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New preclinical research has brought to light a mechanism by which proton pump inhibitors (PPIs) impair vascular responsiveness, potentially increasing the risk of adverse events in patients with acute coronary syndromes (ACS) and perhaps the broader population of those without recognized cardiovascular disease. The concept is described in a paper published online July 3, 2013, ahead of print in Circulation.

PPIs appear to trigger a biochemical pathway apart from CYP2C19-related interference with clopidogrel metabolism, a drug-drug interaction that prompted controversial warnings by the US Food and Drug Administration (FDA) with regard to omeprazole in 2009 and esomeprazole in 2011.

In the current research, investigators led by John P. Cooke, MD, PhD, of Texas Methodist Hospital Research Institute (Houston, TX), performed cell culture and other preclinical studies that linked PPI use with adverse effects on coronary vessels, primarily via elevation of the enzyme asymmetric dimethylarginine (ADMA).

Zeroing in on ADMA

Specifically, in a biochemical assay, PPIs inhibited the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH), which helps to regulate ADMA levels. The inhibitory effect was seen in the full-dose range for 6 types of PPI, suggesting a class effect.

Two PPIs, esomeprazole and lansoprazole, increased intracellular levels of ADMA by about 30%, most likely by inhibiting DDAH activity. ADMA is an endogenous inhibitor of nitric oxide synthase (NOS), which has vasoprotective effects.

Furthermore, in cultured endothelial cells, omeprazole dose-dependently reduced levels of nitrogen oxide as well as active endothelial NOS, thereby impairing vascular reactivity. In a mouse model, lansoprazole increased serum ADMA levels by about 20% over a 5-week period.

The authors observe that, based on data from several studies, ADMA has become an emerging risk factor for cardiovascular events, and the increase in ADMA levels induced by PPIs may potentially explain the association between the drugs and cardiovascular events in patients with ACS.

Risk May Extend Beyond Cardiac Patients

“Of perhaps greater concern,” they add, “an elevation of plasma ADMA of this magnitude, if the data [are] translated to humans, might increase the hazard ratio for MACE and mortality in adults not recognized to have cardiovascular disease.”

Dr. Cooke and colleagues acknowledge that their cell culture dose was five- to tenfold higher than the plasma concentration obtained with a typical oral dose of PPI. But, they add, “repeated dosing of PPIs to attain consistent suppression of gastric acidity could impair normal vascular endothelial function.” Moreover, the ADMA elevation observed in normal mice treated with a PPI is “of a magnitude that would significantly increase cardiovascular risk in a human.”

In addition, both renal insufficiency and a loss-of-function genetic polymorphism for DDAH production have been associated with elevated levels of ADMA.

“Our proposed biological mechanism for the association between PPIs and MACE is more consistent with the available human data than previously proposed drug-drug interactions,” the authors contend, noting that diminished efficacy has been seen in patients receiving PPIs in conjunction with antiplatelet agents not requiring CYP2C19 activation.

In light of these experimental findings, the researchers used a data-mining technique to probe the MI risk of patients with gastroesophageal reflux disease (GERD) who were being treated with a PPI or an H2-receptor antagonist. The results “support the hypothesis that PPI use may pose an independent and enhanced risk for MI in the general population,” they report.

Thinking ‘Outside the Box’

“The most important thing about this study is that it gets people to think outside the box,” Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), told TCTMD in a telephone interview. “There are a trillion papers on clopidogrel and PPIs, and you can always show an effect, but the amount of clinical data [showing an interaction] is trivial.”

The study researchers “used well-established techniques to show us a mechanism that none of us had thought of,” Dr. Kleiman continued. “The next thing to do is to look for the presence of a cardiovascular effect.” He endorsed the strategy of revisiting the early randomized trials of PPIs in GERD patients to look for a previously unrecognized signal of cardiovascular harm, citing the precedents of belated investigations into the adverse effects of NSAIDs and the so-called glitazones.

In a telephone interview with TCTMD, Steven R. Steinhubl, MD, of Scripps Translational Science Institute (La Jolla, CA), noted that even before the controversy over a potential interaction between PPIs and clopidogrel, a couple of studies showed that PPIs had a dose-dependent negative effect on myocardial contractility. ADMA is 1 novel potential mechanism that may explain adverse cardiovascular impact, but there are others, he said.

Unfortunately, the FDA largely ignored several observational studies and subanalyses from randomized trials suggesting that PPIs had adverse effects unrelated to drug-drug interaction, Dr. Steinhubl said, although admittedly most were small and confounding was a likely explanation for the substudies.

A ‘Warning Flag’

This mechanistic study will not and should not immediately affect practice, Drs. Steinhubl and Kleiman agreed. “But it’s a warning flag,” Dr. Steinhubl added, “and when you look at the totality of the data, I think there is convincing evidence of concern that requires a very hard look at many things, such as over-the-counter availability of PPIs.”

He also decried the casualness with which some clinicians discharge many patients who present with chest pain that turns out not to be cardiac on a prescription for PPIs. In addition, prophylactic use of PPIs in stented patients on dual antiplatelet therapy should probably be limited to those at high risk due to prior GI bleeding, he suggested.

Even with such caution, exposure to these agents would remain high, Dr. Steinhubl pointed out, with some studies indicating that about 30% of cardiac patients have GERD and may already be on chronic PPI therapy.

Going forward, Dr. Steinhubl said he would like to see the FDA mandate a review of large novel datasets from real-world patients to explore the cardiovascular risk of PPIs. “That’s going to be tough because they’re a huge market and there is a lot of history of the FDA saying, ‘No problem,’ which makes it harder to go back [and take a second look],” he acknowledged.

Fortunately, he added, today’s large data networks include detailed information, making it possible to home in on virtually any group that may be more susceptible to harm from PPIs, such as the post-ACS population or those with renal insufficiency.

Related Stories:

• PLATO Analysis: PPIs Problematic with Both Ticagrelor, Clopidogrel
• FDA Repeats Warning on Concomitant Use of Clopidogrel, Omeprazole
• Consensus Statement Supports Judicious Use of PPIs Plus Antiplatelet Therapy