Neurogastroenterology & Motility. 2020;32:e13844. wileyonlinelibrary.com/journal/nmo | 1 of 9 https://doi.org/10.1111/nmo.13844 © 2020 John Wiley & Sons Ltd 1 | INTRODUCTION Non-cardiac chest pain, defined as recurrent chest pain that is indis- tinguishable from ischemic anginal pain after a reasonable workup has excluded a cardiac etiology, is a prevalent disorder resulting in high healthcare utilization and significant work absenteeism. 1 An important step in identifying the underlying mechanisms behind NCCP was the recognition that gastro-esophageal reflux disease (GERD) is the most common contributing factor, affecting 40%-50% of the patients. 1 The mechanism by which gastro-esophageal reflux causes chest pain in some patients and heartburn in others remains to be elucidated. In patients with non-GERD-related symptoms, esophageal motility disorders and functional chest pain are the Received: 22 January 2020 | Revised: 20 February 2020 | Accepted: 9 March 2020 DOI: 10.1111/nmo.13844 ORIGINAL ARTICLE Proton-pump inhibitor use and the development of new ischemic heart disease in non-cardiac chest pain patients Yeseong Kim 1 | Stephen Ganocy 2 | Ronnie Fass 3 Abbreviations: CI, confidence interval; DM, diabetes mellitus; H2RA, histamine-2- receptor antagonist; HLD, hyperlipidemia; HTN, hypertension; ICM, ischemic cardiomyopathy; IHD, ischemic heart disease; NCCP, non-cardiac chest pain; NNH, number needed to harm; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PPI, proton-pump inhibitor; STEMI, ST-elevation myocardial infarction. 1 Department of Internal Medicine, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA 2 Data Management & Statistical Analysis Unit, Mood Disorders Program, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH, USA 3 Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA Correspondence Ronnie Fass, Division of Gastroenterology and Hepatology, Case Western Reserve University, Esophageal and Swallowing Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. Email: ronnie.fass@gmail.com Abstract Background: The growing reports regarding cardiac-related adverse events of chronic proton-pump inhibitors (PPI) treatment, a mainstay therapy of non-cardiac chest pain (NCCP), have raised concerns about alteration of the natural course in NCCP patients using PPI. We aimed to determine if NCCP patients receiving PPI have a higher risk of developing ischemic heart disease (IHD) compared to those not receiving PPI therapy. Methods: Three groups of NCCP patients were included; PPI, histamine-2 receptor antagonist (H2RA), and no antireflux treatment. Diagnosis of NCCP had to precede diagnosis of IHD by at least 30 days, and in those receiving antireflux treatment at 30 days after starting the medication. Data analysis was corrected for 6 known con- founding factors for IHD including hyperlipidemia, hypertension, obesity, smoking status, male gender, and diabetes mellitus. Key Results: Of the patients on PPI or H2RA, 1280 and 250, respectively, devel- oped IHD. Patients on PPI therapy displayed an increased odd of developing ischemic heart disease compared to patients never placed on therapy (OR 1.14, 95% CI 1.03- 1.25, P-value .0093). Patients placed on H2RA therapy did not show a statistically significant change in risk compared to patients who were not placed on therapy (OR 0.90, 95% CI 0.77-1.06, P-value .2049). Number needed to harm in the PPI and H2RA groups was 17 and 45, respectively. Conclusions: PPIs confer a statistically significant, but marginal effect on the risk of IHD development in NCCP patients. Thus, PPI use in NCCP only minimally alters the overall benign natural course of the disease. KEYWORDS data analysis, histamine H2 antagonists, myocardial ischemia, non-cardiac chest pain, proton- pump inhibitors Click here to view the Podcast for this paper.