Putting proton pump inhibitors into perspective

William Simonson, PharmD, BCGP, FASCP
Oregon State University, Corvallis, OR, USA

One of the most pertinent geriatric drug therapy mantras is “It’s a lot easier to start a drug than it is to stop a drug.” Medications that are considered to be safe and rather innocuous and medications that don’t always have a clear indication for use are much more likely to be started, not closely evaluated or reconsidered, and be used for periods of time longer, sometimes much longer, than necessary. One of the best examples of excessive use of a class of medications is the proton pump inhibitors (PPIs). This column is devoted to providing an updated perspective of the use of PPIs and will review some of the consequences of long-term PPI administration including comments on some new scientific studies.

As a class, proton pump inhibitors have been a remarkable success. Numerous PPIs exist both as prescription and over the counter (OTC) medications and include omeprazole (Prilosec
), esomeprazole (Nexium
), pantoprazole (Protonix
) and lansopra-zole (Prevacid
). The first prescription PPI became available in the US in 1989 and approval for OTC sale was granted in 2003. PPIs have been heavily promoted to prescribers and widely advertised to consumers. PPI use in the US includes 100 million prescriptions per year and countless numbers of OTC purchase with sales totaling well more than $10 billion annually. More than 20 million Americans a year take a PPI.1 No doubt PPIs have done a stellar job con-trolling the symptoms of conditions related to excess stomach acid to the point where many people take a PPI chronically for months or years. In spite of their effectiveness, and apparent safety after short-term administration, new findings indicate that chronic administration may be associated with problems that the short-term therapy evaluated in the original PPI research did not reveal. In response to this concern, the FDA has issued a series of communications warning of a number of potential problems associated with PPIs including fractures, increased likelihood of C. difficile infection and low magnesium levels.

The FDA has looked at several epidemiological studies that re-ported an increased risk of fractures of the hip, wrist and spine. They found that those at greatest risk for fracture were individuals who had received high doses of PPIs or used them for longer than one year. Also, those over age 50 were at greater risk of fracture. The FDA points out that, while these observational studies show that fractures are associated with PPI use, they cannot prove that PPIs actually caused the fracture. As the saying goes, “association does not mean causation.”2 The FDA recommends that, since PPIs are effective in treating a variety of GI conditions, patients should not stop taking their PPI unless directed by their health care professional. Another suggestion is that patients should be reminded that OTC PPIs should only be used as directed for no more than three 14-day treatment courses in one year and, if heartburn continues, they should speak with their health care professional.3 The FDA has also announced that PPIs may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD).4 Cunningham et al. determined that the use of PPIs within the previous 8 weeks was associated with a 2.5-fold higher risk of CDAD.5 The FDA points out that a diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve.

The FDA also published an alert that prescription PPIs may cause low serum magnesium levels if taken for prolonged periods of time (in most cases more than one year) which can result in serious adverse events including muscle spasm (tetany), irregular heart-beat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms.6 Treatment of hypomagnesemia generally requires magnesium supplements. Treatment in patients taking a PPI and who have hypomagnesemia may also require stopping the PPI.

In addition to the FDA warnings, some studies have demonstrated a statistically significant association between the use of PPIs and the occurrence of numerous other medical conditions. One potential PPI complication is dementia. Some studies have found a relationship between PPI use and dementia, however, due to multiple confounding factors in the older populations studied, this association does not prove that PPIs actually cause dementia. A 2017 study published in the Journal of the American Geriatrics Society evaluated more than 10,000 individuals and found that there was actually a decreased risk of cognitive decline in those taking PPIs regularly or occasionally but the researchers concluded that more trials are needed to confirm their findings.7 At this point, my interpretation of these studies is that PPIs do not cause dementia but I’ll be following the literature to look for new studies.

The FDA has looked at the cardiac effect of PPIs and in 2007 stated their continued belief that long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of heart problems.8 However, a recent study mined data from the medical records of nearly three million patients and found that PPI use was associated with a 20% increase in heart attack risk.1 As with the dementia studies discussed above this study demonstrated an association which does not mean causation. We need to stay tuned for further studies of this potential problem.

Chronic kidney disease (CKD) has also been attributed to PPIs but again, studies were observational and no conclusion can be made re: actual causation of CKD by PPIs.9

Perhaps more ominous are studies suggesting that PPI use leads to an increase in overall mortality. One study using a computer-simulated model and literature-derived estimates of risk for upper GI bleeding, hospital-acquired pneumonia and C. difficile infections concluded that new initiation of PPI therapy in hospitals led to an increase in hospital mortality in roughly 90% of simulated patients.5 A more recent study involving 350,000 mostly male US veterans showed that PPI use was associated with an increase in risk of death during the study period.10 The authors of the study address potential biologic mechanisms underpinning the association of PPI use and risk of death. They propose numerous cellular and genetic mechanisms derived from rat and human studies that are too complex and too detailed for this brief review but they do conclude that the plausible clinical course leading to heightened risk of death is likely mediated by the occurrence of one or more of the adverse events associated with PPI use including kidney disease, dementia, hypomagnesemia, C. difficile infection or osteoporotic fracture.10
Importantly, the authors note that PPIs “are often overprescribed, rarely deprescribed and frequently started inappropriately during a hospital stay, and their use extended for long-term duration without appropriate medical indication.”10

The documented problems caused by PPIs including fractures, C difficile infections and hypomagnesemia and the possible association of PPIs with dementia, heart attack and death, in the face of widespread and long-term PPI use, should put us on-guard. Studies estimate that between 53% and 69% of PPI prescriptions are for inappropriate indications and who knows how often OTC PPIs are used inappropriately.10

It appears that the short-term risks of PPIs are small and not generally associated with appropriate use of OTC PPI which is up to three courses of 14 days yearly (every 4 months) for control of frequent heart burn. Yet, many patients, especially those on chronic therapy, are likely candidates to be weaned from chronic PPI therapy. Deprescribing guidelines for PPIs can be initiated using an algorithmic approach which can provide guidance to decrease or discontinue therapy in appropriate patients.11

The take home message for all medications, including prescription and OTC PPIs, is another important geriatric drug therapy mantra – “medications should be used in the elderly only if the potential risk exceeds potential benefit.”

References

1. Some Heartburn Drugs May Boost Risk of Heart Attack, Study Finds. Stanford Medicine News Center. Available at: https://med.stanford.edu/news/all-news/2015/06/some-heartburn-drugs-may-boost-risk-of-heart-attack-study-finds.html. Accessed 9 October 2017.
2. Kendrick Malcolm. Association Does not Mean Causation. Available at: https://drmalcolmkendrick.org/2012/03/23/association-does-not-mean-causation/. Accessed 9 October 2017.
3. Proton Pump Inhibitors (PPIs) Video: Transcript. US Food and Drug Administra-tion. Information for Healthcare Professionals (drugs). Available at: https://drmalcolmkendrick.org/2012/03/23/association-does-not-mean-causation/. Accessed 9 October 2017.
4. United States Food and Drug Administration. FDA Drug Safety Communication: Clostridium Difficile Associated Diarrhea can be Associated with Stomach Acid Drugs Known as Proton Pump Inhibitors (PPIs). Available at: https://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm221675.htm. Accessed 9 October 2017.
5. Barnes MN. Overuse of proton pump inhibitors in the hospitalized patient. US Pharm. 2015;40:HS22eHS25.
6. Low Magnesium Levels can be Associated with Long-term Use of Proton Pump Inhibitor Drugs (PPIs). United States Food and Drug Administration. FDA Drug Safety Communication. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm245011.htm. Accessed 9 October 2017.
7. Goldstein FC, Steenland K, Zhao L, et al. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Amer Geriatr Soc. 2017;65:1969e1974. https://doi.org/10.1111/jgs.14956.
8. Update of Safety Review – Follow-up to the August 9, 2007 Communication about the Ongoing Safety Review of Omeprazole and Esomeprazole. United States Food and Drug Association. Available at: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm143258.htm. Accessed 9 October 2017.
9. Clinical Update. Recent Safety Data: Implications for Use of Proton Pump In-hibitors. Pharmacy Times:1e6. Available at: https://s3.amazonaws.com/pharmacytimes/v1_media/_pdf/R821_LAYOUT_PPI_Suppl_withCoverTip_12011
   6. pdf. Accessed 9 October 2017.
10. Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 2017 Jul 4;7(6):e015735. https://doi.org/10.1136/bmjopen-2016-015735.
11. Farrell B, Pottie K, Thompson W, et al. Deprescribing proton pump inhibitors. Can Fam Physician. 2017;63(5):354e364. http://www.cfp.ca/content/63/5/354.long.