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Cost-effectiveness of alcohol use treatments in patients with alcohol-related cirrhosis

Open AccessPublished:December 14, 2020DOI:https://doi.org/10.1016/j.jhep.2020.12.004

      Highlights

      • Alcohol use treatments improve outcomes in patients with alcohol-related cirrhosis.
      • Medication-assisted therapies and counseling are cost-effective or cost-saving.
      • Different assumptions on costs and effectiveness do not shift main findings.
      • Wider use of these interventions should be encouraged.

      Background & Aims

      Alcohol use treatment such as medication-assisted therapies (MATs) and counseling are available and effective in promoting alcohol abstinence. We sought to explore the cost-effectiveness of different alcohol use treatments among patients with compensated alcohol-related cirrhosis (AC).

      Methods

      We simulated a cohort of patients with compensated AC receiving care from a hepatology clinic over their lifetimes. We estimated costs (in 2017 US$) and benefits in terms of quality-adjusted life years (QALYs) gained from healthcare and societal perspectives. Transition probabilities, costs, and health utility weights were taken from the literature. Treatment effects of FDA-approved MATs (acamprosate and naltrexone) and non-FDA approved MATs (baclofen, gabapentin, and topiramate) and counseling were based on a study of employer-insured patients with AC. We calculated incremental cost-effectiveness ratios (ICERs) and performed one-way and probabilistic sensitivity analyses to understand the impact of parameter uncertainty.

      Results

      Compared to a do-nothing scenario, MATs and counseling were found to be cost-saving from a healthcare perspective, which means that they provide more benefits with less costs than no intervention. Compared to other interventions, acamprosate and naltrexone cost the least and provide the most QALYs. If the effectiveness of MATs and counseling decreased, these interventions would still be cost-effective based on the commonly used $100,000 per QALY gained threshold. Several sensitivity and scenario analyses showed that our main findings are robust.

      Conclusions

      Among patients with compensated AC, MATs and counseling are extremely cost-effective, and in some cases cost-saving, interventions to prevent decompensation and improve health. Health policies (e.g. payer reimbursement) should emphasize and appropriately compensate for these interventions.

      Lay summary

      Alcohol use treatments, including physician counseling and medication-assisted therapies (MATs), improve the outcomes of patients with compensated alcohol-related cirrhosis, though use and access have remained suboptimal. In this study, we found that counseling and MATs are extremely cost-effective, and in some cases cost-saving, interventions to help patients with alcohol-related cirrhosis abstain from alcohol and improve their health. Wider use of these interventions should be encouraged.

      Graphical abstract

      Keywords

      Introduction

      Despite optimal management of their liver disease, patients with alcohol-related cirrhosis (AC) can rapidly decline with continued alcohol intake.
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      and various treatment modalities are available to promote abstinence and prevent relapse. Medication-assisted therapy (MAT) involves the daily intake of drugs, such as acamprosate and naltrexone, which the FDA has approved to increase alcohol aversiveness or reduce alcohol cravings.
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      Disulfiram, another FDA-approved MAT for alcohol use disorder (AUD), is highly hepatotoxic and should not be used in patients with AC. Baclofen, gabapentin, and topiramate are also used to treat AUD, though they have not been approved by the FDA for this use in the US.
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      While clinical trials have demonstrated the effectiveness of alcohol use treatments, little to no studies have focused on patients with alcohol-related liver disease (ALD) such as AC.
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      which has led experts to conditionally recommend its use while calling for additional studies.
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      a key clinical objective in the treatment of ALD. Unfortunately, fewer than 10% of patients with AC receive either counselling or MAT at 1 year after their diagnosis, and these interventions are frequently poorly reimbursed.
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      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      Increased use of alcohol use treatments among patients with AC is likely to be a good investment because of the significant costs that AC and its complications exact on healthcare systems, patients and their families, and society at large. To explore the value of these interventions on the compensated AC patient population, we conducted a cost-effectiveness analysis (CEA) comparing MATs and counseling with each other and to a do-nothing approach. CEA is a widely-used economic evaluation method that compares the costs and benefits of interventions designed to improve health.
      One of CEA’s advantages is its ability to quantify changes in an intervention’s efficiency when different assumptions about its effectiveness and costs are made. CEA is therefore well-suited to explore the efficiency of alcohol use treatments in patients with AC because of uncertainties around their effectiveness and costs.

      Materials and methods

      Overview

      We used a Markov simulation model to project the lifetime costs and health benefits of different alcohol use treatments for a hypothetical cohort of patients with compensated AC. Data on transition probabilities, costs, and health utilities were taken from published peer-reviewed and gray literature (see supplementary information for additional details on parameter estimations and other assumptions). Since no human participants were involved in this study, no ethical approval was sought.
      In addition to a do-nothing approach, the scenarios we modeled are (1) acamprosate and naltrexone, which are FDA-approved MATs; (2) baclofen, gabapentin, and topiramate, which are non-FDA-approved MATs; and (3) counseling (we chose to label this scenario “counseling” to disambiguate from the use of the word “therapy” in MAT), which involves weekly individual therapy with a licensed counselor. We grouped FDA- and non-FDA-approved MATs together because estimates of the effectiveness of these drugs on the AC population combined them into these categories due to low rates of overall use of these medications, particularly in the US.
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      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
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      Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis.
      All interventions are assumed to be provided over 12 weeks. We assumed that patients in all 4 scenarios are receiving medical treatment for their ALD.
      We considered both societal and healthcare perspectives in the analysis. The Impact Inventory (Table S1) lists all the health and non-health costs and effects that were included in each perspective.
      We discounted future benefits and costs to their present value using a 3% rate in the base case analysis.

      Markov model

      A truncated schematic of the Markov cohort model is presented in Fig. 1. The model simulates a cohort of 54-year-old patients with compensated AC, which is the median age reported in the literature.
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      We varied the age of the population between 25–65 in the sensitivity analysis based on a recent study
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      that reported significant increases in AC among young adults in the US. The model, which uses an annual cycle and lifetime time horizon, was programmed in TreeAge Pro 2019 (TreeAge Software Inc., Williamstown, MA).
      Figure thumbnail gr1
      Fig. 1Markov cohort model schematic.
      Root of the schematic shows the four decision alternatives or scenarios – acamprosate or naltrexone, baclofen, gabapentin, and topiramate, counseling, and do-nothing. The shaded circle denotes the common Markov node, and the ovals are the ALD states the simulated cohort progresses through. Each health state is associated with a cost and health utility. Arrows represent transitions and are associated with an annual probability. ALD, alcohol-related liver disease; CC, compensated alcohol-related cirrhosis; DC, decompensated alcohol-related cirrhosis; HCC, hepatocellular carcinoma; Tx, transplantation.
      In our model, all patients start at the compensated AC state, and those who are in one of the intervention arms (Fig. 1) receive a 12-week intervention only once in their lifetime. After receiving the intervention, the cohort then progress through the various ALD health states, namely decompensated AC, HCC, liver transplantation, and death. We did not model alcoholic hepatitis as a separate state, and patients with this clinical syndrome are assumed to be in either the compensated or decompensated AC states. Because of the significant difference in mortality between the first and succeeding years post-transplantation,
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      National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States.
      we separated out the transplantation states into <12 months and ≥12 months (not shown in Fig. 1 for simplicity). We assumed that patients in all ALD states cannot transition back to less-severe health states, though in reality some patients with AC may return and experience the same state again (e.g. recurrent cirrhosis in a post-transplant patient or re-compensation in a previously decompensated patient who stops drinking).

      Data and sources

      Transition probabilities

      Annual transition probabilities were estimated based on previously published rates and probabilities in peer-reviewed literature (Table 1). Natural history and disease progression probabilities were taken from cohort studies and reviews on ALD development.
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      For death after transplantation, we relied on a recent analysis of cohort data from the United Network for Organ Sharing database.
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      We calculated the probability of transplantation among patients with decompensated cirrhosis and HCC using waitlist rates reported from previous studies
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      and liver transplant rates from the Organ Procurement and Transplantation Network annual reports (see supplementary information for more details).
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      Table 1Values for model inputs.
      VariableBaseRangeMean (SD)Distribution[Ref.]
      Annual transition probabilities
       Decompensation among compensated AC patients0.250.1875–0.31250.25 (0.0313)Beta
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
      Range determined by authors.
       HCC development among compensated AC patients0.00190.0011–0.0030.0021 (0.0005)Beta
      • Jepsen P.
      • Kraglund F.
      • West J.
      • Villadsen G.E.
      • Sørensen H.T.
      • Vilstrup H.
      Risk of hepatocellular carcinoma in Danish outpatients with alcohol-related cirrhosis.
       Death among compensated AC patients0.060.03–0.10.065 (0.0175)Beta
      • Parker R.
      • Aithal G.P.
      • Becker U.
      • Gleeson D.
      • Masson S.
      • Wyatt J.I.
      • et al.
      Natural history of histologically proven alcohol-related liver disease: a systematic review.
       HCC development among decompensated AC patients0.0070.0053–0.00880.0071 (0.0009)Beta
      • Jepsen P.
      • Kraglund F.
      • West J.
      • Villadsen G.E.
      • Sørensen H.T.
      • Vilstrup H.
      Risk of hepatocellular carcinoma in Danish outpatients with alcohol-related cirrhosis.
       Transplantation among decompensated AC patients0.07780.0523–0.09030.0713 (0.0095)Beta
      • Lee B.P.
      • Vittinghoff E.
      • Dodge J.L.
      • Cullaro G.
      • Terrault N.A.
      National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States.
      ,
      • McElroy L.M.
      • Likhitsup A.
      • Scott Winder G.
      • Saeed N.
      • Hassan A.
      • Sonnenday C.J.
      • et al.
      Gender disparities in patients with alcoholic liver disease evaluated for liver transplantation.
      Values calculated by authors using the references listed.
       Death among decompensated AC patients0.310.2325–0.38750.31 (0.0388)Beta
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
       Transplantation among HCC patients0.090.0769–0.09980.0884 (0.0057)Beta
      • Goldberg D.
      • French B.
      • Newcomb C.
      • Liu Q.
      • Sahota G.
      • Wallace A.E.
      • et al.
      Patients with hepatocellular carcinoma have highest rates of wait-listing for liver transplantation among patients with end-stage liver disease.
      ,
      • Kwong A.
      • Kim W.R.
      • Lake J.R.
      • Smith J.M.
      • Schladt D.P.
      • Skeans M.A.
      • et al.
      OPTN/SRTR 2018 annual data report: liver.
      Values calculated by authors using the references listed.
       Death among HCC patients0.0550.041–0.0690.055 (0.007)Beta
      • Jepsen P.
      • Kraglund F.
      • West J.
      • Villadsen G.E.
      • Sørensen H.T.
      • Vilstrup H.
      Risk of hepatocellular carcinoma in Danish outpatients with alcohol-related cirrhosis.
       Death within the 1st year of liver transplantation0.090.08–0.090.085 (0.0025)Beta
      • Lee B.P.
      • Vittinghoff E.
      • Dodge J.L.
      • Cullaro G.
      • Terrault N.A.
      National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States.
       Death after the 1st year of liver transplantation0.030.03–0.03250.0313 (0.0006)Beta
      • Lee B.P.
      • Vittinghoff E.
      • Dodge J.L.
      • Cullaro G.
      • Terrault N.A.
      National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States.
      Intervention treatment effects
       Relative risk of decompensation among AC patients who receive acamprosate and naltrexone0.780.72–0.840.78 (0.03)Beta
      • Mellinger J.L.
      • Fernandez A.
      • Shedden K.
      • Winder G.S.
      • Fontana R.J.
      • Volk M.L.
      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      Results from the referenced study were re-analyzed and used as inputs to the model.
       Relative risk of decompensation among AC patients who receive baclofen, gabapentin, and topiramate0.820.795–0.8450.82 (0.01)Beta
      • Mellinger J.L.
      • Fernandez A.
      • Shedden K.
      • Winder G.S.
      • Fontana R.J.
      • Volk M.L.
      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      Results from the referenced study were re-analyzed and used as inputs to the model.
       Relative risk of decompensation among AC patients who receive counseling0.890.87–0.910.89 (0.01)Beta
      • Mellinger J.L.
      • Fernandez A.
      • Shedden K.
      • Winder G.S.
      • Fontana R.J.
      • Volk M.L.
      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      Results from the referenced study were re-analyzed and used as inputs to the model.
      Annual costs (in 2017 US$)
      Only intervention and medical management costs are included here; see Supporting Information for other cost inputs.
       Intervention costs
      Acamprosate and naltrexone1,4191,064–1,7741,419 (178)Gamma
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      • Bray J.W.
      • Aldridge A.
      • Mitra D.
      • Mills M.J.
      • Couper D.J.
      • et al.
      Cost and cost-effectiveness of the COMBINE study in alcohol-dependent patients.
      ,
      U.S. Department of Veterans Affairs
      Pharmaceutical prices.
      Baclofen, gabapentin, and topiramate657493–822658 (82)Gamma
      • Zarkin G.A.
      • Bray J.W.
      • Aldridge A.
      • Mitra D.
      • Mills M.J.
      • Couper D.J.
      • et al.
      Cost and cost-effectiveness of the COMBINE study in alcohol-dependent patients.
      ,
      U.S. Department of Veterans Affairs
      Pharmaceutical prices.
      Individual alcohol cessation counseling1,154334–1,9741,154 (410)Gamma
      • Olmstead T.A.
      • Graff F.S.
      • Ames-Sikora A.
      • McCrady B.S.
      • Gaba A.
      • Epstein E.E.
      Cost-effectiveness of individual versus group female-specific cognitive behavioral therapy for alcohol use disorder.
       Medical management costs
      Compensated AC treatment5,7394,304–7,1735,739 (717)Gamma
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      • Nahon P.
      • Seror O.
      • Laurent A.
      • Rosa I.
      • et al.
      Early detection and curative treatment of hepatocellular carcinoma: a cost-effectiveness analysis in France and in the United States.
      Decompensated AC treatment23,49323,115–23,87123,493 (189)Gamma
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      • Chapko M.K.
      • Mehta R.
      • Dai F.
      • Skanderson M.
      • Aytaman A.
      • et al.
      Healthcare costs related to treatment of hepatocellular carcinoma among veterans with cirrhosis in the United States.
      Hepatocellular carcinoma treatment52,66151,813–53,50952,661 (424)Gamma
      • Kaplan D.E.
      • Chapko M.K.
      • Mehta R.
      • Dai F.
      • Skanderson M.
      • Aytaman A.
      • et al.
      Healthcare costs related to treatment of hepatocellular carcinoma among veterans with cirrhosis in the United States.
      Liver transplantation and treatment293,566220,175–366,958293,567 (36,696)Gamma
      • Thompson J.A.
      • Martinson N.
      • Martinson M.
      Mortality and costs associated with alcoholic hepatitis: a claims analysis of a commercially insured population.
      Routine care for liver transplant patients after 1st year61,400220,175–366,95861,400 (7,675)Gamma
      • Thompson J.A.
      • Martinson N.
      • Martinson M.
      Mortality and costs associated with alcoholic hepatitis: a claims analysis of a commercially insured population.
      Annual health utilities
       Compensated AC0.830.62–10.81 (0.1)Beta
      • McLernon D.J.
      • Dillon J.
      • Donnan P.T.
      Health-state utilities in liver disease: a systematic review.
       Decompensated AC0.650.48–0.810.65 (0.08)Beta
      • McLernon D.J.
      • Dillon J.
      • Donnan P.T.
      Health-state utilities in liver disease: a systematic review.
       Hepatocellular carcinoma0.250.18–0.310.25 (0.03)Beta
      • McLernon D.J.
      • Dillon J.
      • Donnan P.T.
      Health-state utilities in liver disease: a systematic review.
       Transplantation <12 months0.770.58–0.960.72 (0.07)Beta
      • Ratcliffe J.
      • Longworth L.
      • Young T.
      • Bryan S.
      • Burroughs A.
      • Buxton M.
      Assessing health-related quality of life pre– and post–liver transplantation: a prospective multicenter study.
       Transplantation ≥12 months0.780.59–0.980.75 (0.08)Beta
      • Ratcliffe J.
      • Longworth L.
      • Young T.
      • Bryan S.
      • Burroughs A.
      • Buxton M.
      Assessing health-related quality of life pre– and post–liver transplantation: a prospective multicenter study.
      AC, alcohol-related cirrhosis; HCC, hepatocellular carcinoma.
      Range determined by authors.
      Values calculated by authors using the references listed.
      Results from the referenced study were re-analyzed and used as inputs to the model.
      Only intervention and medical management costs are included here; see Supporting Information for other cost inputs.
      The same annual transition probabilities are used in all 4 scenarios; the main difference between the scenarios is the treatment effect applied to the yearly rate of decompensation among patients with AC. To estimate treatment effects, we relied on the unpublished corrected results of a retrospective cohort study that compared the rate of decompensation between patients with AC who received different alcohol use treatments vs. those who did not receive an intervention.
      • Mellinger J.L.
      • Fernandez A.
      • Shedden K.
      • Winder G.S.
      • Fontana R.J.
      • Volk M.L.
      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      The resulting relative risks, which are similar to those reported in a more recent study,
      • Rogal S.
      • Youk A.
      • Zhang H.
      • Gellad W.F.
      • Fine M.J.
      • Good C.B.
      • et al.
      Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis.
      were used as model inputs (Table 1). While our treatment effectiveness estimates are based on observational, real-world data, we do use a large sample of patients with AC and employer-sponsored insurance followed over time, and our estimates reflect real-life effectiveness of alcohol use treatments in the AC population. These estimates also reflect other realities of clinical practice, such as the fact that women are significantly less likely to be provided MAT or counseling than men.
      • Mellinger J.L.
      • Fernandez A.
      • Shedden K.
      • Winder G.S.
      • Fontana R.J.
      • Volk M.L.
      • et al.
      Gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated cirrhosis.
      Unlike other CEAs, we could not rely on data from trials such as the COMBINE Study
      • Anton R.F.
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      • Cisler R.A.
      • Couper D.
      • Donovan D.M.
      • et al.
      Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE Study: a randomized controlled trial.
      or published systematic reviews
      • Jonas D.E.
      • Amick H.R.
      • Feltner C.
      • Bobashev G.
      • Thomas K.
      • Wines R.
      • et al.
      Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis.
      that evaluate the effect of alcohol use treatments on abstinence and/or relapse because these studies do not focus on patients with AC. In some cases, patients with AC have been deliberately excluded from trials because certain treatments can worsen ALD.
      • Addolorato G.
      • Vassallo G.A.
      • Mirijello A.
      • Gasbarrini A.
      Diagnosis and management of alcohol use disorder in patients with liver disease: lights and shadows.
      Because of the uncertainty around our treatment effectiveness estimates, we conducted several sensitivity analyses to explore the impact on our results.

      Costs

      Healthcare costs include healthcare service delivery (e.g. physician and facility fees) and drug costs (Table 1). The routine costs of care for compensated and decompensated AC were based on a previously-published CEA
      • Cadier B.
      • Bulsei J.
      • Nahon P.
      • Seror O.
      • Laurent A.
      • Rosa I.
      • et al.
      Early detection and curative treatment of hepatocellular carcinoma: a cost-effectiveness analysis in France and in the United States.
      and a study on the costs of treating US veterans with cirrhosis,
      • Kaplan D.E.
      • Chapko M.K.
      • Mehta R.
      • Dai F.
      • Skanderson M.
      • Aytaman A.
      • et al.
      Healthcare costs related to treatment of hepatocellular carcinoma among veterans with cirrhosis in the United States.
      respectively. All costs associated with liver transplantation are based on a claims-based analysis of a commercially-insured population in the US.
      • Thompson J.A.
      • Martinson N.
      • Martinson M.
      Mortality and costs associated with alcoholic hepatitis: a claims analysis of a commercially insured population.
      The costs of alcohol use treatments were based on 2 previous CEAs
      • Zarkin G.A.
      • Bray J.W.
      • Aldridge A.
      • Mitra D.
      • Mills M.J.
      • Couper D.J.
      • et al.
      Cost and cost-effectiveness of the COMBINE study in alcohol-dependent patients.
      ,
      • Olmstead T.A.
      • Graff F.S.
      • Ames-Sikora A.
      • McCrady B.S.
      • Gaba A.
      • Epstein E.E.
      Cost-effectiveness of individual versus group female-specific cognitive behavioral therapy for alcohol use disorder.
      that provided detailed cost estimates and whose drug costs we updated using public sources.
      U.S. Department of Veterans Affairs
      Pharmaceutical prices.
      As mentioned previously, we assumed in the base case that all patients receive alcohol use treatments once in their lifetime, so alcohol use treatment costs were only applied once (we vary this assumption in the sensitivity analysis).
      For the societal perspective, we included lifetime productivity and health and consumption costs. We also valued and included time costs or foregone productivity of patients using published estimates of time spent on alcohol use treatments and ALD treatments multiplied by average daily wages (see supplementary information). All costs are in 2017 US dollars (US$).

      Health outcomes and utilities

      We measured health outcomes from each scenario in terms of quality-adjusted life years (QALYs) gained. A QALY represents a year that a person is alive weighted by that person’s health-related quality of life.
      • Weinstein M.C.
      • Torrance G.
      • McGuire A.
      QALYs: the basics.
      QALYs, which have their limitations, are a preferred measure of health in CEAs because they combine quantity and quality of life in one metric and provide a common and consistent metric that can be used to compare different treatments and their efficiency.
      • Neumann P.J.
      • Cohen J.T.
      QALYs in 2018 – advantages and concerns.
      The weights used to calculate QALYs are based on health utilities that typically range from 1 (a year in perfect health) to 0 (death). We took health utility estimates for the various states in the model from the literature (Table 1).
      • McLernon D.J.
      • Dillon J.
      • Donnan P.T.
      Health-state utilities in liver disease: a systematic review.
      ,
      • Ratcliffe J.
      • Longworth L.
      • Young T.
      • Bryan S.
      • Burroughs A.
      • Buxton M.
      Assessing health-related quality of life pre– and post–liver transplantation: a prospective multicenter study.
      Very few preference-based measures of health-related quality of life have been published specifically on patients with ALD; we thus had to rely on available estimates, which include studies that have been done on other chronic liver diseases (e.g. infectious hepatitis). We address uncertainty in utility estimates in the sensitivity analysis.

      Analysis

      Cost-effectiveness

      The summary metric of CEAs is the incremental cost-effectiveness ratio (ICER), defined as the cost per unit of health outcome gained. The ICER is calculated by dividing the incremental costs by the incremental benefits of 2 scenarios. We present ICERs from the healthcare and societal perspectives by comparing each intervention scenario (i.e. acamprosate and naltrexone, baclofen, gabapentin, and topiramate, and counseling) to the do-nothing scenario. As is usually done in CEAs, we arranged the interventions by increasing costs and calculated ICERs while comparing each intervention to the next costlier option.
      An intervention is typically considered cost-effective if its ICER is equal to or below a context-specific cost-effectiveness threshold. The cost-effectiveness threshold represents a decisionmaker’s willingness to pay for an additional unit of health benefit such as QALYs. The threshold can also be seen as a measure of opportunity cost, or the amount of health that is displaced by additional spending in the health sector.
      • Neumann P.J.
      • Cohen J.T.
      QALYs in 2018 – advantages and concerns.
      In this study, we consider an intervention to be cost-effective if its ICER is <$100,000 per QALY gained, a commonly-used threshold in the US.
      • Neumann P.J.
      • Cohen J.T.
      QALYs in 2018 – advantages and concerns.
      We evaluate a lower threshold of $50,000 per QALY in sensitivity analysis.

      Sensitivity analyses

      Sensitivity analyses explore how different assumptions and parameter uncertainty may affect the conclusions about the cost-effectiveness of alcohol use treatments; in this study, we conducted 3 types. The first sensitivity analysis is a one-way sensitivity analysis where each transition probability, cost input, and health utility are varied one at a time from their lowest to highest value (while keeping other parameters at their base value) to understand how extreme values affect the cost-effectiveness of each intervention. Where data were available, low and high values were based on ranges in the literature; for select parameters, the authors determined reasonable bounds which were 25% above and below a given value.
      The second sensitivity analysis is called scenario analysis where we vary certain assumptions in the model; specifically, we vary the number of times patients receive alcohol use treatments. In the base case analysis, we assumed that alcohol use treatments costs were only applied in the first year, and treatment effects lasted over the lifetime of the cohort. We varied this assumption by calculating ICERs where alcohol use treatment costs were applied each year over 5 and 10 years.
      The third type of sensitivity analysis we conducted is probabilistic sensitivity analysis (PSA), where all parameters are varied simultaneously over 10,000 independent trials. We used pre-determined distributions for each parameter input (Table 1). To understand the efficiency of alcohol use treatments across different ages, we varied the age group of the cohort from 25 to 65 years conducting separate PSAs. Using the simulation results, we generated cost-effectiveness acceptability curves to plot the probability that each scenario is cost-effective over a range of reasonable cost-effectiveness thresholds.
      • Braithwaite R.S.
      • Meltzer D.O.
      • King J.T.
      • Leslie D.
      • Roberts M.S.
      What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?.

      Results

      Base case

      The results of the base case analysis are shown in Table 2. Compared to a do-nothing scenario, all 3 alcohol use treatments were cost-saving from a healthcare perspective; this means that the total costs of receiving MATs or counseling is less than not receiving them while producing more QALYs.
      Table 2Base case results from societal and healthcare perspectives.
      InterventionSocietal perspectiveInterventionHealthcare perspective
      QALYs gained
      Refers to lifetime QALYs and are discounted at 3% to present value.
      CostICER compared to do-nothingICER compared to the next most expensive, undominated optionQALYs gained
      Refers to lifetime QALYs and are discounted at 3% to present value.
      CostICER compared to do-nothingICER compared to the next most expensive undominated option
      Acamprosate and naltrexone6.12278,794Cost-savingn.a.Acamprosate and naltrexone6.12249,055Cost-savingn.a.
      Baclofen, gabapentin, and topiramate6.05282,007Cost-savingDominated
      Compared to acamprosate and naltrexone.
      Baclofen, gabapentin, and topiramate6.05250,712Cost-savingDominated
      Compared to acamprosate and naltrexone.
      Do-nothing5.79284,583n.a.Dominated
      Compared to acamprosate and naltrexone.
      Counseling5.94255,044Cost-savingDominated
      Compared to acamprosate and naltrexone.
      Counseling5.94285,1353,724Dominated
      Compared to acamprosate and naltrexone.
      Do-nothing5.79259,101n.a.Dominated
      Compared to acamprosate and naltrexone.
      This table shows the results for the base-case analysis only. Interventions are arranged by increasing costs. ICERs are calculated by dividing incremental costs by incremental QALYs between two interventions. “Cost-saving” (or “dominant”) refers to an intervention that incurs less costs and produces more QALYs compared to its comparator; cost-saving interventions are preferred because they outperform their comparator in both costs and benefits. “Dominated” refers to an intervention that incurs more costs and produces less QALYs compared to its comparator; dominated interventions are rejected because their cost-effectiveness is inferior to their comparator. All costs are in 2017 US$, rounded to the nearest dollar, and have been discounted at 3% to the present.
      ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.
      Refers to lifetime QALYs and are discounted at 3% to present value.
      Compared to acamprosate and naltrexone.
      From a societal perspective, acamprosate and naltrexone and baclofen, gabapentin, and topiramate are also cost-saving when compared to a do-nothing scenario. On the other hand, counseling costs more but produces more QALYs compared to a do-nothing scenario, with an ICER of $3,724 QALY (Table 2). This ICER is significantly less than the $100,000 per QALY gained threshold we use to assess cost-effectiveness.
      After arranging the interventions based on increasing costs, we calculated ICERs while comparing each scenario to the next most costly option. As shown in Table 2, baclofen, gabapentin, and topiramate, counseling, and a do-nothing scenario were dominated by acamprosate and naltrexone from healthcare and societal perspectives; this means that baclofen, gabapentin, and topiramate, counseling, and a do-nothing scenario are costlier and provide less QALYs than acamprosate and naltrexone. All-in-all, we found that only acamprosate and naltrexone are not dominated by any other intervention we evaluated.

      Sensitivity analysis

      One-way sensitivity analysis

      The one-way sensitivity analysis found that all 3 intervention scenarios – acamprosate and naltrexone, baclofen, gabapentin, and topiramate, and counseling – remained cost-saving when compared to a do-nothing scenario from a healthcare perspective, even after extreme values of each parameter were used in the model.
      We show the partial results of the one-way sensitivity analysis for acamprosate and naltrexone in Fig. 2, which shows how the net monetary benefit of the intervention changes as the parameter values are varied between their lowest and highest values in the model. The net monetary benefit is intended to combine the costs and health benefits into a single monetary value and is calculated by multiplying the QALYs gained by a cost-effectiveness threshold (e.g. $100,000 per QALY gained), and then subtracting from the product the total costs of the intervention. We find that the net monetary benefit of acamprosate and naltrexone remains positive even when we use the most extreme values of any parameter, which means that the benefits of the intervention (when monetized) outweigh its costs. When we use a $50,000 per QALY gained threshold (Fig. 3) we find similar results.
      Figure thumbnail gr2
      Fig. 2Net monetary benefit of acamprosate and naltrexone using a $100,000 per QALY gained threshold.
      This tornado diagram shows how the net monetary benefit of acamprosate and naltrexone from a healthcare perspective changes when parameters in the model are varied from their lowest to highest estimated value while keeping the other parameters constant. The net monetary benefit is intended to combine the costs and health benefits into a single monetary value and is calculated by subtracting the costs of an intervention from the product of its QALYs and a cost-effectiveness threshold, which in this case was $100,000 per QALY gained. Only the top 10 most influential parameters are included. The results show that acamprosate and naltrexone have a positive net monetary benefit even when the most extreme values of any parameter are used in the model, which means that the benefits of the intervention outweigh its costs. QALY, quality-adjusted life year; RR, relative risk.
      Figure thumbnail gr3
      Fig. 3Net monetary benefit of acamprosate and naltrexone using a $50,000 per QALY gained threshold.
      This tornado diagram shows how the net monetary benefit of acamprosate and naltrexone from a healthcare perspective changes when parameters in the model are varied from their lowest to highest estimated value while keeping the other parameters constant. The net monetary benefit is calculated by subtracting the costs of an intervention from the product of its QALYs and a cost-effectiveness threshold, which in this case was $50,000 per QALY gained. Only the top 10 most influential parameters are included. The results show that acamprosate and naltrexone have a positive net monetary benefit even when the most extreme values of any parameter are used in the model, which means that the benefits of the intervention outweigh its costs. QALY, quality-adjusted life year; RR, relative risk.
      We found that the utility of compensated AC, the probability of death among patients with compensated AC, and the post-transplantation utility are the most influential parameters on the net monetary benefit of acamprosate and naltrexone (Fig. 1). The treatment effectiveness of acamprosate and naltrexone was the ninth most-influential parameter; only when the treatment effectiveness decreased by 24% (or a change in the relative risk of decompensation from 0.78 to 0.968) did the ICER of acamprosate and naltrexone exceed the $100,000 per QALY gained threshold. Similarly, the treatment effectiveness of baclofen, gabapentin, and topiramate and counseling needed to decrease by 17% (or a change in a relative risk of decompensation from 0.82 to 0.9628) and 9% (or a change in a relative risk of decompensation from 0.89 to 0.9663), respectively, before their ICERs crossed the same cost-effectiveness threshold.
      From a societal perspective, we found that acamprosate and naltrexone no longer becomes cost-saving when (1) the probability of death among patients with compensated AC exceeded 0.033 and (2) the age of the patient cohort exceeded 61 (see Fig. S1).

      Scenario analysis

      After varying the duration in which patients receive MATs and counseling, we found that all 3 intervention scenarios are cost-saving from a healthcare perspective compared to a do-nothing scenario even when these interventions are received annually for 5 or 10 years over the lifetime of patients with compensated AC (Table S5).

      Probabilistic sensitivity analysis

      The average results of the PSA are shown in Table S6. The cost-effectiveness acceptability curve in Fig. 4 plots the probability that each intervention would be preferred at various cost-effectiveness thresholds from a healthcare perspective. Our analysis suggests that acamprosate and naltrexone are most likely to be the optimal choice at any cost-effectiveness threshold, followed by baclofen, gabapentin, and topiramate.
      Figure thumbnail gr4
      Fig. 4Cost-effectiveness acceptability curves.
      Cost-effectiveness acceptability curves summarize the results of probabilistic sensitivity analyses. The curves plot the probability that each scenario is cost-effective over a range of cost-effectiveness thresholds. The figure shows that acamprosate and naltrexone are most likely to be cost-effective compared to any other alternative over all threshold values explored.
      We also conducted PSAs while varying the cohort age to 25, 35, 45, and 65 years, and the results are shown in the Tables S7 and S8. We found that all 3 interventions remain cost-saving from a healthcare perspective when compared to a do-nothing scenario. While counseling and non-FDA-approved MAT are cost-saving across all ages from a healthcare perspective, they cost more and produce more QALYs than the no-intervention scenario from a societal perspective.

      Discussions

      This CEA found that short-term MATs and counseling are extremely cost-effective – and often cost-saving – alcohol use treatments for patients with AC across all ages when compared to no intervention. Among the interventions studied, only acamprosate and naltrexone and baclofen, gabapentin, and topiramate were found to be cost-saving from both healthcare and societal perspectives. Counseling, though dominated by acamprosate and naltrexone, was also cost-effective across all patient ages when compared to a no-intervention scenario. Our results remained robust after various assumptions were modified and parameter uncertainty was taken into account.
      While it is well-known that alcohol cessation reduces morbidity and mortality in patients with AC,
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • Irving H.
      • Baliunas D.
      • Patra J.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      our findings demonstrate the value of alcohol use treatments in clinical settings, especially for younger patients. Current practice guidelines recommend screening and treating heavy alcohol use or AUD among patients with cirrhosis
      • Crabb D.W.
      • Im G.Y.
      • Szabo G.
      • Mellinger J.L.
      • Lucey M.R.
      Diagnosis and treatment of alcohol-related liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases.
      ,
      • Singal A.K.
      • Bataller R.
      • Ahn J.
      • Kamath P.S.
      • Shah V.H.
      ACG clinical guideline: alcoholic liver disease.
      ; in practice, however, few patients with AC receive alcohol treatment. For example, in a privately insured cohort where 72% had mental health or substance abuse coverage, only 0.8% received a prescription for an FDA-approved relapse prevention medication; by the first year after AC diagnosis, only 10% had received a face-to-face visit with a mental health provider.
      • Mellinger J.L.
      • Shedden K.
      • Winder G.S.
      • Tapper E.
      • Adams M.
      • Fontana R.J.
      • et al.
      The high burden of alcoholic cirrhosis in privately insured persons in the United States.
      For patients on Medicaid, other non-private insurance, and those who receive care through the Veteran’s Administration, rates are similarly low,
      • Rogal S.
      • Youk A.
      • Zhang H.
      • Gellad W.F.
      • Fine M.J.
      • Good C.B.
      • et al.
      Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis.
      ,
      • Creedon T.B.
      • Cook B.L.
      Access to mental health care increased but not for substance use, while disparities remain.
      and substance use providers frequently struggle to obtain adequate reimbursement. Finally, medical care for patients with AC is often detached from AUD treatment, with hepatology providers frequently ill-equipped to manage complex AUD independently.
      • Winder G.S.
      • Mellinger J.
      • Fontana R.J.
      Preventing drinking relapse in patients with alcoholic liver disease.
      Our findings support the integration of medical and substance use care for patients with AC, which studies have shown is effective in reducing alcohol relapse, particularly after transplantation.
      • Addolorato G.
      • Mirijello A.
      • Leggio L.
      • Ferrulli A.
      • D’Angelo C.
      • Vassallo G.
      • et al.
      Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center.
      ,
      • Donnadieu-Rigole H.
      • Jaubert L.
      • Ursic-Bedoya J.
      • Hanslik B.
      • Mura T.
      • Gamon L.
      • et al.
      Integration of an addiction team in a liver transplantation center.
      It is important to note that MATs and counseling (vs. no intervention) were found to be cost-saving from a healthcare perspective across all patient ages. Rates of advanced ALD have risen most sharply among young people,
      • Tapper E.B.
      • Parikh N.D.
      Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study.
      and these higher rates of advanced ALD come with a high price tag in both costs and mortality. When considering that many of these young people will have comorbid substance use and mental health disorders, the need for counselling and treatment is even more important.
      • Grant B.F.
      • Goldstein R.B.
      • Saha T.D.
      • Chou S.P.
      • Jung J.
      • Zhang H.
      • et al.
      Epidemiology of DSM-5 alcohol use disorder: results from the epidemiologic survey on alcohol and related conditions III.
      That these interventions appear to be cost-saving in this age group makes the urgency of adequate insurance coverage expansion, linkage to care, and reimbursement rates for AUD treatment even more important.
      Our study also adds to the literature on the cost-effectiveness of alcohol use treatments. Using results from the COMBINE study, Zarkin et al. (2008) and Dunlap et al. (2010) found that MAT (i.e. naltrexone or acamprosate) alone are cost-effective from provider and patient perspectives.
      • Zarkin G.A.
      • Bray J.W.
      • Aldridge A.
      • Mitra D.
      • Mills M.J.
      • Couper D.J.
      • et al.
      Cost and cost-effectiveness of the COMBINE study in alcohol-dependent patients.
      ,
      • Dunlap L.J.
      • Zarkin G.A.
      • Bray J.W.
      • Mills M.
      • Kivlahan D.R.
      • McKay J.R.
      • et al.
      Revisiting the cost-effectiveness of the COMBINE Study for alcohol dependent patients: the patient perspective.
      Both studies, however, only looked at short-term (12 week) and intermediate outcomes (e.g. days abstinent and patients avoiding heavy drinking). Kim et al. (2017) was the first to look at lifetime costs and benefits of counseling and MAT, and they estimated that MAT – when coupled with medical management – are cost-saving from healthcare and societal perspectives.
      • Kim D.D.
      • Basu A.
      • Duffy S.Q.
      • Zarkin G.A.
      Appendix A: worked example: the cost-Eefectiveness of treatments for individuals with alcohol use disorders: a reference case analysis.
      Use of naltrexone in advanced liver disease is, however, not without controversy. Naltrexone, though approved by the FDA for alcohol relapse prevention, carries a black-box warning for hepatotoxicity based on studies showing elevated liver function tests and higher circulating levels of naltrexone and its active metabolite, 6B-naltrexol, in patients with AC.
      • Bertolotti M.
      • Ferrari A.
      • Vitale G.
      • Stefani M.
      • Trenti T.
      • Loria P.
      • et al.
      Effect of liver cirrhosis on the systemic availability of naltrexone in humans.
      A high degree of caution is warranted in prescribing naltrexone where side effects, including withdrawal symptoms and elevated liver function tests, are seen. Patients should undergo a thorough informed consent before prescribing and should be closely monitored.
      Relapse is a lifelong concern in patients with AUD, even after liver transplantation.
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Bouthors A.
      • Rolland B.
      • Saffers P.
      • et al.
      Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: a prospective study.
      While studies have clearly shown that alcohol relapse increases mortality in advanced ALD, people with AUD experience a range of drinking patterns, with periods of lesser alcohol use or total abstinence and other periods of more moderate drinking that can lead to heavier drinking.
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Bouthors A.
      • Rolland B.
      • Saffers P.
      • et al.
      Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: a prospective study.
      These differential ranges of drinking patterns over a lifetime can be challenging to model, but we varied our treatment effects as a way to incorporate uncertainty in adherence and risk of relapse. Future models can more explicitly and deliberately incorporate this as more data becomes available on the natural history of AUD in this population.
      This study has several limitations. First, our costs and transition probabilities are based on disparate sources. Though most are specific to ALD, some were not due to a lack of available data on ALD specifically. However, we addressed parameter uncertainty in the sensitivity analyses by varying the ranges around the median values. Additional research is needed to empirically measure some of the parameter inputs used; specifically, our measure of treatment effectiveness was based on observational data, which introduces uncertainty in our cost-effectiveness estimates. Second, we only considered the impact of clinic-based counseling, and future CEAs can explore other types of psychosocial interventions, such as group therapy, community support networks (e.g. Alcoholics Anonymous), and telehealth AUD treatment. Third, the Markov model necessarily simplifies the clinical experience of patients with ALD and may exclude certain events that affect the estimation of intervention costs and health benefits. For example, we did not include the costs of alcohol withdrawal which are experienced by up to 50% of patients with AUD nor did we model the costs of comorbid substance use or mental health disorders which are experienced by a large fraction of patients with AC.
      • Addolorato G.
      • Mirijello A.
      • Barrio P.
      • Gual A.
      Treatment of alcohol use disorders in patients with alcoholic liver disease.
      Finally, the generalizability of this study is limited to patients with AC who are already seeking care, and the impact of interventions will be necessarily modified by level of engagement in care.
      In conclusion, alcohol use treatment, whether MATs or counseling, proved cost-effective for all patients with AC and even cost-saving for some. Our results support broader coverage and better reimbursement for alcohol use treatments, which improve care and prevent complications among patients with AC.

      Abbreviations

      AC, alcohol-related cirrhosis; ALD, alcohol-related liver disease; AUD, alcohol use disorder; CEA, cost-effectiveness analysis; HCC, hepatocellular carcinoma; ICER, incremental cost-effectiveness ratio; MAT, medication-assisted therapy; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year

      Financial support

      Dr. Mellinger is supported by an NIH NIAAA K23 Career Development award (K23 026333).

      Authors’ contributions

      ALVA and JLM conceived and designed the study, collected and analyzed the data, prepared the manuscript. NM and SEU collected and analyzed data and prepared the manuscript. DWH designed the study, analyzed the data, prepared the manuscript, and provided oversight throughout the study. All authors have approved the final submitted version. ALVA is the guarantor or the study.

      Conflict of interest

      The authors declare no conflicts of interest related to this research.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors extend their gratitude to journal editors and peer reviewers who provided comments on drafts of the manuscript.

      Data availability statement

      All input parameters that were used in the simulation model to generate results presented here are reported in the main text and Supplementary Material.

      Supplementary data

      The following is/are the supplementary data to this article:

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