Cost-Effectiveness of Itopride Hydrochloride for the Treatment of Functional Dyspepsia in Vietnam

Abstract

Background/Objectives: Functional dyspepsia is associated with abdominal pain and nausea, which leads to reduced quality of life, loss of productivity, and economic loss for patients. Itopride hydrochloride (itopride) stimulates the gastrointestinal smooth muscles, thereby promoting gastric emptying. It has been shown to significantly improve symptoms in patients with functional dyspepsia without severe side effects. Itopride has been available in Vietnam for many years; however, the cost-effectiveness of the drug has not been established. The aim of this study is to estimate the cost-effectiveness of itopride for the treatment of functional dyspepsia in Vietnam. Methods: A 3-stage Markov model with the following health states—controlled functional dyspepsia, uncontrolled functional dyspepsia, and dead—was developed. Functional dyspepsia was used to assess itopride over 10 years using 8-week cycles. A broader Vietnamese societal perspective was assumed for the analysis. Input was retrieved from the literature and through local clinical input from physicians in Vietnam. Output was reported as an incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY). A GDP/capita threshold (very cost-effective: 1 × GDP = Vietnamese Dong (VND) 64.1 M, cost-effective: 3 × GDP = VND 192.2 M) was used as recommended by the WHO in Vietnam. One-way and probabilistic sensitivity analyses were performed. Results: Itopride use resulted in an additional 0.28 QALYs at an extra cost of VND 11.2 M. This resulted in an ICER of VND 39.7 M per QALY, which is lower than the threshold of VND 192.2 M. One-way sensitivity analyses showed that the ICER was sensitive to varying the efficacy VND 31.8 M to VND 88.3 M), cost of itopride (ICER: VND 43.1 M to VND 56.5 M), and the health utility values (ICER: VND 45.2 M to VND 55.3 M). More than 80% of the simulations in the probabilistic sensitivity analysis were cost-effective at the 1 × GDP (VND 64.1 M) threshold, and 91.3% were cost-effective at the 3 × GDP (VND 192.2 M) threshold. Conclusion: This study shows that itopride hydrochloride is a very cost-effective treatment for functional dyspepsia in Vietnam, with the ICER (VND 39.7 M/QALY) being even lower than the 1 × GDP (VND 64.1 M) threshold.

1. Introduction

Dyspepsia is a common symptom of gastroesophageal reflux disease and refers to pain or discomfort in the upper abdomen. Globally, the prevalence is projected to be up to 17.6% [1]. It has been estimated that about 70% of these individuals with dyspepsia who have no structural explanation for their symptoms suffer from ‘Functional dyspepsia’ (FD). FD is primarily characterised by discomforting symptoms in the upper gastrointestinal tract [2]. FD is also associated with higher healthcare utilisation compared to the general population. A study by Chuah et al. [3] showed increased healthcare utilisation in patients, such as increased hospitalisation due to gastrointestinal symptoms and investigations (endoscopies, blood tests, etc.). It is evident that functional dyspepsia has a significant burden on the health of patients and incurs both direct costs relating to the treatment of dyspepsia and indirect costs such as loss of income.

In East and Southeast Asia, both acid suppression therapy and prokinetics are established first-line treatments. The 2012 Asian Consensus Report on functional dyspepsia [4] deemed prokinetics to be a first-line treatment option for the PDS subtype and second-line treatment for EPS. At the primary care level, it is advised to administer drugs such as prokinetics, proton pump inhibitor, and a combination of alginate-antacid and acid-suppressive therapy to patients who present with reflux symptoms or have ongoing symptoms that are not fully controlled by acid suppressants [5].

In countries such as China and South Korea, prokinetics are the mainstay therapy recommended for patients with PDS symptoms [6]. Prokinetic agents target this group of patients by enhancing gastric motility by amplifying and coordinating gastrointestinal muscle contractions [7]. These agents include itopride, domperidone, and metoclopramide, among others. In a systematic review and meta-analysis conducted by Pittayanon et al. [8] in 2019, 29 trials were reviewed, which included six prokinetic agents that showed moderate effectiveness against placebo (overall global symptom improvement 40% vs. placebo 26%).

In Vietnam, between 7.8 and 22.4 million are estimated to have functional dyspepsia [9]. Itopride is currently subsidised for the treatment of functional dyspepsia. However, it is not clear whether this is value for money. There are some inherent issues when decision-makers decide to fund a drug. These involve scarcity of funds available (limited budget), the information available, and opportunity cost; that is, by investing in one intervention, we lose the opportunity to fund another. Therefore, to help make these decisions, health technology assessments (HTAs) of drugs are performed. HTAs assess the value for money and typically measure health effects (gains/loss) in both life years gained and quality-adjusted life years using a type of analysis called cost-effectiveness analysis [10]. The use of HTA in Vietnamese healthcare decision-making is still in development and was only introduced in 2014. However, there have been substantive efforts to implement HTA in decision-making when making investments in healthcare [11].

The aim of this study is to estimate the cost-effectiveness of itopride for treatment of naïve patients with newly diagnosed functional dyspepsia when compared to placebo in Vietnam.

2. Results

Itopride resulted in an additional 0.28 QALYs at an extra cost of VND 11.2 M. This resulted in an ICER of VND 39.7 M per QALY, which is lower than the threshold of VND 64.1 M. (see

Table 1. Results.

	QALY	Costs	ICER
Base case	0.28	VND 11.2 M	VND 39.7 M
Without healthcare costs	0.28	VND 12.6 M	VND 44.7 M
Without loss of productivity	0.28	VND 15.2 M	VND 53.9 M
Without both healthcare costs and loss of productivity	0.28	VND 16.7 M	VND 58.9 M

).

The ICER increased to VND 44.7 M and VND 53.0 M when healthcare costs and loss of productivity were removed from the model. Leaving both loss of productivity and healthcare costs out of the cost-effectiveness analysis resulted in an ICER of VND 58.9 M.

Figure 5 displays a tornado diagram with one-way sensitivity analyses. The ICER was sensitive to varying efficacy (ICER: VND 31.8 M to VND88.3 M), cost of itopride (ICER: VND 43.1 M to VND 56.5 M), and health utility values (ICER: VND 45.2 M to VND 55.3 M).

The time horizon and cost of health resources had the least influence on the ICER; varying the time horizon with +/−2 years resulted in an ICER from VND 39.63 M to VND 40.19 M, and varying the cost of the health resources +/−10% resulted in an ICER between VND 39.01 M to VND 40.19 M (see Figure 1).

For the probabilistic sensitivity analysis, 80.9% of the simulations at the 1 × GDP (VND 64.1 M) threshold and 91.3% were cost-effective at the 3 × GDP (VND 192.2 M) threshold (see Figure 2).

3. Discussion

This study examined the cost-effectiveness of itopride for patients suffering from functional dyspepsia using a Markov model. We estimated that patients receiving itopride had an average of 0.28 additional QALYs at a (discounted) net cost of VND 11.2 M. This equated to an ICER of VND 39.7 M per QALY saved. In our probabilistic sensitivity analysis, itopride was found to be cost-effective in more than 90% of the simulations, suggesting that there is limited uncertainty. In our one-way sensitivity analysis decreasing the efficacy by 10% increased the ICER to VND 69.0 M. This is likely to be related to the fact that up to 40% of patients are able to control their dyspepsia symptoms.

The inclusion of productivity loss is uncommon in economic evaluations, with a recent review by Jiang et al. [12] in 2022 finding only 10.2% of economic evaluation studies included productivity loss. Our scenario analysis showed that removing the improvement in productivity in the model results in an increase in ICER to VND 53.9 M.

The treatment of FD differs in various regions, and prokinetics are widely used in Asia. In Western countries, such as the USA and Western Europe, acid suppression with proton pump inhibition (and or Histamine-2 receptor antagonists) is the established treatment [2]. Prokinetics such as itopride do not have market authorisation for the treatment of functional dyspepsia in Western countries. As such, no published cost-effectiveness analysis of any prokinetic for the treatment of functional dyspepsia has been published.

A main weakness of this study is the lack of quality-of-life data in the Vietnamese population. However, the one-way sensitivity analysis showed that the health state utilities used in the model were not the key driver for the cost-effectiveness of itopride. Another limitation of this analysis is that the efficacy data are based on a meta-analysis of clinical trials [8] that only follow patients for 8 weeks, and therefore, outcomes have had to be modelled with respect to long-term treatment of the condition. The model was tested for sensitivity to a time horizon of 3 years, and little sensitivity was detected, with the ICER ranging from VND 39.50 (time horizon = 5 years) to VND 39.61 M.

This study relies on the extrapolation of clinical data beyond the clinical trial as well as the transformation of data from other jurisdictions (e.g., Malaysia). Possible extensions of this cost-effectiveness analysis would be to perform a study that assesses whether itopride would result in the health outcomes that are presented in this paper.

4. Materials and Methods

A 3-stage Markov model with the following health states: controlled FD, uncontrolled FD, and dead was developed (see Figure 3).

The Markov model involved an initial decision of starting treatment with itopride or no treatment (see Figure 4). Patients then transitioned through the different health states. Each model cycle represented 8 weeks over a 3-year time horizon and used a discount rate of 3%.

All patients started with uncontrolled FD and either remained in that stage or transitioned to controlled FD or death. Once in the controlled stage, patients could remain in that stage or transition to death.

4.1. PICO

A standard population, intervention, comparator, and intervention (PICO) framework was used for this cost-effectiveness study [13].

4.2. Population

The population is defined as patients suffering from functional dyspepsia. It is assumed that patients who experienced controlled FD only see a doctor when prescribed the drug, whereas patients who have uncontrolled FD see a doctor 12 times a year based on advice from local clinicians. The cost of visiting a doctor is assumed to be Vietnamese Dong (VND) 243,800, as advised by an expert panel. This assumption was tested through sensitivity analysis by varying the cost by +/−10% as well as performing a scenario analysis where the cost of a visit to a doctor is set to zero.

4.3. Intervention

The intervention that is proposed for the treatment of FD is itopride. Itopride is approved by the Drug Administration of Vietnam for the treatment of FD and is currently reimbursed for use in level 1 + 2 hospitals in Vietnam. Itopride is given three times a day at a dose of 50 mg. A pack of 20 tablets of itopride costs VND 105,520, which means that a daily dose of itopride is (VND 105,520/20) × 3 = VND 15,828.

4.4. Comparator

No other drug is currently reimbursed for the treatment of FD in level 3 + 4 hospitals in Vietnam. Mosapride is approved by the Drug Administration of Vietnam and indicated for the treatment of FD. However, mosapride is not reimbursed for use in level 1 + 2 nor level 3 + 4 hospitals for the treatment of FD and was therefore deemed irrelevant as a comparator. Domperidone is reimbursed for use in both level 1 + 2 hospitals as well as level 3 + 4 hospitals to treat symptoms relating to FD. However, domperidone is not approved by the Drug Administration of Vietnam for the treatment of FD.

No treatment was, therefore, assumed to be the comparator for this cost-effectiveness analysis.

4.5. Outcomes

4.5.1. Efficacy

The most common primary outcome measure in FD is overall global satisfaction questionnaires [14]. These are measured either by a dichotomous response (e.g., yes ⁄no to symptom improvement) or a scoring method, which can either be a Likert scale (categorical) like the Leeds Dyspepsia Questionnaire [15]. The endpoint of adequate relief has been proven to be responsive and reproducible and demonstrates good construct validity in FD clinical trials [14].

A systematic review by Pittayanon et al. [8] estimated the relative risk of not being symptom-free for itopride versus no treatment across six studies to be 0.70 [95% CI: 0.47; 1.03]. For the treatment naïve sub-population, the relative risk was estimated to be 0.68 [0.53; 0.86]. For mosapride the relative risk of being symptom-free versus no treatment was estimated to be 0.91 [0.73; 1.13]. An indirect comparison of itopride vs. mosapride using no treatment as a common comparator was performed using the standard Bucher method [16] and resulted in a relative risk of being symptom-free for 0.81 [0.67; 0.99].

4.5.2. Toxicity

There was no association between any specific prokinetic (except for cisapride) and any adverse events [relative risk 1.09, 95% CI 0.95 to 1.25] observed in the systematic review by Pittayanon et al. [8]. Toxicities were, therefore, not included in the cost-effectiveness analysis.

4.6. Quality of Life

Utility scores are required for economic evaluation as they present a preference-based approach to assessing health-related quality of life. Estimates are scaled with 1.0 representing full health and 0 as equivalent to death. No Vietnamese study was identified estimating a utility score for the health-related quality of life of patients with FD. However, five studies were identified from neighbouring Asian countries, including Malaysia [17,18], Hong Kong [19], South Korea [20], and India [21]. The Malaysian study was the largest of these studies (n = 2000 and n = 2039 rural and urban patients, respectively) and considered the most appropriate for the Vietnamese population. This large cross-sectional study compared the health-related quality of life of those with and without FD. It used a widely accepted generic multi-attribute utility instrument, the EQ-5D-5L, which has been previously considered a valid instrument among patients with dyspepsia [22]. Subsequently, the rural and urban Malaysian studies were pooled to derive an estimate of patients with FD (0.872, SD 0.17) and without FD (0.961, SD 0.099), representing a statistically significant disutility of 0.088 (95% CI: 0.098, 0.080) using a two-tailed t-test. To explore differences in the preferences regarding health-related quality of life between Vietnamese and Malaysian populations, the utility values from the Malaysian and Vietnamese valuation studies were compared. Specifically, the correlation between country-specific utility values for all health states defined by the EQ-5D-5L descriptive system (n = 3126) was assessed using Pearson correlation and plotted for visual comparison (see Figure 5).

The correlation coefficient was 0.941 (95% CI: 0.932, 0.950), indicating a strong correlation [23], and therefore, the Malaysian values were corrected using the correlation coefficient. While this assesses for errors in our estimates based on differences in valuation or valuation error, it does not provide an assessment of any underlying measurement error. That is, whilst the utility value of any given health state is comparable between the Vietnamese and Malaysian populations, it does not consider the difference between how Vietnamese patients may complete the questionnaire compared with Malaysian patients. However, the estimates of disutility applied here are consistent across other countries and as applied in economic evaluations. Regardless, the uncertainty in utility values is explicitly explored in one-way sensitivity analyses and included in the probabilistic sensitivity analysis.

4.7. Cost-Effectiveness Analysis

The cost-effectiveness of the intervention will be described in terms of improvements in health outcomes and costs associated with the intervention compared to the comparator. 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-effectiveness analysis. The ICER is defined as:

$$\mathrm{I}\mathrm{C}\mathrm{E}\mathrm{R}={\displaystyle \frac{{\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l} \mathrm{C}\mathrm{o}\mathrm{s}\mathrm{t}}_{\mathrm{i}\mathrm{t}\mathrm{o}\mathrm{p}\mathrm{r}\mathrm{i}\mathrm{d}\mathrm{e}}-{\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l} \mathrm{C}\mathrm{o}\mathrm{s}\mathrm{t}}_{\mathrm{n}\mathrm{o} \mathrm{t}\mathrm{r}\mathrm{e}\mathrm{a}\mathrm{t}\mathrm{m}\mathrm{e}\mathrm{n}\mathrm{t}}}{{\mathrm{Q}\mathrm{A}\mathrm{L}\mathrm{Y}}_{\mathrm{i}\mathrm{t}\mathrm{o}\mathrm{p}\mathrm{r}\mathrm{i}\mathrm{d}\mathrm{e}}-{\mathrm{Q}\mathrm{A}\mathrm{L}\mathrm{Y}}_{\mathrm{n}\mathrm{o} \mathrm{t}\mathrm{r}\mathrm{e}\mathrm{a}\mathrm{t}\mathrm{m}\mathrm{e}\mathrm{n}\mathrm{t}}}}$$

where:

• Total Cost_itopride = Total cost for itopride
• Total Cost_{no treatment} = Total cost for no treatment
• QALY_itopride = Quality-adjusted life years for itopride
• QALY_{no treatment} = Quality-adjusted life years for no treatment.

To estimate QALYs lived, the years of life lived within any health state are multiplied by the utility value relevant to that health state. In a hypothetical example, if a health state is ascribed a utility value of 0.8, then a year of life lived in this health state is equivalent to 0.8 QALYs lived.

To estimate costs, annual costs are applied to the relevant years of life lived within health states in a manner similar to the application of utility weights. In a hypothetical example, if the yearly healthcare costs associated with a particular health state are $1000, then a subject occupying that health state is assumed to have incurred $1000 of costs.

Implicit in the formulas is the assumption that any transition into and out of that health state occurred halfway through any cycle.

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 [10]. There is no established ICER threshold in Vietnam. For this analysis, the gross domestic product (GDP) per capita for Vietnam is used as a threshold. This is in line with recommendations previously made by the World Health Organization [24], namely that if the ICER is below 1 × GDP, then the intervention is very cost-effective, and if the ICER is between 1 × GDP and 3 × GDP, then the intervention can be considered cost-effective. The GDP for Vietnam was VND 64.1 M (US$2785) in 2020 [25]. The corresponding 1 × GDP is VND 64.1 M, and 3 × GDP is VND 192.2 M.

4.8. Other Outcomes: Productivity

There is currently a discussion with respect to the impact on productivity for patients suffering from uncontrolled functional dyspepsia. Matsuzaki et al. [26] reported a 10.9% decrease in productivity for people suffering from uncontrolled functional dyspepsia. Assuming a 5-day working week, this equates to 8 × 5 days × 10.9% = 4.27 working days in terms of absenteeism every 8 weeks. The average daily income in Vietnam is estimated to be VND 283,472 by the World Bank, which means that the loss of income is estimated to be VND 1,211,218 per cycle. The implications of productivity loss on the cost-effectiveness analysis are tested using a scenario where it is set to zero.

4.9. Sensitivity Analysis

One-way and probabilistic sensitivity analyses were performed by varying the input by +/−10% for cost and efficacy variables. Moreover, the discount rate was examined by varying it to 1% and 5%, and the time horizon was varied to 1 year and 5 years. The Markov model was implemented in Excel on an MS Windows 10 platform. The PSA was performed using @Risk (Palisade).

5. Conclusions

This study shows that itopride hydrochloride is a very cost-effective treatment for functional dyspepsia in Vietnam, with the ICER (VND 39.7 M/QALY) being lower than the 1 × GDP (VND 64.1 M) threshold.