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GERIATRIC THERAPEUTICS
Editors: Michael Woodward, Head, Aged and Residential Care Services, Stephen Campbell, Consultant Geriatrician, Rohan
Elliott, Clinical Pharmacist, Graeme Vernon, Senior Drug Information Pharmacist, Francine Tanner, Clinical Pharmacist,
Austin Health; and Robyn Saunders, Consultant Pharmacist, Victoria.
Peptic Ulcer Disease in Older People
Gregory Lockrey, Lucy Lim
ABSTRACT
Peptic ulcer disease is a common disorder that affects millions
of people worldwide. When complications occur, peptic ulcer
disease can have a major impact on quality of life and on the
utilisation of the health system. Understanding the causative
roles of Helicobacter pylori and non-steroidal anti-inflammatory
drugs has led to changes in management of the disease.
Comorbidities in older people add further complexity to
treatment. This article summarises the clinical aspects of peptic
ulcer disease and outlines principles which enable effective
treatment.
J Pharm Pract Res 2011; 41: 58-61.
INTRODUCTION
The Nobel Prize in Physiology or Medicine 2005 was
awarded jointly to Barry J Marshall and J Robin Warren
‘for their discovery of the bacterium Helicobacter pylori
and its role in gastritis and peptic ulcer disease’. 1,2
Awarding of this prestigious prize highlighted the
importance of peptic ulcer disease and the potential for
improving clinical outcomes and decreasing healthcare
costs.
Older people comprise an increasing proportion of
most Western societies. Peptic ulcer disease has a major
impact on the health system and continues to be a
considerable cause of patient morbidity and mortality.
The past decade has seen the introduction of new antiinflammatory drugs, which theoretically should cause
fewer peptic ulcers. The greater use of aspirin from the
increasing awareness of its positive role in vascular
disease prevention has increased the risk of peptic ulcer
disease. The increasing use of non-aspirin antithrombotic
drugs also contributes to the risk of gastrointestinal
bleeding – the most frequent and life-threatening
complication of peptic ulcers. Therefore, an improved
understanding of peptic ulcer disease offers the
opportunity to prevent occurrence and implement
effective treatment.
AETIOLOGY
Peptic ulcers are defects of the gastrointestinal mucosa
that extend through the muscularis mucosa because of
the presence of acid and pepsin. A peptic erosion is a
similar defect that is superficial and does not penetrate
the muscularis mucosa. However, a peptic erosion cannot
always be distinguished from a peptic ulcer at endoscopy
and the two conditions often coexist. The principal causes
Gregory Lockrey, MBBS, MPH, FRACP, Gastroenterologist, Lucy Lim, MBBS
(Hons), Gastroenterology Registrar, Austin Hospital, Heidelberg, Victoria
Address for correspondence: Dr Gregory Lockrey, Department of
Gastroenterology, Austin Hospital, Heidelberg Vic. 3084, Australia.
E-mail: Gregory.Lockrey@austin.org.au
58
of peptic ulcers are Helicobacter pylori infection, and
the use of non-steroidal anti-inflammatory drugs (NSAID)
and aspirin. Smoking and excessive alcohol intake also
increase the risk of peptic ulcer disease. Age is another
risk factor, possibly a reflection of escalating H. pylori
infection and altered mucosal resistance.
Peptic ulcer disease is the cause of significant
morbidity with patients having a low health-related
quality of life. Gastric bleeding is a common initial
presentation and complications include perforation,
penetration and gastric outlet obstruction. The healthcare
costs of complicated peptic ulcer disease are
considerable; often requiring emergency endoscopy,
hospital admission and surgery.3
Non-Steroidal Anti-Inflammatory Drugs
The incidence of peptic ulcers in NSAID users during
endoscopy is around 20% and this incidence increases
linearly with age. It is estimated that over 50% of NSAID
use is in people over 60 years, of whom approximately
15% take these analgesics. NSAID use is frequently
associated with gastric ulcers, or with bleeding gastric or
duodenal ulcers.4
Cyclo-oxygenase-2 selective (COX-2) inhibitors are
possibly safer than conventional (non-selective) NSAID.
However, one large study demonstrated that the risk of
adverse upper gastrointestinal events increased in both
COX-2 inhibitor and non-selective NSAID users.5 Overall,
the incidence of adverse events was 1.4 per 100 person
years.5 The risk of adverse upper gastrointestinal events
was significantly higher for naproxen, diclofenac and
rofecoxib (OR 1.6 to 2.1) but not celecoxib. The use of
ulcer healing drugs reduces the risk of peptic ulcer disease
except when used in conjunction with diclofenac.6
The risk of bleeding from peptic ulcer disease in nonselective NSAID users is approximately 5-fold but less
for COX-2 inhibitors.7 The risk of bleeding from the upper
gastrointestinal tract depend on a variety of factors, such
as:
• history of previous complicated ulcer (OR 14);
• multiple NSAID use (including aspirin) (OR 8.9);
• high-dose NSAID (OR 7);
• anticoagulant therapy (OR 6.4);
• previous uncomplicated ulcer (OR 6.1);
• age over 70 years (OR 5.6);
• H. pylori infection (OR 3.5); and
• oral corticosteroids (OR 2.2).8
Gastrointestinal bleeding may be secondary to a
drug’s antiplatelet effect, which is supported by the
finding that clopidogrel also increases the risk of upper
gastrointestinal bleeding without ulceration. The
combination of low-dose aspirin with esomeprazole has
a lower rate of gastrointestinal bleeding than clopidogrel
alone.9
Journal of Pharmacy Practice and Research Volume 41, No. 1, 2011.
Increased risk of ulcer bleeding has also been
reported in users of selective serotonin reuptake
inhibitors. This risk is amplified by concomitant NSAID
use. This mechanism of action is not understood.10
Co-therapy with proton pump inhibitors reduces the
risk of NSAID-induced ulcers. Histamine H2-receptor
antagonists, by comparison, are less effective. In one
study, diclofenac plus omeprazole was as safe as celecoxib
alone. Another study reported that celecoxib and
esomeprazole caused less gastrointestinal bleeding than
celecoxib alone (5% vs 8.9% in 12 months).11 The latter
study suggests that there is a small but definite risk of
gastrointestinal bleeding when taking COX-2 inhibitors.
Aspirin
Low-dose aspirin increases the risk of gastrointestinal
bleeding 2-fold. The risk is higher in users with a history
of previous complicated ulcer, advanced age and
concomitant use of corticosteroids, NSAID, clopidogrel
or anticoagulants. 12 Histamine H2-receptor antagonists
are effective in preventing aspirin-induced injury;
however, proton pump inhibitors are more efficacious.13
Aspirin and COX-2 inhibitor users have a 28%
reduced risk of bleeding compared with aspirin and nonselective NSAID users. 14 This bleeding risk must be
weighed up with the benefits of aspirin in primary
prevention of cerebrovascular and coronary events.
Helicobacter pylori Infection
H. pylori infection is the leading cause of peptic ulcer
disease. Nearly all duodenal ulcers and up to two-thirds
of gastric ulcers are H. pylori positive. An increasing
prevalence of infections with age portends more H. pylori
positive ulcers in older people. The debate about the
exact causative mechanism of H. pylori infection
continues; nevertheless effective eradication therapy has
led to the cure of peptic ulcer disease.15,16
Endoscopic and non-invasive diagnostic testing is
widely available. While ‘test then treat’ strategies, usually
general practitioner initiated non-invasive diagnostic
testing, are widely advocated for younger patients, the
preferred approach in older patients is to establish an
accurate diagnosis before starting treatment.17 This is as
new symptoms in older patients, especially alarm
symptoms, such as anaemia, dysphagia/odynophagia,
bleeding, vomiting, weight loss and anorexia, warrant
endoscopy.
The incidence of H. pylori resistance to
clarithromycin is increasing with a resultant reduction in
the efficacy of standard eradication treatments. No longer
are these eradication treatments 90 to 95% successful
and alternative regimens have been proposed.18
Opinions vary as to whether NSAID are independent
risk factors or synergistic with H. pylori for
gastrointestinal bleeding risk, particularly in older
patients.19,20 Regardless of whether NSAID and H. pylori
interact, the combination is frequently encountered and
managing both reduces subsequent ulcer risk.8
While gastrointestinal symptoms may alert the
clinician to peptic ulcer disease, many patients are
asymptomatic. Complications such as bleeding are often
the first presentation of NSAID-related ulcers.6,8 Prompt
recognition will assist early hospital admission for
appropriate management.
Despite a decrease in the incidence of peptic ulcer
bleeding, the rate of mortality has not diminished.
Hospitalisation rates remain high for elderly NSAID users
(new and long-term users) and range from 12 to 22 per
1000 person-years.21 Deaths in this situation are often
due to comorbidities.22
PREVENTION
It is essential to identify individuals at greatest risk of
peptic ulcer disease or upper gastrointestinal
haemorrhage. Preventive strategies are most likely to
benefit patients with:
• previous history of ulcers (particularly complicated);
• multiple NSAID use (including aspirin);
• high-dose NSAID use;
• anticoagulant therapy;
• age over 70 years;
• H. pylori infection; and
• oral corticosteroid use.
Therefore, avoiding NSAID, decreasing the NSAID
dose, or COX-2 inhibitor use may reduce the risk of
complications.
Co-therapy with proton pump inhibitors in low-dose
aspirin or NSAID users is the most effective means of
preventing peptic ulcer disease in high-risk individuals.
Histamine H2-receptor antagonists are also effective in
some situations, but less so than the proton pump
inhibitors.12,13
Empirical H. pylori eradication is standard treatment
for duodenal ulcers. Screening is not routine, except in
populations with a high incidence of gastric cancer. In
2008, the Asia-Pacific Consensus Conference
recommended that: ‘H. pylori infection should be tested
for and eradicated … prior to long-term aspirin or nonsteroidal anti-inflammatory drug therapy in patients at
high risk for ulcers and ulcer-related complications’.23
This is especially true for gastric ulcers, where it is
standard practice to test for H. pylori infection prior to
antibiotic therapy.
MANAGEMENT
The principles of management for peptic ulcer disease
are straightforward and include:
• accurate diagnosis, usually endoscopic, to exclude
malignancy and assess H. pylori status;
• treating the cause, i.e. treat H. pylori if present and
cease causative drug;
• early recognition of complications, with appropriate
intervention as required, e.g. endoscopic or surgical;
• management of comorbidities (important to improve
outcomes);
• healing the ulcer; and
• repeat endoscopy to verify healing of gastric and
complicated duodenal ulcers.
Complicated Peptic Ulcers
Endoscopic intervention within 24 hours of presentation
reduces the duration of hospital stay in older people
with gastrointestinal bleeding. 24 Once endoscopic
haemostasis has been achieved, re-bleeding is greatly
reduced by treatment with intravenous or high-dose oral
proton pump inhibitors.25,26 Generally, 15% to 20% of
patients re-bleed within the first 3 days. In a recent series,
overall mortality secondary to peptic ulcer bleeding
ranged from 4% to 12% and when the bleeding recurred,
the mortality was 10 times higher.25
Journal of Pharmacy Practice and Research Volume 41, No. 1, 2011.
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Medications
Ideally, all NSAID should be ceased and consideration
given to substituting non-selective NSAID with COX-2
inhibitors. To heal peptic ulcers, patients should be
treated with either proton pump inhibitors or histamine
H2-eceptor antagonists. If aspirin or NSAID cannot be
ceased, co-therapy with proton pump inhibitors is more
effective than histamine H2-receptor antagonists (Tables
1 and 2).
Older patients are able to tolerate H. pylori
eradication treatments with limited adverse effects.
However, if compliance may be an issue, a dose
administration aid prepared by pharmacy may be of
benefit.
CONSIDERATIONS
Ulcer Bleeding with Low-Dose Aspirin
If patients experience ulcer bleeding while on low-dose
aspirin, prescribers are often in a quandary about whether
Table 1. Proton pump inhibitor doses for peptic ulcer disease
the aspirin should be ceased or therapy continued with a
Drug
Standard doses
Higher doses
proton pump inhibitor. It is necessary to weigh up the
cardiovascular and gastrointestinal risks of individual
Esomeprazole
20 mg daily
40 mg twice daily
patients. As aspirin has ulcerogenic and antiplatelet
Lansoprazole
30 mg daily
30 mg twice daily
effects, it is not surprising that a recent study concluded
20 mg twice daily or 40 mg daily that continuing aspirin in patients who bleed from peptic
Omeprazole
20 mg daily
ulcer disease may increase the risk for recurrent bleeding
Pantoprazole
40 mg daily
40 mg twice daily
but this may potentially reduce mortality rates.27
Rabeprazole
20 mg daily
20 mg twice daily
Some studies have suggested that cardiovascular
events or reduced drug efficacy are more frequent in
Table 2. Histamine H2 -receptor antagonist doses for peptic
clopidogrel users who take a proton pump inhibitor (often
ulcer disease
to reduce ulcer/bleeding risk from concomitant aspirin or
NSAID use). This increased risk has not been reported
Drug
Standard doses
with pantoprazole.
Famotidine
20 mg twice daily
Several authors have urged caution in drawing
Nizatidine
150 mg twice daily
conclusions from such studies, because they were
Ranitidine
150 mg twice daily
uncontrolled for important confounding factors,
particularly comorbidities or were not randomised.28,29
If patients test positive for H. pylori infection, it is Laine and Hennekens29 concluded that there was no
imperative that H. pylori be eradicated. In Australia, H. difference in cardiovascular events in those on both
pylori eradication is recommended for 7 days with clopidogrel and proton pump inhibitors.
esomeprazole+ amoxycillin+clarithromycin (Nexium Hp7,
Nevertheless, the US Food and Drug Administration
Klacid Hp7) – the only combination available on the has issued an alert for health professionals about a drug
Pharmaceutical Benefits Scheme (Table 3).
interaction between clopidogrel and omeprazole and urge
caution in this situation.30 Some go further and claim that
Table 3. Helicobacter pylori eradication therapy
current evidence does not justify a conclusion that proton
pump inhibitors are associated with cardiovascular events
Proton pump
Antibiotic
inhibitor
Duration among clopidogrel users. Ex-vivo studies of platelet
function may or may not be related to a clinical endpoint
amoxycillin 1 g clarithromycin omeprazole or
7 days
in patients. The authors add that changing to another
twice daily
500 mg twice
esomeprazole 20 mg
daily
twice daily
proton pump inhibitor or histamine H 2 -receptor
antagonists is not supported by any randomised study.31
For Penicillin Allergy
Another consideration may be to switch the lowmetronidazole clarithromycin omeprazole or
7 days
dose
aspirin for clopidogrel. A study from Hong Kong
400 mg twice
500 mg twice
esomeprazole 20 mg
reported that clopidogrel use was associated with more
daily
daily
twice daily
than 10 times the risk of ulcer bleeding compared with
low-dose aspirin plus esomeprazole use.32 Yet, many
When clarithromycin resistance is suspected or recommend clopidogrel in this situation.32
eradication is not successful, a variety of alternative
treatments have been proposed. The Asia-Pacific FUTURE
Consensus Conference concluded: ‘There appears to be Peptic ulcer disease in older people is complex, not just
an increasing rate of resistance to clarithromycin and because ulcer disease is multifactorial with different
metronidazole in parts of Asia, leading to reduced efficacy treatments, but because older people have numerous
of proton pump inhibitor-based triple therapy. There are comorbidities, and their regular medications may interact
insufficient data to recommend sequential therapy as an with the drugs used to treat or prevent ulcers and their
alternative first-line therapy in Asia. Salvage therapies complications.
that can be used include: (i) standard triple therapy that
The future should see tailoring of therapy to patients’
has not been previously used; (ii) bismuth-based risk categories, i.e. ulcer disease recurrence,
quadruple therapy; (iii) levofloxacin-based triple therapy; gastrointestinal bleeding, and cardiovascular.
and (iv) rifabutin-based triple therapy’.23
Competing interests: None declared
Some of these drugs (e.g. bismuth, tetracycline,
furazolidone) are available in Australia via the Special References
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Received: 21 June 2010
Revisions requested after external review: 7 February 2011
Revised version received: 21 February 2011
Accepted: 15 March 2011
Journal of Pharmacy Practice and Research Volume 41, No. 1, 2011.
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