‘Reassuring’ Safety Data on PPI Therapy

In a novel analysis accounting for protopathic bias, proton pump inhibitor (PPI) therapy was not associated with increased risk for death due to digestive disease, cancer, cardiovascular disease (CVD), or any cause, although the jury is out on renal disease.

“There have been several studies suggesting that PPIs can cause long-term health problems and may be associated with increased mortality,” Andrew T. Chan, MD, MPH, gastroenterologist and professor of medicine, Massachusetts General Hospital and Harvard Medical School, told Medscape Medical News.

“We conducted this study to examine this issue using data that were better able to account for potential biases in those prior studies. We found that PPIs were generally not associated with an increased risk of mortality,” Chan said.

The study was published online in Gastroenterology.

‘Reassuring’ Data

The findings are based on data collected between 2004 and 2018 from 50,156 women enrolled in the Nurses’ Health Study and 21,731 men enrolled from the Health Professionals Follow-up Study.

During the study period, 10,998 women (21.9%) and 2945 men (13.6%) initiated PPI therapy, and PPI use increased over the study period from 6.1% to 10.0% in women and from 2.5% to 7.0% in men.

The mean age at baseline was 68.9 years for women and 68.0 years for men. During a median follow-up of 13.8 years, a total of 22,125 participants died — 4592 of cancer, 5404 of CVD, and 12,129 of other causes.

Unlike other studies, the researchers used a modified lag-time approach to minimize reverse causation (protopathic bias).

“Using this approach, any increased PPI use during the excluded period, which could be due to comorbid conditions prior to death, will not be considered in the quantification of the exposure, and thus, protopathic bias would be avoided,” they explain.

In the initial analysis that did not take into account lag times, PPI users had significantly higher risks for all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases compared with nonusers.

However, when applying lag times of up to 6 years, the associations were largely attenuated and no longer statistically significant, which “highlights the importance of carefully controlling for the influence of protopathic bias,” the researchers write.

Cause of Death

No-Lag Hazard Ratio (95% CI)

6-Year Lag Hazard Ratio (95% CI)

All causes

1.19 (1.13-1.24)

1.04 (0.97-1.11)


1.30 (1.17-1.44)

1.07 (0.89-1.28)


1.13 (1.02-1.26)

0.94 (0.81-1.10)

Respiratory disease

1.32 (1.12-1.56)

1.20 (0.95-1.50)

Digestive disease

1.50 (1.10-2.05)

1.38 (0.88-2.18)

However, despite applying lag times, PPI users remained at a significantly increased risk for mortality due to renal diseases (hazard ratio, 2.45; 95% CI, 1.59-3.78).

The researchers caution, however, that they did not have reliable data on renal diseases and therefore could not adjust for confounding in the models. They call for further studies examining the risk for mortality due to renal diseases in patients using PPI therapy.

The researchers also looked at duration of PPI use and all-cause and cause-specific mortality.

For all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, the greatest risks were seen mostly in those who reported PPI use for 1-2 years. Longer duration of PPI use did not confer higher risk for mortality for these endpoints.

In contrast, a potential trend toward greater risk with longer duration of PPI use was observed for mortality due to renal disease. The hazard ratio was 1.68 (95% CI, 1.19-2.38) for 1 to 2 years of use and gradually increased to 2.42 (95% CI, 1.23-4.77) for 7 or more years of use.

Notably, when mortality risks were compared among PPI users and histamine H2 receptor antagonist (H2RA) users without lag time, PPI users were at increased risk for all-cause mortality and mortality due to causes other than cancer and CVD compared with H2RA users.

But again, the strength of the associations decreased after lag time was introduced.

“This confirmed our main findings and suggested PPIs might be preferred over H2RAs in sicker patients with comorbid conditions,” the researchers write.

‘Generally Safe’ When Needed

Summing up, Chan said, “We think our results should be reassuring to clinicians that recommending PPIs to patients with appropriate indications will not increase their risk of death. These are generally safe drugs that when used appropriately can be very beneficial.”

Offering perspective on the study, David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, noted that a “major continuing criticism of the allegations of harm by PPIs has been that these most commonly come from retrospective analyses of databases that were not constructed to evaluate these endpoints of harm.”

“Accordingly, these reports have multiple potentials for stratification bias and typically have low odds ratios for supporting the purported causality,” Johnson told Medscape Medical News.

“This is a well-done study design with a prospective database analysis that uses a modified lag-time approach to minimize reverse causation, ie, protopathic bias, which can occur when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected,” Johnson explained.

Echoing Chan, Johnson said the finding that PPI use was not associated with higher risk for all-cause mortality and mortality due to major causes is “reassuring.”

“Recognizably, too many people are taking PPIs chronically, when they are not needed. If needed and appropriate, these data on continued use are reassuring,” Johnson added.

This work was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. Chan has consulted for OM1, Inc, Bayer Pharma AG, and Pfizer Inc for topics unrelated to this manuscript and Boehringer Ingelheim for litigation related to ranitidine and cancer. Johnson reports no relevant financial relationships.

Gastroenterology. Published online June 30, 2022. Full text

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