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Vonoprazan in the management of gastric/peptic ulcers: a systematic review of safety data

Introduction Although potassium-competitive acid blockers (P-CABs) prompted safety concerns when first developed, they ultimately proved to have a favourable safety profile. Aim To assess the safety of vonoprazan in the management of gastroesophageal reflux disease (GERD), peptic ulcers, or gastroduodenal mucosal lesions induced by chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs). Material and methods From March to June 2021, a literature search was conducted using Medline via PubMed, Cochrane library, Lilacs, SciELO, and Centre for Reviews and Dissemination (CRD) electronic databases. After applying the eligibility criteria, 10 studies were included in this review. Of these 10 articles, vonoprazan was used as initial therapy in 6 and as maintenance therapy in 4. Adverse event rates were similar for vonoprazan and proton-pump inhibitors (PPIs). Conclusions Our findings suggest that vonoprazan is a safe option for the management of erosive oesophagitis, gastric/peptic ulcers, or peptic ulcers induced by chronic use of aspirin or NSAIDs.


Introduction
Acid-related diseases result from distinct but overlapping pathogenic mechanisms that involve acid effects on an oesophagogastric duodenal mucosa with diminished defence. While gastroesophageal reflux disease (GERD) represents the most frequently observed acid-related disorder, peptic ulcers and ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) are also important acid-related diseases [1,2].
The symptoms associated with acid-related diseases affect health-related quality of life and work productivity. Serious complications such as oesophageal stricture, ulceration, Barrett's oesophagus, or cancer may develop without effective treatment [3].
Proton pump inhibitors (PPIs) were introduced in the late 1980s and dramatically improved gastric acid-related conditions [4]. Nowadays, PPIs dominate in acid-related disease management worldwide [5][6][7][8]. However, despite their efficiency, PPIs may exhibit delay in symptom improvement, low bioavailability, fast metabolism, drug interactions, variable sustainability of acid suppression, enteric-coated pharmaceutical form, and more effective action on the nocturnal acidity breakthrough, among other limitations that together lead to unmet acid-related disease management needs [9]. In this scenario, potassium-competitive acid blockers (P-CABs) have emerged to promote a better antisecretory effect that addresses these unmet needs, including the rapid improvement of symptoms, refractory GERD, and nocturnal acid reflux related to disease management [10].
The first P-CAB used in clinical practice was revaprazan, and it has been available in South Korea and India since 2007, but there are no reports that it is more effective than PPIs for acid-related conditions [4]. Vonoprazan became available in Japan in 2015 to treat gastric ulcer, duodenal ulcer, and erosive oesophagitis, and to prevent low dose aspirin-or NSAID-induced peptic ulcer recurrence, and tegoprazan was approved as Gastroenterology Review 2022; 17 (4) a treatment for GERD in South Korea in July 2018 [4,11,12].

Aim
Because of the advent of new P-CABs and their efficacy profile, we conducted a systematic review to assess the safety of vonoprazan in the management of patients diagnosed with GERD oesophagitis, with peptic ulcers, or those with ulcers induced by chronic use of aspirin or NSAIDs.

Study design
In order to answer to the proposed objectives, a systematic review of the available literature was conducted. The research question was defined according to the PICO model (population; intervention; control; outcome) [13]. Studies that evaluated vonoprazan safety when used as a treatment strategy for patients diagnosed with GERD oesophagitis were searched, along with studies that concerned vonoprazan treatment of peptic ulcers induced by chronic use of aspirin or NSAIDs or gastric/duodenal ulcer.

Search strategy
A literature search was conducted on 20 June 2021 using Medline via PubMed, Cochrane library, Lilacs, Sci-ELO, and Centre for Reviews and Dissemination (CRD) electronic databases for the terms listed in Table I. Additionally, manual searches of bibliographic references and abstracts of selected publications complemented the electronic searches.

Eligibility and inclusion and exclusion criteria
Studies to be considered eligible should meet the following inclusion criteria: meta-analyses, systematic reviews and phase III or IV randomized controlled trials (RCTs), or observational studies; studies involving patients using vonoprazan to treat GERD oesophagitis, gastric/duodenal ulcers or those in chronic use of aspirin or NSAIDs; and analysis with potassium pump inhibitor as a comparator or without comparator and safety endpoints. Furthermore, all articles under at least one of the following conditions were excluded: narrative reviews, guidelines, consensus articles, editorials, case reports, or case series; studies involving patients with Helicobacter pylori or with ulcers due to endoscopic submucosal dissection; studies using animal models; and articles published in other languages than English, Portuguese, and Spanish.

Data synthesis
Data extracted from the included studies were synthesized and reported as tables and figures. Additionally, information was stratified according to a comparator arm (none or PPI).

Study selection
A total of 130 studies were retrieved from the database, including duplicates. After applying eligibility criteria, 32 articles were selected for full-text reading by 2 reviewers. Finally, 10 studies were included in this review ( Figure 1). Table II shows the included studies list and the description of their general characteristics according to the comparator type. Of the 10 articles included in the analysis, 7 were compared to lansoprazole, 2 against different doses of vonoprazan, and 1 in a single arm. The number of patients ranged from 19 to 850, totalling 3618 patients included in the selected studies. Patients were followed for a period of up to 52 weeks.

Vonoprazan use as initial therapy
Six studies considering the use of vonoprazan as initial therapy were included in the analysis [16][17][18][19][20][21]. Information about treatment-emergent adverse events is shown in Table III. Several adverse events with frequen-cy > 5% reported in the studies are described in Table IV. Okanobu et al. reported the absence of adverse events during the study period but did not provide details on assessments, so it was not described in respective tables [16].
Similar frequencies of treatment-emergent adverse events, serious adverse events, and those leading to treatment discontinuation were reported by the studies (Table III). Gastrointestinal disorders were the most frequently observed events (Table IV).

Vonoprazan use as maintenance therapy
Considering vonoprazan as maintenance therapy, a total of 4 studies were included in the analysis [22][23][24][25]. Table V shows information about treatment-emergent adverse events, while several adverse events with frequency > 5% reported in the studies are described in Table VI. As observed for vonoprazan use as initial therapy, a similar pattern of adverse events occurrence was found in several comparator arms. Nasopharyngitis was the most frequently observed event (Table VI).

Discussion
This systematic review was conducted to assess the safety of vonoprazan in the management of patients diagnosed with GERD oesophagitis, gastric/peptic ulcers, or peptic ulcers induced by chronic use of aspirin or NSAIDs. Considering the drug efficacy profile and safety data available in the current literature, this study adds important knowledge to disease management. P-CABs were first described in the 1980s with SCH28080. This compound showed the capacity to in-  hibit gastric acid secretion in humans and animals, beyond inhibition of H + ,K + -ATPase via competitive interaction with K + site of the enzyme. Despite the favourable results, hepatic toxicity after prolonged administration led to the discontinuation of clinical studies. More recently, several SCH28080 derivative compounds were developed including vonoprazan, which is one of the drugs from P-CABs class available for use in clinical practice [12,26].
Considering the initial concern about hepatic toxicity, we found 1 study in our systematic review that assessed the occurrence of this outcome. Xiao et al. reported safety events among patients with the diagnosis of erosive oesophagitis treated with P-CABs and PPIs.  Liver function abnormalities were observed in 0.9% of the 235 patients treated with lansoprazole 30 mg, but no events were observed in the group treated with vonoprazan 20 mg (n = 244) [17]. The frequency of treatment-emergent adverse events in general ranged from 6.0% to 87.6%, and those related to the treatment from 4.8% to 19.3%. The great variability observed across the studies' estimates is related to whether the treatment was an initial or a maintenance therapy. Regarding serious adverse events, the occurrence ranged from 0.0% to 16.3% and from 0.0% to 2.0% for total and those related to treatment, respectively [16][17][18][19][20][21][22][23][24][25].
In general, the safety profile of vonoprazan was similar to that observed for lansoprazole, a potent PPI [17,[19][20][21][23][24][25]. This finding confirms previous data reported in the current literature. He et al. conducted a systematic review and meta-analysis to compare the efficacy, safety, and tolerance of vonoprazan with PPIs in the treatment of peptic ulcers resulting from endoscopic submucosal dissection. The study reported a similarity between groups, with an insignificant relative risk for adverse events (RR = 0.65; 95% CI: 0.31-1.38) [3]. Recently, Chen et al. also reported that vonoprazan and PPIs have similar safety profiles (RR = 1.08; 95% CI: 0.96-1.22) in a meta-analysis considering patients with GERD [27].   All the studies included in this review were conducted in eastern countries. This may be pointed out as a matter of concern because populations from such countries have slower metabolizers and the safety profile may differ from that in western populations [28]. Jenkins et al. conducted 2 phase I studies in order to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. Treatment-emergent adverse events were observed among 9 of 60 subjects in the Japanese cohort and in 10 of 48 subjects in the UK cohort, while no serious adverse events were observed in both studies [29]. These data suggest that the metabolization profile of eastern populations has no impact on the safety of vonoprazan.
Despite the important results observed in the present study, some limitations should be highlighted. Language limits led us to exclude all publications in languages other than English, Portuguese, or Spanish. This may be considered as a major limitation of this study. In addition, a meta-analysis of the available data would provide more robust results to determine the outcome of interest.

Conclusions
The study findings suggest that vonoprazan has a favourable safety profile, especially when compared to PPIs (such as lansoprazole). Thus, considering efficacy data previously reported, it may be considered as a good and safe therapeutic option for the management of acid-related diseases.