Model to Calculate Harms and Benefits of Early vs Delayed Liver Transplantation for Patients With Alcohol-Associated Hepatitis

Abstract

Background & aims: Early liver transplantation (without requiring a minimum period of sobriety) for severe alcohol-associated hepatitis (AH) is controversial: many centers delay eligibility until a specific period of sobriety (such as 6 months) has been achieved. To inform ongoing debate and policy, we modeled long-term outcomes of early vs delayed liver transplantation for patients with AH.

Methods: We developed a mathematical model to simulate early vs delayed liver transplantation for patients with severe AH and different amounts of alcohol use after transplantation: abstinence, slip (alcohol use followed by sobriety), or sustained use. Mortality of patients before transplantation was determined by joint-effect model (based on Model for End-Stage Liver Disease [MELD] and Lille scores). We estimated life expectancies of patients receiving early vs delayed transplantation (6-month wait before placement on the waitlist) and life years lost attributable to alcohol use after receiving the liver transplant.

Results: Patients offered early liver transplantation were estimated to have an average life expectancy of 6.55 life years, compared with an average life expectancy of 1.46 life years for patients offered delayed liver transplantation (4.49-fold increase). The net increase in life expectancy from offering early transplantation was highest for patients with Lille scores of 0.50-0.82 and MELD scores of 32 or more. Patients who were offered early transplantation and had no alcohol use afterward were predicted to survive 10.85 years compared with 3.62 years for patients with sustained alcohol use after transplantation (7.23 life years lost). Compared with delayed transplantation, early liver transplantation increased survival times in all simulated scenarios and combinations of Lille and MELD scores.

Conclusions: In a modeling study of assumed carefully selected patients with AH, early vs delayed liver transplantation (6 months of abstinence from alcohol before transplantation) increased survival times of patients, regardless of estimated risk of sustained alcohol use after transplantation. These findings support early liver transplantation for patients with severe AH. The net increase in life expectancy was maintained in all simulated extreme scenarios but should be confirmed in prospective studies. Sustained alcohol use after transplantation significantly reduced but did not eliminate the benefits of early transplantation. Strategies are needed to prevent and treat posttransplantation use of alcohol.

Keywords: 6-month rule; ACCELERATE-AH; Markov model; drinking.

Figure 1.. State-transition diagram for a microsimulation model comparing an early versus delayed liver transplant strategy in patients with severe alcohol-associated hepatitis.

At any given time a patient occupies one of the health states represented by rectangles in the model schematic. Arrows between states depict possible transitions based on probabilities. At any given time, a patient can transition to a death state from any of the above health states (these transitions arrows are not shown in the figure for clarity).

Figure 2A.. Overall life expectancy by offering early LT (dark blue) versus delayed LT (light blue): base case and by varying rates of alcohol use.

Base case analysis assumes equivalent incidence of sustained alcohol use and slips after liver transplant (LT) in both early and delayed LT scenarios. Scenario 1 assumes all patients after early LT have sustained alcohol use and no patient after delayed LT has any alcohol use. Scenario 2 assumes no patient offered delayed has any alcohol use in the 6-month pre-LT period. Scenario 3 assumes no patient offered early LT has any alcohol use after LT.

Figure 2B.. Life-Expectancy with Early, 1-Month, 3-Month, and 6-Month Delayed LT

In our base case analysis, early LT vs. 6-month delay, life expectancy was 6.55 vs. 1.46 years, respectively. When shortening the period of mandated sobriety in the delayed LT arm to 3-months, life expectancy was 2.32 years. With a 1-month delay, life expectancy in the delayed LT arm was 3.92 years.

Figure 3.. Net difference in life years, comparing early versus delayed liver transplant, stratified by UNOS region.

The national (black bar) net survival benefit of offering early versus delayed liver transplant was 5.09 years. In Region 3 (highest net survival benefit) life expectancy was 6.96 years with early LT versus 1.55 years with delayed LT, with a net gain of 5.42 life-years. In Region 9 (lowest net survival benefit), life expectancy was 6.25 years with early LT versus 1.42 with delayed LT, with a net gain of 4.83 life years.

Figure 4.. Net survival benefit of early LT (versus delayed LT) by Lille and MELD scores.

This figure shows the net survival benefit of early LT at any combination of Lille and MELD score. For example, with an initial MELD of 35 and Day 7 Lille score of 0.87, the net survival benefit of early LT was 5.0 life-years. With an initial MELD of 16 and Day 7 Lille score of 0.48, the net survival benefit of early LT was 2.0 life-years.