Letter to the Editor: Optimizing Helicobacter pylori eradication and cardiovascular risk assessment in long-term aspirin users: Methodological perspective

Abstract

This letter discusses the recent study by Semeya et al concerning Helicobacter pylori eradication and cardiovascular disease progression in chronic aspirin users. We commend the authors for their robust, real-world study design focusing on a complex cohort on multi-agent antithrombotic therapies, and for their detailed integration of histopathological classification. Based on their findings, we offer a constructive discussion on balancing the safety profiles of intensified eradication protocols in elderly recipients, particularly regarding renal impairment and drug-drug interactions. We also explore the specific pathophysiological pathways, such as virulent CagA-positive strain molecular mimicry and lipid metabolism disruptions, that drive secondary anti-inflammatory effects following infectious trigger removal. Lastly, we address the feasibility boundaries of advanced endoscopic surveillance, advocating for a targeted, risk-stratified paradigm to optimize long-term clinical outcomes in this vulnerable population.

Key Words: Helicobacter pylori; Aspirin; Peptic ulcer bleeding; Cardiovascular disease; Real-world evidence

Core Tip: Semeya et al provided exceptional real-world evidence of the benefits of Helicobacter pylori eradication for chronic aspirin users. To further upgrade this multidisciplinary clinical model, we discuss the safety boundaries of intensified alternative therapies in elderly patients and the specific pathophysiological cascades driving vascular stability. Rather than universal screening, we propose a highly targeted, risk-stratified surveillance approach utilizing advanced imaging to safely balance clinical justification with cost-effectiveness thresholds.

TO THE EDITOR

We read with great interest the study by Semeya et al[1], demonstrating that Helicobacter pylori (H. pylori) eradication reduces peptic ulcer bleeding and correlates with attenuated cardiovascular disease (CVD) progression in chronic aspirin users. The authors deserve commendation for utilizing a robust real-world cohort with complex multi-agent antithrombotic regimens and integrating granular histopathological classification.

The study provides a realistic appraisal of the challenges in managing H. pylori in high antibiotic-resistance regions, where a 14-day levofloxacin-based triple therapy yielded an eradication rate of 51.9%. This finding underscores a valuable clinical opportunity: In such environments, transitioning to more potent first-line regimens, such as bismuth quadruple therapy or potassium-competitive acid blocker-based regimens, could ensure that a higher proportion of these vulnerable patients achieve the protective threshold of complete clearance[2]. Such regimens might further minimize the proportion of the cohort that remains exposed after failed primary treatment. While escalating to bismuth quadruple therapy or potassium-competitive acid blocker-based regimens is warranted in high-resistance regions, their use in vulnerable, aged antiplatelet recipients requires caution. Empiric bismuth use carries systemic accumulation and neurotoxicity risks in elderly aspirin users with age-related renal impairment. Concurrently, profound acid suppression by potassium-competitive acid blockers may alter the metabolic activation and bioavailability of co-administered antiplatelet agents, necessitating careful scrutiny to avoid therapeutic antagonism or augmented bleeding hazards.

The attenuation in CVD progression within a 6-month follow-up is an intriguing finding that merits a highly cautious mechanistic interpretation. The clinical interpretation of this 6-month outcome hinges entirely on the definition of CVD progression, which Semeya et al[1] pre-specified as a composite endpoint including new coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), unstable angina hospitalization, or worsening of the Canadian Cardiovascular Society angina class, rather than hard atherosclerotic endpoints or major adverse cardiovascular events. Because anatomical atherosclerotic lesion remodeling typically evolves over a years-long trajectory, the observed 6-month clinical benefit should be interpreted as hypothesis-generating rather than a mechanistically established conclusion[3]. Rather than definitive plaque stabilization, this short-term clinical divergence is more likely attributable to a transient reduction in systemic inflammatory responses residual confounding variables.

As a correspondence on an observational study, it is essential to acknowledge inherent methodological limitations. These include potential selection bias and critical unmeasured confounders, such as variations in patients’ socioeconomic status or baseline adherence to concurrent cardioprotective medications (e.g., lipid-lowering and antihypertensive therapies), which could inadvertently skew the documented cardiovascular trajectories and risk overstating the strength of the evidence. To rigorously validate these preliminary observations, future studies with extended longitudinal follow-up should incorporate subgroup analyses tracking serial measurements of key pro-inflammatory and matrix-degrading biomarkers, including highly sensitive C-reactive protein, interleukin-1β, interleukin-6, tumor necrosis factor-α, and matrix metalloproteinases 2 and 9. Mechanistically, this hypothesis-generating timeline warrants a deeper, pathway-specific grounding beyond a generalized inflammatory surge. Short-term vascular risk modulation may be driven by specific cascades, including molecular mimicry by virulent CagA-positive H. pylori strains. This process triggers antibody cross-reactivity with vascular smooth muscle cells, compromising atheroma stability. Concurrently, direct bacterial disruptions of host lipid metabolism, characterized by systemic lipid dysregulation and the accumulation of pro-atherogenic lipids, may further accelerate subclinical vascular trajectories[4]. Supplementing these cohorts with aspirin dosage stratification (81-325 mg) would resolve a pivotal clinical controversy: Whether aggressive eradication can safely modulate the enhanced, dose-dependent bleeding risks of higher secondary prevention regimens without terminating essential antiplatelet therapies.

There is a need for sustained, high-safety antithrombotic management. Long-term endoscopic surveillance utilizing color Doppler endoscopic ultrasound to evaluate the size and vascular morphology of incidental subepithelial lesions, complemented by ultrasound capsule endoscopy, would provide a non-invasive, high-resolution paradigm to systematically monitor subclinical mucosal injuries across the entire gastrointestinal tract[5-7]. While acknowledging that these imaging modalities are resource-intensive, operator-dependent, and costly, this intensive surveillance architecture is not proposed for universal screening. Rather, it is intended as a highly targeted, risk-stratified paradigm for individuals exhibiting refractory mucosal disease or high-risk lesions. Its clinical justification and patient acceptability must be balanced against the cumulative socioeconomic costs of recurrent peptic ulcer bleeding hospitalizations, and future health-economic evaluations are warranted to define its cost-effectiveness thresholds in this vulnerable cohort.

CONCLUSION

Semeya et al[1] have made a significant contribution to the multidisciplinary care of aspirin users. We believe that combining such robust real-world data with potent, risk-stratified eradication protocols and targeted surveillance strategies will further optimize long-term safety and dual-system outcomes in these complex patients.