Comparative efficacy and pharmacological heterogeneity of individual potassium-competitive acid blockers: A systematic review and network meta-analysis

Table 1 Characteristics of included randomized controlled trials comparing potassium-competitive acid blocker vs proton pump inhibitor for Helicobacter pylori eradication (n = 30 studies, 32 comparisons)

Number	Ref.	Year	Country	P-CAB	PPI	Design	Regimen	Antibiotics	Days	Eradication success in P-CAB group (n = 4020)	Eradication success PPI group (n = 3619)
1	Murakami et al[18]	2016	Japan	VPZ 20 mg	LPZ 30 mg	RCT, DB, NI	Triple	AMO + CLR	7	300/324 (92.6%)	243/320 (75.9%)
2	Maruyama et al[19]	2017	Japan	VPZ 20 mg	RPZ/LPZ	RCT, OL	Triple	AMO + CLR	7	69/72 (95.8%)	48/69 (69.6%)
3	Sue et al[20]	2018	Japan	VPZ 20 mg	PPI mix	RCT, OL	Triple	AMO + CLR	7	48/55 (87.3%)	39/51 (76.5%)
4	Chey et al[3] (Triple)	2022	United States/Europe	VPZ 20 mg	LPZ 30 mg	RCT, DB, NI	Triple	AMO + CLR	14	222/262 (84.7%)	201/255 (78.8%)
5	Chey et al[3] (Dual)	2022	United States/Europe	VPZ 20 mg	LPZ 30 mg	RCT, OL	Dual	AMO	14	208/265 (78.5%)	201/255 (78.8%)
6	Choi et al[21]	2022	Korea	TPZ 50 mg	LPZ 30 mg	RCT, DB, NI	Triple	AMO + CLR	7	110/175 (62.9%)	106/175 (60.6%)
7	Han et al[22]	2023	China	VPZ 20 mg	RPZ 20 mg	RCT, OL	Dual	AMO	10	308/345 (89.3%)	293/345 (84.9%)
8	Huang et al[23]	2023	China	VPZ 20 mg	ESO 20 mg	RCT, OL	Triple	AMO + Bi	14	38/40 (95.0%)	32/40 (80.0%)
9	Kim et al[24]	2023	Korea	TPZ 50 mg	BQT (LPZ)	RCT, DB	BQT	Bi + MTZ + TC	14	84/105 (80.0%)	82/106 (77.4%)
10	Lu et al[25]	2023	China	VPZ 20 mg	BQT (ESO)	RCT, OL, NI	BQT	AMO + FUR + Bi	14	74/78 (94.9%)	73/78 (93.6%)
11	Peng et al[26]	2023	China	VPZ 20 mg	Modified BQT (PACB) (ESO)	RCT, OL, MC	Dual	AMO	14	142/158 (89.9%)	128/158 (81.0%)
12	Qian et al[27]	2023	China	VPZ 20 mg	BQT (ESO)	RCT, OL	Dual	AMO (HD)	10	114/125 (91.2%)	110/125 (88.0%)
13	Wang et al[28]	2023	China	VPZ 20 mg	BQT (RPZ)	RCT, OL	Dual	AMO	14	70/74 (94.6%)	67/77 (87.0%)
14	Chen et al[29]	2024	China	VPZ 20 mg	ILA 5 mg	RCT, OL, NI	Dual	AMO	14	38/45 (84.4%)	38/45 (84.4%)
15	Cheung et al[30]	2024	HK	VPZ 20 mg	BQT (ESO)	RCT, OL	Dual/Triple	AMO ± CLR	14	96/100 (96.0%)	92/100 (92.0%)
16	DWP14012[31]	2024	Korea	FXP 40 mg	LPZ 30 mg	RCT, DB, Ph3	Triple	AMO + CLR	14	184/220 (83.6%)	166/213 (77.9%)
17	Huang et al[32]	2024	China	VPZ 20 mg	BQT (ILA)	RCT, OL, MC	Dual	AMO	10	96/103 (93.2%)	81/101 (80.2%)
18	Kong et al[33]	2024	China	VPZ 20 mg	BQT (ESO)	RCT, OL, NI	Dual	AMO	10	158/184 (85.8%)	155/184 (84.2%)
19	Lee et al[34]	2024	Korea	TPZ 50 mg	BQT (ESO)	RCT, OL, NI	Seq	AMO + CLR to MTZ	10	176/202 (87.1%)	171/204 (83.8%)
20	Liang et al[35]	2024	China	VPZ 20 mg	Modified BQT (PACB) (ESO)	RCT, OL, MC	Triple + Bi	AMO + Bi	14	251/300 (83.7%)	247/297 (83.2%)
21	Lin et al[36]	2024	China	TPZ 50 mg	BQT (ESO)	RCT, OL	Dual	AMO	14	184/214 (86.0%)	91/107 (85.0%)
22	Tan et al[37]	2024	China	KVP 20 mg	ESO 20 mg	RCT, DB, NI	BQT	Bi + AMO + CLR	14	252/287 (87.8%)	236/286 (82.5%)
23	Zhou et al[38]	2024	China	VPZ 20 mg	ESO 20 mg	RCT, OL, MC	Dual	AMO	10	245/287 (85.4%)	217/283 (76.7%)
24	Cheng et al[39]	2025	China	TPZ 50 mg	BQT (ESO)	RCT, OL, MC	Dual/BQT	AMO/Bi + CLR	14	138/160 (86.3%)	115/149 (77.2%)
25	Fan et al[40]	2025	China	VPZ 20 mg	BQT (ESO)	RCT, OL	Dual	AMO	14	200/252 (79.4%)	216/252 (85.7%)
26	Fan et al[41]	2026	China	TPZ 50 mg	BQT (ESO)	RCT, OL, MC	Dual	AMO	14	56/76 (73.7%)	57/76 (75.0%)
27	Han et al[42]	2025	China	VPZ 20 mg	Modified BQT (PACB) (ESO)	RCT, OL	Triple	AMO + CLR	14	154/175 (88.0%)	127/175 (72.6%)
28	Park et al[43] (50 mg)	2026	Korea	TPZ 50 mg	LPZ 30 mg	RCT, DB, NI	Triple	AMO + CLR	14	100/113 (88.5%)	100/123 (81.3%)
29	Park et al[43] (100 mg)	2026	Korea	TPZ 100 mg	LPZ 30 mg	RCT, DB, NI	Triple	AMO + CLR	14	104/119 (87.4%)	100/123 (81.3%)
30	Shekeban et al[44]	2025	Egypt	VPZ 20 mg	STT (ESO)	RCT, OL	Dual/triple	AMO ± CLR	14	77/88 (87.5%)	37/44 (84.1%)
31	Tai et al[45]	2025	Taiwan	VPZ 20 mg	RPZ 20 mg	RCT, OL	Dual	AMO	14	53/61 (86.9%)	49/60 (81.7%)
32	Yan et al[46]	2025	China	VPZ 20 mg	BQT (ESO)	RCT, OL, MC	BQT	Bi + DOX + MTZ	14	150/166 (90.4%)	118/166 (71.1%)

P-CAB: Potassium-competitive acid blocker; VPZ: Vonoprazan; TPZ: Tegoprazan; KVP: Keverprazan; FXP: Fexuprazan; LPZ: Lansoprazole; RPZ: Rabeprazole; ESO: Esomeprazole; ILA: Ilaprazole; AMO: Amoxicillin; CLR: Clarithromycin; MTZ: Metronidazole; FUR: Furazolidone; DOX: Doxycycline; Bi: Bismuth; TC: Tetracycline; BQT: Bismuth quadruple therapy; STT: Standard triple therapy; RCT: Randomized controlled trial; DB: Double-blind; OL: Open-label; NI: Non-inferiority; MC: Multicenter; Ph3: Phase 3; HD: High-dose; Seq: Sequential; PACB: Proton pump inhibitor, amoxicillin, clarithromycin, bismuth.

Table 2 Characteristics of included erosive esophagitis randomized controlled trials (n = 10 studies)

Number	Ref.	Year	Region	P-CAB	PPI	n (overall)	Healing rate in P-CAB group (overall) (n = 2370)	Healing rate in PPI group (overall) (n = 1826)	Healing rate in P-CAB group (LA C/D) (n = 612)	Healing rate in PPI group (LA C/D) (n = 438)
1	Ashida et al[47]	2015	Japan	VPZ 5-40 mg	LPZ 30 mg	686	524/554 (94.6%)	123/132 (93.2%)	184/199 (92.5%)	40/46 (87.0%)
2	Ashida et al[48]	2016	Japan	VPZ 20 mg	LPZ 30 mg	404	203/205 (99.0%)	190/199 (95.5%)	75/75 (100%)	63/72 (87.5%)
3	Xiao et al[49]	2020	China	VPZ 20 mg	LPZ 30 mg	468	220/238 (92.4%)	210/230 (91.3%)	64/76 (84.2%)	55/68 (80.9%)
4	Laine et al[50]	2023	United States/Europe	VPZ 20 mg	LPZ 30 mg	1024	478/514 (92.9%)	431/510 (84.5%)	163/177 (92.1%)	125/174 (71.8%)
5	Chen et al[51]	2022	China	KVP 20 mg	LPZ 30 mg	238	114/119 (95.8%)	107/119 (89.9%)	22/24 (91.7%)	20/25 (80.0%)
6	Oh et al[52]	2025	South Korea	ZPZ 20 mg	ESO 40 mg	282	141/144 (97.9%)	131/138 (94.9%)	6/6 (100%)	5/6 (83.3%)
7	Lee et al[53]	2022	South Korea	FXP 40 mg	ESO 40 mg	218	106/107 (99.1%)	110/111 (99.1%)	NR	NR
8	Zhuang et al[54]	2024	China	FXP 40 mg	ESO 40 mg	328	146/165 (88.5%)	145/163 (89.0%)	41/51 (80.4%)	43/47 (91.5%)
9	Lee et al[55]	2019	South Korea	TPZ 50/100 mg	ESO 40 mg	300	192/201 (98.5%)	92/99 (92.9%)	~4/4 (100%)	NR
10	Zhu et al[56]	2025	China	TPZ 50 mg	ESO 40 mg	248	112/123 (91.1%)	116/125 (92.8%)	NR	NR

Los Angeles classification C/D data summary by potassium-competitive acid blocker: (1) Zastaprazan [acid dissociation constant (pKa) of 995]: 100% vs 83.3% (+16.7%, n = 6/arm); (2) Keverprazan (pKa of 912): 91.7% vs 80.0% (+11.7%, n = 24-25/arm); (3) Vonoprazan (pKa of 906): 84.0%-100% vs 71.8%-86.7% (pooled +13.4%); (4) Fexuprazan (pKa of 904): 80% vs 91% (-11%, inferior to proton pump inhibitor despite high-pKa); and (5) Tegoprazan (pKa of 51): 100% vs not reported (data limited). P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor; VPZ: Vonoprazan; TPZ: Tegoprazan; KVP: Keverprazan; FXP: Fexuprazan; ZPZ: Zastaprazan; LPZ: Lansoprazole; ESO: Esomeprazole; NR: Not reported; LA: Los Angeles classification.

Table 3 Results of meta-analysis for the potassium-competitive acid blocker vs proton pump inhibitor efficacy in clarithromycin-resistant Helicobacter pylori infections

Ref.	Year	Country	P-CAB	Comparator	Eradication success in P-CAB group	Eradication success in PPI group	Δ (%)	OR	95%CI
Murakami et al[18]	2016	Japan	VPZ	LPZ	82/100 (82.0)	46/115 (40.0)	+42.0%	6.83	3.63-12.86
Chey et al[3] (triple)	2022	United States/Europe	VPZ	LPZ	48/73 (65.8)	23/72 (31.9)	+33.9%	4.09	2.05-8.17
Chey et al[3] (dual)	2022	United States/Europe	VPZ	LPZ	39/56 (69.6)	23/72 (31.9)	+37.7%	4.89	2.30-10.40
Tan et al[37]	2024	China	KVP	ESO	121/145 (83.5)	97/126 (77.0)	+6.5%	1.51	0.83-2.76
Park et al[43]	2026	Korea	TPZ	LPZ	11/23 (47.8%)	11/31 (35.5%)	+12.3%	1.67	0.56-5.01
Pooled (random effects, 5 studies, n = 813)								3.32	1.79-6.16

P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor; OR: Odds ratio; VPZ: Vonoprazan; KVP: Keverprazan; LPZ: Lansoprazole; ESO: Esomeprazole.

Table 4 Risk of bias assessment for Included randomized controlled trials

Ref.	Design	D1: Randomization	D2: Deviations	D3: Missing data	D4: Measurement	D5: Reporting	Overall
H. pylori eradication RCTs (n = 30, 32 comparisons)
Murakami et al[18]	DB, NI	Low (computer, stratified)	Low (DB)	Low (FAS/PPS)	Low (UBT)	Low (Ph3)	Low
Maruyama et al[19]	OL	Some (quasi-random: Odd/even MRN)	Some (OL)	Low (complete follow-up)	Low (UBT)	Low (primary outcome reported)	Some
Sue et al[20]	OL	Low (Web-based minimization)	Some (OL)	Low (minimal dropout)	Low (UBT)	Low (pre-registered outcome)	Some
Chey et al[3] (triple)	DB, NI	Low (Web-based central, block size 6)	Low (DB, double-dummy)	Low (mITT analysis, balanced dropout)	Low (central lab blinded UBT)	Low (pre-registered primary endpoint)	Low
Chey et al[3] (dual)	OL	Low (central web-based)	Some (OL arm)	Low (mITT analysis)	Low (central lab blinded UBT)	Low (pre-registered endpoint)	Some
Choi et al[21]	DB, NI	Low (stratified block)	Low (double-dummy design)	Low (FAS analysis, minimal dropout)	Low (blinded UBT/histology)	Low (protocol-specified outcomes)	Low
Han et al[22]	OL	Low (computer-generated sequence)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (outcomes per protocol)	Some
Huang et al[23]	OL	Low (random number table)	Some (OL)	Low (complete follow-up)	Low (objective UBT/histology)	Low (primary outcome reported)	Some
Kim et al[24]	DB	Low (stratified block)	Low (DB active-controlled)	Low (mITT/PP both reported)	Low (blinded UBT)	Low (pre-registered outcomes)	Low
Lu et al[25]	OL, NI	Low (block randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Peng et al[26]	OL, MC	Low (central randomization)	Some (OL MC)	Low (FAS analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Qian et al[27]	OL	Low (computer randomization)	Some (OL)	Low (complete follow-up)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Wang et al[28]	OL	Low (randomized, method NR)	Some (OL)	Low (per abstract)	Low (objective UBT outcome)	Some (conference abstract only)	Some
Chen et al[29]	OL, NI	Low (central randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Cheung et al[30]	OL	Low (computer-generated, opaque envelopes)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
DWP14012[31]	DB, Ph3	Low (IWRS centralized)	Low (DB Ph3)	Low (ITT analysis)	Low (blinded UBT)	Some (conference abstract only)	Some
Huang et al[32]	OL, MC	Low (central randomization)	Some (OL MC)	Low (FAS analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Kong et al[33]	OL, NI	Low (computer randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Lee et al[34]	OL, NI	Low (stratified block)	Some (OL Seq)	Low (mITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Liang et al[35]	OL, MC	Low (block randomization 1:1)	Some (OL MC)	Low (ITT analysis)	Low (objective UBT/histology)	Low (pre-registered outcomes)	Some
Lin et al[36]	OL	Low (computer randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (Primary outcome reported)	Some
Tan et al[37]	DB, NI	Low (computer-generated sequence)	Low (DB)	Low (FAS analysis)	Low (blinded UBT/histology)	Low (pre-registered outcomes)	Low
Zhou et al[38]	OL, MC	Low (central randomization)	Some (OL MC)	Low (mITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Cheng et al[39]	OL, MC	Low (computer randomization)	Some (OL MC)	Low (ITT analysis)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Fan et al[40]	OL	Low (computer randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Fan et al[41]	OL, MC	Low (central randomization)	Some (OL MC)	Low (ITT analysis)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Han et al[42]	OL	Low (computer randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (primary outcome reported)	Some
Park et al[43] (50mg)	DB, NI	Low (IWRS seed-allocated codes)	Low (DB)	Low (FAS analysis)	Low (UBT)	Low (pre-registered outcomes)	Low
Park et al[43] (100mg)	DB, NI	Low (IWRS seed-allocated codes)	Low (DB)	Low (FAS analysis)	Low (UBT)	Low (pre-registered outcomes)	Low
Shekeban et al[44]	OL	Low (computer randomization)	Some (OL)	Low (complete follow-up)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Tai et al[45]	OL	Low (computer randomization)	Some (OL)	Low (ITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Yan et al[46]	OL, MC	Low (central randomization)	Some (OL MC)	Low (ITT analysis)	Low (objective UBT outcome)	Low (pre-registered outcomes)	Some
Erosive esophagitis RCTs (n = 10)
Ashida et al[47]	DB	Low (central randomization)	Low (DB)	Low (complete follow-up)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Ashida et al[48]	DB	Low (central randomization)	Low (DB Ph3)	Low (ITT analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Xiao et al[49]	DB	Low (IWRS randomization)	Low (DB Ph3)	Low (FAS analysis)	Low (central blinded endoscopy)	Low (pre-registered outcomes)	Low
Laine et al[50]	DB	Low (IWRS central randomization)	Low (DB Ph3)	Low (mITT analysis)	Low (central blinded endoscopy)	Low (pre-registered outcomes)	Low
Chen et al[51]	DB	Low (computer randomization)	Low (DB)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Oh et al[52]	DB	Low (IWRS randomization)	Low (DB Ph3)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Lee et al[53]	DB	Low (stratified randomization)	Low (DB)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Zhuang et al[54]	DB	Low (central randomization)	Low (DB)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Lee et al[55]	DB	Low (stratified randomization)	Low (DB)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low
Zhu et al[56]	DB	Low (central randomization)	Low (DB)	Low (FAS analysis)	Low (blinded endoscopy)	Low (pre-registered outcomes)	Low

RCTs: Randomized controlled trials; DB: Double-blind; OL: Open-label; NI: Non-inferiority; MC: Multicenter; Ph3: Phase 3; UBT: Urea breath test; ITT: Intention-to-treat; mITT: Modified intention-to-treat; FAS: Full analysis set; PP: Per-protocol; IWRS: Interactive Web Response System; H. pylori: Helicobacter pylori.

Table 5 GRADE summary of findings (by outcome)

Outcome	Number of studies	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Effect estimate	Certainty
H. pylori eradication (P-CAB vs PPI)	30 RCTs (32 arms)[3,18-46]	Not serious1	Not serious	Not serious	Not serious	Undetected	OR = 1.49 (95%CI: 1.27-1.74)	High
EE healing 8-week (P-CAB vs PPI)	10 RCTs[47-56]	Not serious	Not serious	Not serious	Serious2	Undetected	OR = 1.47 (95%CI: 1.03-2.09)	Moderate

¹Possible concerns due to open-label design in some Helicobacter pylori randomized controlled trials; however, not downgraded because outcome assessment (urea breath test) is objective and unlikely influenced by lack of blinding.

²Downgraded one level: Some individual potassium-competitive acid blockers (zastaprazan, keverprazan) had only 1 randomized controlled trial each with wide confidence intervals.

P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor; EE: Erosive esophagitis; OR: Odds ratio; RCTs: Randomized controlled trials; H. pylori: Helicobacter pylori.