Primary Care Corner with Geoffrey Modest MD: PPIs and increased mortality

A large longitudinal study of US veterans found a 25% increased risk of death associated with proton pump inhibitor (PPI) usage (see 10.1136/ bmjopen-2016-015735)​.


— the researchers assessed three cohorts of patients, with 5.7 years of follow-up after the first acid suppression therapy prescription was written, and all patients had at least one outpatient serum creatinine value before acid suppression therapy was chosen:

— primary cohort: new users of PPI or H2 blockers (n=349,312)

— PPI versus no PPI users (n= 3,288,092)

— PPI versus no PPI and no H2 blocker (n= 2,887,030)

— covariates assessed included age, race, gender, renal function, number of outpatient serum creatinine measurements, number of hospitalizations, diabetes, hypertension, cardiovascular disease, peripheral arterial disease, cerebrovascular disease, chronic lung disease, cancer, hepatitis C, HIV, dementia, and diseases associated with acid suppression therapy for such GI conditions as GERD, upper GI bleeding, ulcer disease, H. pylori infection, Barrett’s esophagus, achalasia, stricture, esophageal adenocarcinoma.

— Analyzing the difference between the baseline demographics of these different groups: those on PPIs were older (eight months), and had more diabetes, hypertension, cardiovascular disease, and hyperlipidemia than the overall cohort, however looking at their numbers, these differences were on the order of 1% or less. The differences between those put on H2 blockers and PPIs was somewhat more significant, more typically on the order 5%.



— overall PPI use was associated with a 25% increased risk of death vs H2 blockers, HR 1.25 (1.23-1.28)

— using high dimensional propensity scoring (see below) there was a 16% increased risk, HR 1.16 (1.13-1.18)

— comparing PPI use to no PPI use, a 15% increased mortality risk, HR 1.15 (1.14-1.15)

— comparing PPI used to neither PPI nor H2 blockers, a 23% increased risk, HR 1.23 (1.22-1.24)

— in patients without underlying gastrointestinal conditions (those conditions being the ones noted above), those on PPI had 24% increased risk of death vs H2 blocker, HR 1.24 (1.21 1.27)

— among new PPI users, there was a graded association between the duration of exposure and the risk of death (all statistically significant, as compared to those who have taken PPIs <30 days): 5% increased mortality risk for those on PPIs 31-90 days, 17% for 91-180 days, 31% for 181-360 days, 51% for 361-720 days, all of these controlled for the array of comorbidities and risk factors above.



— the above analysis included both propensity scoring, a means to statistically equalize the PPI versus non-PPI users for all of the covariates above, as well as high dimensional propensity scoring, which controlled for an additional potential 500 variables to further minimize confounding

— a recent blog reviewed the risks and benefits of PPIs from the perspective of the American Gastroenterological Association, assessing the literature on the PPI association with kidney disease, dementia, bone fractures, small intestinal bacterial overgrowth, non-typhoidal Salmonella, Campylobacter, spontaneous bacterial peritonitis, C. difficile, pneumonia, calcium/iron/magnesium deficiency, B12 deficiency, and GI malignancies.

— There is also emerging in vitro evidence that PPIs can result in inhibition of lysosomal acidification and impairment of proteostasis, potentially increasing oxidative stress, endothelial dysfunction, telomere shortening, and accelerated human endothelial senescence. In addition animal studies suggest that PPIs decrease the regenerative capacity of livers following partial hepatectomy.

— This VA study, as well as these others reviewed by the AGA, is an observational one. For observational studies, the increased risk found is on the lower side to be significant. The impressive aspects of the study include the fact that it is huge, that they have controlled for a lot of variables (though they do not have specific data on obesity, smoking, and the use of specific medications including anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatories); that the risk was independent of prior GI symptoms, and that there was a clear dose-response curve (and the 51% increase in those on PPIs for >1 year is getting more impressive). In addition, looking at survival curves for those on PPIs versus H2 blockers, the difference increases linearly over time (ie the curves are splaying apart)


— As mentioned in previous blogs, PPIs are significantly overprescribed, in part exacerbated by their availability over the counter, with studies suggesting that 53-69% are used for inappropriate indications, that the risks of PPIs are poorly understood by patients as well as perhaps some clinicians, that many patients even with severe GI symptoms respond well to H2 blockers or antacids, and that it is often difficult for an array reasons for clinicians and patients to step down therapy to H2 blockers or antacids (e.g., clinicians having relatively limited time with patients are more likely to discuss other pressing medical or psychosocial problems as opposed to spending time trying to convince a patient to step down their therapy; and patients may well be so satisfied with the effectiveness of the PPI, perhaps prescribed by a specialist which might sway them more towards taking the PPI, that they are reluctant to give H2 blockers or antacids a fair trial).

–In my experience with many patients on PPIs, often they self-titrate to use them intermittently, but in any event are usually quite willing to try H2 blockers or antacids when I express my concern about the potential long-term problems by continuing to take such a potent drug when usually a less potent and possibly less harmful one often works as well.