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• Re: Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans
  Titilope. O. Olanipekun, Abimbola Chris-Olaiya
  Published on: 14 July 2017

• Published on: 14 July 2017

  Re: Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans

  • Titilope. O. Olanipekun, Resident Physician Department of Internal Medicine, Morehouse School of Medicine, Atlanta Georgia
  • Other Contributors:
    • Abimbola Chris-Olaiya, Resident Physician

  We read with great interest the longitudinal study by Xie et al on the Risk of death among users of Proton Pump Inhibitors (PPI) (1). The study findings suggest that there is an overall increased risk of death among PPI users when compared with histamine H2 receptor antagonists (H2 blockers) users and people who are not on either medication. We also acknowledge the efforts of the authors to statistically eliminate potential bias associated with an observational study design like this. However, we would like to highlight a few points which we believe should be considered when interpreting the results of the study.

  The authors externally adjusted for the use of other therapeutics including anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs as potential confounders. However, it is not clear if Selective Serotonin Receptor Inhibitors (SSRIs) used in the treatment of Post-Traumatic Stress Disorder (PTSD) were considered and adjusted for. The Veteran population which forms the data set for this study has a higher prevalence of PTSD than the general population and is often prescribed SSRIs (2). The SSRIs are metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) leading to significantly higher levels of SSRIs in the body and potential risk of increased adverse effects (3). Some of the adverse effects of SSRIs including suicide risk could significantly contribute to mortality in the popu...

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  We read with great interest the longitudinal study by Xie et al on the Risk of death among users of Proton Pump Inhibitors (PPI) (1). The study findings suggest that there is an overall increased risk of death among PPI users when compared with histamine H2 receptor antagonists (H2 blockers) users and people who are not on either medication. We also acknowledge the efforts of the authors to statistically eliminate potential bias associated with an observational study design like this. However, we would like to highlight a few points which we believe should be considered when interpreting the results of the study.

  The authors externally adjusted for the use of other therapeutics including anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs as potential confounders. However, it is not clear if Selective Serotonin Receptor Inhibitors (SSRIs) used in the treatment of Post-Traumatic Stress Disorder (PTSD) were considered and adjusted for. The Veteran population which forms the data set for this study has a higher prevalence of PTSD than the general population and is often prescribed SSRIs (2). The SSRIs are metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) leading to significantly higher levels of SSRIs in the body and potential risk of increased adverse effects (3). Some of the adverse effects of SSRIs including suicide risk could significantly contribute to mortality in the population studied, especially in the presence of co-morbidities like cardiovascular diseases.

  Though the study demonstrated a linear graded association between duration of PPI exposure and risk of death among new users, we believe the gradient effect cannot be effectively ascertained without analyzing the dose of PPIs that was actually taken by the study subjects. The study cohort consists mostly of the elderly, and evidence has shown increased risk of accidental prescription drug abuse and overdose in this population (4 - 6). PPIs, just like every other medication, if used above the intended dose could cause deleterious adverse effects. Therefore, without the data on the dose of PPI among users, it might be inaccurate to associate duration of use in isolation with increased risk of mortality.

  As expected of an observational study, it is difficult to validate cause and effect. The cause of death in the study population is not known and the mortality noted could possibly be secondary to underlying medical conditions and not necessarily treatment with PPIs. Figure 1 from the study analysis showed that an estimated 10% of the population on PPIs died within 1 year (1). As the authors mentioned, the biologic mechanism behind the observed mortality risk from PPI use is not clear. Nevertheless, one would expect the latency period between PPI exposure and any mortality risk to be more than 1 year. Again, this strongly suggests the deaths may not entirely be linked to treatment with PPI as there could be a significant contribution from underlying medical problems.

  The study analysis suggests an increased mortality risk with PPI use compared with H2 blocker use. However, the severity of medical conditions in the H2 blocker and PPI groups was not accounted for. Taking cardiovascular disease, for instance, the authors controlled for the presence of heart disease in both groups and not severity. It is quite possible that people with mild heart disease could have been prescribed an H2-blocker while people with severe heart disease were put on a PPI. This would create a bias towards an increased risk of mortality in the PPI group which is not related to use as suggested by the researchers.

  Overall, we appreciate the authors for a well-conducted research. In light of evidence from other studies linking PPI use to a host of medical problems, findings from this study further emphasize the need for judicious use of PPI. Healthcare providers should regularly review prescriptions with patients and constantly provide education on the risks of continued use of medications without any clinical indication. Lastly, more studies should be conducted on the risk of PPIs using a database that is more representative of the general population to enable generalizability of study findings.

  References
  1. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-aly Z. Risk of death among users of Proton Pump Inhibitors : a longitudinal observational cohort study of United States veterans. 2017;1–12.
  2. Alexander W. Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans: Focus on Antidepressants and Atypical Antipsychotic Agents. P T. 2012;37(1):32–8.
  3. Gjestad C, Westin AA, Skogvoll E, Spigset O. Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline. Ther Drug Monit. 2015;37(1):90–7.
  4. Hernandez SH, Nelson LS. Prescription Drug Abuse: Insight Into the Epidemic. Clin Pharmacol Ther. 2010;88(3):307–17.
  5. Seniors and Prescription Drug Addiction by AgingCare( 04/17/12, http://www.agingcare.com/Articles/Seniors-and-Prescription-Drug-Addictio...)
  6. Elderly at Risk for Prescription Drug Abuse by The Partnership at DrugFree.org( 04/17/12, http://www.drugfree.org/join-together/addiction/elderly-at-risk-for-pres...)

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  Conflict of Interest:
  None declared.

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