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Adverse Effects Associated With Proton Pump InhibitorsAdam Jacob Schoenfeld, MD; Deborah Grady, MD, MPH Proton pump inhibitors (PPIs) have been among the most
Table. Evidence Supporting the Potential Adverse Effects widely prescribed medications in the United States for of Proton Pump Inhibitor Drugs decades. This is largely due to 2 very common uses of PPIs: treatment of dyspepsia and prevention of gastrointesti- Lazarus et al,3 2015 Chronic kidney disease nal bleeding among patients Antoniou et al,4 2015 Acute kidney disease Antoniou et al,4 2015 Acute interstitial nephritis therapy, coupled with the belief that PPIs have few adverse Cheungpasitporn et al,5 effects. However, mounting evidence demonstrates that PPIs are associated with a number of adverse effects and are Kwok et al,6 2012 overprescribed. This issue was highlighted in JAMA Internal Medicine's launch of the Less Is More series in 2010.1,2 Since then, additional evidence of adverse effects of PPIs has Filion et al,8 2014 accumulated. In this issue of JAMA Internal Medicine, Lazarus et al3 add chronic kidney disease to the list of pos- Zhou et al,9 2015 sible harms of PPIs.
Abbreviation: OR, odds ratio.
To collate data on the adverse effects of PPIs, we sur- veyed recent studies focusing on systematic reviews. Mostof the evidence supporting the adverse effects of PPIs is people 66 or older, rates of acute kidney injury and acute observational. Thus, it is possible that PPI users are sicker interstitial nephritis were 2.5- and 3-fold higher in PPI users than nonusers, or that adverse effects are caused by other compared with nonusers. In a nested case-control study10 of drugs or conditions associated with PPI use. However, some 184 480 patients 18 years or older, renal disease was 2-fold adverse effects have been documented by multiple high- more common in patients who had used PPIs compared quality observational studies and are likely causal (Table).
with those who had not after controlling for multiple poten- Herein, we summarize recent data on the adverse effects of tial confounding variables.
Hypomagnesemia has been associated with increased risk of Among 10 439 patients followed for 13.9 years in the Athero- kidney disease and nonrecovery of renal function after acute sclerosis Risk in Communities study,3 the risk of chronic kidney injury. When severe, hypomagnesemia can lead to kidney disease was 50% higher in PPI users compared with muscle weakness, tetany, convulsions, cardiac arrhythmias, nonusers. The findings of this study are strengthened by a and hypotension. Based on case reports, the US Food and thorough assessment of potential confounding using both Drug Administration (FDA) issued a warning in 2011 that use multivariable and propensity score adjusted analyses, by a of PPIs may cause low serum magnesium levels if taken for dose response with higher risk among patients using twice prolonged periods of time, and noted that magnesium daily compared with once daily PPI dosing, and by higher supplementation alone may not correct low serum magne- risk among PPI users compared with patients using hista- sium levels unless the PPI is discontinued.11 Subsequently, a mine H antagonists—a comparison group that should con- meta-analysis5 of 9 observational studies including 109 798 trol for potential bias and confounding. Finally, the findings participants found that PPI users had a 40% higher risk of were replicated in a second large cohort using administra- hypomagnesemia compared with nonusers.
tive data from patients in the Geisinger Health System.3 Useof PPIs may lead to chronic kidney disease through recur- rent acute kidney injury or hypomagnesemia. Although this Clostridium difficile Infection is a large, high-quality observational study, additional con- Proton pump inhibitors reduce gastric acidity, which may pro- firmation would be helpful, especially since chronic kidney mote bacterial colonization in the gastrointestinal tract, in- disease is a common condition.
creasing the risk of infection. A meta-analysis6 that included Use of PPIs is also associated with increased risk of 39 studies showed a 74% higher risk of developing C difficile acute kidney injury, possibly mediated through acute inter- infection, as well as 2.5-fold higher risk of recurrent C difficile stitial nephritis. In a population-based study4 of 290 592 infection among PPI users compared with nonusers. Based on (Reprinted) JAMA Internal Medicine Published online January 11, 2016
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Opinion Editorial these data, the FDA published a safety alert in 2015 warning among patients prescribed clopidogrel and treated with of the association of PPIs and C difficile infection.11 omeprazole or esomeprazole.13 It is not clear how to resolvethese conflicting findings. The observational studies are much larger than the randomized trials and provide "real- Reduced gastric acidity and increased bacterial colonization world" experience. However, the observational studies are in the stomach related to PPI use may also lead to increased prone to selection bias and confounding, which are mini- rates of pneumonia. A meta-analysis7 of 5 observational mized by randomization. In summary, we do not find clear studies showed that the risk of community-acquired pneu- evidence that PPIs increase risk for coronary events in monia was 34% higher among patients using PPIs compared patients on clopidogrel.
with nonusers, and that the risk was higher with increasingdoses of PPIs. Risk for hospital-acquired pneumonia was not increased. A retrospective cohort study using Use of PPIs may decrease bone density and increase fracture administrative data evaluated the risk of hospitalization risk by reducing intestinal calcium absorption. Many obser- for community-acquired pneumonia among more than vational studies have shown an association between PPI use 4 million patients newly prescribed nonsteroidal anti- and increased risk of fractures, prompting the FDA to pub- inflammatory drugs from 8 regions in Canada, the United lish a safety alert in 2010 noting a possible increased risk of States, and the United Kingdom. Among patients who were fractures among PPI users.11 A recent meta-analysis9 of 18 also started on therapy with a PPI (presumably for preven- observational studies that included 244 109 fractures found tion of dyspepsia, ulceration, and bleeding), there was no that compared with nonuse, PPI use was associated with a increased risk of hospitalization for community-acquired 26% higher risk of hip fracture, a 58% higher risk of spine pneumonia compared with nonusers.8 The results of this fracture, and a 33% higher risk for fracture at any site, even study may be more reliable than other observational studies after short-term use of less than 1 year.
because the study population was restricted to patientswithout known gastric or esophageal disease, and analyses were adjusted using high-dimensional propensity scores to Available evidence suggests that PPI use is associated with control for potential confounding.
an increased risk of both acute and chronic kidney disease,hypomagnesemia, C difficile infection, and osteoporotic Cardiovascular Events fractures. Caution in prescribing PPIs should be used in Patients with coronary disease and those who have under- patients at high risk for any of these conditions. Given the gone coronary procedures are generally prescribed anti- association with kidney disease and low magnesium levels, platelet therapy to reduce the risk of coronary events. Pro- serum creatinine and magnesium levels should probably be ton pump inhibitors are often prescribed along with monitored in patients using PPIs, especially those using antiplatelet therapy to prevent gastrointestinal bleeding.
The commonly used antiplatelet agent, clopidogrel, is Given the evidence that PPI use is linked with a number metabolized to the active form by liver enzymes that also of adverse outcomes, we recommend that patients and clini- metabolize PPIs, suggesting that competitive metabolism by cians discuss the potential benefits and risks of PPI treat- PPIs might lead to reduced activation of clopidogrel, ment, as well as potential alternative regimens such as hista- reduced antiplatelet effects, and increased cardiovascular mine H receptor antagonists or lifestyle changes, before events. In fact, pharmacologic studies demonstrate that PPIs are prescribed. In patients with symptomatic gastroin- adding PPIs to clopidogrel results in reduced platelet inhibi- testinal reflux, ulcer disease, and severe dyspepsia, the ben- tion, and this finding led the FDA in 2009 to warn against efits of PPI use likely outweigh its potential harms. However, combining clopidogrel and PPIs.11,12 A meta-analysis13 of 31 for less serious symptoms and for prevention of bleeding in observational studies found that patients using PPIs with low-risk patients, potential harms may outweigh the ben- clopidogrel have about a 30% increased risk of cardiovascu- efits. A large number of patients are taking PPIs for no clear lar events compared with nonusers of PPIs. However, none reason—often remote symptoms of dyspepsia or "heartburn" of the 4 randomized clinical trials identified by this sys- that have since resolved. In these patients, PPIs should be temic review found an increased risk of coronary events stopped to determine if symptomatic treatment is needed.
ARTICLE INFORMATION Conflict of Interest Disclosures: None reported.
3. Lazarus B, Yuan C, Wilson FP, et al. Proton pump
Author Affiliations: University of California,
inhibitor use and the risk of chronic kidney disease San Francisco, San Francisco (Schoenfeld, Grady); [published online January 11, 2016]. JAMA Intern Med.
San Francisco VA Medical Center, Medicine, 1. Grady D, Redberg RF. Less is more: how less
San Francisco, California (Grady).
health care can result in better health. 4. Antoniou T, Macdonald EM, Hollands S, et al.
Corresponding Author: Adam Jacob Schoenfeld,
Proton pump inhibitors and the risk of acute kidney MD, University of California, San Francisco, 3333 injury in older patients: a population-based cohort 2. Katz MH. Failing the acid test: benefits of proton
California St, Ste 265, PO Box 0936, San Francisco, pump inhibitors may not justify the risks for many 5. Cheungpasitporn W, Thongprayoon C,
Published Online: January 11, 2016.
Kittanamongkolchai W, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic JAMA Internal Medicine Published online January 11, 2016 (Reprinted)
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Editorial Opinion review and meta-analysis of observational studies.
pneumonia: replicated cohort studies with 12. Focks JJ, Brouwer MA, van Oijen MG, Lanas A,
Bhatt DL, Verheugt FW. Concomitant use of 6. Kwok CS, Arthur AK, Anibueze CI, Singh S,
9. Zhou B, Huang Y, Li H, Sun W, Liu J.
clopidogrel and proton pump inhibitors: impact on Cavallazzi R, Loke YK. Risk of Clostridium difficile Proton-pump inhibitors and risk of fractures: an platelet function and clinical outcome: a systematic infection with acid suppressing drugs and update meta-analysis [published online October 13, 2015]. Osteoporos Int. 13. Melloni C, Washam JB, Jones WS, et al.
Conflicting results between randomized trials and 7. Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee
10. Klepser DG, Collier DS, Cochran GL. Proton
observational studies on the impact of proton KS. Use of acid-suppressive drugs and risk of pump inhibitors and acute kidney injury: a nested pump inhibitors on cardiovascular events when pneumonia: a systematic review and meta-analysis.
case-control study. coadministered with dual antiplatelet therapy: systematic review. 11. Proton Pump Inhibitors Information. 2015;
8. Filion KB, Chateau D, Targownik LE, et al;
CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired Accessed November 12, 2015.
(Reprinted) JAMA Internal Medicine Published online January 11, 2016
Copyright 2016 American Medical Association. All rights reserved.
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