Patients undergoing percutaneous coronary intervention (PCI) often require long-term antiplatelet therapy to prevent adverse cardiovascular (CV) events. However, the use of antiplatelet agents can increase the risk for upper gastrointestinal (GI) complications, such as ulcers and bleeding. In patients diagnosed with ischemic heart disease (IHD), GI bleeding is associated with ischemic complications and high mortality rates, and the risk for death increases when antiplatelet drugs are temporarily discontinued. As such, prevention of GI bleeding is vital [1-3].

Proton pump inhibitors (PPIs) are commonly used to mitigate the GI side effects of antiplatelet therapy. Novel potassium-competitive acid blockers (P-CABs) have recently emerged as potential alternatives to PPIs for managing GI symptoms. Unlike PPIs which irreversibly bind to H⁺/K⁺-ATPase, P-CABs competitively and reversibly inhibit acid secretion. In 2015, a P-CAB was approved for use in Japan. A recent study reported that vonoprazan was as effective as lansoprazole in preventing peptic ulcer recurrence in Japanese patients undergoing long-term low-dose aspirin treatment [4]. Additionally, the P2Y12 reaction units in patients receiving aspirin and prasugrel in combination after PCI were not significantly different between the vonoprazan and PPIs groups [5]. Furthermore, a nationwide database study involving 16415 patients in Japan revealed vonoprazan to be non-inferior to PPIs in terms of upper GI bleeding occurrence over a 6-month period in patients with IHD receiving ≥2 antithrombotic agents [6]. Tegoprazan is a P-CAB developed in Korea and, similar to vonoprazan, it has demonstrated stronger and faster effects than PPIs. It has been available in Korea since 2019 and has demonstrated efficacy in improving GI symptoms in patients with acid-related diseases [7]. A previous Japanese study reported that vonoprazan reduced the risk for GI bleeding more efficiently than PPIs; however, no study has yet reported on the CV risk. Additionally, no studies have compared the effects of tegoprazan vs. PPIs in patients undergoing antithrombotic therapy after PCI.

The present study aimed to compare the clinical outcomes of tegoprazan vs. PPIs in patients receiving antiplatelet therapy after PCI. Specifically, we evaluated the incidences of upper GI and CV complications in patients who received tegoprazan or PPIs in combination with antiplatelet therapy. By comparing the outcomes of these two treatment approaches, we aimed to determine whether tegoprazan could be used as an alternative to PPIs for the management of GI and CV complications associated with antiplatelet therapy after PCI.

Results of this retrospective, single-center study indicated no significant differences in GI or CV adverse events between patients receiving tegoprazan or PPIs in combination with antiplatelet therapy after PCI. Kaplan–Meier analyses suggested comparable cumulative event trends for both GI and CV outcomes. Cox regression analyses yielded supportive evidence, with HRs of 0.34 (95% CI 0.04–2.97) for GI events and 0.57 (95% CI 0.15–2.19) for CV events, indicating similar risk between the two treatment groups.

P-CABs, including tegoprazan, exert stronger acid-suppressing effects than PPIs, and have demonstrated non-inferior or superior results in several clinical studies. Considering the strong acid-suppressing effect of P-CABs, the GI protective effect accompanying antiplatelet therapy may be expected to be similar or superior in patients taking P-CABs compared with those taking PPIs. A large population-based study from Japan revealed the non-inferiority of vonoprazan vs. PPI in terms of the occurrence of upper GI bleeding over a 6-month period in patients with IHD [6]. In our study, the similar rates of adverse GI events between the tegoprazan and PPIs groups suggest that tegoprazan is equally effective in reducing the risk of peptic ulcer and upper GI bleeding. This is particularly encouraging because it provides an alternative treatment option for patients who may not tolerate or respond well to PPI therapy.

Concerns regarding the interactions between PPIs and clopidogrel have been raised because PPIs may reduce the conversion of clopidogrel to its active metabolite via CYP450 enzymes [8]. Some studies have reported increased CV risk with concomitant PPI and clopidogrel use [9-12], although these data were largely from observational studies [13]. Very few studies have evaluated the interaction between P-CABs and clopidogrel. Vonoprazan is metabolized via CYP3A4 and additional pathways, whereas tegoprazan is primarily metabolized by CYP3A4. No significant difference was reported in P2Y12 reaction units in patients receiving aspirin and prasugrel in combination after PCI between the vonoprazan and PPIs groups [5]. Our study found comparable rates of CV adverse events, suggesting that tegoprazan does not compromise CV safety when used with antiplatelet agents.

Studies have often considered PPI as a class, with conflicting reports regarding CV outcomes. Omeprazole and esomeprazole have been reported to have greater CV effects [14,15], whereas pantoprazole and rabeprazole have been reported to have mild or unlikely CV effects [16-19]. Because tegoprazan is mainly metabolized by CYP3A4, it is expected to be relatively safe from CV risk(s), which is consistent with our exploratory findings. In real-world practice, PPI prescriptions are heterogeneous and are often administered at low doses due to insurance restrictions. This heterogeneity may have influenced the outcomes; therefore, direct comparison with a fixed standard dose of tegoprazan should be interpreted with caution.

GI bleeding after PCI is associated with increased mortality and morbidity [20]. Risk factors for GI bleeding include the presence of underlying diseases, older age, history of peptic ulcers or bleeding, and the use of antithrombotic agents or NSAIDs [21,22]. In our study, aspirin use, concomitant NSAID use, and history of ulcers were more frequent in the tegoprazan group. However, no difference in upper GI bleeding was observed, suggesting that tegoprazan provides effective GI protection.

Findings of the present study have several important clinical implications. First, tegoprazan has been shown to offer a valuable exploratory alternative to patients who require antiplatelet therapy but are at a high risk for GI complications. By effectively managing GI symptoms without compromising CV safety, tegoprazan enhances the overall benefit-risk profile of antiplatelet therapy. Second, the comparable clinical outcomes between tegoprazan and PPIs suggest that tegoprazan could be considered as a first-line option for GI protection in patients taking antiplatelet agents after PCI.

This study, however, also had several limitations. First, as a retrospective, single-center study, the baseline characteristics of the tegoprazan and PPIs groups were not fully comparable, with higher-risk patients potentially preferentially prescribed tegoprazan (confounded by indication). No statistical adjustment was performed for these differences, thus limiting the causal interpretation of the observed outcomes. Second, baseline gastritis or ulcer status could not be confirmed endoscopically, and GI events were primarily evaluated based on symptoms or evidence of bleeding; thus, asymptomatic lesions may have been missed. Third, low-dose and heterogeneous PPI prescriptions, common due to Korean insurance policies and concerns regarding long-term side effects, may bias the interpretation compared with a fixed standard dose of tegoprazan. Finally, the overall number of GI and CV outcome events was relatively small, which raising the possibility of insufficient statistical power and type II errors. Therefore, these findings should be regarded as exploratory and hypothesis generating rather than confirmatory.

In conclusion, among patients who underwent antiplatelet therapy after PCI, there were no significant differences in GI or CV complications between tegoprazan and PPIs users. Further large prospective randomized controlled trials are warranted to confirm these preliminary results and provide more robust evidence regarding the efficacy and safety of tegoprazan in this patient population are warranted.