Efficacy and safety of potassium-competitive acid inhibitors in the treatment of gastroesophageal reflux: a systematic review and meta-analysis

Abstract

Background

Gastroesophageal reflux disease (GERD) is a common disease caused by reflux of gastric contents to the esophagus. Proton-pump inhibitors (PPIs) are recommended as a first-line therapy to treat GERD. Recently, the potassium-competitive acid inhibitors have been increasingly in use in clinical practice. We aimed to evaluate the efficacy and safety of P-CABs in GERD.

Methods

We searched PubMed, the Cochrane Library, EMBASE and Web Of Science for publications regarding randomized controlled trials comparing potassium-competitive acid inhibitors to PPI monotherapy or Placebo with respect to efficacy and safety in GERD (until April 2023). The primary outcome was an absence or global symptom improvement and the incidence of adverse events in GERD. The quality of the included literature was assessed using the bias assessment tool recommended in the Cochrane Systematic Assessor’s Handbook 5.1.0. We use RevMan 5.3 software for Meta-analysis, sensitivity analysis and publication bias analysis.

Results

Of the 991 screened studies, 14 studies including 4868 participants were analyzed. The ORs for the healing rates of GERD with P-CABs versus PPI/Placebo were 2.10 (95% confidence interval [CI] 1.53–2.88), additionally, 1.09 (95% CI 1.05–1.14), 1.03 (95% CI 1.00–1.06) and 1.03 (95% CI 0.99-1.06) in Weeks 2, 4, and 8, respectively. The effectiveness rate of the experimental group was significantly higher than that of the control group (RR 1.73; 95% CI 1.27–2.36). The overall OR of Incidence of adverse events with P-CABs versus PPI/Placebo was 1.08 (95% CI 0.88–1.12). Overall, the risk of bias was low to some concerns. Furthermore, sensitivity analyses confirmed the robustness of the study’s conclusion.

Conclusions

Our findings suggest that potassium-competitive acid inhibitors is non-inferior to PPIs as therapy for patients with GERD. The safety outcomes for potassium-competitive acid inhibitors are similar to those for PPIs.

Keywords:

• Potassium-competitive acid inhibitors
• gastroesophageal reflux
• meta-analysis

Introduction

Gastroesophageal reflux disease (GERD) is a widespread condition primarily manifested by symptoms such as acid regurgitation and heartburn, which arise due to the reflux of stomach acid [1]. The incidence of GERD has been on the rise globally, with prevalence rates varying from 10% to 20% in Western countries and 2.5–7.8% in East Asia [2]. The hallmark indicators of GERD are heartburn, characterized by a burning sensation in the chest that can radiate to the neck, and acid reflux. In some cases, patients may experience atypical symptoms like chest pain, difficulty swallowing (dysphagia), coughing, or belching [3]. These symptoms can significantly impact a patient’s quality of life, including their daily activities, work performance, and overall mood. Therefore, it is crucial to manage the secretion of stomach acid promptly to alleviate GERD symptoms and prevent further complications. Proton pump inhibitors (PPIs), a class of antacid medications, are currently the frontline treatment for GERD. They function by inhibiting the release of acid in response to meals and during the night. Despite their efficacy in reducing acid production, PPIs have been associated with several adverse effects, including hypochlorhydria and increased susceptibility to enteric, respiratory, and urinary tract infections due to elevated gastric pH. Recent comprehensive evaluations have indicated that the long-term use of PPIs may pose additional risks, particularly for elderly patients with kidney diseases and those predisposed to fractures [4]. However, the effectiveness of PPIs is limited by their short half-lives and the necessity of stomach acid activation for them to bind effectively to proton pumps. Moreover, PPIs require several days to become effective and have a slow onset of action, which may lead to treatment resistance or recurrence of symptoms [5,6]. In light of these limitations, there is a clear need for an alternative acid-suppressing medication that is not only safe and well-tolerated but also offers comparable or superior efficacy to PPIs. Such a medication would provide a valuable option for patients suffering from GERD, potentially improving their treatment outcomes and overall quality of life.

Potassium-competitive acid blockers (P-CABs) represent a cutting-edge class of medications designed to manage acid-related disorders, presenting a promising alternative to proton pump inhibitors (PPIs) [7]. As reversible, competitive antagonists of the H+/K + ATPase proton pump, P-CABs offer a more potent, swift, and enduring suppression of stomach acid [8]. These agents demonstrate a more pronounced and longer duration of acid inhibition compared to PPIs and maintain their stability in acidic conditions [9]. The principal P-CABs that have been introduced into clinical practice include Vonoprazan, Tegoprazan, and Keverprazan. Randomized controlled trials (RCTs) have demonstrated that P-CABs possess efficacy and safety profiles that are at least as favorable as those of PPIs, with Vonoprazan showing particularly comparable results to Lansoprazole in the treatment of GERD [9]. While the therapeutic efficacy of Vonoprazan has been extensively analyzed through meta-analyses, the performance and safety of other P-CABs remain to be fully explored. To address this gap in knowledge, we have conducted a comprehensive meta-analysis that synthesizes both direct and indirect evidence from multiple RCTs to evaluate and compare the efficacy and safety of P-CABs against PPIs and Placebo. Our study aims to yield valuable insights for clinicians, equipping them with the information necessary to enhance maintenance treatment for patients with GERD who experience recurrent episodes. The findings of our meta-analysis are expected to illuminate the comparative benefits and potential risks associated with P-CABs and PPIs, thereby guiding healthcare professionals in making informed decisions regarding the optimal pharmacological interventions for GERD management. By providing a more nuanced understanding of the available treatment options, we hope to contribute to the ongoing effort to improve patient outcomes and overall gastrointestinal health.

Materials and methods

Protocol registration

The protocol of the present review was registered and allocated the identification number CRD42023437496 in the PROSPERO database, hosted by the National Institute for Health Research, University of York, Center for Reviews and Dissemination.

Search strategy

We conducted a systematic search of PubMed, Embase, Web of Science and Cochrane Library databases for randomized controlled trials (published for all years up to Apr 30,2023; English publication only) using the search terms ‘Gastroesophageal reflux disease; GERD; reflux’ and ‘potassium-competitive acid blockers; vonoprazan; Vonoprazan fumarate; Tegoprazan; Keverprazan’. The results are shown in Figure 1. All the enrolled studies using the strategy were checked independently by two researchers; and disagreements were resolved either with mutual discussions or by involving a third author. Additionally, the articles that met al.l inclusion criteria were enrolled in this meta-analysis.

Figure 1. The search process (e.g. Pubmed).

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) diagnosed of GERD, (2) had to be RCTs,(3)treated with P-CAB,(4) published in English language. Studies were excluded for reasons including:(1) reviews, (2) systematic reviews, (3) themes do not match, and (4) ending indicators do not match.

Literature screening and data extraction

The literature was screened independently by two researchers according to inclusion and exclusion criteria, and disagreements were resolved through discussion or with the assistance of a third party. Information extracted included first author and year of publication, number of patients, interventions, duration of treatment, outcome indicators, and so on.

The quality of included studies was evaluated according to the bias risk assessment tools recommended in the Cochrane Manual of Systematic Evaluators 5.1.0, including: Random allocation method, whether to implement allocation hiding, whether to blind the research object, the implementer of treatment plan and the measurement of research results, whether the result data is complete, whether the results are selectively reported, and whether there are other biases. Each item is classified as ‘low risk bias’ ‘high risk bias’ and ‘unclear’.

Ethical statement

Ethics approval was not needed because of the nature of this study(meta analysis).

Statistical analysis

Review Manager software (Version 5.3, The Cochrane Collaboration, 2014) and Stata software were applied for data synthesis and meta-analysis. Forest plots were used to present the results of the meta-analysis. Variability between studies was assessed using both the Cochran Q statistic (with p < 0.05 indicating significant heterogeneity) and Higgin’s I² index (I² < 30% as mild heterogeneity, 30–60% as moderate heterogeneity, and >60% as severe heterogeneity) [10–12]. Odds ratios (ORs) were used as the effect index for the enumeration data, and the effect size was expressed as 95% confidence intervals (CIs). A heterogeneity test was performed for each outcome. Random-effects model analysis was conducted for the heterogeneity statistic I² ≥ 50%, while fixed-effects model analysis was performed for the heterogeneity statistic I² < 50%. Funnel plots and Egger’s test were used to evaluate publication bias [13,14].

Results

Included studies

Our systematic search strategy yielded a substantial collection of 991 original articles, with the selection process and outcomes visually detailed in Figure 2. Through a rigorous screening process, we eliminated 383 duplicate entries and 553 articles that were deemed irrelevant to our research focus. Additionally, 42 studies were excluded as they did not adhere to the predefined inclusion criteria for this meta-analysis. The stringent application of these criteria ultimately culminated in the inclusion of 14 randomized controlled trials (RCTs) in our analysis.

Figure 2. Flow diagram of study selection. Fourteen RCTs were included in the meta-analysis.

Study characterization

The distinctive features of the randomized controlled trials (RCTs) included in our meta-analysis are presented in Table 1. The collective participant pool spanned 4878 individuals, with 2432 allocated to the experimental group and 2446 to the control group. The experimental group received treatment with potassium-competitive acid blockers (P-CABs), while the control group was administered either proton pump inhibitors (PPIs) or a placebo. The assessment of treatment outcomes was systematically structured across four distinct time intervals: 2, 4, 8, and 24 weeks. The primary objectives of this meta-analysis were to ascertain the efficacy and safety of P-CABs by examining various metrics, including the incidence of adverse events, the rates of healing, and the overall efficiency of the treatment.

Table 1. Characteristics of the included RCTs.

Author year	Total patients (N)	Number of patients		Interventions		Course of treatment	Ending indicators
		Experimental (P-CAB)	Control (PPI/Placebo)	Experimental (P-CAB)	Control (PPI/Placebo)
Ashida 2015 [17]	276	132	144	Vonoprazan 20 mg	Lansoprazole 30 mg	4 weeks	①②③
Ashida 2016 [18]	404	205	199	Vonoprazan 20 mg	Lansoprazole 30 mg	8 weeks	①②③
Kinoshita 2016 [19]	549	271	278	Vonoprazan 20 mg	Placebo	4 weeks	①
Ashida 2018 [20]	405	204	201	Vonoprazan 20 mg	Lansoprazole 15 mg	24 weeks	①
Kinoshita 2019 [21]	483	238	245	Vonoprazan 10 mg	Placebo	4 weeks	①③
Lee 2019 [22]	180	92	88	Tegoprazan 50 mg	Esomeprazole 40 mg	8 weeks	①③
Oshima 2019 [23]	32	16	16	Vonoprazan 20 mg	Lansoprazole 30 mg	2 weeks	①②
Sakurai 2019 [24]	47	22	25	Vonoprazan 20 mg	Esomeprazole 20 mg	4 weeks	①②
Xiao 2020 [25]	456	232	224	Vonoprazan 20 mg	Lansoprazole 30 mg	8 weeks	①②③
Kim 2021 [26]	205	106	99	Tegoprazan 50 mg	Placebo	4 weeks	①
Lee 2022 [27]	218	107	111	Fexuprazan 40 mg	Esomeprazole 40 mg	8 weeks	①③
Chen 2022 [28]	238	119	119	Keverprazan 20 mg	Lansoprazole 30 mg	8 weeks	①②
Cho 2023 [29]	351	174	177	Tegoprazan 25 mg	Lansoprazole 15 mg	24 weeks	①
Laine 2023 [30]	1024	514	510	Vonoprazan 20 mg	Lansoprazole 30 mg	8 weeks	①②

Note: ① Incidence of adverse events κHealing rates ③ Efficiency rates.

Quality evaluation

The included studies were RCTs; thirteen studies introduce the randomized methods, only one study does not. Three studies report allocation concealment methods; all studies provided details of missing visits, dropouts or conducted intentional analyses; one study did not use allocation concealment; two study did not use blinding; all studies had data complete, none reported results selectively, and none were clear about the existence of other sources of bias. The results are shown in Figures 3 and 4.

Figure 3. Risk of bias bar chart.

Figure 4. Risk of bias summary chart.

Efficiency rates

Six studies [15–20] reported the efficiency rates for P-CABs treatment. Heterogeneity test results showed that there was no heterogeneity across individual studies (p = 0.30, I² = 18%). Therefore, the fixed effects model was selected to pool OR from individual studies. Figure 5 shows P-CABs treatment had better efficiency rates than treatment with PPIs/Placebo (Odds ratio (OR) = 1.73; 95% confidence interval (CI): 1.27–2.36; p < 0.001).

Figure 5. Forest plots for efficiency rates.

Healing rates

Six studies [15,16, 21–24] reported the healing rates for P-CABs treatment. Heterogeneity test results showed that there was no heterogeneity across individual studies (p = 0.46, I² = 0%). Therefore, the fixed effects model was selected to pool OR from individual studies. Figure 6 shows P-CABs treatment had better healing rates than treatment with PPIs/Placebo (Odds ratio (OR) = 2.10; 95% confidence interval (CI): 1.53–2.88; p < 0.05).

Figure 6. Forest plot for healing rates.

Subgroup analysis of healing rates

Subgroup analysis according to different time periods. At 2 weeks of treatment, it shows P-CABs treatment had better healing rates than treatment with PPIs/Placebo (Risk ratio (RR) = 1.09; 95% confidence interval (CI):1.05–1.14; p < 0.05). At 4 weeks of treatment(Risk ratio (RR) = 1.03; 95% confidence interval (CI): 1.00–1.06; p = 0.58), At 8 weeks of treatment(Risk ratio (RR) = 1.03; 95% confidence interval (CI): 0.99–1.06; p = 0.12). Shown as Figure 7. The healing rates of the two groups was not statistically significant.

Figure 7. Forest plots for subgroup analysis of healing rates.

Incidence of adverse events

Adverse events occurrence is a key indicator for evaluating drug treatment. Here, we compared incidence of adverse events between P-CABs group and PPIs/Placebo group. Adverse events were reported in 14 studies [15–28]. Figure 8 shows no significant difference between P-CABs treatment and PPIs/Placebo treatment on adverse events occurrence (OR = 1.08, 95% CI: 0.88–1.12; p = 0.78), and no significant heterogeneity was found across studies (p = 0.92, I² = 28%).

Figure 8. Forest plots for incidence of adverse events.

Figure 9. Forest plots for incidence of different adverse events.

Subgroup analysis of different adverse events

The results showed that the incidence of diarrhoea, upper respiratory tract infection, nasopharyngitis, gastroenteritis and blood creatine phosphokinase increased were compared and none of the differences were statistically significant. (Odds ratio (OR) = 0.67; 95% confidence interval (CI): 0.39–1.14; p = 0.14); (Odds ratio (OR) = 0.67; 95% confidence interval (CI): 0.38–1.18; p = 0.17); (Odds ratio (OR) = 0.93; 95% confidence interval (CI): 0.63–1.37; p = 0.73); (Odds ratio (OR) = 1.49; 95% confidence interval (CI): 0.56-3.94; p = 0.43); (Odds ratio (OR) = 1.59; 95% confidence interval (CI): 0.61–4.14; p = 0.14). Shown as Figure 9.

Sensitivity analysis

To assess whether any study had a dominant effect on the meta-analysis, we excluded one study at a time and analyzed its effect on the main summary estimate. On this analysis, no single study significantly affected the outcome or the heterogeneity.

Publication bias

Based on visual inspection of the funnel plot (Figure 10) as well as quantitative measurement that used the Bgger regression test. The results of the Bgger test showed that t = 0.18, p = 0.85, there was no evidence of publication bias for technical and clinical success outcomes.

Figure 10. Funnel plot (incidence of adverse events).

Discussion

The objectives of gastroesophageal reflux disease (GERD) management are multifaceted, encompassing the alleviation of symptoms, the healing of esophageal inflammation, the maintenance and prevention of further inflammation, and the overall improvement of patients’ quality of life. Proton pump inhibitors (PPIs) have long been considered the cornerstone of GERD therapy, with their efficacy in managing many aspects of the condition well-established [29]. However, despite the significant success of PPIs, there remain several therapeutic needs that are yet to be fully satisfied [30–32]. The challenges faced in treating advanced erosive esophagitis (EE), non-erosive reflux disease (NERD), nocturnal heartburn, the need for maintenance therapy, and refractory GERD are notable examples of these unmet demands. The standard dosing of PPIs may not consistently achieve adequate gastric acid suppression for all patients due to inherent pharmacological constraints [33]. In light of these limitations, potassium-competitive acid blockers (P-CABs) emerge as a promising alternative to PPIs. P-CABs are characterized as reversible, competitive antagonists of the H+/K + ATPase pump. They offer a more potent, swift, and enduring suppression of gastric acid, setting them apart as a potentially superior treatment option for GERD. The unique mechanism of action and the efficacy profile of P-CABs position them as a compelling choice for clinicians and patients seeking more effective and sustained control of GERD symptoms and complications.

The findings of this comprehensive study revealed a noteworthy improvement in both the efficiency and healing rates among patients in the experimental group, which utilized potassium-competitive acid blockers (P-CABs), compared to those in the control groups. Subgroup analysis provided further insight, indicating that after a mere two weeks of treatment, the experimental group experienced a marked increase in healing rates compared to the control group. However, at the 4 and 8-week marks, the healing rates between the two groups were found to be quite similar, underscoring the rapid onset of action of P-CABs and their capacity to expedite patient relief. P-CABs demonstrate a robust and enduring inhibition of acid secretion, which is more pronounced than that observed with proton pump inhibitors (PPIs). This is attributed to the rapid protonation of P-CABs in the stomach’s acidic environment, allowing for swift accumulation within the acidic secretory tubules [29]. Vonoprazan, a widely employed P-CAB in clinical settings, boasts an acid-suppressive effect that is independent of the proton pump status, and its bioavailability remains unaffected by the presence or absence of food [26]^. For patients with GERD that exhibit resistance to PPIs, P-CABs present a viable alternative. Supporting evidence comes from a study by Iwakiri K et al. which demonstrated that vonoprazan, at dosages of 20 mg and 40 mg, effectively inhibited gastric acid secretion over a 24-h period, facilitating the healing of erosive esophagitis in patients who had previously not responded to PPI therapy [34]. P-CABs emerge as an efficacious and cost-effective option in comparison to traditional PPIs, owing to their faster, more potent, and sustainable acid inhibitory effects. Two additional studies indicated that Vonoprazan, when compared to Lansoprazole, could decrease the number of treatment days and lower treatment costs, positioning it as a preferred choice for the acute medical management of GERD [35,36]. Furthermore, the incidence of adverse drug events was found to be statistically comparable between the two patient groups. The most frequently reported adverse events included diarrhea, upper respiratory tract infections, nasopharyngitis, gastroenteritis, and elevated blood creatine phosphokinase levels, with no significant difference in occurrence between the experimental and control groups. This suggests that P-CABs do not compromise the safety of GERD treatment. While the studies included in this analysis spanned treatment durations of 2 to 24 weeks, they did not address the long-term efficacy of P-CABs, necessitating further research into this aspect. Moreover, in the majority of the studies reviewed, the experimental intervention was Vonoprazan, with limited representation of other P-CABs. Consequently, more extensive and diverse clinical randomized controlled studies are warranted to definitively establish the effectiveness of P-CABs in the treatment of GERD.

While the current meta-analysis provides valuable insights into the efficacy and safety of potassium-competitive acid blockers (P-CABs) in the treatment of gastroesophageal reflux disease (GERD), there are several limitations that must be acknowledged. Firstly, the exclusion of non-English language studies introduces the potential for geographical bias, as this may have led to the omission of relevant research from other regions. Secondly, the absence of an analysis examining the relationship between dosage and treatment efficacy leaves a gap in understanding the optimal dosing regimens for P-CABs. Thirdly, the majority of the included trials featured short follow-up durations, which precludes a comprehensive assessment of long-term efficacy and safety. Fourthly, while the majority of the studies compared P-CABs against lansoprazole, only three studies utilized esomeprazole, and there exists a dearth of studies comparing P-CABs with other commonly used PPIs, such as pantoprazole, rabeprazole, and omeprazole. This limits the generalizability of the findings and the comparative understanding of P-CABs’ performance relative to the full spectrum of PPIs available. Additionally, our study documented the effects of P-CABs versus PPI or placebo, because of the inclusion of placebo, lumping these data together will potentially overestimate the differences in favour of P-CAB. Lastly, the quality of some of the included literature was suboptimal, which may impact the robustness of the pooled results. Despite these limitations, the collective evidence suggests that P-CABs are at least as effective as PPIs in managing GERD, without compromising the safety of treatment.In light of these constraints, future research should aim to address these gaps by incorporating a more diverse range of PPIs, extending follow-up periods to assess long-term outcomes, and including studies from a broader geographical range to minimize bias. By doing so, the medical community can attain a more nuanced and comprehensive understanding of the role of P-CABs in the therapeutic landscape of GERD management.

Conclusion

P-CABs are not inferior to PPI in healing and efficacy of GERD. Still, there is also no difference in the incidence of adverse reactions. The P-CAB is also relatively safe compared with PPI; however, only short-term effects were evaluated. Further RCTs in different populations, and more variable use of P-CABs are needed to confirm findings of P-CABs being the more potent and quicker acid suppressant and the alternative to PPIs. Similarly, long-term safety and efficiency data of P-CABs are greatly needed.

Acknowledgments

Xinxu Zhou and Hui Duan made significant contributions to the study concept and design, data collection, analysis and interpretation of data, and drafting of the research; Qian Li supervised the data analysis and made strict revisions to the critical intellectual content of the article; Qiong Wang and Xiaobin Sun participated in the design of the article and revised the article. This version of the article has received finally by final permission for submissions from all authors.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Authors received no specific funding for this work.