PPPI; proton pump inhibitor, H2RA: histamin-2 receptor antagonist, HR: hazard ratio, CI: confidence interval, NNH: number needed to harm.
The Bradford-Hill criteria provide another framework used to guide an evaluation of the causal association between drugs in the post market period and adverse events. Originally developed to examine the causal relationships between public health exposures such as smoking and air pollution (which cannot ethically be randomized) and poor health outcomes it is also a useful framework for evaluating the harm profile of drugs. One of the Bradford-Hill criteria is biologic plausibility – there is a biological explanation for how the ‘exposure’ could cause the ‘harm’ from what is known.
Xie et al, 2019 report on what may be a universal mechanism of harm with PPI use and one that is consistent with their findings of specific but varied causes of increased mortality. When scientists at the Centre for Cardiovascular Regeneration in Huston, Texas, cultured microvascular epithelial cells they aged faster in media with clinically significant amounts of the PPI esomeprazole 27. The endothelial cells that line blood and lymph vessels are present throughout the body. Basic science studies showed that exposure to PPIs impaired endothelial lysosomal acidification, enzyme activity and proteostasis resulting in endothelial dysfunction. Moreover, the telomere length was shortened (a possible sign of aging) in the esomeprazole treated group. Xie et al, 2019 also points out that there are two general biological mechanisms by which PPI use can be linked to excess deaths: worsening of pre-existing diseases (ex. existing cardiovascular and kidney disease) or the occurrence of new disease states 18. This is only one avenue by which long-term PPI use may adversely affect human health. Also plausible are hypomagnesemia, drug interactions, reduced absorption of selected nutrients, increased gastric microbiota and small intestine bacterial overgrowth, reduced immune response, tubular-interstitial inflammation, increased bone turnover and accumulation of amyloid in the brain 28.
PPIs use was also significantly associated with renal insufficiency even after adjusting for acute interstitial nephritis (AIN) in the Xie et al, 2019 VA cohort analysis. AIN is a drug reaction known to be caused by PPI 29. SR of observational studies have found PPIs to be associated with chronic kidney disease (CKD)30. The finding of continued renal insufficiency even after adjustment suggested the existence of unrecognized AKI or chronic latent renal injury18.