Association of PPIs with Mortality Disputed

Previously reported associations between the use of proton pump inhibitors (PPIs) and a higher risk of death may have attributed mortality to the therapy rather than the condition being treated, according to a recent investigation published in Clinical Gastroenterology and Hepatology.

The researchers noted that the apparent link between PPI use and mortality was found primarily in observational studies, which may have a protopathic bias—the association of morbidity and mortality to the treatment being given to participants, rather than to the participants’ condition. A randomized controlled trial of PPIs, in contrast to the observational investigations, showed no such association between health risks and PPI use.

To shed light on the discrepancy, the researchers analyzed a cohort of 1,930,728 Medicare beneficiaries, correcting for protopathic bias by using a lag-time approach that disregards any study drugs administered 90 days before each death. The study team used a Cox regression analysis with propensity score adjustments.

Among the study participants, the researchers found a 4.2% death rate (n = 80,972) during a median follow-up period of 3.8 years, resulting in an unadjusted death rate per 1000 person-years of 9.85. The death rate for PPI users was 14.31, while that of nonusers of PPIs was 7.93, yielding an increased risk of mortality among PPI users of 10% (adjusted HR 1.10; 95% CI 1.08-1.12).

However, when the researchers applied the lag-time of 90 days, they found that the mortality rate of participants who used PPIs compared with those who did not use PPIs dropped to virtually zero (adjusted HR=1.01; 95% CI 0.99-1.02).

“Given the usage patterns of PPIs in patients with conditions that may presage death, protopathic bias may explain the association of PPIs with increased risk of death reported in observational studies,” the researchers stated.


—Rebecca Mashaw



Baik SH, Fung KW, McDonald CJ, The mortality risk of proton pump inhibitors in 1.9 Million US seniors: an extended Cox survival analysis. Clin Gastroenterol Hepatol. Published online January 10, 2021. doi:10.1016/j.cgh.2021.01.014