March/April 2020

Medication Monitor: The Dark Side of Proton Pump Inhibitors
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 13 No. 2 P. 5

Despite being effective for gastrointestinal disorders, these medications are associated with significant risks and increased mortality.

Proton pump inhibitors (PPIs) are frequently used to treat gastrointestinal (GI) disorders such as dyspepsia, gastroesophageal reflux disease, erosive esophagitis, and NSAID-induced ulcers. The acid-suppressing medications are among the most commonly used classes of medication in the United States—an estimated 7.8% of the adult population take prescription PPIs.1

The proven efficacy and ease of availability of prescription and over-the-counter (OTC) PPI products (see table) have contributed to their widespread use and, possibly, the common belief these medications can be used with minimal safety concerns. However, over the past decade there’s been mounting evidence that PPI use may be associated with significant risk, including an elevated risk of acute kidney injury, chronic kidney disease (CKD), bone fractures, infections, possible dementia, and increased mortality.

Concerns About Inappropriate Use
As much as two-thirds of PPI use has been described as being inappropriate.2 OTC PPI products are recommended to be used only for occasional heartburn for a 14-day course of therapy and up to three times per year. Instead, many patients use the products for all GI symptoms and continue their use indefinitely without the supervision of a prescriber. In other cases, prescribers continue to renew PPI prescriptions indefinitely, despite treatment guidelines recommending that they reevaluate use after eight weeks. The failure of prescribers to instruct patients about when or how to discontinue the medications can lead to indefinite PPI use despite there being no clear indication for its need.3,4 For example, in the ambulatory care setting, 46% to 63% of patients prescribed PPIs have been described as having no GI complaint or documented indication for antisecretory therapy.5

With extended use, efforts to discontinue PPIs can be complicated due to rebound hypersecretion, which can occur when the body’s normal gastric acid has been suppressed and PPI use ends. In 60% to 90% of patients taking PPIs for at least two to three months, increased gastric acid secretion can occur when the PPI is stopped.6 For these patients, a step-down approach to another GI medication such as a H2 blocker or slowly reducing the dose can help with efforts to discontinue the PPI.

Nutritional and Infection Risk
Adequate stomach acid is required to help with the digestion of food and also serves as a barrier to pathogens that may be ingested. By effectively reducing the production of hydrochloric acid in the stomach, PPI use results in increased stomach pH, which can limit absorption of nutrients (eg, calcium, vitamin B12, magnesium) while also encouraging bacterial growth.

Clostridium difficile–Associated Diarrhea (CDAD)
CDAD, which is characterized by watery stool, abdominal pain, and fever, should be considered in patients taking PPIs who develop refractory diarrhea.7

Patients taking PPIs have been shown to have 1.4 to 2.75 times greater risk of developing CDAD than do patients not receiving PPI therapy. CDAD can also be especially concerning in hospitals, with 1 in 533 hospitalized patients taking PPIs developing CDAD. One study found that patients with no recent hospitalization have an increased CDAD infection risk after only two days of PPI use, while patients with a hospital admission within the previous 30 days have an increased risk after only one day of therapy.8

Pneumonia
There’s increasing evidence that PPI use is associated with increased pneumonia risk, both with short-term and long-term use. One report indicated that one additional case of hospital-acquired pneumonia occurs for every 111 non-ICU patients treated with PPIs for at least three days.9

In one study, 75,000 adults older than 60 who had taken prescribed PPIs regularly over a two-year period were shown to have a higher rate of pneumonia compared with those who did not take PPIs.10 The increased risk of pneumonia may be associated with the reflux of gastric contents along with bacteria in the esophagus.

Gastroenteritis
Gastroenteritis—the stomach flu—is a short-lived viral illness with symptoms such as vomiting and diarrhea. In a recent study comparing 233,000 French adult patients taking PPIs continuously with 627,000 patients who were not taking the drugs, those taking PPIs were 80% more likely to experience the stomach flu.11

Osteoporosis and Fracture Risk
PPI-associated reductions in the dietary absorption of calcium and vitamin B12 can contribute to osteoporosis and increased risk of hip, wrist, and spine fractures. The risk appears to be dependent on more than one year’s use of PPI therapy, with persons older than 70 being at greatest risk.12

PPIs can also reduce the effectiveness of bisphosphonates (eg, alendronate), which are used to help reduce bone loss from osteoporosis and prevent hip fractures. Patients older than 70 taking PPIs with the bisphosphonate alendronate experienced a significantly increased fracture risk, and when PPI therapy was given together with alendronate for two years or more, the potential hip fracture protection was negated.12

Hypomagnesemia
Decreased GI absorption of magnesium associated with PPI use can lead to hypomagnesemia, causing neuromuscular disturbances (eg, tremors, seizures), cardiac arrhythmias, hypoparathyroidism, osteomalacia, and osteoporosis, as well as concurrent metabolic disorders (eg, hypocalcemia and hypokalemia). PPI use with other medications associated with the loss of magnesium (eg, loop and thiazide diuretics, aminoglycosides, foscarnet) may be especially problematic.13

Renal Concerns
In a population-based study involving nearly 300,000 patients, those started on PPI treatment had a more than two-fold increase in the short-term risk for hospital admission with acute kidney injury relative to patients who were not prescribed these drugs.14

A large observational study using data from the Atherosclerosis Risk in Communities cohort and the Geisinger Health System found that use of PPIs increased the risks of CKD, CKD progression, and end-stage renal failure. According to the study, more than one-half of those who went on to experience kidney damage had no prior history of acute kidney injury before taking the drugs.15

Dementia
Several studies have reported associations between PPI use and dementia; however, findings are conflicting. An analysis of 13,864 participants from the Nurses’ Health Study II who completed testing of cognitive function—which is the key predictor of dementia later in life—found no convincing evidence to support that PPI use increases dementia risk.16

Mortality Risk
In another study, researchers evaluated medical records from the VA. The data from the cohort included 157,625 people who had been prescribed PPIs and 56,842 people who had been prescribed H2 blockers (eg, ranitidine, famotidine). Patients were predominately male, white, and 65 years of age or older, and had received treatment for up to a decade. Researchers estimated 45.2 excess deaths per every 1,000 persons taking PPIs, with the risk of death increased with the duration of treatment even when study participants had taken low doses of PPIs. The findings showed associations with cardiovascular disease, stomach cancer, and CKD.17

Recommendations
To help reduce the risks associated with PPI use, prescribers should do the following:

• Increase patient awareness about the possible risks associated with PPIs.

• Actively look for opportunities to deprescribe PPIs.

• Recommend using the lowest possible doses for the shortest possible duration.

• Limit long-term PPI use to persons requiring routine NSAIDs and those with severe esophagitis, Barrett’s esophagus, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and bleeding ulcers.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999-2012. JAMA. 2015;314(17):1818-1831.

2. Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users. Arch Intern Med. 2010;170(9):747-748.

3. Hamzat H, Sun H, Ford JC, Macleod J, Soiza RL, Mangoni AA. Inappropriate prescribing of proton pump inhibitors in older patients: effects of an educational strategy. Drugs Aging. 2012;29(8):681-690.

4. Pandolfino J. Discontinuation of proton pump inhibitor therapy and the role of esophageal testing. Gastroenterol Hepatol (N Y). 2013;9(11):747-764.

5. Rotman SR, Bishop TF. Proton pump inhibitor use in the U.S. ambulatory setting, 2002-2009. PLoS One. 2013;8(2):e56060.

6. Osefo N, Ito T, Jensen RT. Gastric acid hypersecretory states: recent insights and advances. Curr Gastroenterol Rep. 2009;11(6):433-441.

7. FDA drug safety communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). FDA website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-clostridium-difficile-associated-diarrhea-can-be-associated-stomach. Updated May 9, 2017.

8. Dial SM. Proton pump inhibitor use and enteric infections. Am J Gastroenterol. 2009;104 Suppl 2:S10-S16.

9. Fohl AL, Regal RE. Proton pump inhibitor-associated pneumonia: not a breath of fresh air after all? World J Gastrointest Pharmacol Ther. 2011;2(3):17-26.

10. Zirk-Sadowski J, Masoli JA, Delgado J, et al. Proton-pump inhibitors and long-term risk of community-acquired pneumonia in older adults. J Am Geriatr Soc. 2018;66(7):1332-1338.

11. Vilcu A, Sabatte L, Blanchon T, et al. Association between acute gastroenteritis and continuous use of proton pump inhibitors during winter periods of highest circulation of enteric viruses. JAMA Netw Open. 2019;2(11):e1916205.

12. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med. 2011;171(11):998-1004.

13. Florentin M, Elisaf MS. Proton pump inhibitor-induced hypomagnesemia: a new challenge. World J Nephrol. 2012;1(6):151-154.

14. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015;3(2):E166-E171.

15. Wyatt CM. Proton pump inhibitors and chronic kidney disease: is it time to sound the alarm? Kidney Int. 2016;89(4):732-733.

16. Wod M, Hallas J, Andersen K, García Rodríguez LA, Christensen K, Gaist D. Lack of association between proton pump inhibitor use and cognitive decline. Clin Gastroenterol Hepatol. 2018;16(5):681-689.

17. Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;365:l1580.