in the SCS group (26.4% vs 12.7%) which is impressive, but again this failed to reach significance. The trends are encouraging, but the lack of significance is disappointing, the trial having not been powered for overall EAD rates. An increase cohort size and a focus on EADs could have led to more dramatic results with potentially significance in many of the outcomes. An interesting note is the preservation fluid used in HMP-O2 was Vasosol, a UW-like solution with the addition of nitric oxide donors and vasodilators, this is the first HMP RCT across all organs to utilise this solution and could, in part be responsible for some of the beneficial trends. Unfortunately, the study was not sufficiently powered to compare continuous HMP-O2 with end-ischaemic HMP-O2 and SCS, the overall storage duration being comparable, but the percentage of that time being perfusion obviously being highest in the continuous group. They demonstrate safety and non-inferior efficacy of a novel portable device, which as it becomes more popular and people become more familiar with placing livers on device at retrieval more data should emerge on continuous HMP-O2, this trial was an important step.
Expert Review
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review: This is a very interesting randomised controlled trial in liver transplantation, and an important step in the clinical implementation of a new device (the Lifeport Liver Transporter from Organ Recovery Systems). Hypothermic machine perfusion (HMP) with oxygenation was compared to standard static cold storage prior to transplant. The study was set up as a non-inferiority trial, and hence was smaller than it may have been if designed to demonstrate superiority of one treatment. The non-inferiority design was done specifically to obtain 510(k) device clearance in the USA. Randomisation was stratified for MELD score and DCD status to maintain a distribution between study arms. Primary outcome was Early Allograft Dysfunction (EAD). Approximately 40% of grafts in the HMP arm were put on the pump immediately at retrieval, demonstrating the portability of the device and safety in travel. Statistical analysis of the primary outcome proved non-inferiority of oxygenated HMP, but did not demonstrate superiority either. However, the rate of EAD in the control arm was far better than was expected; in the trial it was only 16%, when 30% had been used for the power calculation. When conducting a subgroup analysis of Extended Criteria Donor (ECD) livers, there was a significant benefit of oxygenated HMP, given the higher baseline risk of 33% EAD with static cold storage in this subgroup. This trial report gives very reassuring information regarding the implementation of oxygenated HMP using this device, its ease of use, portability and safety. The benefit is seen in the ECD livers, and there is the possibility of benefits for standard criteria livers as well (for example PNF and biliary strictures) that may have been statistically significant and more clearly demonstrated in a larger trial
Methodological quality
Jadad score 3
Allocation concealment YES
Data analysis PER PROTOCOL
Study Details
Aims: To assess if HMP-O2 improves liver transplant outcomes compare to cold storage.
Interventions: Livers were randomised to intervention, which was HMP-O2 on the Lifeport Liver Transporter device, perfused with Vasosol, or control, which was static cold storage.
Participants: 179 adult whole liver transplant recipients.
Outcomes: The primary outcome was early allograft dysfunction (EAD) as defined by the Olthoff criteria. Secondary outcome measures were PNF, AKI, graft survival, biliary complications. Vascular complications and death. Additional exploratory outcomes were hospital LOS, ICU LOS, lactate clearance, bleeding, incisional hernia and SAEs.
Follow Up: 12 months
Metadata
Funding: Industry funding
Publication type: Randomized Controlled Trial, Multicenter Study, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT03484455
Organ: Liver
Language: English
Author email: james.guarrera@rutgers.edu
MeSH terms: Humans; Liver Transplantation; Organ Preservation; Constriction, Pathologic; Liver; Perfusion; Reperfusion Injury