Use of Statins After Liver Transplantation Is Associated With Improved Survival

Results of a Nationwide Study

Chiara Becchetti; Melisa Dirchwolf; Jonas Schropp; Giulia Magini; Beat Müllhaupt; Franz Immer; Jean-François Dufour; Vanessa Banz; Annalisa Berzigotti; Jaume Bosch

Disclosures

Aliment Pharmacol Ther. 2022;56(7):1194-1204. 

In This Article

Abstract and Introduction

Abstract

Background: There is limited information on the effects of statins on the outcomes of liver transplantation (LT), regarding either their use by LT recipients or donors.

Aim: To analyse the association between statin exposure and recipient and graft survival.

Methods: We included adult LT recipients with deceased donors in a nationwide prospective database study. Using a multistate modelling approach, we examined the effect of statins on the transition hazard between LT, biliary and vascular complications and death, allowing for recurring events. The observation time was 3 years.

Results: We included 998 (696 male, 70%, mean age 54.46 ± 11.14 years) LT recipients. 14% of donors and 19% of recipients were exposed to statins during the study period. During follow-up, 141 patients died; there were 40 re-LT and 363 complications, with 66 patients having two or more complications. Treatment with statins in the recipient was modelled as a concurrent covariate and associated with lower mortality after LT (HR = 0.35; 95% CI 0.12–0.98; p = 0.047), as well as a significant reduction of re-LT (p = 0.004). However, it was not associated with lower incidence of complications (HR = 1.25; 95% CI = 0.85–1.83; p = 0.266). Moreover, in patients developing complications, statin use was significantly associated with decreased mortality (HR = 0.10; 95% CI = 0.01–0.81; p = 0.030), and reduced recurrence of complications (HR = 0.43; 95% CI = 0.20–0.93; p = 0.032).

Conclusions: Statin use by LT recipients may confer a survival advantage. Statin administration should be encouraged in LT recipients when clinically indicated.

Introduction

Liver transplantation (LT) is considered the ultimate curative option for end-stage liver disease and for non-resectable hepatocellular carcinoma (HCC). Although survival rates after LT have progressively improved over the years, the first year post-LT remains the critical period, summing 46% of the total deaths and 67% of re-LT.[1] Initial outcomes are mainly determined by surgical or peri-operative problems leading to primary non-function or delayed graft function and ultimately to re-LT. In contrast to this, long-term outcomes are mainly affected by de novo or recurrent malignant tumours and cardiovascular disease.[2]

Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) widely used in the treatment of dyslipidemia and prophylaxis of cardiovascular events.[2,3] It has long been recognised that part of the benefits attributed to statins in cardiovascular disease are due to their pleiotropic effects that influence vascular remodelling and reverse endothelial dysfunction, among others.[4] These pleiotropic effects may likely explain the beneficial effects of statins in other conditions, such as sepsis[5] and cancer.[6,7] Recent studies reported beneficial effects of statins on chronic liver diseases, both in pre-clinical models[8–10] and in clinical studies.[11–13] These range from improvement of hepatic sinusoidal endothelial function, leading to a reduction in intrahepatic vascular tone and portal pressure, to a decreased fibrogenesis that may translate into preventing disease progression and facilitating its regression.[14] Statins have also been shown to protect from lipopolysaccharide-induced acute-on-chronic liver failure (ACLF) in cirrhotic rats[15] and to prevent liver function impairment after hypovolemic shock.[16,17] Interestingly, in preclinical models statins protect against ischemia/reperfusion injury in young and aged animals[18] and prolong liver graft preservation both in normal and liver grafts with steatosis considered at high-risk of ischemia/reperfusion injury.[19] Furthermore, epidemiological studies in large cohorts of patients with chronic liver disease suggest a protective effect of statins reducing the rate of progression to cirrhosis, liver decompensation, development of HCC and death.[20,21] Classical indications for statins, including the treatment and prevention of cardiovascular diseases, may be relevant for the long-term outcome after LT.[22] Moreover, the effects of statins protecting from ischemia/reperfusion injury could be beneficial in the early phase after LT, by reducing the incidence and severity of biliary and vascular complications. Therefore, we hypothesize that statin use in LT recipients may favourably influence the transition to adverse outcomes, including re-LT, severe and recurrent biliary-vascular complications, and death.

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