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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)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Universita Torino User on 01/20/2016
Editorial Opinion
review and meta-analysis of observational studies.
pneumonia: replicated cohort studies with
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Bhatt DL, Verheugt FW. Concomitant use of
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Cavallazzi R, Loke YK. Risk of
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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
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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
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(Reprinted) JAMA Internal Medicine Published online January 11, 2016
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Source: http://www.gastrodurand.com.ar/clases/2016-adverseeffectsassociatedwithprotonpumpinhibitors.pdf
SOUTHERN ASSOCIATION OF INSTITUTIONAL DENTISTS — Self-Study Course Module 9 CLINICAL CONCERNS IN DENTAL CARE FOR PERSONS WITH MENTAL ILLNESS Purpose of this Module The information presented in this module is intended to provide the institutional dental staff with a compre- hensive discussion of oral health care for persons with mental illness in institutional settings as well as thechallenges faced by the dental profession treating these persons in outpatient settings.
For Alumni potlight And Friends Of East High January 2009 East High Alumni Heritage Hall: Angels Making History Newly inducted "Angels" prepare to cut the ribbon on the Heritage Hall dis-play, left to right, Anthony Ortega, Barry Hirschfeld, Philip Bailey, Allegra The Alumni Heritage Hall display is on the third floor outside of the East library.