Understanding Protopathic Bias and Safety of Proton Pump Inhibitors & COVID-19 Worldwide Nadir

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C-H Lo et al. Gastroenterol 2022; 163: 852-861. Open Access! Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality

Background: “A major challenge that pharmacoepidemiologic studies often face is the susceptibility to protopathic bias. Protopathic bias occurs when a pharmaceutical agent is prescribed for an early manifestation of a disease and then appears to cause the disease when it is eventually diagnosed…Here, we used a modified lag-time approach to investigate the association between PPI use and all-cause and cause-specific mortality”

Methods: This was a prospective cohort study using data collected from the Nurses’ Health Study (2004–2018) and the Health Professionals Follow-up Study (2004–2018). Study participants: 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years.

Key findings:

Upon applying lag times of up to 6 years, the mortality associations were attenuated and no longer statistically significant:

  • All-cause mortality: HR, 1.04; 95% CI, 0.97–1.11
  • Cancer: HR, 1.07; 95% CI, 0.89–1.28
  • Cardiovascular diseases: HR, 0.94; 95% CI, 0.81–1.10
  • Respiratory diseases: HR, 1.20; 95% CI, 0.95–1.50
  • Digestive diseases: HR, 1.38; 95% CI, 0.88–2.18

Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality.

My take: This study provides convincing evidence that PPI use does not increase the risk of mortality. Protopathic bias can make PPI use appear to increase the risk of mortality (HR, 1.19 in this study) compared to PPI non-users. It is still a good idea to use these agents for appropriate indications and at appropriate doses.

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Beached Fishing Boats Jules Achille Noel. The Art Institute of Chicago.

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Also, worldwide COVID-19 deaths are at a low point since the beginning of the pandemic (both reported and estimated excess deaths).