Proton-pump inhibitors have been the mainstay of many gastroesophageal disorders. 21 million people in the U.S. received a prescription for PPIs in 2009, associated with a cost of $13 billion globally.
Unsurprisingly, there are signals of harm from PPIs that are not completely understood. It is recognized gastric pH is part of the body’s natural immune defense mechanism, and increased pH as a result of PPI use increases susceptibility to infection. Additionally, some concerns have been documented regarding CPY2C19 inhibition, resulting in decreased clopidogrel activity. However, multiple studies also point to increased vascular risk with PPIs that do not significantly inhibit CPY2C19.
These authors further explore the hypothesis the mechanism of PPI vascular risk has nothing to do with CPY2C19. They find, through high-throughput chemical screening, that PPIs directly inhibit dimethylarginine dimethylaminohydrolase (DDAH). This enzyme metabolizes asymmetrical dimethyarginine (ADMA), which is further responsible for inhibiting nitric oxide synthase (NOS). In clinical terms, inhibition of NOS is a bad thing, and consistent with multiple clinical studies demonstrating increased ADMA activity is associated with cardiovascular death.
The in vivo portion of this study is limited by mouse model, but they do show a dose-dependent decrease in tissue nitric oxide associated with omeprazole administration. The end clinical result of this would be increased oxidative stress, reduced vasodilator function, and otherwise impaired vasoprotective mechanisms.
It’s an interesting translational study uncovering a reasonable hypothesis for the recurrent themes of observed PPI harms. It also tailors neatly into the prior clinical trial evidence suggesting PPI use in upper GI bleeding decreases bleeding-related deaths, while increasing non-bleeding deaths, resulting in no net mortality benefit.
The International Consensus and the American College of Gastroenterology guidelines say PPIs “may” be considered prior to endoscopy to downstage lesion severity, while NICE states PPIs should not be offered prior endoscopy for non-variceal UGIB. The most recent Cochrane Review on the topic show no patient-oriented benefits to PPI prior to endoscopy. I think it’s very reasonable to make an individualized decision whether the risks and costs associated with PPI use outweigh the benefits of acute clot stabilization in UGIB.
“Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”
www.ncbi.nlm.nih.gov/pubmed/23825361