1. health and fitness
2. therapy

386
the red section
nature publishing group
Treatment of GERD and Proton Pump Inhibitor
Use in the Elderly: Practical Approaches and
Frequently Asked Questions
Shannon Scholl, MD, MPH1, Evan S. Dellon, MD, MPH1 and Nicholas J. Shaheen, MD, MPH1
Am J Gastroenterol 2011;106:386–392; doi:10.1038/ajg.2010.409
The care of acid-related diseases such as
gastroesophageal reflux disease (GERD) in
the elderly patient presents challenges not
found in younger populations. Concurrent
comorbidities, medication interactions,
and the physiology of aging all conspire
to change the presentation and natural
history of these diseases in older patients.
Clinicians caring for geriatric patients
must therefore be aware of these changes
to provide optimal care for GERD and to
use acid-suppressive therapies to their best
advantage in the elderly population.
Below, we address several questions
that commonly occur in caring for acidrelated disease in the elderly population.
Although the recommendations proposed
below do not represent the only, or necessarily the “best,” way to care for all elderly
patients, they are solutions supported
by evidence found in elderly cohorts to
produce satisfactory results. The United
Nations’ definition of “elderly” is those
aged 60 or older, but, given the average
life expectancy in the United States, the
discussion below is focused primarily on
those 70 years and older.
Does the clinical presentation of GERD
change as patients age?
In the elderly population, as in the general
population, more than 40% have occasional
symptoms of GERD and 20% have weekly
Center for Esophageal Diseases and Swallowing,
University of North Carolina at Chapel Hill, Chapel
Hill, North Carolina, USA. Correspondence:
Nicholas J. Shaheen, MD, MPH, Center for
Esophageal Diseases and Swallowing, University
of North Carolina School of Medicine, CB#7080,
Chapel Hill, North Carolina 27599-7080, USA.
E-mail: [email protected]
1
The American Journal of Gastroenterology
symptomatic GERD. But as patients age,
the severity of heartburn diminishes, while
its complications become more frequent
(1–3). In a study of 12,000 patients aged
18–75 with endoscopically documented
erosive esophagitis, severe heartburn was
seen in 30% of patients aged more than
70 years with erosive esophagitis (compared with 47% of patients aged 31–40),
and severe esophagitis (defined as Los
Angeles grade C or D) was seen in 35% of
elderly patients vs. 25% of patients aged
31–40 among those with severe heartburn
(Figures 1 and 2) (4). Thus, while elderly
patients may have severe heartburn, severe
esophagitis may be present without the
hallmark accompanying symptoms. This is
probably due to several factors, including
decreased perception of mucosal damage.
Elderly patients without the typical symptom of heartburn may instead complain of
more atypical symptoms, including respiratory symptoms and vomiting (5). This
has important implications for patient
management. Aware clinicians should
have a low threshold for investigation and/
or empirical therapy in this patient population. Upper endoscopy in the elderly
with GERD will demonstrate a higher
yield of Los Angeles grade C or D erosive
esophagitis, Barrett’s esophagitis, and adenocarcinoma and, in most subjects, can be
done with a great degree of safety (6,7).
What are the most common side effects
of proton pump inhibitors?
Most mortality in GERD results from
esophageal adenocarcinoma. All data
suggesting that proton pump inhibitors
(PPIs) retard the development of dysplasia
and/or cancer are retrospective and weak
(8–10). Therefore, for most subjects suffering from GERD, the medication is used
primarily to address symptoms. Although
the decrement in quality of life associated
with GERD is substantial (11,12), the low
rate of morbidity and mortality means
that medications used to address GERD
must have excellent safety profiles to justify their use. Diarrhea, abdominal pain,
constipation, and headache are the most
common side effects of PPIs but are limiting in relatively few patients and typically
respond to dose reduction or discontinuation in those subjects. The risk of fundic
gland polyps (lesions with negligible, if
any, risk of dysplasia) may be increased
(13). No data support the cessation of PPI
use in subjects in whom they are otherwise indicated on account of the development of fundic gland polyps.
Serious complications of PPI use
appear to be rare and may result from
profound acid suppression and secondary
hypergastrinemia, hypochlorhydria, and
achlorhydria. The incidence of antibioticassociated Clostridium difficile colitis is
twice as high in PPI users. The putative
mechanism of this increased risk is that
hypochlorhydria prevents sterilization
of the upper gastrointestinal (GI) tract,
permitting colonization by pathogenic
species (14). By the same mechanism, the
risk of community-acquired pneumonia
is increased approximately twofold (15).
The same effect is seen, to a lesser degree,
in users of H2-receptor antagonists,
which supports the theory that reduction of the gastric acid barrier may be to
blame. However, studies investigating the
Volume 106 | march 2011 www.amjgastro.com
the red section
50
40
Patients (%)
35
40
30
30
25
20
20
15
10
Patients (%)
10
5
0
0
<21
21−30
31−40
41−50
51−60
61−70
>70
Figure 1. Prevalence of severe esophagitis by age-decade cohort.
(Adapted from ref. 4.)
effect of PPIs on community-acquired
pneumonia have been confounded by the
diagnosis of GERD, and it is unknown
whether GERD itself or the PPI use is the
predisposing factor. Concerns regarding hip fracture in the setting of PPI use
are addressed below. Additionally, recent
data suggest the potential for significant
medication interactions, which have
raised concerns about increased cardiac
events in subjects on PPIs. These issues
are also discussed below.
Given that both community-acquired
pneumonia and C. difficile infection are
more common and carry higher risks of
morbidity and mortality as patients age
(16), the associations described above
deserve special attention in the elderly
population. However, it should be noted
that the majority of data supporting these
more significant risks of PPI therapy are
derived from retrospective studies of large
databases, and such research is subject to
multiple forms of bias. Despite the weakness of the data supporting these risks,
to minimize side effects, PPIs should be
applied only when clinically indicated, at
the minimum effective dose.
Is it appropriate to change the PPI dose
for elderly or obese patients?
There are no data to support the use
of reduced doses of PPIs on the basis
of age alone. Pharmacokinetic studies
of omeprazole and lansoprazole show
© 2011 by the American College of Gastroenterology
<21
21−30
31−40
41−50
51−60
61−70
>70
Figure 2. Prevalence of severe heartburn by age-decade cohort.
(Adapted from ref. 4.)
reduced clearance (17,18) and increased
bioavailability (17) of these PPIs in
patients in the eighth and ninth decades
of life as compared with younger patients,
but, because of considerable overlap in the
pharmacokinetic profiles of the groups,
dose adjustment is not recommended.
There is no difference in the metabolism
of esomeprazole in elderly and middleaged patients with GERD (19).
PPI metabolism occurs via the cytochrome P450 system in the liver (20).
Clinically significant abnormalities of PPI
metabolism are rare and do not increase
in a healthy aged population. In elderly
subjects with normal hepatic function,
dose adjustment is not recommended.
Obesity is an independent risk factor for
GERD and erosive esophagitis, so these
patients frequently require PPI therapy.
There are many reasons to suspect that
an altered dose of PPI might be required
for obese patientsthey may have more
severe symptoms or a larger volume of
distribution of drug, and they often have
comorbid liver disease in the form of
hepatic steatosis. However, to date, no
study has shown an altered pharmacokinetic profile in obese patients for either
PPIs or H2-receptor antagonists. In fact,
despite the increased severity of GERD
with increasing body mass index (21,22),
there is no difference in the response to
comparable PPI doses in obese compared
with lean patients.
Is there a significant interaction
between PPIs and clopidogrel?
Concerns about PPI use in the setting
of concurrent clopidogrel therapy were
heightened in 2009, when a study by Ho
et al. in JAMA showed a higher rate of
acute coronary syndrome and/or mortality in 8,205 veterans who used PPIs and
clopidogrel (29.8%) vs. clopidogrel alone
(20.8%) (23). This was a retrospective
cohort study and had several limitations
inherent to that design. However, there
is a plausible biological mechanism supporting the interaction: ex vivo platelet
aggregation studies showed an interaction
between PPIs and clopidogrel due to inhibition of the CYP enzyme subclass that
converts clopidogrel to its active metabolite (24). Subsequent platelet aggregation
assays supported an interaction but did
not evaluate the clinical results of such an
interaction. Later in 2009, an analysis of
2,208 subjects enrolled in a French registry following acute coronary syndrome
failed to show a difference between clopidogrel users taking PPIs and those taking
clopidogrel alone (25).
Two recent clinical studies and one in
vitro aggregometry study evaluated the
effect of pantoprazole, a weaker inhibitor of the CYP2C19 enzyme, on the effect
of clopidogrel. All of them showed less
interaction with pantoprazole than with
omeprazole (26,27) or esomeprazole (27)
or in comparison with all other PPIs (28),
The American Journal of Gastroenterology
387
388
the red section
raising hopes that pantoprazole could
be safely used in these patients. However, a more recent retrospective study of
1,033 patients readmitted to the hospital
for acute myocardial infarction or stent
placement showed similar rates of rehospitalization for users of pantoprazole vs.
other PPIs (29).
Results of an industry-sponsored study
evaluating the clinical significance of an
interaction between PPIs and clopidogrel
have recently been released in abstract
form. The COGENT (Clopidogrel and the
Optimization of Gastrointestinal Events)
study randomized subjects in need of
clopidogrel because of either recent acute
coronary syndrome or stent placement
into a clopidogrel and an omeprazole
plus clopidogrel group. All patients were
maintained on dual antiplatelet therapy
with aspirin. Deaths from cardiovascular
events were then assessed in both groups
over a median of 4 months. The resulting
survival curves for myocardial infarction, revascularization, and composite
cardiovascular events for the treatment
and placebo groups are superimposable,
providing striking evidence for a lack
of interaction between omeprazole and
clopidogrel. However, the survival curves
for composite GI events do show a protective effect of omeprazole (P = 0.007),
suggesting that PPI use can ameliorate the
GI effects of aspirin in this patient population. These results from a large, randomized, well-controlled prospective trial
provide evidence that omeprazole is safe
when used with dual antiplatelet therapy
and provides important protection from
GI complications. However, the validity
of the trial was challenged because of its
premature terminationthe sponsor of
the trial declared bankruptcy, and all trial
proceedings immediately halted before
completion of the study (30).
Because of the unclear nature of the data
surrounding an interaction between PPIs
and clopidogrel, on 17 November 2009, the
US Food and Drug Administration (FDA)
issued a warning regarding the concomitant use of clopidogrel and PPIs, stating,
“New data show that when clopidogrel and
omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients
The American Journal of Gastroenterology
Table 1. Risk categories for endoscopic procedures
High risk
Low risk
Polypectomy
Diagnostic: EGD ± biopsy
Biliary sphincterotomy
Diagnostic: flexible sigmoidoscopy ± biopsy
Pneumatic or bougie dilation
Diagnostic: colonoscopy ± biopsy
PEG placement
ERCP without sphincterotomy
EUS with FNA
Biliary/pancreatic stent without sphincterotomy
Laser ablation and coagulation
EUS without FNA
Treatment of varices
Enteroscopy
EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; PEG, percutaneous endoscopic gastrostomy.
Adapted from ref. 43.
at risk for heart attacks or strokes who use
clopidogrel to prevent blood clots will not
get the full effect of this medicine if they
are also taking omeprazole” (31). Given
the divided nature of the data on this issue,
the need for the warning is unclear. An
alternative approach being used by some
physicians—dosing one medication in the
morning and the other at night—may be
ineffective. The most recent package insert
for clopidogrel reports an unreferenced
study of 72 patients that showed that split
dosing did not reduce the interaction. For
now, physicians should warn patients of
a potential interaction. When possible,
avoidance of coadministration of omeprazole and clopidogrel may be warranted
until the potential interaction is better
understood. In cases of patients who are
considered to be at high risk for GI bleeding, the risk of reduced activity of clopidogrel must be weighed against the risk of
GI bleeding, and decisions about treatment
must be made on a case-by-case basis.
What other medication interactions do
I need to consider when prescribing
PPIs?
Polypharmacy is common in elderly
populations, and therefore medication
interactions take on special importance
in older patient populations. Fortunately,
there have been very few significant medication interactions associated with PPI
use. As noted above, metabolism by the
CYP450 superfamily of enzymes may lead
to rare inhibition or potentiation of simi-
larly metabolized drugs, such as warfarin,
diazepam, and phenytoin, but these occur
so rarely (less than one adverse event per
million prescriptions) that they are not
considered clinically significant (32–34).
PPIs are metabolized via the CYP2C19
subclass, a minor pathway for metabolism
of the weaker R-warfarin enantiomer of
warfarin, raising the levels of this minor
metabolite by up to 12% (35). Omeprazole
may be the most active in this regard (36).
Although not formally recommended, in
subjects who have had marked lability of
drug levels or in those with severe clinical syndromes, the clinician may wish
to check for stability of the international
normalized ratio or phenytoin level after
a new PPI prescription is initiated.
Should PPIs be used to protect against
GI complications of low-dose aspirin?
Given the high prevalence of coronary
artery disease in the elderly, the use of
cardioprotective aspirin is frequent in
this population (37). Since the risk of
gastroduodenal ulceration also increases
with age, prophylaxis against the GI
complications of aspirin in the setting
of cardioprotection is a commonly faced
clinical issue in the elderly population.
Aspirin exerts its gastropathic effects by
direct epithelial damage and by inhibition of mucosal prostaglandin production, which reduces mucosal defenses
including mucus and bicarbonate secretion, reducing blood flow, and reducing
epithelial-cell turnover and repair (38).
Volume 106 | march 2011 www.amjgastro.com
the red section
Table 2. Summary of recommendations for anticoagulation cessation
Avoid cessation of antiplatelet therapies after PCI with stent placement when possible
Avoid cessation of clopidogrel (even when aspirin is continued) within the first 30 days after PCI and
either DES or BMS when possible
Defer elective endoscopic procedures—possibly for up to 12 months, if clinically acceptable, from the
time of PCI and DES placement
Perform high-risk endoscopic procedures 5–7 days after clopidogrel therapy and 3–5 days after
cilostazol cessation. Aspirin should be continued when possible
Resume antiplatelet therapy after the procedure, once hemostasis has been achieved
Continue clopidogrel and aspirin in patients undergoing elective low-risk endoscopic procedures
BMS, bare-metal stent; DES, drug-eluting stent; PCI, percutaneous coronary intervention.
Adapted from ref. 45.
The risk of GI bleeding in patients using
low-dose aspirin is approximately twice
the rate with placebo and carries a 5%
case-fatality rate when severe enough
to require admission (39). The risk of
bleeding is increased in those who have
a history of prior GI events, are older,
or use anticoagulants, corticosteroids,
or high-dose or multiple nonsteroidal
anti-inflammatory drugs (NSAIDs).
Cyclooxygenase-2-selective NSAIDs are
less gastropathic, but use of low-dose
aspirin largely obviates their gastroprotective effects. PPIs have been found to
be superior to full-dose ranitidine and
placebo for the healing of NSAID-associated ulcers irrespective of Helicobacter
pylori status, in a dose-dependent manner (40–42). The lowest effective dose of
aspirin (and other NSAIDs) should be
used, and risk factors for bleeding should
be assessed, with application of PPIs in
high-risk groups, as noted above.
How should we manage patients
receiving antiplatelet therapy who need
endoscopy?
In considering an endoscopic procedure on
an anticoagulated patient, the risk of ongoing or procedure-related bleeding must be
weighed against the risk of thromboembolic events such as cerebrovascular accident
or myocardial infarction following discontinuation of anticoagulation. Low-risk
procedures such as diagnostic esophagogastroduodenoscopy, endoscopic ultrasound (without fine-needle aspiration),
endoscopic retrograde cholangiopancre© 2011 by the American College of Gastroenterology
atography (without sphincterotomy), and
colonoscopy (without polypectomy) do not
require cessation of anticoagulants. Biopsy
with forceps is considered a low-risk procedure. High-risk procedures (polypectomy,
percutaneous endoscopic gastrostomy
placement, fine-needle aspiration, sphincterotomy, and dilatation) do warrant cessation of anticoagulation, which is typically
discontinued 3–5 days (cilostazol) or 5–7
days (aspirin, clopidogrel) before the procedure (Table 1) (43).
Clopidogrel–aspirin dual therapy is
used to prevent stent thrombosis following
percutaneous coronary intervention, as
primary prevention of myocardial infarction in patients with unstable angina or
nonintervenable coronary artery disease,
and as secondary prevention of myocardial infarction and cerebrovascular accidents and in those with a prior history of
the same (44,45). If clopidogrel alone must
be stopped within the first 30 days following bare-metal stent or drug-eluting stent
placement, the risk of restenosis is low,
estimated at 1–4%, the highest risk being in
patients with longer stent lengths (suggesting more severe disease) and lower ejection
fraction (46–51). Cessation of both aspirin
and clopidogrel is associated with a higher
risk of acute coronary syndrome and STelevation myocardial infarction and also
confers a shorter time to stent thrombosis
(7 days for those on no antiplatelet therapy
vs. 122 days for patients still on aspirin)
(52). As the current American Society for
Gastrointestinal Endoscopy guidelines
indicate that standard doses of aspirin and
other NSAIDs do not increase the risk of
significant bleeding with polypectomy and
sphincterotomy (43,53–55), aspirin should
be discontinued for colonoscopy or endoscopic retrograde cholangiopancreatography only if there is an additional strong
clinical indication to do so. Cessation of
clopidogrel alone beyond 30 days from
bare-metal stent placement is common and
does not confer increased risk of thrombosis over a short period of time. Similarly,
short-term cessation of clopidogrel alone
beyond 6 months from drug-eluting stent
placement does not confer significant
risk if aspirin is continued (46). But as a
general principle, for elective procedures
that would require interruption of antiplatelet therapy (such as routine screening
colonoscopy with polypectomy), deferral
until 12 months after percutaneous coronary intervention with drug-eluting stent
placement is preferable.
There is no evidence that bridging with
heparin reduces the risk of thrombotic
events when antiplatelet therapy is discontinued (56,57). Table 2 summarizes
the recommendations for anticoagulation
cessation.
When is it appropriate to do screening
upper endoscopy on the elderly patient
with chronic GERD?
Weekly heartburn symptoms are present
in 20% of elderly patients and, as noted
above, often portend more severe endoscopic disease than comparable symptoms
in younger patients. Increasing age is a risk
factor for Barrett’s esophagus and esophageal adenocarcinoma. But the presence of
heartburn is not a reliable predictor for the
presence of Barrett’s esophagus in this age
group, because conversion to columnar
epithelium may be associated with loss of
symptomatic heartburn (58). Even when
present, symptomatic heartburn is not
a reliable risk factor for Barrett-related
cancer because 40% of those with a new
diagnosis of esophageal adenocarcinoma
report an absence of prior weekly heartburn. Clearly, any elderly patient with
heartburn that is unresponsive to PPI and/
or with dysphagia should be considered for
endoscopy. But screening of patients with
uncomplicated chronic heartburn of any
The American Journal of Gastroenterology
389
390
the red section
age is controversial, because of the lack of
direct evidence demonstrating a mortality
benefit. As a result, the value of endoscopic
screening of subjects with chronic GERD
symptoms of any age for Barrett’s esophagus is highly contested. Economic modeling suggests that screening of white men
aged more than 50 years with heartburn
symptoms for at least 5 years is probably
cost-effective (59). Moreover, regardless
of age, any patient with alarm symptoms
such as weight loss, anemia, dysphagia,
or GI bleeding should undergo screening
endoscopy.
When is it appropriate to stop
performing surveillance endoscopy
for elderly patients with Barrett’s
esophagus?
When Barrett’s esophagus is diagnosed,
surveillance for dysplasia and adenocarcinoma is often performed. Approximately
5% of patients diagnosed with Barrett’s
will develop adenocarcinoma, and the risk
is greatest in patients aged 65–74 years
(60–62). However, the risk of cancer in any
given patient in a calendar year is small,
estimated at 0.5% per year. For this reason,
frequent surveillance of all patients with
nondysplastic Barrett’s is not cost-effective (59). Current guidelines recommend
repeating endoscopy with four-quadrant
biopsies within one year after the initial
diagnosis of Barrett’s to detect any prevalent dysplasia. Following that, decisionanalysis studies suggest that endoscopic
surveillance of persistent nondysplastic
Barrett’s could be performed every 5 years
(63). Surveillance should be ended when
the life expectancy is less than 1 year or the
patient could not be expected to tolerate
endoscopic or surgical therapy in the event
of a cancer diagnosis (64). Given the rise
of endoscopic therapy for dysplastic Barrett’s esophagus (65,66), and the increasing
life expectancy of the elderly in the United
States, thinking about when to stop surveillance is evolving. Given that most patients
who can tolerate surveillance endoscopy
can also tolerate some form of endoscopic
therapy, and that the onset of adenocarcinoma of the esophagus is late in life, clinicians should not use chronological age
alone as a reason to stop surveillance. CanThe American Journal of Gastroenterology
cer death may be averted and life extended
in otherwise healthy subjects without lifelimiting comorbidity even late in life with
well-timed endoscopic intervention.
Does PPI use affect vitamin B12
absorption?
Vitamin B12 is liberated from protein
sources with the help of gastric acid. There
has been concern that PPI use would interfere with this process, leading to B12 malabsorption and deficiency. Studies comparing
healthy controls with PPI users have had
conflicting results (67–69). There may be
a decline in B12 levels in long-term (>3year) users of PPI, but this has not been
shown to result in clinical disease (70).
The elderly are at risk for development of
pernicious anemia and should be screened
for B12 deficiency if macroblastic anemia is
detected. Otherwise, routine monitoring
of vitamin B12 or other vitamins in chronic
PPI users is not necessary.
Does PPI use increase the risk of hip
fracture in the elderly?
A 2006 article by Yang et al. (71) in JAMA
gained media attention by suggesting that
PPI use conferred an increased risk of hip
fracture in patients 50 years of age or older.
In this study, higher dose and duration of
PPI use conferred an odds ratio (OR) of
1.59 (95% confidence interval 1.39–1.80)
for use for more than 3 years. Two other
studies found similar results, with the largest odds ratio being 1.92 (1.16–3.18) after
7 years of PPI use (72,73). All of the studies
were retrospective case-control designs (a
design that is subject to multiple forms of
bias), and none of the studies controlled for
vitamin D levels or fall risk. Importantly, a
recent study was unable to show an association of PPIs with increased fracture in
those without risk factors (74).
Reduced calcium absorption in the
hypochlorhydric stomach is a proposed
mechanism of increased fracture risk.
This concern originates from studies of
human subjects whose plasma calcium
and 24-hour urinary calcium levels were
reduced following concomitant calcium
carbonate and PPI administration (75).
A recent case–control study evaluated the
effect of PPIs on osteoporosis and bone
mineral density in a Manitoba registry of
21,933 patients (76). These investigators
found no relationship between PPI use and
osteoporosis or PPI use and loss of bone
mineral density over 5 years. These data
cast doubt on the hypothesis that PPIs promote bone loss. Regardless of the divided
nature of these data, on 25 May 2010, the
FDA issued a warning regarding the possible link between hip, wrist, and spine
fractures and PPI use. The FDA mandated
changes in the labels of all prescription
and over-the-counter PPI preparations
on the basis of these data and advised that
“healthcare professionals and users of proton pump inhibitors should be aware of the
possible increased risk of fractures of the
hip, wrist, and spine with the use of proton pump inhibitors, and weigh the known
benefits against the potential risks when
deciding to use them” (77).
In summary, studies evaluating PPIs
and fracture risk are methodologically
limited, and divided in their conclusions. There is some suggestion of a small
increase in fracture risk with an odds
ratio less than 2. The mechanism of any
increase in fracture risk is unclear but may
not occur through reduction of bone density. PPIs should be used only for appropriate clinical indications at the lowest
effective dose, and the possible increased
risk of hip fracture should be disclosed
to patients. In those who require highdose, long-term PPIs, osteoporosis and
fall risk should be assessed and modified
as appropriate through the use of calcium
supplements and/or bisphosphonates.
Conclusion
In summary, elderly patients represent
a special population with respect to PPI
therapy and acid-peptic disease. They have
more severe esophagitis and are at the
highest risk for complications of GERD,
including Barrett’s esophagus and esophageal adenocarcinoma. They often have
comorbidities that require NSAIDs or
antiplatelet therapy, which put them at risk
for GI bleeding and represent challenges
for management during endoscopic intervention. And they are often on multiple
medications, raising concern regarding
medication interactions.
Volume 106 | march 2011 www.amjgastro.com
the red section
Fortunately, PPI use has a favorable sideeffect profile and few significant drug interactions. Adverse effects of PPI therapy may
include an increased risk of C. difficile colitis, community-acquired pneumonia, and
hip fracture. The latter is an area of active
research and current controversy. A common-sense approach to pharmacotherapy
should be applied: prescribe PPIs only to
patients for whom therapy is indicated, and
do so at the smallest effective dose.
The effect of PPIs on clopidogrel is an
area of active research. A recent large prospective study showed no effect of PPIs on
myocardial infarction, but the FDA has
placed a warning on clopidogrel, citing this
interaction. The package insert does not
support split dosing as a means of avoiding
the interaction. For now, physicians should
dose PPIs judiciously in these patients and
warn them of the potential interaction.
In the setting of recent coronary stent
placement, prior stent thrombosis, or
prior cerebrovascular accident, clopidogrel should be discontinued only if
necessary, and preferably not within the
first 30 days following stent placement,
when the risk of in-stent stenosis is highest. In all situations, aspirin should be
continued as monotherapy if possible,
even in high-risk procedures. A PPI is
recommended as gastroprotection in
elderly patients who require daily aspirin
or other NSAID therapy.
Physicians should have a low threshold
for prescribing PPIs for elderly patients
who have symptomatic GERD and should
be alert for atypical presentations. There is
no evidence for adjusting the dose of PPI
for elderly or obese patients. Chronological age should not be used as a sole criterion for discontinuing Barrett’s dysplasia
surveillance; virtually any patient who can
tolerate endoscopy can tolerate endoscopic
ablative therapies.
CONFLICT OF INTEREST
Guarantor of the article: Nicholas J.
Shaheen, MD, MPH.
Specific author contributions:
Shannon Scholl and Evan S. Dellon
authored the paper; Nicholas J. Shaheen
edited the paper.
Financial support: None.
© 2011 by the American College of Gastroenterology
Potential competing interests:
Dr Shaheen receives research funding from
Takeda Pharmaceuticals, AstraZeneca,
Procter & Gamble, BÂRRX Medical, CSA
Medical, and Oncoscope Inc. He is a consultant for AstraZeneca, CSA Medical, and
Oncoscope Inc.
References
1. Zhu H, Pace F, Sangaletti O et al. Features of
symptomatic gastroesophageal reflux in elderly
patients. Scand J Gastroenterol 1993;28:235–8.
2. Manabe N, Yoshihara M, Sasaki A et al.
Clinical characteristics and natural history of
patients with low-grade reflux esophagitis. J
Gastroenterol Hepatol 2002;17:949–54.
3. Collen MJ, Abdulian JD, Chen YK. Gastroesophageal reflux disease in the elderly: more
severe disease that requires aggressive therapy.
Am J Gastroenterol 1995;90:1053–7.
4. Johnson DA, Fennerty MB. Heartburn severity
underestimates erosive esophagitis severity in
elderly patients with gastroesophageal reflux
disease. Gastroenterology 2004;126:660–4.
5. Raiha I, Hietanen E, Sourander L. Symptoms
of gastro-oesophageal reflux disease in elderly
people. Age Ageing 1991;20:365–70.
6. Horiuchi A, Nakayama Y, Hidaka N et al. Lowdose propofol sedation for diagnostic esophagogastroduodenoscopy: results in 10,662
adults. Am J Gastroenterol 2009;104:1650–5.
7. Qureshi WA, Zuckerman MJ, Adler DG et al.
ASGE guideline: modifications in endoscopic
practice for the elderly. Gastrointest Endosc
2006;63:566–9.
8. El-Serag HB, Aguirre TV, Davis S et al. Proton
pump inhibitors are associated with reduced
incidence of dysplasia in Barrett’s esophagus.
Am J Gastroenterol 2004;99:1877–83.
9. Hillman LC, Chiragakis L, Shadbolt B et al.
Effect of proton pump inhibitors on markers
of risk for high-grade dysplasia and oesophageal cancer in Barrett’s oesophagus. Aliment
Pharmacol Ther 2008;27:321–6.
10.Nguyen DM, El-Serag HB, Henderson L et al.
Medication usage and the risk of neoplasia in
patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2009;7:1299–304.
11.Lippmann QK, Crockett SD, Dellon ES et al.
Quality of life in GERD and Barrett’s esophagus is related to gender and manifestation of
disease. Am J Gastroenterol 2009;104:2695–
703.
12.Ofman JJ. The economic and quality-of-life
impact of symptomatic gastroesophageal reflux
disease. Am J Gastroenterol 2003;98:S8–14.
13.Jalving M, Koornstra JJ, Wesseling J et al.
Increased risk of fundic gland polyps during
long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 2006;24:1341–8.
14.Dial S, Alrasadi K, Manoukian C et al. Risk of
Clostridium difficile diarrhea among hospital
inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ
2004;171:33–8.
15.Laheij RJ, Sturkenboom MC, Hassing RJ et al.
Risk of community-acquired pneumonia and
use of gastric acid-suppressive drugs. JAMA
2004;292:1955–60.
16.Slotwiner-Nie PK, Brandt LJ. Infectious diarrhea in the elderly. Gastroenterol Clin North
Am 2001;30:625–35.
17.Landahl S, Andersson T, Larsson M et al.
Pharmacokinetic study of omeprazole in
elderly healthy volunteers. Clin Pharmacokinet
1992;23:469–76.
18.Flouvat B, Delhotal-Landes B, Cournot A et
al. Single and multiple dose pharmacokinetics
of lansoprazole in elderly subjects. Br J Clin
Pharmacol 1993;36:467–9.
19.Hasselgren G, Hassan-Alin M, Andersson T et
al. Pharmacokinetic study of esomeprazole in
the elderly. Clin Pharmacokinet 2001;40:145–
50.
20.Robinson M, Horn J. Clinical pharmacology
of proton pump inhibitors: what the practising
physician needs to know. Drugs 2003;63:2739–
54.
21.Hampel H, Abraham NS, El-Serag HB. Metaanalysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann
Intern Med 2005;143:199–211.
22.Jacobson BC, Somers SC, Fuchs CS et al. Bodymass index and symptoms of gastroesophageal
reflux in women. N Engl J Med 2006;354:2340–
8.
23.Ho PM, Maddox TM, Wang L et al. Risk of
adverse outcomes associated with concomitant
use of clopidogrel and proton pump inhibitors
following acute coronary syndrome. JAMA
2009;301:937–44.
24.Gilard M, Arnaud B, Cornily JC et al. Influence of omeprazole on the antiplatelet action
of clopidogrel associated with aspirin: the
randomized, double-blind OCLA (Omeprazole
CLopidogrel Aspirin) study. J Am Coll Cardiol
2008;51:256–60.
25.Simon T, Verstuyft C, Mary-Krause M et al.
Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med
2009;360:363–75.
26.Cuisset T, Frere C, Quilici J et al. Comparison
of omeprazole and pantoprazole influence on
a high 150-mg clopidogrel maintenance dose:
the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized
study. J Am Coll Cardiol 2009;54:1149–53.
27.Neubauer H, Engelhardt A, Kruger JC et al.
Pantoprazole does not influence the antiplatelet
effect of clopidogrel: a whole blood aggregometry study after coronary stenting. J Cardiovasc
Pharmacol 2010;56:91–7.
28.Juurlink DN, Gomes T, Ko DT et al. A
population-based study of the drug interaction
between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713–8.
29.Stockl KM, Le L, Zakharyan A et al. Risk of
rehospitalization for patients using clopidogrel
with a proton pump inhibitor. Arch Intern Med
2010;170:704–10.
30.Bhatt B. Is there an interaction between
clopidogrel and proton pump inhibitors: the
COGENT trial. Clinical Cardiology, 104th edn.
2009.
31.US Food and Drug Administration. Information for Healthcare Professionals: Update to the
Labeling of Clopidogrel Bisulfate (Marketed as
Plavix) to Alert Healthcare Professionals About
a Drug Interaction With Omeprazole (Marketed as Prilosec and Prilosec OTC) <http://
www.fda.gov/Drugs/DrugSafety/Postmarket-
The American Journal of Gastroenterology
391
392
the red section
DrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm> (17 November 2009).
32.Labenz J, Petersen KU, Rosch W et al. A
summary of Food and Drug Administrationreported adverse events and drug interactions
occurring during therapy with omeprazole,
lansoprazole and pantoprazole. Aliment Pharmacol Ther 2003;17:1015–9.
33.Kahrilas PJ, Shaheen NJ, Vaezi MF. American
Gastroenterological Association Institute
technical review on the management of gastroesophageal reflux disease. Gastroenterology
2008;135:1392–413.
34.Humphries TJ. Clinical implications of drug
interactions with the cytochrome P-450 enzyme
system associated with omeprazole. Dig Dis Sci
1991;36:1665–9.
35.Sutfin T, Balmer K, Bostrom H et al. Stereoselective interaction of omeprazole with warfarin
in healthy men. Ther Drug Monit 1989;11:176–
84.
36.Andersson T. Pharmacokinetics, metabolism
and interactions of acid pump inhibitors. Focus
on omeprazole, lansoprazole and pantoprazole.
Clin Pharmacokinet 1996;31:9–28.
37.Taha AS, Angerson WJ, Prasad R et al. Upper
gastrointestinal bleeding and the changing use
of COX-2 non-steroidal anti-inflammatory
drugs and low-dose aspirin. Aliment Pharmacol
Ther 2007;26:1171–8.
38.Ekstrom P, Carling L, Wetterhus S et al. Prevention of peptic ulcer and dyspeptic symptoms
with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug
therapy. A Nordic multicentre study. Scand J
Gastroenterol 1996;31:753–8.
39.Targownik LE, Nabalamba A. Trends in management and outcomes of acute nonvariceal
upper gastrointestinal bleeding: 1993-2003.
Clin Gastroenterol Hepatol 2006;4:1459–66.
40.Agrawal NM, Campbell DR, Safdi MA et
al. Superiority of lansoprazole vs ranitidine
in healing nonsteroidal anti-inflammatory
drug-associated gastric ulcers: results of a
double-blind, randomized, multicenter study.
NSAID-Associated Gastric Ulcer Study Group.
Arch Intern Med 2000;160:1455–61.
41.Blandizzi C, Tuccori M, Colucci R et al. Clinical
efficacy of esomeprazole in the prevention and
healing of gastrointestinal toxicity associated
with NSAIDs in elderly patients. Drugs Aging
2008;25:197–208.
42.Yeomans N, Lanas A, Labenz J et al. Efficacy of
esomeprazole (20 mg once daily) for reducing
the risk of gastroduodenal ulcers associated
with continuous use of low-dose aspirin. Am J
Gastroenterol 2008;103:2465–73.
43.Eisen GM, Baron TH, Dominitz JA et al. Guideline on the management of anticoagulation and
antiplatelet therapy for endoscopic procedures.
Gastrointest Endosc 2002;55:775–9.
44.Sabatine MS, Cannon CP, Gibson CM et
al. Addition of clopidogrel to aspirin and
fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med
2005;352:1179–89.
45.Chen ZM, Jiang LX, Chen YP et al. Addition of
clopidogrel to aspirin in 45,852 patients with
The American Journal of Gastroenterology
acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607–21.
46.Becker RC, Scheiman J, Dauerman HL et al.
Management of platelet-directed pharmacotherapy in patients with atherosclerotic
coronary artery disease undergoing elective
endoscopic gastrointestinal procedures. J Am
Coll Cardiol 2009;54:2261–76.
47.Leon MB, Baim DS, Popma JJ et al. A clinical
trial comparing three antithrombotic-drug
regimens after coronary-artery stenting. Stent
Anticoagulation Restenosis Study Investigators.
N Engl J Med 1998;339:1665–71.
48.Mauri L, Hsieh WH, Massaro JM et al.
Stent thrombosis in randomized clinical
trials of drug-eluting stents. N Engl J Med
2007;356:1020–9.
49.Cutlip DE, Baim DS, Ho KK et al. Stent thrombosis in the modern era: a pooled analysis
of multicenter coronary stent clinical trials.
Circulation 2001;103:1967–71.
50.Iakovou I, Schmidt T, Bonizzoni E et al. Incidence, predictors, and outcome of thrombosis
after successful implantation of drug-eluting
stents. JAMA 2005;293:2126–30.
51.Aoki J, Lansky AJ, Mehran R et al. Early stent
thrombosis in patients with acute coronary
syndromes treated with drug-eluting and bare
metal stents: the Acute Catheterization and
Urgent Intervention Triage Strategy trial. Circulation 2009;119:687–98.
52.Sianos G, Papafaklis MI, Daemen J et al.
Angiographic stent thrombosis after routine
use of drug-eluting stents in ST-segment
elevation myocardial infarction: the importance of thrombus burden. J Am Coll Cardiol
2007;50:573–83.
53.Cotton PB, Lehman G, Vennes J et al. Endoscopic sphincterotomy complications and their
management: an attempt at consensus. Gastrointest Endosc 1991;37:383–93.
54.Freeman ML, Nelson DB, Sherman S et al.
Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;335:909–18.
55.Shiffman ML, Farrel MT, Yee YS. Risk of bleeding after endoscopic biopsy or polypectomy
in patients taking aspirin or other NSAIDS.
Gastrointest Endosc 1994;40:458–62.
56.Collet JP, Montalescot G, Blanchet B et al.
Impact of prior use or recent withdrawal of
oral antiplatelet agents on acute coronary syndromes. Circulation 2004;110:2361–7.
57.Vicenzi MN, Meislitzer T, Heitzinger B et al.
Coronary artery stenting and non-cardiac surgery: a prospective outcome study. Br J Anaesth
2006;96:686–93.
58.Johnson DA, Winters C, Spurling TJ et al.
Esophageal acid sensitivity in Barrett’s esophagus. J Clin Gastroenterol 1987;9:23–7.
59.Inadomi JM, Sampliner R, Lagergren J et al.
Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis.
Ann Intern Med 2003;138:176–86.
60.Williamson WA, Ellis FH Jr, Gibb SP et al.
Barrett’s esophagus. Prevalence and incidence of adenocarcinoma. Arch Intern Med
1991;151:2212–6.
61.Spechler SJ, Robbins AH, Rubins HB et al.
Adenocarcinoma and Barrett’s esophagus. An
overrated risk? Gastroenterology 1984;87:927–
33.
62.Cameron AJ. Epidemiology of columnar-lined
esophagus and adenocarcinoma. Gastroenterol
Clin North Am 1997;26:487–94.
63.Provenzale D, Schmitt C, Wong JB. Barrett’s
esophagus: a new look at surveillance based on
emerging estimates of cancer risk. Am J Gastroenterol 1999;94:2043–53.
64.Wang KK, Wongkeesong M, Buttar NS. American Gastroenterological Association technical
review on the role of the gastroenterologist
in the management of esophageal carcinoma.
Gastroenterology 2005;128:1471–505.
65.Overholt BF, Lightdale CJ, Wang KK et al.
Photodynamic therapy with porfimer sodium
for ablation of high-grade dysplasia in Barrett’s
esophagus: international, partially blinded,
randomized phase III trial. Gastrointest Endosc
2005;62:488–98.
66.Shaheen NJ, Sharma P, Overholt BF et al.
Radiofrequency ablation in Barrett’s esophagus
with dysplasia. N Engl J Med 2009;360:2277–
88.
67.Koop H, Bachem MG. Serum iron, ferritin,
and vitamin B12 during prolonged omeprazole
therapy. J Clin Gastroenterol 1992;14:288–92.
68.Marcuard SP, Albernaz L, Khazanie PG.
Omeprazole therapy causes malabsorption of
cyanocobalamin (vitamin B12). Ann Intern
Med 1994;120:211–5.
69.Schenk BE, Festen HP, Kuipers EJ et al. Effect of short- and long-term treatment with
omeprazole on the absorption and serum
levels of cobalamin. Aliment Pharmacol Ther
1996;10:541–5.
70.Koop H. Review article: Metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther
1992;6:399–406.
71.Yang YX, Lewis JD, Epstein S et al. Long-term
proton pump inhibitor therapy and risk of hip
fracture. JAMA 2006;296:2947–53.
72.Vestergaard P, Rejnmark L, Mosekilde L. Proton
pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the
risk of fracture. Calcif Tissue Int 2006;79:76–83.
73.Targownik LE, Lix LM, Metge CJ et al. Use of
proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319–26.
74.Kaye JA, Jick H. Proton pump inhibitor use and
risk of hip fractures in patients without major
risk factors. Pharmacotherapy 2008;28:951–9.
75.Graziani G, Como G, Badalamenti S et al.
Effect of gastric acid secretion on intestinal phosphate and calcium absorption in
normal subjects. Nephrol Dial Transplant
1995;10:1376–80.
76.Targownik LE, Lix LM, Leung S et al. Protonpump inhibitor use is not associated with osteoporosis or accelerated bone mineral density
loss. Gastroenterology 2010;138:896–904.
77.US Food and Drug Administration. FDA Drug
Safety Communication: Possible Increased Risk
of Fractures of the Hip, Wrist, and Spine With
the Use of Proton Pump Inhibitors <http://
www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/
ucm213206.htm> (25 May 2010).
Volume 106 | march 2011 www.amjgastro.com