PPIs: adding (airway) insult to (kidney) injury?

Abstract

Acid inhibitors such as omeprazole, esomeprazole, and ranitidine are a godsend to many pregnant women who experience frequent heartburn, but new research suggests that this relief might come at the expense of increased allergies and asthma in their children. The study is the latest in a long line describing various health risks associated with these drugs, particularly proton-pump inhibitors (PPIs), which are commonly used to treat gastro-oesophageal reflux disease (GORD), erosive oesophagitis, and peptic ulcer disease. Is it time for the safety of these drugs to be re-evaluated? Heartburn medications—which include H2 receptor antagonists (H2RA) like ranitidine and PPIs such as omeprazole and esomeprazole—have long been considered safe during pregnancy, having no effect on foetal development. And although some earlier studies had hinted at an increased risk of childhood asthma due to PPI use in pregnancy, others found no link. A new systematic review and meta-analysis of eight epidemiological studies and more than 1·3 million children now reports that children of mothers who took a PPI or H2RA during their pregnancies were more likely to visit a doctor for asthma symptoms. It is important to note that this finding shows only an association, rather than causality, and that the nature of the included studies means that the association could simply be the result of residual confounding. Nevertheless, for more than a decade, researchers have reported various PPI-associated adverse effects, including nutritional deficiencies, bacterial gut infections, bone fractures, and even heart attacks. So far this year, PPIs have been in the news with reports of increased risk of food poisoning and bacterial gut infections. Last year their long-term use was linked to dementia risk, chronic kidney disease, and end-stage renal disease—findings accompanied by massive media coverage. The evidence for kidney damage was based on two studies, both observational. In a cohort study of more than 10 000 individuals with no kidney disease at baseline, those who took a PPI were reported to have a significantly increased risk of developing chronic kidney disease compared with those who hadn't taken such drugs. Another study showed that long-term PPI users were more likely to develop chronic kidney disease and end-stage renal disease compared with those taking H2RAs. These reports fuelled a series of lawsuits in the USA, with plaintiffs claiming that drug companies intentionally failed to warn consumers of potentially serious renal risks associated with long-term use of the medication. However, when considering the weight of evidence, it is important to reiterate that these conclusions were based on observational studies, which cannot prove causation and are notoriously fraught with bias. In short, the evidence is inconclusive. And although the drugs' warning labels mention only acute kidney inflammation—making no mention of more serious kidney diseases—they also caution against long-term daily use. Guidelines are appropriately cautious about long-term PPI use, generally emphasising the importance of ensuring that the benefits of PPIs (like any drug) outweigh the risks and, where appropriate, advising use of the lowest possible dose, and intermittently rather than daily. Randomised trials support this advice, showing that most patients with GORD whose symptoms resolve do well with intermittent use thereafter. However, this contrasts with the claims of several of the plaintiffs in the US lawsuits, who say they took the drugs daily and continuously for 2–5 years under the guidance of their doctors. Indeed, a number of studies have shown that acid suppressants are heavily overprescribed, and often for indications for which they are not recommended. Perhaps more worrying is the fact that millions of people take over-the-counter PPIs, and that many take them regularly and indefinitely—consumption that is virtually impossible to monitor or regulate. More and better research is required to solidify any connection between gastroprotectant drugs and adverse health effects. It is also worth noting that, although evidence to date suggests an increased relative risk for various adverse effects, absolute risks are fairly small. And one must not forget that for those with a clear clinical indication for their use, the benefits of such drugs—including on patient quality of life—are clear, and outweigh their risks when appropriately administered and regularly reviewed. Nonetheless, the small increases in absolute risk are potentially clinically important given the number of people using these drugs, especially those taking them for no clear reason. Thus it is perhaps time to revisit the broad availability of gastroprotectants—especially PPIs—over the counter, or at least time for better pharmacovigilance.