Chronic liver disease is a costly health problem that is increasing in prevalence in China. Intrahepatic cholestasis (IHC), such as alcoholic liver disease and non-alcoholic fatty liver disease, are the leading causes of chronic liver disease. In China, the recommended treatments for IHC are S-Adenosylmethionine (SAMe) and ursodeoxycholic acid (UDCA). Despite its use as a supplement in liver disease in China and worldwide, no studies assessing the cost-effectiveness or cost-utility of SAMe compared with UDCA in IHC have been identified in the literature. The aim of this study is to assess the cost-effectiveness of SAMe compared with UDCA in a Chinese clinical setting. The modelled economic evaluation was undertaken using two paralleled decision-analytic Markov models: SAMe compared with placebo and UDCA compared with placebo. The results show that SAMe yielded an additional 3.49 QALYs at CNY263,417 per 100 patients, resulting in an ICER of CNY75,423 compared to placebo. UDCA resulted in a gain of 0.87 QALYs at an additional cost of CNY358,197 per 100 patients and an ICER=CNY410,361 compared to placebo. SAMe is dominating UDCA with an ICER of -CNY36,175, and it is estimated to be a cost-effective option for improving health outcomes and saving costs in China.
Research Article
Cost-effectiveness analysis of S-ademetionine compared with ursodeoxycholic acid for the treatment of Intrahepatic Cholestasis in China
https://doi.org/10.21203/rs.3.rs-4716061/v1
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Chronic liver disease
SAMe
UDCA
paralleled Markov model
cost-effectiveness
China
Cholestasis is a disorder of bile formation, secretion, or excretion such that bile flow is impeded from entering the duodenum and bloodstream. Intrahepatic cholestasis (IHC), a dysfunction of hepatocytes or the lesion or obstruction of bile canaliculi, is more common than extrahepatic cholestasis. The major causes of IHC are sepsis, toxaemia, cholangitis, cirrhosis (any cause), malignant and benign infiltrating disorders (tumours), vascular disorders, genetic disorders, autoimmune-, alcoholic- or viral-hepatitis, parenteral nutrition, and pregnancy [1].
The characteristic initial presentation of cholestasis is an increase in serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels [2]. In the early stages, patients may be clinically asymptomatic or present with the non-specific symptoms of fatigue, anorexia, nausea or upper abdominal discomfort. Symptoms with cholestatic-specificity are jaundice, pruritus, steatorrhea, xanthoma, and osteoporosis. Elevated direct bilirubin levels are associated with jaundice. However, an increase in serum bile acid is a more sensitive early indicator of cholestasis (though less sensitive than ALP) [2]. Cholestasis that persists for over 6 months is deemed chronic and can aggravate liver damage. When hepatocyte injury is induced, increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are seen [1].
Treatment for IHC involves the removal of aetiological factors and the use of drugs to improve clinical symptoms and liver injury. Aetiological treatment may include surgery, discontinuation of the causative agent (e.g. alcohol or drug) or anti-virals. In China, the treatment for IHC caused by a variety of liver diseases is S-Adenosylmethionine (SAMe) or ursodeoxycholic acid (UDCA), as recommended by the Chinese Society of Hepatology, Chinese Society of Gastroenterology and Chinese Society of Infectious Diseases of the Chinese Medical Association [1].
In cholestatic patients, the accumulation of bile acids in hepatocytes causes hepatocyte injury. SAMe is a participant in the body’s transculturation and aminopropylation pathways [3]. The majority of SAMe metabolism occurs in the liver, as this is where most of the methylation reactions take place and where half of the precursor molecule, methionine, is located [4]. The hepatic synthesis of SAMe from dietary methionine, an essential amino acid, is catalysed by the methionine adenosyl transferase (MAT) enzymes MATI and MATIII. Healthy adults produce 6–8g of SAMe per day [5]. The liver’s most abundant methyltransferase enzyme, glycine N-methyltransferase (GNMT), is responsible for most of the hepatic utilisation of SAMe [6]. Liver methionine metabolism is altered in liver dysfunction, so inhibition of MAT activity results in decreased SAMe biosynthesis. An adequate supply of SAMe is necessary to supply methyl groups for the body’s numerous (399 in mammals) SAMe-dependent methyltransferases. Given the importance of SAMe in methylation pathways in general and to normal hepatic physiology, there is a growing body of evidence linking SAMe depletion with the inducement of liver injury [6] [7]. Clinical trials have reported an improvement in the biochemical parameters of liver function (serum transaminases) in liver injury with SAMe supplementation which has been established as a therapy in many countries around the world [3] [5]. SAMe supplementation exists in oral and parenteral formulations, with the bioavailability of the parenteral form superior [4].
Ursodeoxycholic acid (UDCA) is a physiological constituent of human bile acid, comprising approximately 1 to 3%. UDCA, which is the predominant bile acid in black bear’s bile, has been a traditional Chinese medicine since the Tang dynasty (618–907 AD) administered in powder form as a remedy for liver diseases. UDCA is mainly absorbed in the small intestine before uptake into the liver, conjugating with amino acids into its active form. The beneficial effect of UDCA is via the stimulation of biliary secretion from hepatocytes, along with the expression of transporter proteins necessary for this process [8].
In China, intrahepatic cholestasis (IHC), with alcoholic liver disease and non-alcoholic fatty liver disease the leading causes, is a costly health problem that is increasing in prevalence. Although hepatocellular changes are reversible in the early stages, persistence and severity of the disease can progress to fibrosis, cirrhosis, possible hepatocellular carcinoma, and subsequent liver failure or liver cancer [9], and China bears > 50% of the global burden of liver cancer [10]. Despite its use as a supplement in liver disease worldwide, no studies assessing the cost-effectiveness or cost-utility of SAMe compared with UDCA in IHC have been identified in the literature.
The aim of this study is to assess the cost-effectiveness of SAMe compared with UDCA in a Chinese clinical setting.
The modelled economic evaluation was undertaken using two paralleled decision-analytic Markov models: comparing SAMe with no treatment (placebo in clinical trials) and UDCA with no treatment. (Figure 1). The utilisation of parallel models stems from the lack of clinical trial data directly comparing SAMe with UDCA. The two modelled outcomes were subsequentially compared to generate the final difference in ICER between SAMe and UDCA. The Markov models involved an initial decision of starting treatment with SAMe, UDCA, or placebo. Patients then transitioned through different health states. Each model cycle represented 2 weeks over a 2-year time horizon and used a discount rate of 3%. Sensitivity analysis was applied to the time horizon of ± 1 year and to the discount rate of ± 2%.
The Markov model has three health states (Figure 2): moderate/severe cholestatic disease (i.e., elevated liver function tests), mild cholestatic disease (i.e., normal liver function tests), and death.
The cost-effectiveness of the intervention was described in terms of improvements in health outcomes and costs associated with the interventions. The net cost per unit of health outcome benefit gained from the intervention is the incremental cost-effectiveness ratio (ICER), which is the main outcome of interest in cost-utility analysis. For example, the ICER of SAMe compared with placebo is defined as:
To estimate QALYs lived, the years of life lived within any health state are multiplied by the utility value relevant to that health state. To estimate costs, annual costs are applied to the relevant years of life lived within health states, similar to the application of utility weights. The formulas implicitly assume that any transition into and out of that health state occurs halfway through any cycle. The same model method was applied to UDCA compared with placebo. The two ICERs were then compared. The intervention is considered cost-effective where the ICER falls below the decision maker’s maximum willingness to pay for the health benefits, also referred to as the decision threshold (8). There is no established ICER threshold in China, and therefore, this study uses an ICER threshold set to 3 x GDP/capita for China, which was CNY 270,000 in 2022.
A broader Chinese societal perspective is taken in this cost-effectiveness analysis.
Costs
The first intervention that is proposed for the treatment of moderate intrahepatic cholestasis is SAMe. SAMe is given once a day at a dose of 1500- 2000 mg, or 3 tablets [11] . A pack of 10 tablets (500mg per tablet) of SAMe costs CNY 171.90 (lowest bidding price, PVBP excluded), which leads to 5 packs of consumption every 2 weeks with the cost of 5 × 171.9 = CNY 859.5.
The second intervention is UDCA. UDCA is given once a day at a dose of 750 mg or 3 tablets. A pack of 25 tablets (250 mg per tablet) cost CNY 210.2 (lowest bidding price, PVBP excluded), which lead to 2 packs of consumption every 2 weeks with the cost of 2 × 210.2 = CNY 420.4.
Since there is no peer-reviewed literature to indicate the usage of healthcare resources by patients diagnosed with intrahepatic cholestasis in China, an expert panel of physicians from China advised the frequency of visiting clinics, hospitals, and specialists for patients who experienced IHC. From the expert panel’s feedback, patients who experienced moderate IHC see a doctor 6 times a year and have blood tested 5 times a year on average. A small group of patients (0.08%) also need to visit specialists 6 times a year. The cost of visiting a doctor is advised to be CNY 830 per time. The cost of visiting a specialist is advised to be an extra CNY 2171 per time on average. The cost of a blood test is CNY 50 per test. Overall, the healthcare cost for patients with severe/moderate IHC is assumed to be (CNY830*6) + (CNY2171*6*0.08%) + (CNY50*5) = CNY 5241.4 per year. Sensitivity analysis varying the cost +/- 10% and a scenario analysis, where the cost of a visit to a doctor is set to zero, were performed.
Efficacy
The effectiveness of the treatment is categorised based on SAMe clinical trials targeting various types of liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, drug-induced liver impairment, and intrahepatic cholestasis of pregnancy.
ALP was selected as the biomarker to evaluate IHC severity in the Markov models[12, 13]. The percentage change in ALP for treatment versus placebo derived from three studies was 28.9% versus 7.6% for SAMe and 6.0% versus 5.4% for UDCA, summarised (Table 1). Studies were weighted where necessary using inverse variances.
Table 1. Percentage change in ALP for the indirect comparison of SAMe versus UDCA with placebo.
|
|
Treatment |
Baseline ALP; ± change (U/L) |
% change |
Study weight |
Weighted % change |
|
Frezza (1990) [14] |
SAMe |
268; -77 |
28.9% |
100% |
28.9% |
|
Placebo |
284; -22 |
7.6% |
100% |
7.6% |
|
|
Summary, total % change |
SAMe |
28.9% |
|||
|
Placebo |
7.6% |
||||
|
Leuschner (2010) [15] |
UDCA |
165; -11 |
6.4% |
68% |
4.4% |
|
Placebo |
173; -9 |
5.5% |
68% |
3.7% |
|
|
Lindor (2004) [16] |
UDCA |
155; -8 |
5.2% |
32% |
1.7% |
|
Placebo |
154; -8 |
5.3% |
32% |
1.7% |
|
|
Summary, total % change |
UDCA |
6.0% |
|||
|
Placebo |
5.4% |
||||
The diagnostic criteria for cholestatic liver diseases have historically been ALP levels higher than 1.5 × the upper limit of normal (ULN) [1]. This was presented in the European Association for the Study of the Liver guideline for the management of cholestatic liver diseases in 2009 [17], and subsequently endorsed by the Chinese Association of Hepatology in 2015 [1]. The normal ALP range for adults is 30 to 120 IU/L [18]. This corresponds to an ALP level of ≥180 IU/L for IHC patients. A baseline ALP level of IU was calculated from available literature (Table 2).
Table 2. Baseline ALP values of IHC patients at study commencement.
|
First author (year) |
Baseline ALP (IU/L) |
N |
|
Choudhuri (2014)[19] |
276.5 |
67 |
|
Fiorelli (1999) intramuscular group [20] |
259.5 |
276 |
|
Fiorelli (1999) intravenous group [20] |
276.5 |
253 |
|
Frezza (1990) treatment group [14] |
270.0 |
110 |
|
Frezza (1990) comparison group [14] |
282.0 |
110 |
|
Ivashkin (2018) [21] |
241.2 |
72 |
|
Leuschner (2010) treatment group [15] |
165.0 |
95 |
|
Leuschner (2010) comparison group [15] |
173.0 |
91 |
|
Lindor (2004) treatment group [16] |
154.7 |
79 |
|
Lindor (2004) comparison group [16] |
154.4 |
86 |
|
Manzillo (1992) treatment group [22] |
289.2 |
99 |
|
Manzillo (1992) comparison group [22] |
295.8 |
85 |
|
Qin (2000) treatment group [23] |
195.5 |
15 |
|
Qin (2000) comparison group [23] |
190.6 |
15 |
|
Virukalpattigopalratnam (2013) [24] |
230.6 |
96 |
|
SUM (ALP × N) |
354,672 |
|
|
SUM (N) |
1,549 |
|
|
Summary, baseline ALP (IU/L) |
229 |
|
A time horizon of two years was chosen on the basis that UDCA is a long-term therapy, requiring many months of administration for treatment effectiveness [25].
The proportion of IHC patients reporting the symptoms of fatigue, pruritus and jaundice was 79.7%, 49.5% and 47.0%, respectively at study commencement (considered IHC onset with severe/moderate disease severity) and 33.3%, 11.4% and 24.4% respectively at study conclusion (considered mild disease severity) with study weights calculated using inverse variances in RevMan 5.4 (Table 3).
Table 3. Percentage of IHC patients presenting with symptoms fatigue, pruritus and jaundice.
|
|
% reporting (n/N) |
Study weight |
Weighted % reporting |
||
|
First author (year) |
Study start |
Study end |
Study start |
Study end |
|
|
FATIGUE |
|||||
|
Choudhuri (2014) [19] |
80% (195/243) |
38% (92/243) |
25.2% |
20.2% |
9.5% |
|
Ivashkin (2018) [21] |
82% (59/72) |
51% (37/72) |
24.6% |
20.2% |
12.6% |
|
Perlamutrov (2014) [26] |
81% (85/105) |
11% (12/105) |
24.9% |
20.2% |
2.8% |
|
Virukalpattigopalratnam (2013) [24] |
76% (184/243) |
33% (79/243) |
25.3% |
19.2% |
8.2% |
|
Summary, total % reporting fatigue |
|
|
|
79.7% |
33.3% |
|
PRURITUS |
|||||
|
Choudhuri (2014) [19] |
36% (88/243) |
10% (24/243) |
20.1% |
7.3% |
2.0% |
|
Ivashkin (2018) [21] |
54% (39/72) |
11% (8/72) |
19.8% |
10.7% |
2.2% |
|
Perlamutrov (2014) [26] |
81% (85/105) |
7% (7/105) |
19.8% |
16.0% |
1.3% |
|
Virukalpattigopalratnam (2013) [24] |
39% (95/243) |
17% (42/243) |
20.1% |
7.9% |
3.5% |
|
Manzillo (1992) [22] |
38% (129/343) |
12% (42/343) |
20.1% |
7.6% |
2.5% |
|
Summary, total % reporting pruritus |
|
|
|
49.5% |
11.4% |
|
JAUNDICE |
|||||
|
Choudhuri (2014) [19] |
81% (197/243) |
56% (136/243) |
25.1% |
20.3% |
14.0% |
|
Ivashkin (2018) [21] |
39% (28/72) |
17.5% (13/72) |
24.8% |
9.6% |
4.5% |
|
Perlamutrov (2014) [26] |
20% (21/105) |
2% (2/105) |
24.8% |
5.0% |
0.5% |
|
Virukalpattigopalratnam (2013) [24] |
48% (116/243) |
21% (51/243) |
25.2% |
12.0% |
5.4% |
|
Summary, total % reporting jaundice |
|
|
|
47.0% |
24.4% |
Quality of life
The quality of life (QoL) used in this model is determined by the primary IHC score and the comorbidities, including jaundice, pruritus, and fatigue, in two different health states. The mean Short Form 6 Dimension (SF-6D) utility score of chronic liver patients is 0.79 [27]. Patients in severe/moderate state have a QoL score of 0.68. Patients with pruritus have the SF-6D QoL score of 0.613-0.706 = -0.093; patients with fatigue have the following utility score: 0.576-0.732 = -0.156 [28]; and patents with jaundice have a utility score of 0.63-0.67 = -0.04 [29].
Total QoL utility is calculated as:
Primary IHC + Jaundice × percentage of Jaundice + Pruritus × percentage of pruritus + Fatigue × percentage of fatigue.
Patients in different treatment groups will have different percentages of comorbidities (Table 4).
Table 4: Quality of life input table.
|
|
QoL |
|
Utility by severity |
|
|
Mild IHC |
0.79 |
|
Severe/moderate IHC |
0.68 |
|
Pruritus |
|
|
IHC without pruritus |
0.706 |
|
IHC with pruritus |
0.613 |
|
Reduction by pruritus |
-0.093 |
|
Fatigue |
|
|
IHC without fatigue |
0.732 |
|
IHC with fatigue |
0.576 |
|
Reduction by fatigue |
-0.156 |
|
Jaundice |
|
|
IHC without jaundice |
0.67 |
|
IHC with jaundice |
0.63 |
|
Reduction by jaundice |
-0.04 |
Sensitivity analysis
One-way and probabilistic sensitivity analyses were performed by varying the input by +/- 10% for cost and efficacy variables. The discount rate was examined by varying it to 1% and 5%, and the time horizon was varied from 1 year to 3 years. Probabilistic sensitivity analysis was performed using @Risk by Palisade.
Microsoft Excel (Microsoft 365 MSO version 2304, Microsoft Corporation) on the Windows 10 platform was used for the economic evaluation, and RevMan 5.4 was used for the meta-analysis.
SAMe yielded an additional 3.49 QALYs at CNY263,417 per 100 patients, resulting in an ICER of CNY75,423 compared to the placebo. The cost difference was driven by CNY343,786 in drug costs but offset with -CNY80,368 in health care costs. UDCA resulted in a gain of 0.87 QALYs at an additional cost of CNY358,197 per 100 patients and an ICER = CNY410,361. The costs were split into CNY378,284 in drug costs and -CNY20,086 in health care costs. This means that the extended cost-utility of SAMe would be 3.49–0.87 = 2.62 QALYs at a cost of CNY263,417-CNY358,197 = -CNY94,780. While the drug costs were similar, the same health care costs were four (-CNY80,368/-CNY20,086 = 4) times lower than UDCA. Compared with the suggested ICER threshold, the SAMe is cost-effective vs placebo with an ICER less than 1x GDP/capita, and the UDCA is not cost-effective vs placebo with an ICER over 3x GDP/capita. SAMe is dominating UDCA (ICER = -CNY36,175) in terms of cost-effectiveness in improving health outcomes and saving costs (Table 5).
| SAMe | Placebo | UDCA | Placebo | Difference between SAMe and UDCA | |
|---|---|---|---|---|---|
| Costs (CNY) | |||||
| Drug costs | 343,786 | 0 | 378,284 | 0 | |
| Health care costs | 40,194 | 120,562 | 1,40,650 | 160,737 | |
| Total costs | 383,9800 | 120,562 | 518,934 | 160,737 | |
| Difference | 263,418 | 358,197 | -94,779 | ||
| QALYs | |||||
| IHC | 154.4 | 152.7 | 152.2 | 151.8 | |
| Co-morbidities | -15.1 | -16.9 | -17.3 | -17.8 | |
| Total QALYs | 134.9 | 134.1 | |||
| Difference | 3.49 | 0.87 | 2.62 | ||
| Incremental cost-effectiveness ratio | |||||
| ICER | 75,423 | 410,361 | SAMe dominating UDCA (-36,175) | ||
The one-way sensitivity analysis showed that the ICER of SAMe was sensitive to varying the daily dosage of SAMe, the SAMe costs, the QALYs, and the healthcare costs (Fig. 3). For UDCA, the one-way sensitivity analysis showed that the ICER was sensitive to varying the daily dosage, the costs of UDCA, and the QALYs (Fig. 4). The responding rate for SAMe had the least influence on the ICER of SAMe, and the healthcare costs had the least influence on the ICER of UDCA.
The probabilistic sensitivity analyses showed that UDCA was a cost-effective alternative to placebo in 63.2% of the simulations, which were below the CNY 270,00 threshold, whereas 91.7% of the simulations for SAMe were below the threshold.
This research integrated and utilised the peer-reviewed literature and the evidence of costs in Chinese societal perspectives and demonstrated that SAMe yielded more QALYs and saved more costs compared with UDCA. Whilst cost-effectiveness studies for the treatment of major liver diseases, such as non-alcoholic fatty liver disease, exist, cost-effectiveness/cost-utility literature for IHC is extremely limited. IHC is a feature of several liver diseases, both acute and chronic. Due to the potentially unique pathogenesis of each disease, disease severity and progression will vary for subgroups of IHC sufferers. To avoid complexity, and as parameter estimates were not available for specific subgroups of IHC patients, our analysis did not attempt to model disease progression for all possible cholestatic conditions.
We also observed that certain clinical trials were carried out for a considerable amount of time in the past, and various factors could be attributed to the causes and progression of IHC. In pursuit of optimal outcomes, we addressed and evaluated uncertainties associated with the input data to a certain degree through sensitivity analysis.
In conclusion, SAMe is estimated to be a more cost-effective option than UDCA for treating IHC in China.
ALP Alkaline phosphatase
ALT Alanine aminotransferase
AST Aspartate aminotransferase
CNY Chinese Yuan
GDP Gross Domestic Product
GGT Gamma-glutamyl transferase
GNMT Glycine N-methyltransferase
ICER Incremental Cost-Effectiveness Ratio
IHC Intrahepatic cholestasis
MAT Methionine adenosyl transferase
PVBP Price value of a basis point
QALYs Quality-adjusted life years
QoL Quality of life
SAMe S-ademetionine
SF-6D The Short Form 6 Dimension algorithm
UDCA Ursodeoxycholic acid
ULN Upper limit of normal
Funding
Abbott Products Operations AG, Switzerland, fully funded the study.
Competing Interests
Hansoo Kim, Juntao Lyu, Ruth Royle, and Joshua Byrnes performed the cost-effectiveness analysis as part of their employment with Griffith University. Abbott Products Operations AG, Switzerland, fully funded the study and publication. Kyoo Kim and Mauricio Morales-Castillo are employees at Abbott Products Operations AG, Switzerland.
Author Contributions
Material preparation, data collection and analysis were performed by Hansoo Kim, Juntao Lyu, Ruth Royle, and Joshua Byrnes. The draft of the manuscript was reviewed by Kyoo Kim and Mauricio Morales-Castillo. All authors commented on previous versions of the manuscript.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable. This research did not involve human participants or animals.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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Competing interest reported. Hansoo Kim, Juntao Lyu, Ruth Royle, and Joshua Byrnes performed the cost-effectiveness analysis as part of their employment with Griffith University. Abbott Products Operations AG, Switzerland, fully funded the study and publication. Kyoo Kim and Mauricio Morales-Castillo are employees at Abbott Products Operations AG, Switzerland.