
==== Front
Clin Transl Gastroenterol
Clin Transl Gastroenterol
CLTG
CT9
Clinical and Translational Gastroenterology
2155-384X
Wolters Kluwer Philadelphia, PA

39072507
CTG-24-0064
10.14309/ctg.0000000000000754
00001
3
Review Article
Review Article
Efficacy and Safety of Potassium-Competitive Acid Blockers vs Proton Pump Inhibitors for Peptic Ulcer Disease or Postprocedural Artificial Ulcers: A Systematic Review and Meta-analysis
https://orcid.org/0009-0003-4347-6500
Wang Wen-xin 1
Li Rui-jie 1463707701@qq.com

Li Xiong-fei 1931737894@qq.com

1 The First Clinical College of Chongqing Medical University, Chongqing, China.
Correspondence: Wen-xin Wang. E-mail: wyyx5358979323@163.com.
9 2024
29 7 2024
15 9 e126 2 2024
19 7 2024
© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

INTRODUCTION:

Peptic ulcer disease (PUD) and postprocedural artificial ulcers are common ulcer disease. For them, proton pump inhibitor (PPI) and potassium-competitive acid blocker (P-CAB) are commonly used in clinical practice. PPI requires acid, time, and multiple doses, but P-CAB has fewer limitations. We compared the efficacy, safety, and prevention of PPI and P-CAB in PUD or artificial ulcer.

METHODS:

We searched PubMed, ClinicalTrials.gov, Embase, Cochrane Library, and Web of Science databases for all studies. All eligible randomized controlled trials up to August 5, 2023, were included. Healing rates, shrinking rates, treatment-emergent adverse events rates, and recurrence rates were measured. Risk of bias, sensitivity analyses, and heterogeneity were also performed.

RESULTS:

Twenty researches that were selected from 926 screening studies and in total 6,551 participants were included. The risk ratio (RR) of healing rate with P-CABs vs PPIs of PUD at 4 weeks was RR 1.01 (95% confidence interval 0.98–1.04). In addition, the healing rate distinction of artificial peptic ulcer was RR 1.04 (0.89–1.22), and the shrinking rate was mean difference 0.10 (−1.30–1.51). The result of treatment-emergent adverse event rate of PUD was RR 1.11 (0.91–1.35), and the delayed bleeding rate of artificial ulcer was RR 0.35 (0.16–0.80). The RR for recurrence rate of drug-related ulcers was 0.45 (0.25–0.81).

DISCUSSION:

P-CAB is noninferior in healing artificial ulcer and PUD, also the incidence of treatment-emergent adverse events. But, there may be a statistical advantage in holding back delayed bleeding and preventing drug-induced ulcers. More standardized experiments are needed for further applications and more precise conclusions.

KEYWORDS:

artificial ulcer
meta-analysis
potassium-competitive acid blocker
proton pump inhibitor
peptic ulcer disease
OPEN-ACCESSTRUE
==== Body
pmcINTRODUCTION

Peptic ulcer disease (PUD) is a type of acid-induced damage characterized by the denuded mucosa of stomach or duodenum that extends to submucosa or muscularis propria. According to the guidelines for PUD from the Japanese Society of Gastroenterology, peptic ulcers are divided into hemorrhagic gastric ulcers (GU) and duodenal ulcers (DU), Helicobacter pylori–infected ulcers, drug-induced ulcers, non–H. pylori and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant GUs, and so on (1). They were conventional PUDs, and we also isolated one ulcer caused by endoscopic submucosal dissection (ESD) into a separate group called artificial ulcer. It is caused by ESD and leads to injury of submucosa and below. Artificial ulcer has different etiology and pathophysiology with conventional PUD, but their clinical manifestations and treatment methods are the same.

The treatment widely used in clinical practice for treating these ulcers is to suppress the secretion of gastric acid (2). The gastric proton pump enzyme H⁺/K⁺-ATPase, which plays a crucial role in the final stages of gastric acid secretion, is one of the main targets in the pharmacological remedy. Currently, there are 2 main classes of drugs targeting this enzyme in the market: proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) (3).

PPIs are used worldwide to treat acid-related diseases, including gastroesophageal reflux, digestive ulcer disease, erosive esophagitis, and H. pylori infection, among other indications for PPI use (4). This class of drugs are prodrugs activated by gastric acid. They irreversibly form covalent bonds with cysteine residues of the H+/K+ ATPase to impair acid secretion. Despite their overall therapeutic effect in acid-related disorders, some aspects of PPIs are inadequate. First, the plasma half-life of PPIs is brief, leading to its insufficiency in constant inhibition of gastric acid secretion. Second, PPIs are considered prodrugs that undergo activation in the presence of the gastric acid environment, the effect of which is affected by food intake, and they are not stable in acid conditions (5). Third, the onset action of PPIs is slow, and it needs 2–3 days to reach maximum acid-inhibitory efficacy (6). Fourth, PPIs are metabolized dominantly by CYP2C19 that has 4 phenocytes, and 2 of them (extensive metabolizers and ultrarapid metabolizers) affect the efficacy and activation process of PPIs (7). Fifth, PPI has an inhibitory effect only on active proton pumps, but not on resting proton pumps. These pharmacological limitations of PPIs mentioned above have pushed the development of P-CABs forward.

P-CABs, a new class of drugs, exert their inhibitory effects by blocking the potassium-binding site on the H+/K+-ATPase in a reversible and competitive manner (8). These kinds of drugs were first developed in the 1980s (9). Development of previous P-CABs such as SCH28080 and AZD0865 was halted because of concerns of a potential link to liver damage and hepatotoxicity (10). But recently, the subtypes used in clinical are revaprazan, vonoprazan, and tegoprazan. P-CAB is the most promising agent to change the treatment standard of acid-related disorders theoretically (11–13). Compared with PPIs, P-CABs hold acid stability, removing the need for enteric coating or timing of administration 30 minutes before meals (14,15). On the other hand, P-CABs, unlike prodrugs, act directly on the proton pump and do not require activation. This mechanistic distinction allows P-CABs to rapidly achieve peak plasma concentrations and exert their therapeutic effects (16–18). It is not subject to the same restrictions on administration timing as PPIs because it possesses a longer half-life (7–8 hours) (16). Similarly, in a population of healthy adults in the United States, vonoprazan shows a superior suppression of gastric acid compared with lansoprazole (19), resulting in rapider, stronger, and more sustained acid suppression (10). Furthermore, unlike PPIs, vonoprazan is primarily metabolized by CYP3A4, with additional contributions from CYP2B6, CYP2C19, and CYP2D6 (20). This suggests that the acid suppression effect of vonoprazan may be less affected by variations in the CYP2C19 (20).

To further elucidate the clinical disparities between these 2 medications, a comparative analysis was conducted to assess their efficacy and safety in treating different types of ulcers. In addition, data were gathered to determine which drug was more effective for prevention. Notably, there has been no previous comparison of treatment-emergent adverse events (TEAEs) after treatment with P-CABs and PPIs. Furthermore, we also aimed to investigate the common complications associated with artificial ulcers, including delayed bleeding, perforation, stenosis, and pneumonia (21).

We hope that the new comparisons can provide some help in addressing these clinical questions. In this article, we describe the main findings of our analysis.

METHODS

We performed and reported this systematic review with the help of prespecified criteria (22) outlined by the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (23). The study protocol was registered with PROSPERO (number CRD42022308000).

Study design and search strategy

To reach the study objective, population, intervention, control, and outcome model was used. Consequently, we conducted a comprehensive search for studies that assessed the comparison between P-CABs and PPIs in treating PUD or artificial ulcer.

One investigator (W.-w.X.) searched 5 databases: PubMed, ClinicalTrials.gov, Embase, Web of Science, and Cochrane Library. No date, age, sex, or language restrictions were specified. The coverage dates for this review begin at the inception of each database and end on August 5, 2023.

The search strategy contained 3 keywords, linked using the AND operator:Potassium-competitive acid blocker/P-CAB/potassium-competitive acid inhibitor/vonoprazan/TAK438/TAK-438/takecab/revaprazan/YH1885/YH-1885/tegoprazan;

Proton pump inhibitor/PPl/dexlansoprazole/esomeprazole/lansoprazole/omeprazole/pantoprazole/rabeprazolel/ilaprazole;

peptic ulcer disease/peptic ulcer/gastroduodenal ulcer/gastric ulcer/stomach ulcer/duodenal ulcer/artificial ulcer.

We include randomized controlled clinical trials (RCTs) but excluded quasi-randomized trials and historically controlled clinical trials.

Study selection

Duplicate articles were removed in EndNote (version X9). Two review authors (R.j.-L and W.-x.W.) independently filtrated titles and abstracts of the nonrepetitive studies and cast away nonrelevant studies. After that, 2 review authors (R.j.-L and W.-x.W.) independently evaluated articles to check whether they met the inclusion criteria. Disagreements were made clear through discussion with a third review author (X.-f.L.).

Studies were eligible for inclusion if they (i) had full text available; (ii) were RCTs; and (iii) evaluated the efficacy and safety or recurrence (O) of P-CABs (I) vs PPIs (C) for treating PUD and postprocedural artificial ulcers (P).

Studies were excluded if they (i) were not published in English; (ii) were reviews, letters, case series, conference proceedings, or unpublished studies. (iii) not met inclusion criteria; (iv) not conform to the requirements of the ethics; (v) no suitable data; and (vi) medications other than PCABs or PPIs were used during the trial.

Data extraction

A standardized template, adapted from the Cochrane Handbook (Version 5.1.0), was applied to extract data on study characteristics (authors, year of publication, place of implementation, registration number, and funding sources), study methods (aims, design, duration, participants, diagnostic and exclusion criteria, sequence generation method, blind method, and treatments), results (definition of results, results, adverse reactions, and data missing), and authors' stated conclusions.

We collect the results data and related information, such as definition, time, analysis, and so on, including the following: (i) healing rate: Ulcers were regarded as healed if the white coating was not visible or red scar or white scar were observed by endoscopy (24–26). (ii) Shrinking rate: ([initial ulcer size] − [ulcer size at 4 weeks after ESD])/(initial ulcer size) 100%. (iii) TEAE rate: an adverse event occurring after receiving the study drug (26). (iv) Delayed bleeding rate: hematemesis or melena that required endoscopic hemostasis and decreased hemoglobin levels by more than 2 g/dL within 4 weeks after ESD (27). (v) Recurrence rate: the rate of peptic ulcer recurrence during the 24-week treatment period (28).

Two paired reviewers (R.-j.L. and X.-f.L.) independently extracted this information from each study and resolved disagreements through discussion and consultation with a third review author (W.-x.W.).

Risk-of-bias assessment

The risk-of-bias assessment was made on the basis of the criteria provided in the Cochrane Handbook (version 5.1.0). Two review authors (R.-j.L. and X.-f.L.) individually appraised the quality of the studies. We figured out discrepancies by discussion with a third review author (W.-x.W.).

We considered 7 items for each study: (i) generation of the random sequences; (ii) allocation concealment; (iii) personnel blind methods; (iv) end blinded evaluation; (v) result data integrity; (vi) selective outcome report; and (vii) other sources of bias.

Statistical analysis

The outcomes were estimated by risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). MD was used for shrinking rate, and RR was used for others. We used I2 statistics on behalf of a quantification to the level of heterogeneity. If I2 < 50%, P > 0.05, a fixed-effects model will be used in the meta-analysis. All analyses of data were calculated by Review Manager (version 5.4).

Each result received a sensitivity analysis, and the robustness of the results was evaluated by the leave-one-out analysis. We also performed subgroup analysis and controlled outcome recording time to standardize the results.

RESULTS

Study selection and characteristics

Figure 1 shows the study screening process. For example, the article “Vonoprazan vs proton pump inhibitors for postendoscopic submucosal dissection bleeding in the stomach: a multicenter population-based comparative study” appeared to meet the inclusion criteria, but it was not an RCT and was ultimately excluded.

Figure 1. Summary of study search and study selection process (flow chart).

Table 1 summarizes the main characteristics of the included studies.

Table 1. Characteristics of included studies investigating the outcomes of P-CAB and PPI in PUD and artificial ulcer

First author	Blinding	Time	Participants	Types	Treatment	Outcomes	Uncompleted	
Ai Hirai 2018 (29)	Not blind	April 2015–May 2017	127	Post-ESD gastric ulcers	61 vonoprazan 20 mg/d
vs
66 lansoprazole 30 mg/d	Delayed bleeding rate: 5.4% vs 5.3%	22	
Daisuke Kawai 2021 (15)	Not blind	April 2015–December 2017	168	Post-ESD gastric ulcers	85 vonoprazan 20 mg/d
vs
83 lansoprazole 30 mg/d	4-wk healing rate: 20.0% vs 16.9%
8-wk healing rate: 77.6% vs 84.3%
4-wk shrinking rate: 96.3% vs 95.1%
8-wk shrinking rate: 100%
Delayed bleeding rate: 0 vs 4%	14	
Hiromitsu Ban 2020 (30)	Not blind	September 2015–August 2018	196	Post-ESD gastric ulcers	101 vonoprazan 20 mg/d
vs
95 lansoprazole 30 mg/d	4-wk healing rate:11.9% vs 12.6%
4-wk shrinking rate: 94.0% vs 93.4%
8-wk shrinking rate: 99.8% vs 99.9%
Delayed bleeding rate: 2.0% vs 3.2%	20	
Hiroto Miwa 2016 (26)	Double-blind	November 2011–December 2012 (GU) and October 2011–February 2013 (DU)	456 (GU) and 358 (DU)	DU and GU	231 (GU)/178 (DU) vonoprazan 20 mg/d
vs
225 (GU)/180 (DU) lansoprazole 30 mg/d	GU: 4-wk healing rate: 73.2% vs 75.6%
Healing rate: 93.5% (8 wk) vs 93.8%
TEAE rate: 26.6% vs 33.2%
DU: 4-wk healing rate: 93.8% vs 94.4%
Healing rate: 95.5% (6 wk) vs 98.3%
TEAE rate: 34.4% vs 28.6%	_	
Hiroyuki Komori 2019 (25)	Not blind	April 2015–January 2016	33	Post-ESD gastric ulcers	18 vonoprazan 20 mg/d
VA
15 rabeprazole 10 mg/d	4-wk healing rate: 0
4-wk shrinking rate:93.3% vs 96.6%	7	
Izumi Tsuchiya 2017 (31)	Single-blind	April 2015–June 2016	80	Post-ESD gastric ulcers	39 vonoprazan 20 mg/d
vs
41 esomeprazole 20 mg/d	8-wk healing rate: 94.9% vs 78.0%
Delay bleeding rate: 0 vs 7.3%	10	
Kazuya Takahashi 2016 (32)	Not blind	August 2015–March 2016	26	Post-ESD gastric ulcers	14 vonoprazan 20 mg/d
vs
12 lansoprazole 30 mg/d	4-wk shrinking rate: 95.3% vs 97.2%
Delay bleeding rate: 0	4	
Kenta Hamada 2018 (27)	Not blind	May 2015–June 2016	130	Post-ESD gastric ulcers	64 vonoprazan 20 mg/d
vs
66 lansoprazole 30 mg/d	4-wk healing rate: 81% vs 80%
Delayed bleeding rate: 4.3% vs 5.7%	9	
Nian-di Tan 2023 (33)	Double-blind	September 2020–March 2021	360	DU	180 keverprazan 20 mg/d
vs
178 lansoprazole 30 mg/d	4-wk healing rate: 83.9% vs 80.3%
TEAE rate: 57.8% vs 59.0%	11	
Nian-di Tan 2022 (34)	Double-blind	September 2019–March 2020	180	DU	55 keverprazan 20 mg/d OR 61 keverprazan 30 mg/d
vs
64 lansoprazole 30 mg/d	4-wk healing rate: 87.27% (K20) 90.16% (K30) vs 79.69%
TEAE rate: 43.64% (K20) 63.93% (K30) vs 64.06%	12	
Takashi Ichida 2018 (24)	Not blind	September 2015–December 2017	82	Post-ESD gastric ulcers	43 vonoprazan 20 mg/d
vs
39 esomeprazple 20 mg/d	4-wk healing rate: 20.9% vs 15.4%
8-wk healing rate: 90.7% vs 99.3%
4-wk shrinking rate: 94.6% vs 93.8%
8-wk shrinking rate: 99.7% vs 99.3%
Delayed bleeding rate: 2.33% vs 10.2%	2	
Takashi Kawai 2014 (35)	Double-blind	—	612	Patients with a PUD history had the long-term LDA therapy	202 TAK-438 10 mg/d OR 202 TAK-438 20 mg/d
vs
217 lansoprazole 15 mg/d	24-wk recurrence rate: 0.5% (T10) 1.5% (T20) vs 2.8%
AE rate: 71.3% (T10) 75.7% (T20) vs 67.7%
Delayed bleeding rate: 0 (T10) 0 (T20) vs 2.9%	_	
Takashi Kawai 2017 (28)	Double-blind and single-blind	October 2011–April 2013 and March 2012–October 2013	574 and 405	Patients with a PUD history had the long-term LDA therapy	188 vonoprazan 10 mg/d OR 186 vonoprazan 20 mg/d
vs
200 lansoprazole 15 mg/d	24-wk recurrence rate: 0.5% (V10) 1.5% (V20) vs 2.8%
TEAE rate: 87.6% (V10) 87.1% (V20) vs 84.8%
Delayed bleeding rate: 0 (V10) 0 (V20) vs 2.9%	47	
Takeda 2020 (36)	Double-blind	April 2017–July 2019	496	DU	248 TAK-438 20 mg/d (or BID)
vs
248 lansoprazole 30 mg (or BID)	4-wk healing rate: 89.2% vs 88.4%	37	
Takeda 2020 (37)	Double-blind	April 2017–May 2020	217	GU	107 TAK-438 20 mg/d (or BID)
vs
110 lansoprazole 30 mg (or BID)	4-wk healing rate: 76.1% vs 82.1%	17	
Xiaohua Hou 2022 (38)	Double-blind	May 2017–July 2019	533	DU	265 vonoprazan 20 mg
vs
268 lansoprazole 30 mg	4-wk healing rate: 89.2% vs 88.4%
TEAE rate: 74.1% vs 64.9%	35	
Yasuaki Ishii 2018 (39)	Not blind	May 2015–May 2017	53	Post-ESD gastric ulcers	27 vonoprazan 20 mg/d
vs
26 esomeprazple 20 mg/d	4-wk healing rate: 8.0% vs 11.5%
8-wk healing rate: 88.9% vs 84.6%
4-wk shrinking rate: 96.8% vs 97.5%
8-wk shrinking rate: 100%
Delayed bleeding rate: 0	7	
Yu Kyung Cho 2020 (40)	Double-blind	May 2016–December 2018	278(efficacy)/304(safety)	GU	92 tegoprazan 50 mg/d OR 97 tegoprazan 100 mg/d
vs
89 lansoprazole 30 mg per d	4-wk healing rate: 90.63% (T50) 91.92% (T100) vs 89.25%
8-wk healing rate: 94.79% (T50) 94.95% (T100) vs 95.70%
TEAE rate: 18% (T50) 23% (T100) vs 25%	28	
Yuji Mizokami 2014 (41)	Double-blind	_	642	Patients with a PUD history had the long-term NSAID therapy	218 TAK-438 10 mg/d OR 212 TAK-438 20 mg/d
vs
212 lansoprazole 15 mg/d	24-wk recurrence rate: 3.3% (T10) 3.4% (T20) vs 5.5%
AE rate: 71.6% (T10) 71.7% (T20) vs 76.7%
Delayed bleeding rate: 1.4% (T10) 1.0% (T20) vs 2.0%	_	
Yuji Mizokami 2017 (42)	Double-blind and single-blind	October 2011–June 2013 and April 2012–December 2013	588 and 357	Patients with a PUD history had the long-term NSAID therapy	209 vonoprazan 10 mg/d OR 192 vonoprazan 20 mg/d
vs
187 lansoprazole 15 mg/d	24-wk recurrence rate: 3.3% (V10) 3.4% (V20) vs 5.5%
TEAE rate: 84.4% (V10) 82.5% (V20) vs 88.1%
Delayed bleeding rate: 1.4% (V10) 1.0% (V20) vs 2.0%	54	
DU, duodenal ulcer; ESD, endoscopic submucosal dissection; GU, gastric ulcer; LDA, low-dose aspirin; NSAIDs, anti-inflammatory drugs; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; PUD, peptic ulcer disease; TEAE, treatment-emergent adverse event.

The results of the bias analysis are shown in Figures 2 and 3.

Figure 2. Risk-of-bias graph. Green for low risk of bias (+), yellow for unclear risk of bias (?), and red for high risk of bias (−).

Figure 3. Risk-of-bias summary. Green for low risk of bias (+), yellow for unclear risk of bias (?), and red for high risk of bias (−).

Healing rates at 4 weeks and 6/8 weeks of conventional PUD

The analysis involved 8 studies and 2,701 patients. We split the results into 3 parts: week 4, week 6 (DU), and week 8 (GU) (Figure 4).

Figure 4. Forest plots comparing the healing rates of conventional PUD patients receiving P-CAB or PPI at week 4 and week 6/8. Fixed-effects model; CI, confidence interval; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; PUD, peptic ulcer disease; RR, risk ratio.

4-week healing rates: There were no statistical differences between the 8 studies (RR 1.01, 95% CI 0.98–1.04), with a low heterogeneity degree (df = 7, P = 0.24, I2 = 24%). The healing rates at 6 weeks (DU) had been reported in 5 studies, with (RR 1.00, 95% CI 0.99–1.02, I2 = 4%). The 8-week healing rates (GU) of P-CAB were not different from PPI (RR = 0.99, 95% CI = 0.95–1.02, I2 = 0%). There was no difference among 4, 6, and 8 weeks (df = 2, P = 0.58, I2 = 0%).

Healing rates of artificial ulcer at 4 weeks

Eight hundred nineteen participants of 7 studies had reported the healing rates from artificial ulcer. One of the studies was not included in the calculations because the resulting data could not be converted into the form required (25). As shown in the figure (Figure 5), no apparent distinction was observed (RR = 1.04, 95% CI = 0.89–1.22, I2 = 0%).

Figure 5. Forest plots comparing the healing rates of patients with artificial ulcer at 4 weeks. CI, confidence interval; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; PUD, peptic ulcer disease.

Shrinking rates at 4 weeks and 8 weeks of artificial ulcer

Five studies had provided data on the 4- and 8-week shrinking rates. The treatment of them was vonoprazan 20 mg/d vs lansoprazole 30 mg/d (3/5) (15,30,32) and vonoprazan 20 mg/d vs esomeprazple 20 mg/d (24,39). The findings were divided into 2 subgroups, shrinkage rates of 4 and 8 weeks, respectively (Figure 6). P-CAB exhibited a negligible enhancement in comparison with PPI (4 weeks: MD = 0.10, 95% CI = −1.30∼1.51, I2 = 0; 8 weeks: MD = −0.04, 95% CI = −0.24∼0.16, I2 = 0). Most of the data were not original data and had some transformation, which may cause bias.

Figure 6. Forest plots comparing the shrinking rates of artificial ulcer patients at 4 weeks and 8 weeks.CI, confidence interval; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; PUD, peptic ulcer disease.

Rates of TEAEs of conventional PUD

Two thousand eight hundred twenty-five participants of 8 studies had documented the rates of TEAEs (Table 2). One of the studies included 2 experiments (26). Figure 7 shows that there is considerable heterogeneity in the results (df = 7, P < 0.01, I2 = 82%). The TEAE rates associated with P-CABs showed no variance from that of PPIs (RR = 1.11, 95% CI = 0.91–1.35, I2 = 82%).

Table 2. Type of TEAEs observed in conventional PUD articles

	Gastrointestinal disorders	Infections and infestations	Nervous system disorders	Tumor	Cardiac disorders	Abnormal liver function	Urinary system disorders	Serum gastrin concentration increased	
Hiroto Miwa 2016 (DU/GU)	✓		✓					✓	
Hiroto Miwa 2016 (DU/GU)	✓		✓					✓	
Nian-di Tan 2022	✓					✓	✓	✓	
Nian-di Tan 2023	✓		✓		✓	✓	✓	✓	
Takeda 2020 (DU)	✓	✓	✓	✓				✓	
Takeda 2020 (GU)		✓		✓	✓			✓	
Yu Kyung Cho 2020	✓	✓	✓		✓			✓	
Xiaohua hou 2022		✓	✓					✓	
DU, duodenal ulcer; GU, gastric ulcer; PUD, peptic ulcer disease; TEAE, treatment-emergent adverse event.

Figure 7. Forest plots comparing the TEAE rates of patients of conventional PUD. CI, confidence interval; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; PUD, peptic ulcer disease; TEAE, treatment-emergent adverse event.

Incidence rates of delayed bleeding of artificial ulcer

Seven hundred seventy-seven participants of 9 studies about artificial ulcer had provided data on the incidence rate of complications. In each of these articles, delayed bleeding was mentioned as a symbolic complication after ESD. Perforation was mentioned in 3 of them (15,30,31). One involved pneumonia (30). One involved drug-induced hepatic injury (25). The incidence of delayed bleeding was shown in Figure 8. The data indicated that the delayed bleeding rates with P-CABs were lower than those of PPIs (RR = 0.35, 95% CI = 0.16–0.80, I2 = 0).

Figure 8. Forest plots comparing the incidence rates of delayed bleeding of patients with artificial ulcers.

Recurrence rates of preventive treatment between P-CAB and PPI

Four studies had documented the recurrence rates when using NSAID or low-dose aspirin (LDA) for a long time with a PUD history (28,35,41,42). All treatments were P-CABs (vonoprazan or TAK-438) 10 mg/d vs PPI (lansoprazole) 15 mg/d, and the results were recorded at week 24. The outcomes are shown in Figure 9 below. P-CABs were found to be statistically more effective than PPI (RR = 0.45, 95% CI = 0.25–0.81, I2 = 0).

Figure 9. Forest plots comparing the recurrence rates of patients with a PUD history and the long-term NSAID/LDA therapy. LDA, low-dose aspirin; NSAID, nonsteroidal anti-inflammatory drug; PUD, peptic ulcer disease.

DISCUSSION

We studied 2 types of ulcers, including conventional PUD and artificial ulcer. The results of conventional PUD include efficacy, safety, and prevention of recurrent. The results cover the efficacy and safety of artificial ulcer.

For efficacy of conventional ulcer, our results are consistent with existing research (20,43). Available evidence and our study indicate that no significant variation was identified between P-CABs and PPIs in the healing rates of GUs and DUs (1,43). Studies have shown that P-CABs have rapid action because they do not have to excite the proton pump (10,44,45). In the introduction, we also elaborate on the advantages of P-CABs. However, this velocity difference does not appear in our results. We guessed that the early (≤2 weeks) data were insufficient, and PPI had caught up in the observation time (≥4 weeks), which could be confirmed in the erosive esophagitis disease (43). Since the endpoint for PUD treatment is typically week 4 or week 6/8, we can assume that treatment rates are comparable.

For efficacy of postprocedural artificial ulcer from ESD, the conclusions of existing studies are controversial. Some found P-CABs perform better, whereas others found no significant improvement (2,30,46–49). Our datas demonstrate that there is no difference in healing rate and shrinkage rate between them. In addition, it has also been suggested that the shrinkage rate of artificial ulcers varies after 6 weeks (31). Our results do not agree with this statement, our associated 8-week results again support the equivalence.

For safety, the TEAE rate of conventional PUD needs further investigation. As shown in Table 2, each article contains inconsistent TEAEs. For example, gastrointestinal symptoms, such as bleeding in one article and diarrhea in another, can vary in severity. As shown in Figure 7, we found a large heterogeneity in the result. This may be related to different definitions of TEAEs, different criteria for adverse reactions, and different characteristics of the participants. Similarly, the type and dose of the drug and H. pylori infection may also contribute to the heterogeneity. We are looking forward to more comparable data to get more reliable conclusions.

Short-term treatments present little risk; however, certain studies have indicated that long-term use of PPIs could potentially lead to the development of distinct mucosal alterations, community-acquired pneumonia, and chronic kidney disease (50–53). Long-term treatment with P-CAB and PPI may result in increased serum levels of gastrin and pepsinogen and may increase the risk of hyperextension (54–56). How to compare the safety of the 2 drugs and how to balance efficacy and safety may be directions for future research.

For safety of artificial ulcer, the result shows that PCABs can significantly reduce the complication rate of artificial ulcer than PPI, represented by delayed bleeding. This may mean that routine use of PCABs to prevent and treat complications after ESD will be a better choice.

For prevention of recurrent, this is about NSAID or LDA long-term therapy-induced ulcers. Guidelines recommend discontinuing NSAID and taking antiulcer medications for NSAID-induced ulcer and PPIs with continuous LDA therapy for LDA-induced ulcer (1). But, discontinuation of NSAIDs may lead to disease recurrence (57,58). Although the continuous use of LDA may elevate the risk of bleeding, discontinuation of LDA can potentially heighten the risk of cerebral or cardiovascular events (59–61). Therefore, the prevention of ulcers becomes very important, especially in people with a history of PUD. Our results suggest that PCAB is better for prevention. More data are expected to demonstrate this conclusion.

There are several limitations to this study. First, the definitions of outcomes are not fully consistent across studies and may lead to the high heterogeneity. Second, the raw data are not directly used in the analysis and are transformed. Ultimately, there are many other factors that have not been analyzed, such as the CYP2C19 genotype (7). But, we collected as many clinical studies as we could and conducted a comprehensive and rigorous comparison between P-CAB and PPI in PUD and artificial ulcer in many aspects.

We believe that both PCAB and PPI can be chosen when treating conventional PUD, but PCAB may be a better choice when treating artificial ulcers and preventing drug-induced ulcers. Hopefully, this will play a part in the future treatment and prevention of ulcers.

CONFLICTS OF INTEREST

Guarantor of the article: Wen-xin Wang.

Specific author contributions: W-x.W.: formal analysis; methodology; project administration; writing—original draft preparation (methods, results, and discussion); and writing—review and editing. R.-j.L.: validation; visualization; and writing—original draft preparation (introduction). X-f.L.: validation and writing—original draft preparation (results). Conceptualization; data curation; investigation; and other parts were performed together.

Financial support: None to report.

Potential competing interests: None to report.

ACKNOWLEDGEMENT

We thank Zhe Chen for his great contribution to the study design and data collection. We appreciate the help of Zhima Li with the data check.
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