From the AGA Journals

‘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, both in Boston, told this news organization.

“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,” Dr. 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 2,945 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 – 4,592 of cancer, 5,404 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.

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


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