Proton pump inhibitors and vascular function: A prospective cross-over pilot study

Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) 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 previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. 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, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.