Optimal strategies for mitigating gastrointestinal bleeding in patients receiving antiplatelet therapy: Real-world study

Abstract

BACKGROUND

Aspirin and clopidogrel are cornerstone antiplatelet agents for cardiovascular prevention but substantially increase the risk of gastrointestinal (GI) bleeding. Although proton pump inhibitors (PPIs) are recommended for gastroprotection in high-risk patients, the comparative efficacy of alternative protective agents (PAs), including H2 receptor antagonists (H2RAs) and rebamipide, has not yet been fully elucidated in real-world clinical settings. Rebamipide is a mucoprotective agent by the pleiotropic mechanism such as enhancing PG synthesis, anti-oxidation, antiinflammation, promoting mucosal repair, and increasing mucus production. Evidence is particularly limited regarding combination strategies, risk stratification, and agent-specific benefits of antiplatelet regimens.

AIM

To identify the optimal gastroprotective strategy for preventing significant hemoglobin drop (SHD) in patients exposed to mucosal-damaging antiplatelet agents.

METHODS

We conducted a retrospective cohort study consisting of 98404 patients who received aspirin and/or clopidogrel at Samsung Medical Center between 2002 and 2019. The primary endpoint was SHD, defined as a hemoglobin decline > 2 g/dL. We performed a self-controlled case series (SCCS) analysis of 3649 patients and matched landmark analysis of 14008 patients. Patients were stratified into high- and low-risk groups for GI bleeding based on established clinical criteria, including age, prior GI events, concomitant medications, and comorbidity burden.

RESULTS

In the SCCS analysis, most PA strategies use reduced SHD risk compared with mucosal damaging agent alone. For single PA use, PPI showed larger protective effect [adjusted incidence rate ratio (IRR) 0.42; 95% confidence interval (CI): 0.34-0.53], compared to rebamipide (IRR 0.68; 95%CI: 0.50-0.53) and H2RA (IRR 0.75; 95%CI: 0.63-0.90). Concomitant PAs strategies resulted in a greater reduction in SHD risk than single PA strategies. Consistent results were observed in the high-risk subgroups, whereas no significant benefit was observed in low-risk patients. Additional matched landmark analyses confirmed protective effects of PA monotherapies in aspirin-alone users, while no agent significantly reduced SHD in clopidogrel-alone users.

CONCLUSION

Combination therapy with rebamipide and PPIs most effectively prevented hemoglobin decline in high-risk antiplatelet users, while PPI monotherapy sufficed for aspirin alone. Findings support individualized, risk-based gastroprotection strategies.

Keywords: Gastrointestinal bleeding; Aspirin; Clopidogrel; Proton pump inhibitor; Rebamipide; Antiplatelet therapy; High risk; Low risk; Protective agents; Real-world study

Core Tip: Aspirin and clopidogrel increase the risk of gastrointestinal bleeding; however, the comparative effectiveness of these mucosal protective agents remains unclear. In a large real-world cohort, we found that proton pump inhibitor monotherapy provided substantial protection, whereas combination therapy with rebamipide offered the greatest risk reduction, particularly in high-risk patients. No significant benefit was observed in clopidogrel-alone users or low-risk populations. These findings support a personalized, risk-stratified approach to gastroprotection, and suggest that combination mucosal protective strategies may provide incremental benefits beyond standard regimens.