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

Abstract

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.

Keywords: asymmetric dimethylarginine; cardiovascular risk factors; dimethylarginine dimethylaminohydrolase; nitric oxide; proton pump inhibitors.

Conflict of interest statement

Conflict of Interest Statement

YTG and JPC are inventors on patents owned by Stanford University that protect the use of agents that modulate the NOS/DDAH pathway therapeutically. They are also co-founders of Altitude Pharma Inc, a biotech developing products that regulate the NOS/DDAH pathway.

© The Author(s) 2015.

Figures

Figure 1

A pilot clinical study designed to evaluate the effect of a proton pump inhibitor (PPI) on vascular function.

Figure 2

Evaluation of test-retest variability of the EndoPAT technique. Study participants were assessed for vascular function using the Reactive Hyperemia Index (RHI) score (Y-axis) twice during the run in period of 2 weeks (X-axis) before they were allocated to receive PPI (Prevacid) or placebo control. Data shows plot of each replicate with the Mean values connected.

Figure 3

Comparison of the vascular effect of the proton pump inhibitor (PPI) Prevacid by EndoPAT. Data in panel A shows bargraph of Mean plus SEM values of the difference in Reactive Hyperemia Index (RHI) score between PPI and placebo group. In B, the effect of PPI treatment on vascular function is compared by study participants between healthy subjects (“non-CVD”) and subjects with history of cardiovascular disease (“CVD”). ns = not significant at p

Figure 4

Effect of the proton pump inhibitor (PPI) Prevacid on plasma concentration of asymmetric dimethylarginine (ADMA). A) shows a trend towards an increase in absolute change in ADMA in plasma collected when a study participant is on PPI in comparison to placebo. B) shows subgroup analysis of plasma ADMA within the study groups comparing healthy participants (“non-CVD”) with participants who had history of cardiovascular disease (“CVD”). ns = not significant at p < 0.05.

Figure 5

Correlation of EndoPAT score and plasma ADMA concentration. The y-axis shows the Reactive Hyperemia Index (RHI) score for vascular function gathered from study participants during multiple visits whereas the x-axis represents the negatively correlated plasma levels of ADMA in micromolar during these visits.