see related editorial on page x
nature publishing group 1
© 2016 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
THE RED SECTION
HOW I APPROACH IT
Concerns about the possible side e ects of proton pump inhibi-
tors (PPIs) have been raised since their introduction in the 1980s,
including gastric carcinoids, gastric carcinoma, decreased absorp-
tion of minerals (e.g., iron, calcium) and vitamin B-12, fractures,
enteric infections (e.g., C . di cile ), pneumonia, hypomagne-
semia, and cardiovascular events ( 1 ). is year studies reporting
associations with chronic kidney disease (CKD) and dementia
had widespread media coverage ( 2,3 ), prompting renewed con-
cern and many questions from patients and physicians regarding
long-term PPI use.
INTERPRETING RESULTS OF OBSERVATIONAL STUDIES
e recent studies about CKD and dementia, similar to many
prior studies assessing PPI risk, are retrospective observational
studies. e intervention (PPI) is not assigned at random but is
related to patient characteristics: e.g., PPI prescribed because of
older age, nonsteroidal anti-in ammatory drugs (NSAID)/aspi-
rin use, gastrointestinal symptoms. is results in di erences
between PPI users and non-users in factors that may impact study
outcomes and confound results.
Residual bias is always a concern in observational studies,
even with statistical adjustment, because all confounding fac-
tors are not recorded or even known. When e ect sizes are small
(odds/hazard ratio<2), it is not possible to determine whether
the association is valid or the result of residual bias. Hazard
ratios for PPI use and dementia or CKD were ≤1.5 ( 2,3 ). Never-
theless, if a true cause-and-e ect exists, even small e ect sizes
can result in meaningful risk for common interventions and
conditions.
CONDITIONS WITH POTENTIAL LONG-TERM PPI USE
Gastroeseophageal re ux disease
Most patients can do well with symptom-driven intermittent
or on-demand therapy. A large prospective double-blind study
showed that most gastroeseophageal re ux disease (GERD)
patients (two-thirds with erosive esophagitis) who stopped therapy
a er heartburn resolution did well with intermittent 2–4-week
courses of daily therapy reinstituted if twice-weekly heartburn
recurred: 70% had 0–1 relapses and 30% changed to daily PPI
therapy during almost 1-year follow-up ( 4 ). Furthermore, mul-
tiple double-blind placebo-controlled trials of on-demand PPI
therapy reveal that ~80–100% of patients are willing to continue
on-demand therapy, with ~60–80% decrease in PPI consumption
compared with daily therapy ( 5 ).
Guidelines suggest that patients with known erosive esophagitis
remain on daily maintenance PPI due to the higher risk of
recurrent erosions on placebo, H2RAs, or on-demand PPI ( 6,7 ).
However, no data document that intermittent esophageal ero-
sions are harmful or lack of daily PPI increases the risk of develop-
ing Barrett’s esophagus ( 6 ), and the risk of complications such as
stricture with GERD is extremely low ( 8 ). erefore, improvement
in symptoms and quality-of-life is the primary goal of therapy
for almost all GERD patients. Even when PPIs are prescribed daily,
patients commonly stop and start therapy, de ning their own ade-
quate symptom control ( 9,10 ).
B a r r e t t ’ s e s o p h a g u s
Observational studies suggest that PPIs may decrease progres-
sion to neoplastic Barrett’s esophagus ( 11 ). American College
of Gastroenterology (ACG) guidelines recommend that patients
with Barrett’s esophagus receive once-daily PPI but qualify the
recommendation, stating PPIs “deserve consideration” in Barrett’s
patients without re ux symptoms ( 12 ). American Gastroentero-
logical Association (AGA) guidelines recommend that risks and
potential bene ts of long-term PPI be discussed carefully with
Barrett’s patients ( 13 ). Given the 0.1% annual risk for progression
of non-dysplastic Barrett’s esophagus to adenocarcinoma ( 14,15 ),
any absolute bene t will be small.
Nonsteroidal anti-in ammatory drugs
Guidelines recommend PPI or misoprostol co-therapy in NSAID
users with increased risk for bleeding: e.g., age >65 years; high-
dose/multiple NSAIDs; prior ulcer; concurrent anti-thrombotics
or corticosteroids ( 16 ). Randomized trials document that PPI
Long-Term PPI Use: Balancing Potential Harms
and Documented Benefi ts
L o r e n L a i n e , M D
1
,
2
a n d A n i l N a g a r , M D
1
,
2
Am J Gastroenterol advance online publication, 26 April 2016; doi: 10.1038/ajg.2016.156
1
Section of Digestive Diseases, Yale School of Medicine , New Haven , Connecticut , USA ;
2
VA Connecticut Healthcare System , West Haven , Connecticut , USA .
Correspondence: Loren Laine, MD, Section of Digestive Diseases, Yale School of Medicine , P.O. Box 208019 , New Haven , Connecticut 06520-8019 , USA .
E-mail: [email protected]
HOW I APPROACH IT
The American Journal of GASTROENTEROLOGY www.amjgastro.com
2
THE RED SECTION
HOW I APPROACH IT
co-therapy decreases endoscopic ulcers ( 17 ) and recurrent ulcer
bleeding ( 18 ).
Anti-platelet agents
Guidelines recommend PPIs in patients with increased risk of bleed-
ing: e.g., history of ulcer or gastrointestinal bleeding, concomitant
anti-thrombotic, age>60 years plus corticosteroid therapy ( 19 ). Ran-
domized trials in low-dose aspirin users document that PPIs reduce
endoscopic ulcers ( 20 ), recurrent ulcer bleeding ( 21 ), and, in those
taking concomitant clopidogrel, upper gastrointestinal bleeding ( 22 ).
D y s p e p s i a
PPI therapy is recommended for patients ≤55 years of age
with uninvestigated dyspepsia who are H . pylori negative or in
populations with H. pylori prevalence <10% ( 23,24 ): randomized
trials show that PPIs are more e ective than placebo, antacids,
or H2RAs (number-needed-to-treat=5)( 25 ). A 4–8-week course
is suggested, with another course if symptoms recur ( 23,24 ).
Guidelines do not speci cally recommend long-term daily PPIs
but state that patients who respond can be managed without
further investigation and long-term self-directed therapy may
be considered ( 23,24 ). PPI therapy has a smaller bene t for
functional dyspepsia: number-needed-to-treat=10–15 ( 26,27 ).
Table 1 includes conditions for which AGA and ACG guidelines or
Food and Drug Administration approvals support long-term daily
PPI use ( 6,7,12,13,16,19,28 ).
WHAT WE TELL PATIENTS AND PHYSICIANS ABOUT
LONG-TERM PPI USE
Because of inherent risk of bias and low e ect sizes we cannot
conclude that associations of PPIs and adverse outcomes such as
dementia and CKD in recent observational studies are valid, and
patients should not accept these reports as fact. Nevertheless, we
cannot conclude that risks do not exist. us, as with any medica-
tion, we need to ensure that bene ts outweigh potential risk. If
PPIs are indicated, using the lowest e ective dose and, if possible,
intermittent rather than daily therapy hopefully should decrease
the risk of potential side e ects.
NSAIDs/anti-platelet agents
e bene t of daily PPI in high-risk patients taking NSAIDs
and/or anti-platelet agents is well documented and exceeds the
small and uncertain risks.
GERD
We suggest that patients taking PPIs for GERD stop therapy >2
weeks a er symptoms resolve, use H2RAs or antacids for infrequent
symptoms, employ adjunctive life-style modi cations, and institute
intermittent PPI courses of ≥2–4 weeks for symptom recurrence
(≥2 episodes per week). On-demand therapy is also reasonable.
If patients require daily PPI to control symptoms, we reassure
them: the gain in quality-adjusted-life-years with long-term symp-
tom control in all such patients should far exceed any decrease due
to possible rare, serious adverse events. In patients greatly con-
cerned about side e ects, the reduced quality of life due to worry
about side e ects may exceed the gain achieved with symptom
control—and patients may choose to accept symptoms or try other
therapies (e.g., surgery).
B a r r e t t ’ s e s o p h a g u s
In Barrett’s patients not requiring daily PPI for GERD symptoms,
we suggest that the absolute risk reduction in cancer is uncertain
and low (1% in 15–20 years assuming 50–67% relative risk reduc-
tion), as is the risk of serious adverse events.
Table 1 . Conditions with AGA/ACG guideline recommendations or FDA approval supporting long-term daily PPI ( 6,7,12,13,16,19,28 )
Condition Comments FDA approval
Maintenance of symptom control in
GERD
Intermittent or on-demand PPI courses to achieve adequate symptom
control should be used whenever possible
Symptomatic GERD treatment only
approved for 4–8 weeks
Maintenance of healing of erosive
esophagitis
No data document that intermittent erosions are harmful; hence, symptom-
driven intermittent or on-demand PPI is reasonable if adequate symptom
control
Most PPIs approved without time limit,
but prescribing information states that
this has only been studied for 12 months
Barrett’s esophagus (unrelated to
GERD symptoms or esophagitis)
Observational data suggest that PPIs may decrease progression to neoplasm.
In the absence of the need to treat GERD, guidelines state that PPIs de-
serve consideration or that risks and potential benefi ts should be discussed
carefully with patient
No
NSAID users with increased risk Randomized trials show decreased endoscopic ulcers and ulcer rebleeding Approved for durations up to 12 weeks
and 6 months
Anti-platelet agent users with
increased risk
Randomized trials in low-dose aspirin users show decreased endoscopic
ulcers, ulcer rebleeding, and, in those taking concomitant clopidogrel,
upper gastrointestinal bleeding
No
Pathological hypersecretory condi-
tions (Zollinger–Ellison Syndrome)
High-dose, multiple daily doses may be needed Approved without time limit
ACG, American College of Gastroenterology; AGA, American Gastroenterological Association; FDA, Food and Drug Administration; GERD, gastroeseophageal refl ux
disease; NSAID, nonsteroidal anti-infl ammatory drugs; PPI, proton pump inhibitor.
HOW I APPROACH IT
© 2016 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
3
THE RED SECTION
HOW I APPROACH IT
Patient preference is key in decisions regarding long-term PPIs
in patients with GERD or Barrett’s esophagus.
D y s p e p s i a
If PPIs are e ective we use intermittent therapy, although some
patients may require long-term daily PPIs to control symptoms.
Inappropriate/unstated indications
e most important intervention we perform is stopping PPIs in
the many patients without appropriate indications. For example,
many hospitalized patients receive PPIs, which are then continued
as outpatient treatment. Yet, PPI use is inappropriate in as many
as ~70–80% of these patients ( 29,30 ). Even uncertain rare risk is
unacceptable if a medication provides no clear bene t.
CONFLICT OF INTEREST
Guarantor of the article: Loren Laine, MD.
Speci c author contributions: L.L. and A.N.: reviewing literature
and dra ing manuscript.
Financial Support: None.
Potential competing interests : Loren Laine: data safety monitoring
board—Bayer; expert review for patent litigation regarding speci c
formulation of an NSAID-PPI combination. Anil Nagar: none.
REFERENCES
1 . S h e e n E , T r i a d a lopoulos G . Adverse e ects of long-term proton pump
inhibitor therapy . Dig Dis Sci 2011 ; 56 : 931 – 50 .
2 . L a z a r u s B , C h e n Y , W i l s o n F P et al. Proton pump inhibitor and the risk of
chronic kidney disease . JAMA Intern Med 2016 ; 176 : 238 – 46 .
3 . G o m m W , v o n H o l t K , ome F et al. Association of proton pump inhibi-
tors with risk of dementia. A pharmacoepidemiological claims data
analysis . JAMA Neurol 2016 ; 73 : 410 – 6 .
4. Bardhan KD , Muller-Lissner S , Bigard MA et al. Symptomatic gastro-
oesophageal re ux disease: double blind controlled study of intermittent
treatment with omeprazole or ranitidine . Br Med J 1999 ; 318 : 502 – 7 .
5. Pace F , Tonini M , Pallotta S et al. Systematic review: maintenance treatment
of gastro-oesophageal re ux disease with proton pump inhibitors taken
‘on-demand’ . Aliment Pharmacol er 2007 ; 26 : 195 – 204 .
6 . K a h r i l a s P J , S h a h e e n N J , V a e z i M F . A m erican gastroenterological associa-
tion technical review on the management of gastroesophageal re ux disease .
Gastroenterology 2008 ; 135 : 1392 – 413 .
7. Katz PO , Gerson LB , Vela MF . Guidelines for the diagnosis and management
of gastroesophageal re ux disease . Am J Gastroenterol 2013 ; 108 : 308 – 28 .
8 . S o n t a g S J , S o n n e n b e r g A , S c h n e l l T G et al. e long-term natural history
of gastroesophageal re ux disease . J Clin Gastroenterol 2006 ; 40 : 398 – 404 .
9. Hungin AP , Rubin GP , O'Flanagan H . Long-term prescribing of proton
pump inhibitors in general practice . Br J Gen Pract 1999 ; 49 : 451 – 3 .
10. van Soest EM , Siersema PD , Dieleman JP et al. Persistence and adherence
to proton pump inhibitors in daily clinical practice . Aliment Pharmacol
er 2006 ; 24 : 377 – 85 .
11. Singh S , Kumar S , Singh PP et al. Acid-suppressive medications and risk
of oesophageal adenocarcinoma in patients with Barrett’s oesophagus:
a systematic review and meta-analysis . Gut 2014 ; 63 : 1229 – 37 .
12. Shaheen NJ , Falk GW , Iyer PG et al. ACG clinical guideline: diagnosis
and management of Barrett’s esophagus . Am J Gastroenterol 2016 ; 111 :
30 – 50 .
13. Spechler SJ , Sharma P , Souza RF et al. American Gastroenterological
Association . American Gastroenterological Association medical position
statement on the management of Barrett’s esophagus . Gastroenterology
2011 ; 140 : 1084 – 91 .
14. Hvid-Jensen F , Pedersen L , Drewes AM et al. Incidence of adenocarcinoma
among patients with Barrett’s esophagus . N Engl J Med 2011 ; 365 : 1375 – 83 .
15. Bhat S , Coleman HG , Yousef F et al. Risk of malignant progression in
Barrett’s esophagus patients: results from a large population-based study .
J Natl Cancer Inst 2011 ; 103 : 1049 – 57 .
16. Lanza FL , Chan FK , Quigley EM et al. Practice Parameters Committee
of the American College of Gastroenterology . Guidelines for prevention
of NSAID-related ulcer complications . Am J Gastroenterol 2009 ; 104 :
728 – 38 .
17. Rostom A , Dube C , Wells G et al. Prevention of NSAID-induced gastro-
duodenal ulcers . Cochrane Database Syst Rev 2002 ; CD002296 .
18. Chan FKL , Chung SCS , Suen BY et al. Preventing recurrent upper
gastrointestinal bleeding in patients with Helicobacter pylori infection
who are taking low-dose aspirin or naproxen . N Engl J Med 2001 ; 344 :
967 – 73 .
19. Bhatt DL , Scheiman J , Abraham NS et al. ACCF/ACG/AHA 2008 expert
consensus document on reducing the gastrointestinal risks of antiplatelet
therapy and NSAID use . Circulation 2008 ; 118 : 1894 – 909 .
20. Yeomans N , Lanas A , Labenz J et al. E cacy of esomeprazole (20 mg once
daily) for reducing the risk of gastroduodenal ulcers associated with conti-
nuous use of low-dose aspirin . Am J Gastroenterol 2008 ; 103 : 2465 – 73 .
21. Lai KC , Lam SK , Chu KM et al. Lansoprazole for the prevention of
recurrences of ulcer complications from long-term low-dose aspirin use .
N Engl J Med 2002 ; 346 : 2033 – 8 .
22. Bhatt DL , Cryer BL , Contant CF et al. Clopidogrel with or without
omeprazole in coronary artery disease . N Engl J Med 2010 ; 363 : 1909 – 17 .
23. Talley NJ . American Gastroenterological Association . American Gastro-
enterological Association medical position statement: evaluation of
dyspepsia . Gastroenterology 2005 ; 129 : 1753 – 5 .
24. Talley NJ , Vakil N . Management of dyspepsia . Am J Gastroenterol
2005 ; 100 : 2324 – 37 .
25. Talley NJ , Vakil NB , Moayyedi P . American Gastroenterological Associa-
tion technical review on the evaluation of dyspepsia . Gastroenterology
2005 ; 129 : 1756 – 80 .
26. Moayyedi P , Shelly S , Deeks JJ et al. Pharmacological interventions for
non-ulcer dyspepsia . Cochrane Database Syst Rev 2000 ; CD001960 .
27. Wang WH , Huang JQ , Zheng GF et al. E ects of proton-pump inhibitors
on functional dyspepsia: a meta-analysis of randomized placebo-controlled
trials . Clin Gastroenterol Hepatol 2007 ; 5 : 178 – 85 .
28. Drugs@FDA: FDA approved drug products . Available at: http://www.
accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (accessed on
19 March 2016)
29. o m a s L , C u l l e y E J , G l a d o w s k i P et al. Longitudinal analysis of the costs
associated with inpatient initiation and subsequent outpatient continuation
of proton pump inhibitor therapy for stree ulcer prophylaxis in a large
managed care organization . J Manag Care Phar 2010 ; 16 : 122 – 9 .
30. Leri F , Ayzenberg M , Voyce SJ et al. Four-year trends of inappropriate
proton pump inhibitor use a er hospital discharge . South Med J 2013 ; 106 :
270 – 3 .
