Chronic Use of Proton Pump Inhibitors Increases Heart Risk

Lara C. Pullen, PhD
June 10, 2015
Proton pump inhibitors (PPIs) appear to have a negative effect on vascular function, thereby increasing the risk for myocardial infarction (MI) in the general population, according to a data-mining study. This association has not yet been demonstrated in a randomized controlled trial.
Nigam H. Shah, MBBS, PhD, from Stanford University in California, and colleagues published the results of their data-mining study online June 10 in PLOS ONE. The investigators reviewed more than 16 million clinical documents on 2.9 million individuals for pharmacovigilance data. They describe their approach as a "novel analytical pipeline" and report that PPIs, but not H2 blockers, appear to be associated with an elevated risk for MI.
Specifically, patients with gastroesophageal reflux disease who were exposed to PPIs had a 16% increased risk of MI (95% confidence interval, 1.09 - 1.24). The investigators also documented a twofold (hazard ratio, 2.00; 95% confidence interval, 1.07-fold to 3.78-fold; P = .031) increase in risk for cardiovascular mortality.
Although the researchers acknowledge that PPI usage may be serving as a marker for a sicker population, they believe this is unlikely, given the lack of increased risk seen in patients taking H2 blockers.

Novel Mechanism Suggested
The results build on findings from a cohort of subjects with coronary artery disease who experienced adverse outcomes when prescribed PPIs with clopidogrel. The current study suggests, however, that the risks from PPIs extend from patients with coronary artery disease to the general population. The results also suggest that physicians need to think more broadly about the potential adverse effects from drugs.
"Our observation that PPI usage is associated with harm in the general population — including the young and those taking no antiplatelet agent — suggests that PPIs may promote risk via an unknown mechanism that does not directly involve platelet aggregation. Accordingly, our recent molecular, cellular, physiological, and in vivo data demonstrating that PPIs inhibit DDAH [dimethylargininase] activity may explain how PPIs promote cardiovascular risk, and do so even in individuals not taking clopidogrel. DDAH, an enzyme necessary for cardiovascular health, metabolizes ADMA, an endogenous and competitive inhibitor of nitric oxide synthase," write the authors.
Endothelial nitric oxide is important for maintaining vascular homeostasis. If PPIs are altering nitric oxide production, that would explain their association with harm in the general public.

Risk/Benefit of PPIs
PPIs are "highly effective," explained Nicholas J. Leeper, MD, a Stanford vascular medicine specialist and principal investigator of the study. "Now many of these medicines can be taken without doctor supervision," he said in an interview with Medscape Medical News, noting that many PPIs are available over the counter. "We're not recommending that people stop the drug at this point," he added, although he did suggest that patients reconsider both their need for the specific class of medications as well as their personal baseline risks.
Joel Rubenstein, MD, chair of the American Gastroenterological Association Institute Clinical Practice Section, agrees the results do not support stopping the use of PPIs.
"I would advise against making any changes in the management of patients based on this study. The results are intriguing and deserve further study. But the signal of an association is a weak one, and could easily be due to confounding by other factors, such as obesity, or due to initial misdiagnosis of angina as [gastroesophageal reflux disease]," Dr Rubinstein explained in an email to Medscape Medical News. Dr Rubinstein was not involved in the study.
Dr Leeper also believes their data point to the need for a prospective randomized study to investigate the association between PPIs and MI. His group has performed such a pilot study, and the results are in press. Although underpowered, the pilot study showed a significant trend in support of the association between use of PPI and MI.

Drug Safety
The authors conclude their article by presenting their study as an example of how experimental data can be combined with data-mining approaches to prioritize future drug safety studies.
Dr Leeper emphasized the ability of such big data analysis to improve drug safety, describing "the potential to use this type of approach to look at other drug safety signals." In particular, he explained that had such an automated data mining algorithm been implemented decades ago, the association between lansoprazole exposure and MI would have been flagged in 2000.
Several of the authors of the study are inventors on technology disclosures and/or patents owned by Stanford University that enable the use of clinical text for data mining. Dr Rubinstein has disclosed no relevant financial relationships.
PLOS ONE. Published online June 10, 2015. Full text

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Cite this article: Chronic Use of Proton Pump Inhibitors Increases Heart Risk. Medscape. Jun 10, 2015.

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