Potassium-competitive acid blockers versus proton pump inhibitors in dual antiplatelet therapy: Efficacy, safety and gastroprotection 

Introduction 

Dual antiplatelet therapy (DAPT) is a cornerstone of secondary prevention following percutaneous coronary intervention (PCI), particularly in patients undergoing coronary stent implantation. The combination of aspirin and a P2Y12 inhibitor substantially reduces stent thrombosis and recurrent ischemic events but inevitably increases bleeding risk. Gastrointestinal bleeding is among the most clinically relevant bleeding complications because it can result in hospitalization, interruption of antiplatelet treatment, and adverse cardiovascular outcomes.1,2 

Gastroprotection is therefore an important component of management in patients receiving DAPT who have an elevated risk of gastrointestinal (GI) bleeding. Proton pump inhibitors (PPIs) are currently the most widely used gastroprotective agents because of their established efficacy in suppressing gastric acid secretion and reducing upper GI bleeding.3 However, concerns have emerged regarding the potential interaction between PPIs and clopidogrel, which requires cytochrome P450 2C19 (CYP2C19)-mediated bioactivation. Although the clinical significance of this interaction remains debated, it has encouraged the investigation of alternative acid-suppressive therapies.4 

Potassium-competitive acid blockers (P-CABs) are a newer class of potent acid suppressants that inhibit the gastric H+/K+-ATPase through competitive binding at the potassium-binding site. Unlike conventional PPIs, P-CABs do not require acid-dependent activation and can therefore produce rapid and sustained acid suppression.5 These characteristics have generated interest in their potential use as alternatives to PPIs in patients requiring DAPT. 

 

Pharmacological rationale for P-CABs 

PPIs are prodrugs that accumulate in the acidic secretory canaliculi of gastric parietal cells, where they are activated and subsequently inhibit the proton pump. Their pharmacodynamic effect can therefore be influenced by meal timing, the activity of proton pumps at administration, and interindividual differences in metabolism.5 

P-CABs have a distinct mechanism. By directly and reversibly competing with potassium at the H+/K+-ATPase, they inhibit acid secretion rapidly and independently of acid-mediated activation. Vonoprazan, one of the most extensively studied P-CABs, produces potent and prolonged acid suppression and has a longer duration of action than conventional PPIs.5,6 

Another potential advantage is their relatively limited dependence on CYP2C19 metabolism. This is particularly relevant in patients receiving clopidogrel, because clopidogrel is a prodrug requiring CYP2C19 activation. Some PPIs, particularly those with greater CYP2C19 affinity, have raised concerns about potentially attenuating clopidogrel activity.4 Although randomized evidence has not consistently demonstrated clinically meaningful adverse cardiovascular effects from PPI-clopidogrel combinations, a gastroprotective agent with minimal CYP2C19 interaction remains pharmacologically attractive. 

Evidence for gastroprotection during DAPT 

The most recent evidence directly addressing this clinical question comes from a systematic review and meta-analysis by Elmozugi et al., which evaluated six observational cohort studies involving 42,304 patients receiving DAPT after PCI.1 Among these patients, 14,429 received P-CABs and 27,875 received PPIs. 

The primary outcome was upper GI bleeding . The pooled analysis showed no significant difference in upper GI bleeding between P-CABs and PPIs (OR 1.03, 95% CI 0.77–1.37; P=0.86), with low statistical heterogeneity (I²=4%).1These findings suggest that P-CABs provide gastroprotective effectiveness broadly comparable with that of PPIs rather than demonstrating clear superiority. 

Individual observational studies have produced similar findings. Tsujita et al. reported that upper GI bleeding occurred in 2.82% of patients receiving vonoprazan compared with 3.96% among PPI users, with an adjusted hazard ratio of 0.74 (95% CI 0.48–1.16), supporting the non-inferiority of vonoprazan.1 In a large Korean cohort, Baik et al. also found no significant difference in upper GI bleeding between P-CAB and PPI users receiving DAPT.1 These studies indicate that P-CABs can provide clinically relevant gastroprotection without evidence of inferior performance compared with PPIs. 

Cardiovascular safety 

The potential effect of acid-suppressive therapy on cardiovascular outcomes is particularly important in patients receiving DAPT. Any gastroprotective strategy should ideally reduce GI complications without compromising antiplatelet efficacy. 

The meta-analysis by Elmozugi et al. evaluated major adverse cardiovascular events (MACE) in three studies and found no significant difference between P-CABs and PPIs (OR 0.86, 95% CI 0.66–1.10; P=0.23). Similarly, all-cause mortality did not differ significantly between treatment groups (OR 1.04, 95% CI 0.73–1.48; P=0.84).1 

These findings are reassuring, particularly given the theoretical concern about interactions between acid suppression and clopidogrel. However, the available evidence is observational and therefore cannot definitively establish cardiovascular equivalence. Randomized trials with cardiovascular endpoints are needed before firm conclusions can be drawn. 

Safety and long-term considerations 

P-CABs have generally demonstrated acceptable short- and medium-term tolerability. Reported adverse events with vonoprazan include nasopharyngitis, diarrhea, constipation, gastroenteritis, upper respiratory tract inflammation, and dermatological events.5,7 As with other potent acid-suppressive agents, prolonged elevation of gastric pH may influence gastrin concentrations and other physiological processes. 

Increased serum gastrin concentrations have been reported with vonoprazan and may be greater than those observed with some PPIs.7 However, long-term clinical studies have not demonstrated a clear increase in clinically important gastric pathology. A five-year randomized study comparing vonoprazan with lansoprazole did not demonstrate a significant difference in enterochromaffin-like cell hyperplasia.1 

PPIs have accumulated several decades of clinical experience, whereas long-term real-world safety data for P-CABs remain comparatively limited. This difference should be considered when selecting therapy, particularly for patients who may require prolonged gastroprotection. 

Clinical implications 

The available evidence suggests that P-CABs may be particularly useful in selected patients receiving DAPT. Their rapid onset and potent acid suppression may be advantageous when prompt control of gastric acid secretion is desirable. Their relatively limited CYP2C19 interaction is another potential benefit in patients treated with clopidogrel.5 

However, the available evidence does not currently support replacing PPIs routinely with P-CABs. Current clinical guidelines continue to support PPI therapy for patients undergoing PCI who have a high risk of GI bleeding.8 P-CABs should therefore be viewed as an emerging alternative rather than a universal substitute. 

The distinction is important because the current comparative evidence is derived almost entirely from observational cohorts. Patients receiving P-CABs may differ from PPI users in baseline bleeding risk, comorbidities, concomitant medications, and prescribing patterns. Such confounding can influence apparent treatment effects. 

Future perspectives 

The major evidence gap is the lack of large randomized controlled trials directly comparing P-CABs with PPIs in patients receiving DAPT. Future studies should evaluate not only upper GI bleeding but also clinically significant bleeding, recurrent ischemic events, stent thrombosis, cardiovascular mortality, and all-cause mortality. 

The ongoing PROTECT-HBR trial, which evaluates tegoprazan versus rabeprazole in patients receiving antithrombotic therapy who are at high risk of GI bleeding, may provide important prospective evidence regarding the role of P-CABs in this population. 

Future research should also assess long-term safety, cost-effectiveness, interactions with different P2Y12 inhibitors, and efficacy across diverse ethnic populations. Most currently available studies originate from East Asian populations, which limits the generalizability of findings to other populations. 

Conclusion 

P-CABs represent an important advancement in acid-suppressive therapy and offer several pharmacological advantages over conventional PPIs, including rapid onset, potent and sustained acid suppression, and limited CYP2C19-mediated interaction. Current observational evidence indicates that P-CABs provide comparable protection against upper GI bleeding to PPIs in patients receiving DAPT after PCI, without significant differences in MACE or all-cause mortality However, the certainty of evidence remains very low because of methodological limitations and the absence of randomized comparative trials. Until stronger evidence becomes available, PPIs should remain the established gastroprotective therapy for high-risk patients, while P-CABs may be considered a promising alternative in selected clinical circumstances. 

 

References 

1. Elmozugi T, Al Swayah MB, Altaweel A, Daoud A, Shaker O, Gomaa S, et al. Potassium-competitive acid blockers versus proton pump inhibitors for gastroprotection in patients receiving dual antiplatelet therapy after percutaneous coronary intervention: a systematic review and meta-analysis. Cardiovasc Innov Appl. 2026;11(1):e20260103. 
2. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines. Circulation. 2010;122(24):2619-33. 
3. Mo C, Sun G, Lu ML, Zhang L, Wang YZ, Sun X, et al. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World J Gastroenterol. 2015;21(17):5382-92. 
4. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-23. 
5. Sugano K. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of acid-related diseases. Dig Endosc. 2018;30(4):405-13. 
6. Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2016;55(4):409-18. 
7. Sakurai Y, Mori Y, Okamoto H, Nishimura A, Komura H, Araki T, et al. Acid-inhibitory effects of vonoprazan 20 mg compared with lansoprazole 30 mg in healthy adult male subjects: a randomised open-label cross-over study. Aliment Pharmacol Ther. 2015;42(6):719-30. 
8. Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes. Circulation. 2025.