Simvastatin-Treated Liver Donors May Aid Transplant Patient Outcomes

Liver transplant recipients who received livers from donors treated with simvastatin (FloLipid) had a higher rate of graft survival at 3 months and 6 months, a researcher said.

In a randomized phase II trial of 58 patients, a per-protocol analysis of 57 patients found 100% 90-day and 180-day graft survival rates in patients whose donors were treated with simvastatin. The 180-day rate was significantly higher than patients whose donors were treated with placebo (100% vs 86.21%, respectively, P=0.0415) and the 90-day rate trended towards significance (100% vs 89.66%, P=0.0804), reported Duilio Pagano, MD, PhD, of the University of Pittsburgh and UPMC-Italy.

While the graft survival rates were higher among the simvastatin group in the intention-to-treat (ITT) analysis of 58 patients, neither the 90-day nor the 180-day rates reached significance (96.55% vs 89.66%, P=0.300 and 96.55% vs 86.21%, P=0.160, respectively), he said at a presentation at the American Association for the Study of Liver Diseases (AASLD) virtual meeting.

Pagano noted that the vasoprotective effects of simvastatin could be a viable option to prevent the risk of ischemic reperfusion injury in liver transplant recipients, and was chosen for its safety profile, showing no adverse effects on liver transplant function in pre-clinical studies.

The SIMVAstatin donor treatment before Liver Transplants (SIMVALT) trial was a double-blind trial that enrolled 58 adults, ages 18-65, with end-stage liver disease and/or liver tumors to undergo liver transplant from June 2018 to April 2020. They were randomized to either a group where their donors received a single, intragastric administration of simvastatin 2 hours before liver graft recovery or placebo following brain death (DBD).

There were no significant differences in demographics in the per-protocol population. They had a mean age of 51-55, and about 66%-79% were men. The most common etiology was alcohol-related liver disease, in about a quarter to a third of patients.

In addition to 100% graft survival at 3 and 6 months, the simvastatin group had 100% patient survival in the per-protocol analysis. It was significantly higher than the placebo group at 6 months (100% vs 86.21%, P=0.0415), but nonsignificant at 3 months (100% vs 93.10%, P=0.1572).

Likewise, patient survival between the intervention and control groups in the ITT analysis was nonsignificant at 3 months (96.55% vs 93.10%, P=0.553) and 6 months (96.55% vs 86.21%, P=0.160).

Pagano noted the proportion of patients with severe post-operative (Clavien-Dindo) complications (higher than IIIb) was significantly higher in the placebo group than the simvastatin group (55% vs 25%, P=0.0307).

Examining liver function tests, the authors also noted that there was a significant increase in gamma-glutamyl transferase and alkaline phosphatase levels in the simvastatin group versus the placebo group.

There was one death in the active group that was unrelated to ischemic reperfusion injury, Pagano said, as well as one death related to primary non-function, but the other three deaths were unrelated. However, he emphasized this data was preliminary and this trial was just a “start” prior to a phase III trial for efficacy.

Enrollment was affected by the COVID-19 pandemic, which Pagano said led to premature termination of the study. However, he said that the trial found that simvastatin was safe, which was its primary purpose, and the data supported further research of the drug in phase III trials in this population.