Abstract 437: Dysregulation of Cardiovascular Homeostasis by Proton Pump Inhibitors: Safety Concerns
Background: Proton pump inhibitors (PPIs) are commonly used drugs to treat gastric reflux. Recent retrospective cohorts have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. In addition, we have recently reported seminal preclinical work demonstrating interference of the PPIs with CV homeostasis (Ghebremariam et al; Circulation 2013; 128:845-53). However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm.
Methods: We conducted a controlled cross-over pilot study among 21 adults who are healthy (n = 11) or have established clinical cardiovascular disease (n = 10). Study subjects were assigned to receive a PPI (Prevacid) or a placebo pill once daily for 4 weeks. After a 2 week washout period, participants were crossed-over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function) measured before and after treatment. In addition to the clinical study, we also carried out pharmacovigilance study of PPI use and CV harm using novel data mining approach from a dataset of 1.8 million patients.
Results: In the clinical study, we observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = -0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo. However, these trends did not reach statistical significance, and PPI use was also not associated with impairment in flow mediated vasodilation during the course of this study. Nevertheless, our data mining study revealed increased association of PPI use with CV risk.
Conclusions: In this open-label, cross-over pilot study, PPI use did not significantly influence vascular endothelial function. However, a positive association between PPI use and CV risk in our database study suggests that large number of participants may be needed to be followed up prospectively. Therefore, larger and longer-term trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has increasingly been reported in retrospective cohorts.
Author Disclosures: Y.T. Ghebremariam: Ownership Interest; Modest; Dr. Ghebremariam is an inventor on a patent owned by Stanford University on small molecule modulators of the NOS/DDAH pathway. Ownership Interest; Significant; Dr. Ghebremariam is a co-founder of Altitude Pharmaceuticals; a biotechnology Company developing products that regulate the nitric oxide (NOS)/DDAH pathway. J. Cooke: Ownership Interest; Modest; Dr. Cooke is an inventor on a patent owned by Stanford University on small molecule modulators of the NOS/DDAH pathway. Ownership Interest; Significant; Dr. Cooke is a co-founder of Altitude Pharmaceuticals; a Biotechnology Company developing products that regulate the nitric oxide (NOS)/DDAH pathway. F. Khan: None. R. Thakker: None. P. Chang: None. N. Shah: Research Grant; Modest; Dr. Shah received grant from the Translational Research and Applied Medicine (TRAM) Program in the Department of Medicine at Stanford University. K. Nead: None. N. Leeper: Research Grant; Modest; Dr. Leeper received grant from the Translational Research and Applied Medicine (TRAM) Program in the Department of Medicine at Stanford University.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.