The Budget Impact of Itopride in the Treatment of Functional Dyspepsia in Vietnam

Abbreviations

FGID’s: Functional Gastro-Intestinal Disorders; FD-GERD: FD with Gastroesophageal Reflux Disease; EPS-IBS: Epigastric Pain Syndrome with Irritable Bowel Syndrome; PDS: Postprandial Distress Syndrome; BBB: Blood Brain Barrier; DAV: Drug Administration of Vietnam; ISPOR: International Society for Pharmacoeconomics and Outcomes Research.

Introduction

Functional Dyspepsia is a common upper gastrointestinal condition which commonly presents as postprandial fullness (post meal), early satiation, epigastric pain, and/or epigastric burning [1]. Functional dyspepsia is part of a wider group of Functional Gastro-Intestinal Disorders (FGID’s) which are often unexplained in pathogenesis. Diagnosis can be lengthy as the symptoms often overlap with other gastrointestinal conditions. Thankfully, the presence of functional dyspepsia is not associated with increase in mortality [2].

The diagnosis of functional dyspepsia is defined by the detailed ‘ROME diagnostic criteria’ (An Internationally established criteria developed by experts in the field of gastroenterology). The ROME criteria is now in its 4th iteration: ROME IV definition states that functional dyspepsia have at least one of four the following symptoms: 1) Postprandial fullness; 2) Early Satiety; 3) Epigastric pain; 4) Epigastric burning; and no underlying organic disease [3]. Several factors can affect prevalence from age, gender, ethnicity, smoking status, alcohol consumption, and dietary factors [4]. Modifiable risk factors encompass severe stress, chronic fatigue, smoking, abnormal BMI, and sleep patterns, while non-modifiable risk factors include advanced age, chronic diseases, and female sex [5]. The prevalence of functional dyspepsia globally is variable and has been difficult to determine due evolving definitions used in older literature. Also, the elimination of organic disease in selection of patients for clinical trials poses an inherent challenge for most population-based studies [4, 6]. In a 2024 systematic review and meta-analysis by Lee et al., it was found that the global prevalence of functional dyspepsia varied from 11.9% according to the Rome I criteria to 6.8% according to the Rome IV criteria from 1990 to 2020 [7]. The results were consistent with the Rome Foundation Global Study, showing that women consistently had a significantly higher prevalence than men, and that the prevalence was higher in the 18-39 age group (9.2%) [8]. The prevalence of functional dyspepsia is higher in developing or low-and middle-income countries compared to developed or high-income countries [5, 7].

The 2012 Asian Consensus report on Functional Dyspepsia has suggested that the presentation of sub-types of functional dyspepsia in Asian populations differ to those in to the West [9]. With East and South-East Asian countries, patients predominantly experience Postprandial fullness symptoms more so than the epigastric pain [9]. Two large clinical trials based on endoscopy examination of patient with dyspepsia using the ROME III diagnosis criteria demonstrate the two sperate sub conditions affecting Caucasian and East Asian populations: One trial by Ford et al 2014 based in Canada with mostly white Caucasian patients and the other by Fang et al 2014 based in Taiwan with all ethnic Chinese patients. The Taiwanese study showed 71.9% of patients had the PDS sub-type, and Canadian study showed 40.8% had PDS sub-type and 41.2% with overlap of EPS and PDS [10, 11].

Functional dyspepsia is treated with multiple agents and varying success. The treatment of Functional Dyspepsia differs in various regions. 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 first-line treatment [1]. Thereafter, tricyclic anti-depressants are 2nd line treatments and prokinetics are 3rd line treatments [12].

In East and South-East Asia, both acid suppression therapy and prokinetics are established 1st line treatments. The 2012 Asian consensus report on functional dyspepsia Miwa H, et al. [9] deemed prokinetics to be a first treatment for the PDS subtype, and second-line treatment for EPS. In countries such as China and South Korea, Prokinetics are often mainstay therapy recommended for patients with PDS symptoms [13]. According to the 2023 Asia-Pacific guideline by the Asian Pacific Association of Gastroenterology, the majority of functional dyspepsia patients have an overlapping disorder that is associated with overlap conditions in the Asia-Pacific, such as FD with gastroesophageal reflux disease (FD-GERD), epigastric pain syndrome with irritable bowel syndrome (EPS-IBS), postprandial distress syndrome with IBS (PDS- IBS), and FD-Constipation. The recommended treatment for FD-GERD involves dual histamine H1/H2 receptor blockade, antisecretory agents, neuromodulators, and fundic relaxants. For EPS-IBS, anti-spasmodic agents, tricyclic agents, and dual histamine blockade are typically used. In the case of PDS-IBS, treatment may include prokinetic agents, a low FODMAPs diet, Rixafimin, and herbal medicine. Fecal evacuants, Pan-GI prokinetic agents, and reducing methane production in the gut are common approaches for managing FD-constipation [14].

Due to its’ disease nature being that it is often chronic and recurring in disease course. Research estimates only 20% of patients with functional dyspepsia become symptom free in the long-term [15, 16]. A significant proportion of patients with functional dyspepsia have abnormalities in gastric motility and fundal accommodation. Prokinetic agents target this group of patients by enhancing gastric motility through amplifying and coordinating gastrointestinal muscle contractions [17]. These agents include itopride, mosapride, domperidone, and so forth. In a systematic review and meta- analysis conducted by Pittayanon, et al. [17] reviewed 29 trials which included 6 prokinetic agents showed moderate effectiveness against placebo (overall global symptom improvement 40% vs placebo 26%) [18].

Itopride works by blocking Dopamine (D2) receptors and inhibiting acetylcholinesterase. This reverses the inhibition of gastric motility caused by dopamine receptors and enhances postprandial gastric motility. Itopride’s benefit over other prokinetics is its’ favourable adverse effect profile. It does not cross the blood brain barrier (BBB), and thus does not prolong QT interval or serious cardiac events unlike metoclopramide, and domperidone. It is estimated that there are between 7.8 and 22.4 million Vietnamese people to with functional dyspepsia [6]. Vietnam has one of the highest rates of Helicobacter pylori (H. pylori) infection and related gastrointestinal diseases among Southeast Asian countries. A study conducted by Quach in 2022 found a higher occurrence of functional dyspepsia coexisting with gastroesophageal reflux disease (GERD) in Vietnamese patients, with postprandial distress syndrome being notably prevalent [19].

Vietnam like many other developing South-East Asian countries, most of the health care provided is through public hospitals. There are four levels of public hospitals in Vietnam Central level hospitals (level 1), Provincial level hospitals (level 2), District level hospitals (Level 3) and Commune health stations (level 4) [20]. Itopride is current reimbursed the only prokinetic reimbursed for the treatment of functional dyspepsia in a hospital setting in Vietnam. However, the reimbursement is only for level 1+2 hospitals. In level 3+4 hospitals patients are receiving domperidone instead to alleviate the symptoms of functional dyspepsia, though domperidone does not have formal approval from the Drug Administration of Vietnam (DAV) for the treatment of functional dyspepsia.

This study analyses the financial impact of expanding the access to itopride for patients with functional dyspepsia to include level 3+4 hospitals in Vietnam.

Financial Implications of the Alternative Scenarios

The financial implications with each alternative scenario can be found in (Table 1).

Number patients over time by scenario is depicted in Figure 4. Alternative scenario 1 will result in an increase of 13.7% patients over the 5-year period however, the increase in spending is only 2.3%. Similarly for alternative scenarios 2 and 3: increase in itopride use is 19.8% to 24.6% with spend only increasing 3.3% to 4.2%. The net costs are estimated to be between VND 363,836M (Alternative scenario 1) and VND 365,034M (Alternative scenario 3) in 2023, gradually growing to VND 371,351M (Alternative scenario 1) and VND 385,163M (Alternative scenario 3) in 2027 (Figure 5).

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Discussion

This analysis examined the potential budgetary impact of expanding access to for level 3+4 hospitals in Vietnam. The model included both drug costs and healthcare resource utilization costs. In the base case scenario model, it assumes the base population (itopride not reimbursed for level 3+4 hospitals) treated with itopride to be 779,000. The base case cumulative net spend on Itopride is estimated to be VND 1,797,125M over 5 years.

Three alternative scenario analyses were undertaken using the model and these were 1) flat market uptake, 2) liberal market uptake, and 3) high/increasing market uptake. All three scenarios demonstrate a net budget impact range from VND 41,743M to VND 74,617M cumulative net spend on itopride (2.3% to 4.2% increase drug cost spend) over 5 years. This is considering both the drug costs of itopride and direct medical costs from the Vietnamese government payer perspective. Assuming the high market uptake scenario would only result in a 4.2% increase in overall net spend, and an increase of access treatment to an additional 195,023 patients cumulative over 5 years. Thus, within the context of Vietnamese healthcare budget, this investment would allow more patients to gain access to an efficacious treatment for functional dyspepsia who are mostly in more improvised and rural areas of Vietnam (level 3+4 hospitals).

There are different limitations related to this study. The analyses relied upon several assumptions as well as data availability. Key inputs such as prevalence of functional dyspepsia in Vietnam and proportion of patients treated for functional dyspepsia in Vietnam were based on values reported in non-Vietnamese settings and published clinical trials, many of which were conducted as multinational studies. Another limitation is that clinical inputs specific to the population of patients suffering from functional dyspepsia do not presently exist. However, while data gaps preclude investigating possible implications, this limitation is not expected to bias the results of the analysis, since the same consideration could apply to many of the interventions included in the study.

Through the sensitivity analysis of all scenarios confirmed that the main drivers of cost in the model to be the patient numbers (prevalence, diagnosed, uptake), and duration of treatment. A small cost-saving of VND 49,098 (health resource cost) per patient from reduction of health services when symptom free or experience symptom improvement. However, this does not appear to heavily affect overall financial impact. From the Vietnamese Government budgetary perspective, the financial impact of expanding funding of itopride into level 3+4 hospitals is unlikely to result in a significant financial impact. This was evidenced by the three different scenarios.

Studies examining the budget impact of pharmaceutical investments in Vietnam is limited. One example by Tran, et al. examining the Budget Impact Analysis of Erlotib in Vietnam demonstrated that the funding of this oncology agent would cost the Vietnamese Government 107.8 billion VND.

Functional dyspepsia is a chronic condition and often incurable with significant financial impacts on both the patients and wider healthcare system. Itopride is a relatively inexpensive prokinetic used commonly in Asia. Although some of the clinical evidence for prokinetics in functional dyspepsia is mixed, it should be noted that most of these studies were conducted on western patients (mostly Caucasian) and a significant proportion had already been treated with other agents. The research from Asian literature suggests that the sub-condition affecting East and South Asian populations is postprandial distress syndrome. Logically, prokinetics such as itopride should be more beneficial for PDS, and this is substantiated by the 2012 Asian consensus report and the 2023 Asian-Pacific guidelines and real-life purchasing data from these regions.

Conclusion

Itopride has a unique dual MOA on esophagus and stomach to promote gastric motility and helps patients restore their gastric natural tone. Itopride increases lower esophageal sphincter pressure, accelerates gastric emptying and improves gastroduodenal coordination and does not prolong QT Interval that is devoid of extrapyramidal side effects. As such the broadening of the reimbursement of itopride to include level 3+4 hospitals will provide benefit for between 13.7% (105,923) to 24.6% (89,343) more patients at only 3.3% (VND 41,742M) to 4.2% (VND 74,617M) additional costs over five years. Itopride is deemed to represent great benefit for patients suffering from functional dyspepsia in Vietnam.

Funding

This study was funded by Abbott Products Operations AG, Basal, Switzerland