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PPI Therapy Not Associated With Elevated Mortality

Key findings

  • This analysis of two large prospective U.S. cohorts evaluated associations between the use of proton pump inhibitors (PPIs) and all-cause and cause-specific mortality, with long-term follow-up of 14 years
  • A lag-time approach was used to account for potential protopathic bias—the possibility that individuals with various medical conditions who use PPIs may die of those conditions, not from the use of PPIs
  • In initial analyses that did not consider lag times, PPI use was associated with significantly higher risks of all-cause mortality and mortality due to cancer, cardiovascular diseases, respiratory diseases, digestive diseases, and renal diseases
  • Still, it remains prudent to recommend PPIs only to patients with appropriate indications and for the minimally effective duration

There's growing concern that proton pump inhibitor (PPI) therapy may increase mortality. However, there's potential for "protopathic bias"—individuals with various medical conditions who use PPIs may die of those conditions, not from the use of PPIs.

Researchers at Massachusetts General Hospital conducted a prospective analysis that accounted for this possible bias by incorporating lag times into the definition of PPI exposure. Any increased PPI use during the excluded period, which could be due to comorbid conditions before death, is not considered in quantifying the exposure.

Chun-Han Lo, MD, MPH, formerly a research fellow in the Clinical and Translational Epidemiology Unit, Andrew T. Chan, MD, MPH, chief of the Clinical and Translational Epidemiology Unit and vice chair for clinical research in the Division of Gastroenterology at Mass General, and professor of Medicine at Harvard Medical School, and colleagues report in Gastroenterology that PPI use was not associated with increased overall mortality or mortality from specific medical conditions based on lag-time analysis.


The researchers analyzed data from two ongoing prospective U.S. studies:

  • The Nurses' Health Study, which enrolled 121,700 female registered nurses ages 30 to 55 in 1976
  • The Health Professionals Follow-up Study, which enrolled 51,529 male health professionals ages 40 to 75 in 1986

In the current analyses, 2004 was the baseline date for both cohorts. Participants who reported PPI use before the start of follow-up or had been diagnosed with an upper gastrointestinal disease were excluded, leaving 50,156 women (mean age at baseline 69) and 21,731 men (mean age 68). The median length of follow-up was 14 years.

Initial Analyses

Initial analyses did not consider lag times. Compared with nonusers of PPIs, PPI users had significantly higher risks of:

  • All-cause mortality (HR, 1.19)
  • Any cancer (HR, 1.30)
  • Cardiovascular diseases (HR, 1.13)
  • Respiratory diseases (HR, 1.32)
  • Digestive diseases (HR, 1.50)
  • Renal diseases (HR, 2.09)

Lag-Time Analyses

The researchers then considered two-, four- and six-year lag times. For example, in the two-year lag-time analysis, the exposure status in 2004 was used to model mortality risk starting in 2006.

When the researchers applied longer lag times successively, the initial results were gradually and substantially attenuated. The exception was that the association between PPI use and the risk of death from renal diseases persisted (HR, 2.45).

Duration Analysis

In a duration analysis, the highest hazard ratios were principally observed among individuals who used PPIs for less than two years. The magnitude of risk steadily decreased with a longer duration of PPI use.

However, the duration analysis did show a potential relationship between longer use of PPI therapy and a higher risk of mortality due to renal diseases (HR for 1–2 years of use, 1.68; for ≥7 years, 2.42).

Sensitivity Analysis

When compared with users of histamine-2 receptor antagonists (H2RAs), PPI users were at higher risks of all-cause mortality (HR, 1.14) and mortality due to other causes (HR, 1.21). But again, as longer lag times were applied, associations with all-cause mortality and mortality due to other causes were attenuated to null.

Guidance for Prescribers

This study doesn't support previously reported findings about associations between PPIs and elevated risk of death. Still, it remains prudent to recommend these medications only to patients with appropriate indications and for a minimally effective duration.

PPIs might be preferred to H2RAs in sicker patients with comorbid conditions.

The findings about PPIs and renal disease should be interpreted with caution. In this observational study, it was not possible to adjust for specific medical conditions, so further research is needed.

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