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A FREE CONTINUING EDUCATION LESSON
Update on the Management
of Acid-Related Disorders:
A Canadian Perspective
OBJECTIVES
This professional development activity shares the clinical experience of
experts, demonstrates best clinical
practices, and highlights new clinical trials pertaining to the management of GI acid-related disorders.
At the completion of this activity,
pharmacists should be able to:
1. recognize the clinical impact of acidrelated disorders and associated GI
mucosal injury;
2. outline management strategies for
patients with uninvestigated dyspepsia,
GERD (erosive and non-erosive) and
PUD;
3. identify candidates for GI prophylaxis
in the setting of ASA/NSAID therapy;
4. discuss the role of the pharmacist in
managing patients with, or at risk for,
acid-related disorders.
INSTRUCTIONS
1. After carefully reading this lesson, study
each question and select the one answer
you believe to be correct. Circle the appropriate letter on the attached reply card.
2. Complete the card and mail, or fax
to (416) 764-3937.
3. Your reply card will be marked and
you will be advised of your results within
six to eight weeks in a letter from
Rogers Publishing.
4. To pass this lesson, a grade of 70%
(14 out of 20) is required. If you pass,
your CEU(s) will be recorded with the
relevant provincial authority(ies).
(Note: some provinces require individual
pharmacists to notify them.)
THIS FREE LESSON
IS APPROVED FOR
1.5 CE UNITS
By Doret Cheng, BScPharm, PharmD
and Lisa Burry, BScPharm, PharmD, FCCP
Doret Cheng is an internal medicine clinical pharmacy specialist with an active clinical and research
practice at Mount Sinai Hospital in Toronto. Doret is the Medicine Clinical Coordinator at Mount Sinai
where she deals with patients with dyspepsia as well as those with GI bleeding and other ulcer complications. Doret is currently leading a working group on an initiative to improve GI acid suppressive practices at Mount Sinai Hospital. She is a tutor for the Faculty of Pharmacy at the University of Toronto.
Lisa Burry is a critical care clinical pharmacy specialist with an active clinical and research practice in
the Medical-Surgical Intensive Care Unit at Mount Sinai Hospital in Toronto She is also the Surgical
Clinical Coordinator for Mount Sinai Hospital. Lisa deals with patients with active GI bleeding as well
as those at high risk of other GI ulcer complications. Lisa has provided many presentations to pharmacists and physicians on the management of variceal and non-variceal GI bleeding and is currently
working with Doret Cheng on an initiative to improve GI acid suppressive practices at Mount Sinai
Hospital. She is a tutor for the Faculty of Pharmacy at the University of Toronto.
The authors, reviewers and Pharmacy Practice magazine have each declared that there is no real or
potential conflict of interest with the sponsor of this lesson.
INTRODUCTION
Dyspepsia is the main manifestation of
acid-related conditions: functional or
non-ulcer dyspepsia (FD/NUD), gastroesophageal reflux disease (GERD),
peptic ulcer disease (PUD) and gastric,
esophageal or pancreatic cancer. The
prevalence of dyspepsia in Canada has
been estimated at approximately 29%
and may be as high as 50% in Western
countries.1 It significantly decreases
health-related quality of life and in
Canada, over $670 million is spent on
medication alone.2,3
Dyspepsia is a symptom complex
rather than a disease and its definition
has evolved over the last decade. It is difficult to establish a unifying definition of
dyspepsia since subjective symptoms and
their interpretation vary between
patients, physicians and even culture and
language. The Canadian Dyspepsia
(CanDys) Working Group defines dyspepsia as “a symptom complex of epigastric pain or discomfort thought to originate in the upper gastrointestinal tract,
and [which] may include any of the following symptoms: heartburn, acid regurgitation, excessive burping and/or belching, increased abdominal bloating, nausea, feeling of abnormal or slow digestion or early satiety.”1
The majority of patients with symptoms of upper gastrointestinal (GI) discomfort will present to the community
pharmacy or family physician seeking
SUPPORTED BY AN EDUCATIONAL GRANT FROM
Approved for 1.5 CE units
by the Canadian Council
on Continuing Education in
Pharmacy. File #327-1105.
March 2006
Update on the Management of Acid-Related Disorders: A Canadian Perspective | 1
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advice and/or a diagnosis. It is therefore
crucial that pharmacists recognize the
typical signs and symptoms and more
importantly the alarm features for
appropriate recommendations and referral. Pharmacists are in a prime position
to identify patients who have an acidrelated gastrointestinal disorder, to assess
their level of risk for complications, to
educate patients on self-management,
and to optimize care through collaboration with patients and physicians.
FIGURE 1:
Uninvestigated dyspepsia
NO
NO
Age >50 or alarm features?
• Vomiting
• Bleeding/anemia
• Abdominal mass/
unexplained weight loss
• Dysphagia
DETECTION & MANAGEMENT
OF GASTROINTESTINAL
ACID-RELATED DISORDERS
A) Uninvestigated dyspepsia
Prior to investigational work-up,
patients with dyspeptic symptoms are
considered to have uninvestigated dyspepsia. The CanDys Working Group,
consisting of a multidisciplinary group
of specialists, family physicians and
pharmacists, developed a clinical management tool (CMT) based on best
available evidence and expert opinion for
patients who present with new-onset or
recurrent dyspepsia.1 This tool provides
the primary-care physician with five key
questions to stratify and manage patients
based on clinical features and symptoms
(Fig 1). A unique feature of this tool is
that it highlights and prompts the physician to address the importance of possible non-GI causes of dyspeptic symptoms, which will require further investigation. The alarm symptoms requiring
urgent investigation include vomiting,
evidence of gastrointestinal blood loss or
anemia, abdominal mass or involuntary
weight loss, dysphagia, odynophagia and
chest pain.3 These symptoms may be
suggestive of an organic cause and pharmacists should advise patients to contact
their physicians immediately for further
investigation.
B) GERD
Gastroesophageal reflux disease (GERD)
is defined as “reflux of gastric contents
into the esophagus causing symptoms
sufficient to reduce quality of life and/or
esophageal injury.”3 It is the most common gastrointestinal and acid-related
disorder in Canada. In a survey of over
1,000 Canadians, 17% reported heartburn in the preceding three months and
YES
Other possible causes?
YES
Consider
• Cardiac
• Hepatobiliary
• Medication-induced
• Dietary indiscretion
• Other
Treat as appropriate
Investigate (Endoscopy
recommended)
NO
NSAID and/or regular
ASA use?
YES
Treat as NSAID-induced
(See section on peptic
ulcer disease)
YES
Treat as GERD
(see section on GERD)
YES
Treat as Hp positive
NO
Is dominant symptom
heartburn or regurgitation?
NO
Treat as
Hp negative
NO
Hp test positive?
1. UBT
2. Serology
Adapted from the CanDys Clinical Management Tool.1 ASA=Acetylsalicylic acid;
Hp=Helicobacter pylori; NSAID=Nonsteroidal anti-inflammatory drug;
GERD=Gastroesophageal reflux disease; UBT= Urea breath test
13% had moderate to severe symptoms
on a weekly basis.4 Quality of life is significantly affected, with patients reporting a poorer quality of life than those
with diabetes, hypertension, mild heart
failure or arthritis.5
The typical presentation of GERD
includes heartburn and regurgitation.
Heartburn may wax and wane, and is
usually worsened by lying down and
ingestion of food. In a recent Canadian
study (CADET-PE), reflux esophagitis
was by far the most common endoscopic finding in patients with uninvestigated dyspepsia regardless of the dominant
symptom reported.6 Most patients with
typical GERD symptoms do not undergo investigation; therefore the term
“heartburn-dominant uninvestigated
dyspepsia” encompasses GERD.3 Reflux
disease can also produce atypical symp-
2 | Update on the Management of Acid-Related Disorders: A Canadian Perspective
toms (extraesophageal manifestations)
such as shortness of breath and wheezing, cough, pharyngitis, hoarseness, and
chest pain (see Table 1).
Symptoms of acid reflux are likely
due to poor gastric emptying and contact of esophageal mucosa with acid and
pepsin. Structural and physiological
mechanisms such as the lower
esophageal sphincter (LES), bicarbonate
in saliva, and esophageal peristalsis form
the body’s anatomic defence against
reflux. LES dysfunction due to transient
relaxations and decreased tone,
esophageal peristaltic dysfunction and
abnormal gastric emptying may play a
role in the development of GERD. A
number of factors may alter natural
defence mechanisms and increase the
risk of reflux:
• Lifestyle factors (e.g. smoking, large
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TABLE 1:
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Extraesophageal
manifestations of GERD
ENT
• Cough
• Globus (sensation of lump in the
throat)
• Hoarseness/voice changes
• Laryngeal cancer
• Laryngitis
• Otitis media
• Pharyngitis
• Sinusitis
• Subglottic stenosis
• Vocal cord granulomas
Pulmonary
• Asthma
• Cough
• Chronic bronchitis
• Idiopathic pulmonary fibrosis
• Pneumonia
Miscellaneous
• Chest pain
• Dental erosions
• Sleep apnea
Source: Fennerty MB. Extraesophageal
gastroesophageal reflux disease.
Gastroenterol Clin North Am 1999;
28:861-73.
TABLE 2:
Medications that may
worsen GERD
Drugs that
LES pressure
• Anticholinergic agents
• Barbiturates
• Benzodiazepines
• Caffeine and derivatives (aminophylline,
theophylline)
• Dihydropyridine calcium channel blockers
• Estrogen
• Ethanol
• Narcotics (meperidine, morphine)
• Nicotine (smoking)
• Nitrates
• Progesterone
Drugs that irritate the esophageal mucosa
• ASA
• Bisphosphonates
• Iron
• Non-steroidal anti-inflammatory drugs
• Potassium chloride
• Quinidine
Source: Weinberg DS, Kadish SL. The
diagnosis and management of gastroesophageal reflux disease. Med Clin North
Am 1996; 80: 411-29.
March 2006
meals, fatty foods, caffeine, pregnancy,
obesity, body position and estrogen)
• Medications that lower LES pressure
or cause direct GI irritation (Table 2)
• Hiatus hernia (increased esophageal
exposure to gastric contents)
The severity of symptoms and degree
of mucosal damage correlates with duration of exposure of the esophagus to gastric acid (duration of time pH<4).3
Therapies that prolong gastric acid suppression are therefore desirable for faster
symptom relief and improved healing
rates.
Lifestyle modification appears to have
limited effectiveness for patients with
severe and frequent GERD and welldesigned controlled trials are needed to
make any definitive conclusions regarding clinical efficacy.7 Despite the sparseness of controlled data, clinical experience suggests that patients with mild
symptoms would likely benefit from
strategies such as elevating the head of
the bed, avoiding lying down within two
hours of eating, avoiding food and medication triggers, reducing weight, quitting smoking, and decreasing coffee and
alcohol consumption.3,7
Various comparative trials have
shown that over-the-counter antacids
alone or combined with low-dose histamine-2 receptor antagonists (H2RAs;
e.g. ranitidine 75 mg or famotidine
10 mg) and antireflux agents such as
alginic acid and are effective for symptom relief in mild GERD.3,7,8 There is
suggestion that antacids provide quick
relief and OTC H2RAs provide a longer
duration of relief.9 There are very few
well-designed studies comparing OTC
H2RAs and antacids; however, due to
the availability and safety profile of these
agents, they are reasonable alternatives
for patients with very mild and infrequent symptoms, particularly if symptoms are associated with meals or triggered by certain foods.3
Prokinetic or promotility agents such
as cisapride, metoclopramide and domperidone have been studied in the treatment of GERD. These agents have been
proposed to peristalsis and LES tone.
Cisapride is the only prokinetic agent
that has shown clinical efficacy10; however, it is no longer available on the market
in Canada and is now only available
through the special access program due
to concerns about prolongation of QT
interval, ventricular tachycardia and
death. Due to the paucity of clinically
relevant data, these agents are not recommended alone or in combination with
anti-secretory agents for the long-term
maintenance treatment of GERD.3,11
The 2004 Canadian GERD Consensus
guidelines recommend that a once-daily
proton pump inhibitor (PPI) should be
used for the empirical treatment of
GERD unless symptoms are mild and
infrequent (i.e. fewer than three times
per week).3 This recommendation is
supported by a meta-analysis of 13 trials
in more than 3,000 patients where
PPIs were approximately twice as effective as H2RAs.12 Furthermore, 2 recent
Canadian studies showed that PPIs provide the highest rate of relief during the
first 2-4 weeks of therapy compared to
H2RAs.13,14
The CADET Heartburn-Dominant
(CADET-HR) study13 compared heartburn relief in patients with uninvestigated dyspepsia with PPI or an H2RA.
Three-hundred and ninety patients were
randomized to either omeprazole 20 mg
daily or ranitidine 150 mg twice daily
for the first 4-8 weeks, with an escalation
in therapy to omeprazole 40 or 20 mg,
respectively if symptoms persisted.
Results indicated that a PPI provides
better symptom relief at 4 weeks, but no
difference was observed for subsequent
relapses during a 6-month treatmentfree follow-up period. Forty-seven percent (47%) of patients on ranitidine
required escalation therapy due to inadequate heartburn relief, compared to
26% of patients who had started with
omeprazole. At 4 weeks, the difference
in heartburn relief was 27.8% in favour
of PPI-start strategy (55.1% vs. 27.3%,
p<0.001). The difference in median
times to sustained heartburn resolution
was 24 days in favour of PPI (5 vs. 29
days), and at 4 weeks the PPI-start strategy was better in achieving additional
heartburn relief and sustained effect
(NNT = 4).
The multi-centre CADET-HN
study14 comparing omeprazole, ranitidine, cisapride, or placebo in H pylorinegative primary-care patients with dyspepsia was recently published, providing
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more evidence that PPIs provide better
symptom relief compared to H2RAs and
motility agents. Five-hundred and
twelve patients were randomized to 4
weeks of treatment with omeprazole 20
mg daily, ranitidine 150 mg twice daily,
cisapride 20 mg twice daily or placebo
followed by on-demand therapy for an
additional 5 months. The study’s primary outcome measure was the Global
Overall Severity (GOS) score at 4 weeks,
measuring dyspepsia symptoms. At baseline, included patients reported at least
moderate symptom severity (GOS at
least 4/7). A score of 1 or 2 defined treatment success. Treatment success at 4
weeks was omeprazole 51.1%, ranitidine
36%, cisapride 30.5% and placebo
23.3% (NNT = 4, omeprazole vs. placebo; NNT = 7, omeprazole vs. ranitidine). At 6 months there were no statistically significant differences between
groups in terms of symptom relief.
Evidence of erosive esophagitis (EE)
on endoscopy accounts for up to twothirds of patients with symptoms of
reflux or 5 to 12% of the general population.3 The presence and severity of EE
does not correlate with the severity of
symptoms, however there is a correlation
with complications such as esophageal
strictures and Barrett’s esophagus (BE).
Severity of EE has been graded using the
LA classification system (see Table 3)
based on endoscopic evidence. Multiple
studies and meta-analyses provide evidence that PPIs in acute and long-term
treatment provide significantly greater
symptom relief and healing compared to
H2RAs or cisapride in EE (absolute differences in healing rates of 30-40%).15 In
addition, standard dose PPIs (Table 4)
are more effective than low-dose PPIs.16
Standard dose PPIs (Table 4) have been
compared in 24-hour intragastric pH
studies. According to a 5-way crossover
trial comparing esomeprazole 40 mg to
all other agents at standard doses,
esomeprazole provided a longer duration
of acid suppression (pH>4).17 At this
point, no unifying recommendations
have been made regarding choosing one
PPI over another since the clinical relevance of various direct comparisons is
still under debate.3,18
Barrett’s esophagus (BE), a metaplastic change from normal esophageal squa-
TABLE 3:
The Los Angeles classification system for the endoscopic assessment of
esophagitis
Grade Definition
A
One or more mucosal breaks no longer than 5 mm, none of which extends between
the tops of the mucosal folds.
B
One or more mucosal breaks more than 5 mm long; none of which extends between
the tops of 2 mucosal folds.
C
Mucosal breaks that extend between the tops of 2 or more mucosal folds, but
which involve less than 75% of the esophageal circumference.
D
Mucosal breaks which involve at least 75% of the esophageal circumference.
Source: Lundell L, Dent J, Bennett J, et al. Endoscopic assessment of oesophagitis: Clinical
and functional correlates and further validation of the Los Angeles classification. Gut
1999;45:172-80.
TABLE 4:
Standard daily doses of proton pump inhibitors and H2RAs1,3
Rx
Daily Dose
Management of GERD/Heartburn
Proton Pump Inhibitors
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
40 mg
30 mg
20 mg
40 mg
20 mg
4 weeks* then reassess; if inadequate
response, increase to twice-daily dosing
(4-8 weeks)+
400 mg OD or BID
20 mg OD or BID
150 mg OD or BID
150 mg OD or BID
4 weeks* then reassess; if inadequate
response, change to PPI (4-8 weeks)+
Histamine-2 Receptor Antagonists
Cimetidine
Famotidine
Nizatidine
Ranitidine
*Stop therapy after 4 weeks if symptoms resolved. If symptoms recur, repeat original therapy.
Pts with EE or BE should be on continuous maintenance therapy.
+If no response after 4-8 weeks of intensified therapy, further investigation is warranted.
TABLE 5:
H pylori diagnostic testing
Method
Comments
Endoscopy not required
Urea Breath Test (UBT)
Blood
Fecal antigen
•UBT detects active infection by testing for the enzymatic activity
of bacterial ureases.
•Antibodies can be detected from blood, plasma or serum.
Serology will remain positive for those previously infected as
antibodies remain after eradication.
•Fecal antigen testing identifies active infection by detecting the
presence of antigens in stools.
Endoscopy required
Rapid Urease tests
Histology
Culture
•Endoscopy is highly sensitive for the diagnosis of GU/DU and
allows for biopsies and cytologic brushings in order to differentiate
a benign ulcer from a malignant lesion
•Culture primarily used in research studies
•Much more invasive and expensive compared to UBT, blood and
fecal antigen testing
Adapted from 33,39
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mous epithelium to columnar intestinal
epithelium, is a serious complication of
GERD. The incidence of BE increases
with higher frequency (>3 times per
week), severity and duration (>20 years)
of GERD symptoms. BE has been associated with the development of
esophageal adenocarcinoma; Canadian
data show that the absolute risk of progression to adenocarcinoma in patients
with long-standing GERD is approximately 0.4%.19 Although the likelihood
of gastric or esophageal cancer is relatively low, the prevalence of cancer increases
with age (>50) and with the severity, frequency and duration of GERD symptoms. North American gastroenterology
guidelines recommend lifelong PPI therapy for BE patients along with periodic
endoscopic surveillance.19,20 A strategy
called “once in a lifetime” endoscopy has
been developed for patients with chronic GERD, calling for endoscopy after 10
years of GERD symptoms to identify
patients who have BE. Notwithstanding,
life-long PPI treatment and “once in a
lifetime” endoscopy has not been shown
to reduce the incidence of gastric or
esophageal cancer.19
For patients who fail to respond to
standard-dose therapy and/or with
severe esophagitis (LA Grade C or D, or
stricture), some may obtain relief with
double-dose or longer duration of PPI
therapy.21,22 Recently, there have been
some data to suggest that high-dose PPI
therapy reduces symptoms in patients
with extraesophageal manifestations of
GERD such as non-cardiac chest pain
(NCCP). Two meta-analyses showed
that using higher doses of PPI (omeprazole 40/80 mg or lansoprazole 30 mg)
for up to 4 weeks is a useful and potentially cost-saving strategy to diagnose
and treat patients with NCCP. The small
number of trials and patients included in
these meta-analyses limit their generalizability; therefore more evidence is needed to confirm these results.23,24
C) Functional (non-ulcer) dyspepsia
The diagnosis of functional dyspepsia
(FD), also referred to as non-ulcer dyspepsia (NUD) is defined as 12 weeks or
more of persistent or recurrent dyspepsia
within the last 12 months plus the
absence of evidence that organic disease
March 2006
is likely to explain the symptoms
(including evidence from upper
endoscopy).2 This implies that a complete diagnostic evaluation has been
completed and any obvious structural
abnormality such as PUD or reflux
esophagitis has been ruled out.
Symptoms are frequently described as
ulcer-like (e.g. burning) or dysmotilitylike (e.g. nausea, bloating, early satiety,
anorexia). Several pathophysiologic
mechanisms have been proposed: motility abnormalities, visceral sensory abnormalities, psychological factors or chronic
gastritis secondary to infection. One of
the more prevalent theories currently
being investigated is the possible relation
between Hp infection and FD/NUD.
Dyspepsia has been shown to occur after
intentional Hp infection,25 suggesting a
correlation; however, treatment results
have been inconsistent and the role of
Hp in non-ulcer dyspepsia remains controversial.26-29
Psychosocial factors (e.g. anxiety,
depression and stress) have been shown
in epidemiological studies to be more
prevalent in patients with FD/NUD. A
systematic review evaluated the effects of
psychotherapy, cognitive behaviour therapy, relaxation therapy and guided
imagery or hypnosis.30 The 3 trials
included in the review showed improvement of symptoms at 12 weeks; however, the effect was no different after one
year. Due to the heterogeneity of these
studies, the results were not pooled and
no specific recommendations were
derived. Psychotherapy should be evaluated on an individual basis and considered in patients with a significant psychiatric condition or as an adjunct to
medical management.
The management of FD/NUD is
often based on the predominant symptoms patients report. A plethora of data
has been published and recently a
Cochrane review analyzed 61 pharmacological intervention trials (antacids, bismuth salts, sucralfate, misoprostol, prokinetic agents, H2RAs and PPIs) for
NUD.31 Due to trial limitations and significant heterogeneity, the management
of NUD remains challenging and subjective. Nevertheless, indirect comparisons of the trials suggest that choice of
therapy should be based on individual
dyspepsia symptoms. Prokinetic agents
were significantly better than H2RAs for
symptoms of dysmotility such as nausea
and early satiety, whereas H2RAs were
better for heartburn. The evidence for
antisecretory agents for reflux symptoms
is strongest for PPIs as the studies were
generally of higher methodological
quality. However, due to the significant
overlap in patients with symptoms of
GERD and NUD, management of these
patients mirrors that of GERD. More
evidence is needed with clear delineation
of patients and symptoms before any
conclusions can be made.31
D) Peptic ulcer disease (PUD)
A peptic ulcer is a non-malignant lesion
in the GI mucosa that may be acute,
subacute or chronic. The major forms
are duodenal ulcer (DU) and gastric
ulcer (GU), and it is not uncommon for
patients to develop both simultaneously.
Lifetime prevalence is estimated to be
4-10% and is significantly higher in Hppositive subjects - 10-20%.32-34
In general, a poor correlation exists
between dyspeptic symptoms and presence of ulcers and there is no symptom
complex that can adequately differentiate between GU, DU and NUD.33,34,36
Patients may experience minimal symptoms while others have severe initial
presentation. Classic symptoms have
been described as epigastric pain
between the xiphoid process and the
umbilicus or discomfort characterized by
fullness, bloating, distention or nausea.35,36 Potential complications include
hemorrhage (15-20%), perforation
(5%), and gastric outlet obstruction
(2%).36
Two decades ago, almost all peptic
ulcers were considered to be idiopathic
or due to excess gastric acid, stress or
diet. Although acid injury is necessary
for ulcers to form, acid secretion is normal in almost all patients with GUs and
increased in only one-third of patients
with DUs. Today, it is well known that
PUD is the end result of a number of etiological factors that disrupt GI defence.
H pylori infection and NSAIDs are now
widely accepted as the major contributors to this disequilibrium.33,34 The
remainder of this discussion attempts to
update the reader on new guidelines or
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clinical trials related to Hp, NSAIDs and
the relationship between the two.
i) H pylori
H pylori infects ~ 20% of the western
world’s population; the incidence and
prevalence varying with age and economic status.37,38 Factors associated with
an increased prevalence include low
socio-economic status, poor sanitary
conditions and overcrowding. Up to
20% of those infected with Hp are found
to have PUD, with >90% identification
in DUs and 70-85% in GUs.33,39 Curing
Hp infection will not only reduce the
ulcer recurrence rate but also the risk of
type-B chronic atrophic gastritis, peptic
ulcer dyspepsia, and low-grade gastric
MALT lymphoma.40-42
H pylori can be detected using either
invasive or non-invasive techniques (see
Table 5). Important considerations in
selecting a test are availability, accuracy,
prior treatment for Hp, cost-effectiveness, the appropriateness of endoscopy,
and clinical circumstances that may
affect the results.39,42 As the incidence
and prevalence of Hp seems to be
decreasing in industrialized nations,
including Canada, the role of accurate
testing becomes increasingly important
and primary care diagnostic tests that
were once adequate need reappraisal.42
The 2004 Canadian H pylori Study
Group (CHSG) Consensus does not recommend stool antigen tests as an acceptable tool to diagnose infection in community-based practice based on lack of
sufficient evidence and the need for dedicated and experienced laboratory staff.42
Serology was not considered to be accurate in many Canadian populations
because, as the prevalence of infection
declines, the predictive value of serology
will become less reliable.42,43 For now, the
urea breath test remains first choice
when endoscopy is not indicated.
Since Hp was first cultured from the
human GI tract in 1984, the relationship between it and GI ulcers has been
explored in >3,000 RCTs, with a multitude of data supporting eradication rates
of up to 96% with some regimens.33
Compared with acid suppression alone,
Hp eradication therapy has been well
proven to facilitate ulcer healing and
reduce ulcer recurrence and complica-
TABLE 6:
Regimens for H pylori eradication
Regimen
Comments
Triple Therapy
PPI bid
+
clarithromycin 500 mg bid
+
{amoxicillin 1 g bid
or metronidazole 500 mg bid}
•Duration 7-14 days
•Eradication rates of 80-90% in RCTs
•Clarithromycin 250 mg bid may be used in
metronidazole-based regimens but is inadequate
if combined with amoxicillin
•Metronidazole is typically substituted for amoxicillin
for penicillin allergic patients
Quadruple Therapy
H2RA bid or PPI bid
+
Bismuth subsalicylate
(525 mg) ii tab qid
+
metronidazole 250 mg qid
or 500 mg tid
+
tetracycline 250 mg qid
or 500 mg tid
TABLE 7:
•Ranitidine bismuth citrate was discontinued
from the Canadian market in 2000.
•Ranitidine should not be substituted for ranitidine
bismuth citrate
•Duration 14 days
•Eradication rates of 75-85% in RCTs
Risk Factors for NSAID/ASA-Induced Ulcers and Upper GI Complications
Established
• Advanced age (>65 years)
• History of PUD or ulcer-related complication (e.g. upper GI bleeding)
• High-dose NSAIDs
• ASA (including low cardioprotective dosages)
• Coagulopathy or concomitant anticoagulant or antiplatelet Rx - markedly
increase the risk of bleeding when used concurrently with NSAIDs or ASA.
There is evidence to suggest that antiplatelet drugs such as clopidogrel
and ticlopidine also increase the risk of GI bleeding when used in
combination with NSAIDs or ASA.
• Concomitant illness (e.g., cardiovascular disease, rheumatoid arthritis)
• Concomitant use of corticosteroids
Possible
• NSAID-related dyspepsia
• Duration of NSAID use (however as little as one week exposure has been
reported)
Adapted from 33,52,56-59
tion rates several-fold.33,42 After successful
eradication of Hp, recurrences of PUD
are expected to be <5% annually.33,44
Given the proven importance of eradicating infection, finding the “ideal” regimen is vital. Single- and dual-agent
therapy should not be used because of
the unacceptably low eradication rates
(<70%). CHSG guidelines suggests
quadruple therapy for 10-14 days is as
effective and well tolerated as 7-10 day
PPI-based triple therapy regimens (see
Table 6).42,45,46 However, given the complexity of a quadruple regimen, triple
therapy with a PPI is often made first
choice in practice. Newer evidence is
6 | Update on the Management of Acid-Related Disorders: A Canadian Perspective
emerging to suggest PPI-based triple regimens are more effective if administered
for 14 days, although the increase in
benefits is small (~5%).42,47
Treatment of Hp infection is now
complicated by a growing phenomenon
of antibiotic resistance, which will negatively impact eradication rates and limit
the utility of some of the current
options.42 Pre-treatment antimicrobial
resistance also has an important negative
impact on the efficacy of many regimens. A recent study from Nova Scotia
reported the following pretreatment
resistance rates: clarithromycin, 11%;
metronidazole, 19%; tetracycline, 2%;
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Strategies for Reducing GI Risk in Patients Receiving Chronic NSAID Therapy
Risk∂
Definition
Suggested management
Low
<65 yr, no ASA, no prior ulcer or
GI complication
Non-selective NSAID alone
Moderate One to two risk factors
(e.g., age >65 yr, high-dose
NSAIDs, low-dose ASA)
High
Partially selective NSAID (e.g. meloxicam)
plus PPI or misoprostol; or selective COX-2
inhibitor
≥3 risk factors or concomitant ASA, Selective COX-2 inhibitor plus PPI or
corticosteroids or warfarin
misoprostol*
Very high Prior ulcer or ulcer-related
complication
Selective COX-2 inhibitor plus PPI or
misoprostol* Consider avoiding non-selective
NSAIDs and selective COX-2 inhibitors
*Not studied in prospective RCTs; theoretically useful.
∂ Levels of risk represent general, but not complete agreement among experts. The preferred
strategy for each group remains uncertain and some of the suggested strategies have not
been investigated in appropriate clinical trials.
Compiled from references 56,57,60-62,73-75
and amoxicillin, 0%; confirming published U.S. data.42,48,49
Cases in which the patient has undergone more than one treatment without
successful eradication of Hp infection are
typically difficult to manage with low
likelihood of cure. CHSG suggests
susceptibility testing for those who fail
first-line therapy to guide selection of
the second treatment regimen.42
Traditionally, second-line treatments
have been quadruple agent regimens.
Recently, second-line therapy with a
fluoroquinolone-based triple regimen
(e.g. levofloxacin 250 mg bid + amoxicillin 1 g bid + esomeprazole 40 mg bid
for 10 days) has been explored.50,51
Preliminary results with fluoroquinolones are promising as eradication rates
>80% have been reported but results are
still preliminary and so the use should be
reserved for those who have failed firstline treatments.
ii) NSAID-related PUD
NSAIDs are the second most common
cause of PUD and ulcer-related upper
GI complications.52-55 The most significant NSAID-associated gastrointestinal
toxicities are peptic ulcers (~40% of
chronic users have endoscopic ulcers)
and serious complications (~1.5%) such
as upper GI bleeding and perforations,
that result in significant morbidity and
mortality.42 Given the widespread use
and the incidence of serious GI complications with NSAID (~3%/year), an
March 2006
exposure of 10 million patients could
result in 300,000 potentially fatal complications annually.33,52,56 Risk factors for
ulcers and complications secondary to
NSAIDs are presented in Table 7.
Additive risk is conferred when risk factors are combined.57
Prevention should be considered for
those at increased risk for GI injury or
those who would be at significant risk
for morbidity/mortality if a complication developed. A number of strategies
have been used to reduce the risk of
NSAID-related ulcers and complications: buffering or enteric coating of the
NSAID formulation; antacids; sucralfate; H2RAs; misoprostol; PPIs (see
Table 8). There is insufficient evidence
to support the use of buffer or enteric
coating, antacids or sucralfate in reducing the risk of NSAID-related ulcers and
their complications. H2RA co-therapy
has been shown to be effective in reducing
the risk of endcoscopic duodenal but
not gastric ulcers. Double-dose H2RA
co-therapy was effective at reducing the
risk of endoscopic DU and GU.52,53,55-57,60,61
Misoprostol has been shown to reduce
the risk of ulcer56-58,60-62 and serious ulcerrelated GI complications.57,62 Misoprostol
800 mcg/day was superior to 400 mcg/day
for the prevention of endoscopic gastric
ulcers; a dose response relationship was
not seen with duodenal ulcers.52,53,56,61
However, multiple daily dosing, its
uterotrophic effects, abdominal cramping, and dose-related diarrhea limit its
use. The total daily misoprostol dosage
may be reduced to minimize diarrhea,
but dosages as low as 400 mcg/day may
compromise its gastroprotective effect.
Substantial data has proven concomitant
use of a PPI substantially reduces the risk
of DU and GU associated with non-selective NSAIDs compared to various other
therapies56,57,60,61,64-66 Overall, H2RAs and
PPIs are better tolerated than misoprostol, and reduced NSAID related dyspeptic symptoms.61
An alternative proposed approach has
been to use COX-2 selective NSAIDs, as
it was previously observed that NSAIDs
with greater inhibition of COX-2 versus
COX-1 appeared to be associated with a
lower prevalence of GI ulceration and
erosions on endoscopic evaluation.57,67-69
This review would not be complete
without a brief discussion of the recent
COX-2 trials, despite the fact that in late
2004, evidence became available associating COX-2 use with significant cardiovascular concerns, increased risk of heart
attach and stroke, compared with placebo. Since the publication of this information celecoxib is the only remaining
selective COX-2 agent on the Canadian
market and is typically avoided in those
at risk of cardiovascular events. Two
large multicentre, double-blind trials,
CLASS67 and VIGOR,68 examined the
GI safety of COX-2 agents. Both trials
used high doses of the specific COX-2
inhibitor and selected patients in the
CLASS trial received low-dose ASA.
Initial analysis of the CLASS and
VIGOR trials indicated that both celecoxib and rofecoxib decreased the risk of
developing upper GI clinical events and
complications by ~ 50% when compared
with traditional agents in patients not
taking concomitant low-dose ASA. The
beneficial effects of a COX-2 inhibitor
may abolish the GI safety of these agents
as suggested in the CLASS study posthoc analyses.67 The utility of PPIs in
combination with non-selective NSAID
versus COX-2 selective inhibitors have
been explored as a means to reduce the
risk of recurrent bleeding in Hp-negative
patients with a recent history of ulcerrelated bleeding.70 Results suggest that
using celecoxib monotherapy is as effective as adding a PPI to a non-selective
NSAID among patients with a recent
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Strategies for approaching Hp status in the setting of NSAID Therapy
H pylori Test-&-Treat
Approach
Long-Term
PPI Therapy
✔
✔ with evidence
✘
✘
✔ with evidence
✔
✘
✔ with evidence
✔
✘
a) With a recent ulcer complication
Potential benefit
✔ with evidence
b) At high risk for ulcer complication
Potential benefit
✔
c) At low risk for ulcer complication
✘
✘
Naïve to ASA/NSAIDs
a) Naïve ASA users
b) Naïve NSAIDs users
Chronic ASA users
a) With a recent ulcer complication
b) At high risk for ulcer complication
c) At low risk for ulcer complication
Chronic NSAIDs users
Adapted from 56,70,83-89
history of ulcer bleeding.70,71 There is
growing clinical use of combined COX2 inhibitors with acid suppressive therapy or misoprostol, especially in those
with very high risk of complications or
previous history of PUD events.
Although such combination may offer
theoretically better GI protection, especially in very high risk circumstances, to
date, there are no published outcome trials to establish the benefits of these combinations.61,73
When an active ulcer is suspected or
confirmed, therapy with the NSAID
should be stopped whenever possible
and smoking should be stopped to
improve healing.33,42,52,53 PPIs are the preferred treatment as they provide a rapid
rate of ulcer healing, especially in the setting of complicated, large ulcers.32,39,42,52 If
chronic NSAID therapy must be continued potential options include use of a
COX-2 selective NSAID (e.g. celecoxib), reducing the dosage of the nonselective agent and/or adding concomitant therapy with PPIs or misoprostol.33,52,60 PPIs are the drugs of choice
when the NSAID must be continued, as
potent acid suppression is required to
accelerate ulcer healing.52,53,56
iii) H pylori interaction with ASA/NSAIDs
An interaction between Hp and NSAIDs
is biologically plausible given their different mechanisms of disrupting gastric
mucosal defense but published data did
not always confirm this.62,76-86 A recent
systemic review demonstrated synergism
between Hp and NSAIDs for the development of PUD and ulcer bleeding.87
The risk of PUD was reported to be
~60-fold higher in Hp positive NSAID
users compared with Hp-negative subjects not taking NSAID. Moreover, Hp
infection was shown to increase the risk
of ulcer bleeding by 1.8-fold, NSAID
use by 4.85-fold, and the presence of
both factors by 6.1-fold compared with
the risk of bleeding among Hp-negative
subjects not taking NSAID. Table 9
summarizes the published data in this
area and current clinical practice.56,70,86,88,89
CHSG supports Hp testing and eradication for naïve NSAID users.42,86 A similar
strategy has also been suggested for naïve
ASA users, although the efficacy of such
an approach has not been confirmed. In
chronic ASA/NSAIDs users, recommendations depend on the risk of PUD complications56 and the type of NSAID.
Based on published data, it is reasonable
that any attempt to eradicate Hp infection should follow ulcer healing in the
management of chronic NSAID users,
although the efficacy of such an
approach remains to be confirmed.84,88
The efficacy of Hp eradication in chronic ASA users without a history of PUD
complications has not been evaluated.
organic acid-associated conditions. As
pharmacists are often the first healthcare professionals encountered by the
patient, we are uniquely positioned to
identify, counsel and monitor patients
requiring acute or chronic therapy for
conditions related to gastric acid.
Pharmacists should have a working
knowledge of the pathophysiology of
gastric acid-related diseases, risk stratification, potential under- and over-treated
acid-disorders, as well as the efficacy and
safety of the available pharmacological
agents/regimens.
The patient interview should include
a patient’s past medical and medication
history, the nature and timing of symptoms and the presence of alarm features.
Intervention through education, counselling and recommendation of initial
non-prescription therapies such as
antacids or H2RAs may be appropriate
for patients at low risk. Collaboration
with physicians is vital when pharmacists
identify and refer patients with alarm
symptoms. The patient should be educated regarding the disease state and its
potential consequences.
Through medication reviews, pharmacists can identify:
• Medications that are ulcerogenic or
promote injury to the esophageal
and/or gastric mucosa;
• Medications that exacerbate GERD;
• The pattern of both prescription and
non-prescription NSAID use and
patients who will require gastric protection;
• Patients who are experiencing recurrence or complications of PUD or
GERD;
• Significant drug-drug interactions and
adverse effects;
• Patients who are not adhering to a
prescribed regimen;
• Optimal administration and scheduling of medications and alternative
forms of oral dosing.
The role of the pharmacist as patient
advocate and educator cannot be overstated.
CONCLUSION
ROLE OF THE PHARMACIST
The management of GI acid-related disorders continues to evolve with a wealth
of literature for both functional and
8 | Update on the Management of Acid-Related Disorders: A Canadian Perspective
Important insights are gained as more
literature is published about acid-related
disorders and dyspepsia. Acid-related
disorders include a broad spectrum of
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disease and severity, with dyspepsia the
most common presenting symptom of
all acid-related disorders. Proton pump
inhibitors remain the cornerstone of
medical therapy. The majority of
patients will need empiric therapy after a
thorough clinical history and symptom
description is established. This educational module attempts to highlight
important information and evidencebased updates on the management of
uninvestigated dyspepsia, GERD and
PUD and how this information can be
applied to the Canadian population.
Pharmacists are in a unique and key
position, through patient education and
collaboration with other health-care
providers to optimize the care of patients
with acid-related disorders.
REFERENCES
1. Veldhuzyen van Zanten S, Flook N, Chiba N,
Armstrong D, et al. An evidence-based approach to
the management of uninvestigated dyspepsia in
the era of Helicobacter pylori. CMAJ 2000;162(12
Suppl):S3-22.
2. Talley NJ, Stanghellini V, Heading R, Koch KL, et
al. Functional gastroduodenal disorders. Gut 1999;45
(Suppl 2):I37-42.
3. Armstrong D, Marshal JK, Chiba N, Enns R, et al.
Canadian Consensus Conference on the management
of gastroesophageal reflux disease in adults - update
2004. Can J Gastroenterol 2005;19(1):15-35.
4. Tougas G, Chen Y, Hwang P, Liu M, Eggleston A.
Prevalence and impact of upper gastrointestinal
symptoms in the Canadian population: Findings from
the DIGEST study. Domestic/International Gastroenterology Surveillance Study. Am J Gastroenterol
1999;94:2845-54.
5. Revicki D, Wood M, Maton P, Sorensen S. The
impact of gastroesophageal reflux disease on healthrelated quality of life. Am J Med 1998;104:242-8.
6. Thomson A, Barkun A, Armstrong D, et al. The
prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated
dyspepsia: The Canadian Adult Dyspepsia Empiric
Treatment - Prompt Endoscopy (CADET-PE) study.
Aliment Pharmacol Ther 2003;17:1481-91.
7. Kitchin LI, Castell DO. Rationale and efficacy of
conservative therapy for gastroesophageal reflux disease. Arch Intern Med 1991;151;448-54.
8. Dent J, Brun J, Fendrick A, et al. An evidencebased appraisal of reflux disease management - the
Genval Workshop Report. Gut 1999; 44(Suppl 2): S116.
9. De Vault KR, Castell DO. Updated guidelines for
the diagnosis and treatment of gastroesophageal
reflux disease. Am J Gastroenterol 2005; 100: 190200.
10. Vigneri S, Termini R, Leandro G, et al. A comMarch 2006
parison of five maintenance therapies for reflux
esophagitis. N Engl J Med 1995;333:1106-10.
11. van Inxteren B, Numans ME, Bonis PA, Lau J.
Short-term treatment with proton pump inhibitors,
H2-receptor antagonists and prokinetics for gastrooesophageal reflux disease-like symptoms and
endoscopy negative reflux disease (Cochrane
Review). Cochrane Database Syst Rev 2005:Vol 2:
Available in The Cochrane Library.
12. van Inxteren B, Numans M, Lau J, et al. Short
term treatment of gastroesophageal reflux disease. J
Gen Intern Med 2003; 18: 755-63
13. Armstrong D, Veldhuyzen van Zanten SJO,
Barkun AN, Chiba N, et al. Heartburn-dominant, uninvestigated dyspepsia: A comparison of ‘PPI-start’ and
‘H2-RA start’ management strategies in primary care
- the CADET-HR Study. Aliment Pharmacol Ther
2005;21:1189-202.
14. Veldhuyzen van Zanten SJO, Chiba N,
Armstrong D, Barkun A, et al. A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in
Helicobacter pylori negative, primary care patients
with dyspepsia: The CADET-HN study. Am J
Gastroenterol 2005;100:1477-88.
15. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH.
Speed of healing and symptom relief in grade II to IV
gastroesophageal reflux disease: A meta-analyses.
Gastroenterology 1997;112:1798-810
16. Carlsson R, Dent J, Watts R, et al. Gastrooesophageal reflux disease in primary care: An international study of different treatment strategies with
omeprazole. International GORD Study Group. Eur J
Gastroenterol Hepatol 1998;10:119-24.
17. Miner P, Katz PO, Chan Y, Sostek M. Gastric
acid control with esomeprazole, lansoprazole,
omeprazole, pantoprazole: A five way crossover. Am J
Gastroenterol 2003; 98(12): 2616-20.
18. Vakil N, Fennerty MB. Direct comparative trials
of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and
peptic ulcer disease. Aliment Pharmacol Ther
2003;559-68.
19. Veldhuyzen van Zanten SJO, Bradette M,
Chiba N, Armstrong D, et. al. Evidence-based recommendations for short- and long-term management of
uninvestigated dyspepsia in primary care: An update
of the Canadian Dyspepisa Working Group (CanDys)
clinical management tool. Can J Gastroenterol
2005;19(5):285-303.
20. Sampliner RE. The Practice Parameters
Committee of the American College of
Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus.
Am J Gastroenterol 2002;97:1888-95.
21. Frazzoni M, De ME, Grisendi A, Savarino V.
Effective intro-oesophageal acid suppression in
patients with GERD: Lansoprazole vs pantoprazole.
Aliment Pharmacol Ther 2003; 17: 235-41.
22. Fass R, Murphy U, Hayden C, et al.
Omeprazole 40 mg once a day is equally effective as
lansoprazole 30 mg twice a day in symptom control of
patients with GERD who are resistant to conventional-
dose lansoprazole therapy - a prospective, randomized, multi-centre study. Aliment Pharmacol Ther
2000; 14: 1595-603.
23. Cremonini F, Wise J, Moayyedi P, Talley NJ.
Diagnostic and therapeutic use of Proton pump
inhibitors in non-cardiac chest pain: a meta-analysis.
Am J Gastroenterol 2005; 100: 1226-32.
24. Wang WH, Huang, JQ, Zheng GF, Wong WM, et
al. Is Proton pump inhibitor testing an effective
approach to diagnose gastroesophageal reflux disease in patients with noncardiac chest pain? A metaanalysis. Arch Int Med 2005; 165: 1222-28.
25. Marshall BJ, Armstrong JA, McGechie DB,
Glancy RJ. Attempt to fulfill Koch’s postulates for
pyloric Campylobacter. Med J Aust 1985;142:436-9.
26. McColl K, Murray L, El-Omar E, Dickson A, et
al. Symptomatic benefit from eradicating
Helicobacter pylori infection in patients with nonulcer
dyspepsia. N Engl J Med 1998;339:1869-74.
27. Laine L, Schoenfeld P, Fennerty MB. Therapy
for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001; 134: 361-9.
28. Talley NJ, Janssens J, Lauritsen K, et al.
Eradication of Helicobacter pylori in functional dyspepsia: randomised, double blind placebo controlled
trial with 12 months’ follow up. The Optimal Regimen
Cures Helicobacter Induced Dyspepsia (ORCHID)
Study Group. BMJ 1999; 318: 833-7.
29. Blum AL, Talley NJ, O’Morain C, et al. Lack of
effect of treating Helicobacter pylori infection in
patients with nonulcer dyspepsia. N Engl J Med 1998;
339: 1875-81.
30. Soo S, Moayyedi P, Deeks J, Delaney B, et al.
Psychological interventions for non-ulcer dyspepsia.
Cochrane Database Syst 2003;(2):Available in The
Cochrane Library.
31. Moayyedi P, Soo S, Deeks J, Delaney B, et al.
Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst 2005;(2): Available in
The Cochrane Library.
32. Kuipers EJ, Thijs JC, Festen HP. The prevalence
of Helicobacter pylori in peptic ulcer disease. Aliment
Pharmacol Ther 1995;9(Suppl 2):59-69.
33. Ontario Program for Optimal Therapeutics.
Ontario guidelines for peptic ulcer disease and gastroesophageal reflux. June 2001.
34. Shiotani A, Graham DY. Pathogenesis and
therapy of gastric and duodenal ulcers disease. J Med
Clin N Am 2002;86:1447.
35. American Gastroenterological Association
medical position statement: Evaluation of dyspepsia.
Gastroenterology 1998;114:579-81.
36. Silverstein F, Graham D, Senior J, Davies H,
Struthers B, Bittmann R, Geis G. Misoprostol reduces
gastrointestinal complications in patients with
rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs: A randomized, double-blind,
placebo-controlled trial. Ann Intern Med 1995;123;
241-9.
37. Williams MP, Pounder RE. Helicobacter pylori:
from the benign to the malignant. Am J Gastroenterol
Update on the Management of Acid-Related Disorders: A Canadian Perspective | 9
AZ_CE_GI_0306_E
2/22/06
4:07 PM
Page 10
1999;94(11 Suppl):S11-6
38. Cave DR. Transmission and epidemiology of
Helicobacter pylori. Am J Med 1996;100(5A):12-8S
39. Hunt R, Thomson ABR. Canadian Helicobacter
pylori consensus conference. Can J Gastroenterology
1998;12:31-41.
40. Howden CW. Clinical expressions of
Helicobacter pylori infection. Am J Med 1996;100
(5A):27-32S.
41. Asaka M, Takeda H, Sugiyama T. What role
does Helicobacter pylori play in gastric cancer?
Gastroenterology 1997;113(6 Suppl):S56-60
42. Hunt R, Fallone C, Veldhuyzan van Zanten S,
Sherman P, Smaill F, Flook N, et al. Canadian
Helicobacter study group consensus conference:
Update on the management of Helicobacter pylori An evidence-based evaluation of six topics relevant to
clinical outcomes in patients evaluated for H pylori
infection. Can J Gastroenterol 2004;18(9):547-54.
43. Chiba N, Velduyzen van Zanten SJO. 13C-urea
breath tests are the non-invasive method of choice for
Helicobacter pylori detection. Can J Gastroenterol
1999;13:681-3.
44. Tytgat GN. Current indications for Helicobacter
pylori eradication therapy. Scand J Gastroenterol
1996;31(Suppl 215):70-3.
45. Gene E, Calvet X, Azagra R, Gisbert JP. Triple vs
quadruple therapy for treating Helicobacter pylori
infection: A meta-analysis. Aliment Pharmacol Ther
2003;17:1137-43.
46. Fischback LA, Goodman KJ, Feldman M,
Aragaki C. Sources of varioation of Helicobacter pylori
treatment success in adults worldwide: A meta-analysis. Int J Epidemiol 2002;31:128-39.
47. Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E,
Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and
either metronidazole or amoxicillin for treating
Helicobacter pylori infection. Aliment Pharmacol Ther
2000;14:603-9.
48. Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the United
States: The Surveillance of H pylori Antimicrobial
Resistance Partnership (SHARP) study, 1993-1999.
Ann Intern Med 2002;136(1):13-24.
49. Best L, Cooper-Lesins G, Haldane D, et al.
Helicobacter pylori antibiotic resistance in Canadian
populations. (Abstr) Gastroenterology 2004;126:
S1293
50. Nista EC, Candelli M, Fini L. 10 days levofloxacin-based triple therapy in second line treatment for Helicobacter pylori eradication. (Abstr)
Gastroenterology 2004;126:S576.
51. Gatta L, Ricci C, Zullo A. High eradication rate
with a rescue levofloxacin based treatment for
Helicobacter pylori. (Abstr) Gastroenterology 2004;
126:S574.
52. Del Valle J, Chey WE, Scheiman J. Acid peptic
disorders. In: Yamada T, Alpers D, Kaplowitz N, et al, eds.
Textbook of Gastroenterology, 4th ed. Philadelphia:
Lippincott Williams & Wilkins, 2003:1321-76.
53. Wolfe MM, Lichtenstein DR, Singh G.
Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-99.
54. Chan FK, Leung WK. Peptic ulcer disease.
Lancet 2002;360:933-41.
55. Hawkey Cj. Nonsteroidal anti-inflammatory
drug gastropathy. Gastroenterology 2000;119:52135.
56. Laine L. Approaches to nonsteroidal antiinflammatory drug use in the high-risk patient.
Gastroenterology 2001;120:594-606.
57. Chan FK, Graham KY. Review article:
Prevention of nonsteroidal anti-inflammatory drug
gastrointestinal complications-review and recommendations based on risk assessment. Aliment
Pharmacol Ther 2004;19:1051-61.
58. Derry S, Loke YK. Risk of gastrointestinalhaemorrhage with long-term use of aspirin: Meta
analysis. Brit Med J 2000;321:1183-7.
59. Sorensen HT, Mellemkjaer L, Blot WJ. Risk of
upper gastrointestinal bleeding associated with use of
low-dose aspirin. Am J Gastroenterol 2000;95:221824.
60. Micklewright R, Lane S, Linley W. Review article: NSAIDs, gastroprotection and cyclooxygenase-IIselective inhibitors. Aliment Pharmacol Ther 2003;
17:321-32.
61. Rostom A, Dube C, Wells G, Tugwell P, Welch V,
Jolicoeur E, McGowan J. Prevention of NSAID-induced
gastroduodenal ulcers. The Cochrane Database of systematic reviews. The Cochrane Collaboration 2005.
62. Lanas A, Fuentes J, Benito R. Serrano P,
Bajador E, Sainz R. Helicobacter pylori increases the
risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther 2002;
16:779-86.
63. Silverstein FE, Graham DY, Senior JR.
Misoprostol reduces serious gastrointestinal complications in patients with RA receiving nonsteroidal
anti-inflammatory drugs: A randomized, double-blind,
placebo-controlled trial. Ann Intern Med 1995;123:
241-9.
64. Yeomans ND, Tulassay Z, Juhasz L. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. N Engl
J Med 1998;338:719-26.
65. Hawkey CJ, Karrasch JA, Szczepanski L.
Omeprazole compared with misoprostol for ulcers
associated with nonsteroidal anti-inflammatory
drugs. Omeprazole versus misoprostol for NSAIDinduced ulcer management study group (OMNIUM). N
Engl J Med 1998;338:727-34.
66. Graham DY, Agrawal NM, Campbell DR. Ulcer
prevention in long-term users of nonsteroidal antiinflammatory drugs: Results of a double-blind, randomized, multicenter, active - and placebo-controlled
study of misoprostol vs lansoprazole. Arch Intern Med
2002;162:169-75.
67. Silverstein FE, Faich G, Goldstein JL.
Gastrointestinal toxicity with celecoxib vs nonsteroidal
anti-inflammatory drugs for osteoarthritis and
rheumatoid arthritis. The CLASS study: a randomized
controlled trial. JAMA 2000;284:1247-55.
10 | Update on the Management of Acid-Related Disorders: A Canadian Perspective
68. Bombardier C, Laine L, Reicin A. Comparison
of upper intestinal toxicity of rofecoxib and naproxen
in patients with rheumatoid arthritis. N Engl J Med
2000;343:1520-8.
69. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid
arthritis: Systematic review of randomized controlled
trials. Br Med J 2002;325:619-23.
70. Chan FK, Hung LC, Suen BY. Celecoxib versus
diclofenac and omeprazole in reducing the risk of
recurrent bleeding in patients with arthritis. N Engl J
Med 2002;347:2104-10.
71. Chan FK, Hung LC, Suen BY, Wong V, Hui A, Wu
J, et al. Celecoxib versus diclofenac plus omeprazole
in high-risk arthritis patients: results of a randomized
double-blind trial. Gastroenterology 2004 127(4):
1038-43.
72. Lai K, Chu K, Hui W, Wong B, Hu W, Wong W, et
al. Celecoxib compared with lansoprazole and
naproxen to prevent gastrointestinal ulcer complications. Am J med 2005 118(11):1271-8.
73. Laine L, Bombardier C, Hawkey CJ. Stratifying
the risk of NSAID-related upper gastrointestinal clinical events: Results of a double-blind outcomes study
in patients with rheumatoid arthritis. Gastroenterology
2002;123:1006-12.
74. Dubois RW, Melmed GY, Henning JM, Laine L.
Guidelines for the appropriate use of nonsteroidal
anti-inflammatory drugs, cyclooxygenase-2-specific
inhibitors, and proton pump inhibitors in patients
requiring chronic anti-inflammatory therapy. Aliment
Pharmacol Ther 2004;19:197-208.
75. Derry S, Loke YK. Risk of gastrointestinal
haemorrhage with long-term use of aspirin: Metaanalysis. Br Med J 2000;321:1183-7.
76. Labenz J, Peitz U, Kohl H, Kaiser J,
Malfertheiner P, Hackelsberger A, Borsch G.
Helicobacter pylori increases the risk of peptic ulcer
bleeding: A case-control study. Ital J Gastroenterol
Hepatol 1999;31:110-5.
77. Aalykke C, Lauritsen JM, Hallas J, Reinholdt S,
Krogfelt K, Lauritsen K. Helicobacter pylori and risk of
ulcer bleeding among users of nonsteroidal antiinflammatory drugs: A case-control study.
Gastroenterology 1999;116:1305-30.
78. Ng TM, Fock KM, Khor JL, Teo EK, Sim CS, Tan
AL, Machin D. Non-steroidal anti-inflammatory drugs,
Helicobacter pylori and bleeding gastric ulcer. Aliment
Pharmacol Ther 2000;14:203-9.
79. Papatheodoridis GV, Papadelli D, Cholongitas
E, Vassilopoulos D, Mentis A, Hadziyannis SJ. Effect of
Helicobacter pylori infection on the risk of upper gastrointestinal bleeding in users of non-steroidal antiinflammatory drugs a prospective, case-control study.
Am J Med 2004;116:601-5.
80. Laine L, Marin-Sorensen M, Weinstein WM.
Nonsteroidal anti-inflammatory drug associated gastric
ulcers do not require Hepicobacter pylori for their development. Am J Gastroenterol 1992;87:1398-402.
81. Cullen DJ, Hawkey GM, Greenwood DC,
Humphreys H, Shepherd V, Logan RF, Hawkey CJ.
March 2006
AZ_CE_GI_0306_E
2/22/06
4:07 PM
Page 11
Peptic ulcer bleeding in the elderly: Relative roles of
Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut 1997;41:459-46.
82. Loeb DS, Talley NJ, Ahlquist DA, Carpenter HA,
Zinsmeister AR. Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: The role
of Helicobacter pylori infection. Gastroenterology
1992;102:1899-905.
83. Pilotto A, Leandro G, Di Mario F, Franceschi M,
Bozzola L, Valerio G. Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly:
A case-control study. Dig Dis Sci 1997;42:586-91.
84. Stack WA, Atherton JC, Hawkey GM, Logan RF,
Hawkey CJ. Interactions between Helicobacter pylori
and other risk factors for peptic ulcer bleeding.
Aliment Pharmacol Ther 2002;16:497-506.
85. Santolaria S, Lanas A, Benito R, Perez-Aisa M,
Montoro M, Sainz R. Helicobacter pylori infection is a
protective factor for bleeding gastric ulcers but not for
bleeding duodenal ulcers in NSAID users. Aliment
Pharmacol Ther 1999;13:1511-8.
86. Hunt RH, Bazzoli F. Should NSAID/low-dose
aspirin takers be tested routinely for H pylori infection
and treated if positive? Implications for primary risk of
ulcer and ulcer relapse after initial healing. Aliment
Pharmacol Ther 2004;19(Suppl 1): 9-16.
87. Huang JQ, Sridhar S, Hunt RH. Role of
Helicobacter pylori infection and non-steroidal antiinflammatory drugs in peptic-ulcer disease: A metaanalysis. Lancet 2002;359:14-22.
88. Malfertheiner P, Megraud F, O’Morain C,
Hungin AP, Jones R, Axon A, Graham DY, Tytgat G.
Current concepts in the management of Helicobacter
pylori infection-the Maastricht 2-2000 Consensus
Report. Aliment Pharmacol Ther 2002;16:167-80.
89. Griffin MR, Piper JM, Daugherty JR, Snowden
M, Ray WA. Nonsteroidal anti-inflammatory drug use
and increased risk for peptic ulcer disease in elderly
persons. Ann Intern Med 1991;114:257-63.
QUESTIONS
1. Which case best characterizes a
patient with heartburn that a pharmacist should refer to a physician for further medical evaluation?
a) 50-year-old man who awakens at
night with heartburn, coughing, and
choking
b) 20-year-old student complaining of
indigestion after eating pizza
c) 40-year-old woman who has heartburn once a month
d) 35-year-old man taking OTC H2RAs
for one week
2. What alarm features should trigger
investigation according to the Clinical
Management Tool of the CanDys
Uninvestigated Dyspepsia guidelines?
Choose the best answer.
a) Diarrhea, vomiting, anemia, odynophagia
b) Vomiting, bleeding/anemia, abdominal mass/weight loss, dysphagia
c) Shortness of breath, chest pain,
weight loss, tinnitus
d) Night sweats, heartburn, regurgitation,
shortness of breath
3. Dyspepsia is one of the most common symptom complexes in patients
with acid-related disorders.
a) True
b) False
4. Which statement(s) regarding the
epidemiology and impact of GERD
is/are TRUE?
I. A significant percentage of adults
report monthly heartburn symptoms.
II. Patients with GERD report significant impairment in quality of life.
III. Extraesophageal presentations
March 2006
should rule out GERD.
IV. Heartburn and regurgitation are
the cardinal symptoms of GERD.
a) I, II, and III
b) II and III
c) I and III
d) I, II and IV
5. Which statement(s) regarding the
mechanisms of disease of GERD
is/are FALSE?
I. The main cause of GERD is contact
of the esophageal epithelium with
the acidic contents of the stomach.
II. GERD symptoms may be caused by
a combination of lower esophageal
sphincter dysfunction, esophageal
dysmotility and /or delay in gastric
emptying.
III.The severity of GERD symptoms is
directly related to the degree or
severity of erosive esophagitis.
IV. Drug therapy targeting the underlying motility disorder of the esophagus is largely successful.
a) I, II, and III
b) III and IV
c) I and III
d) IV only
6. Which statement(s) regarding the
clinical presentation and diagnosis of
GERD is/are TRUE?
I. Endoscopy and biopsy are the gold
standard for diagnosis of GERD.
II. All patients with GERD have erosive
esophagitis.
III. Dysphagia, weight loss, and
hematemesis are alarm symptoms
that should immediately prompt
further testing for complications of
GERD, such as stricture, ulcer or
adenocarcinoma.
IV. GERD is considered a progressive
disease, with progression of both
symptoms and esophagitis in all
patients.
a) I, II, and III
b) I and III
c) II and IV
d) III only
CASE STUDY
ND is a 47-year-old male who presents
to his family doctor with a three-month
history of epigastric discomfort. His vitals
are normal and his examination is unremarkable. He is approximately 290 lbs,
approximately 30% over his ideal body
weight and has an erratic eating schedule due to his job. He had been taking
OTC antacids and famotidine 40 mg for
approximately two months but has not
experienced any significant relief. He
denies any bleeding, vomiting or NSAID
use.
7. How should the primary care physician respond to this patient?
a) Treat the patient with eradication regimen that includes antibiotics since
H pylori can be the culprit.
b) Suggest lifestyle modifications, prescribe a PPI for four weeks and then
reassess.
c) Refer the patient to a gastroenterologist for endoscopy.
d) Suggest lifestyle modifications and
continue OTC antacids and/or H2RAs
for symptomatic relief.
8. ND returns to the clinic for followup. The physician gives the patient a
urea breath test and he tests negative
for H pylori. His symptoms have lessened, but have not completely
Update on the Management of Acid-Related Disorders: A Canadian Perspective | 11
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QUESTIONS continued
resolved. What recommendation would
be appropriate to provide to the primary care physician?
a) Treat the patient with an eradication
regimen that includes antibiotics
since H pylori can be the culprit
despite a negative test.
b) Refer the patient to a gastroenterologist for endoscopy.
c) Continue current management and
reassess after another four weeks.
d) Add H2RA to the current regimen for
four weeks and reassess.
9. Which statement(s) regarding
Barrett’s esophagus and esophageal
adenocarcinoma is/are TRUE?
I. Barrett’s esophagus is associated
with long-standing (chronic) reflux
and a risk factor for esophageal
adenocarcinoma.
II. The risk of adenocarcinoma is
extremely high, especially in
patients with Barrett’s esophagus.
III. Treatment of GERD with PPIs has
been shown to decrease the incidence of Barrett’s esophagus.
IV. Patients who have had chronic
reflux for more than 10 years
should receive a “once in a lifetime” endoscopy to assess for
Barrett’s esophagus.
a) I, II and III
b) II and III
c) I and IV
d) all of the above
10. Since few trials have directly compared different PPIs, whether the different pharmacokinetic properties of
these drugs translate into significant
clinical differences is unknown.
a) True
b) False
11. Clinical studies indicate that the
most effective acid-suppression medications belong to which class of
drugs?
a) Antacids
b) PPIs
c) H2RAs
d) Sucralfate
12. Proton pump inhibitors have been
shown to play a significant role in:
a) Eradicating H pylori in the context of
a triple therapy with antibiotics;
b) Protecting against NSAID-induced
duodenal ulcers, not gastric ulcers;
c) None of the above.
d) (a) and (b)
13. H pylori is a pathogen associated
with the development of:
a) GERD
b) NSAID-induced ulcers
c) PUD
d) All of the above
14. Mark, a 39-year-old construction
worker, had symptoms of PUD and was
found to be H pylori positive. He
received triple therapy treatment with
lansoprazole + clarithromycin + amoxicillin (HP-PACÆ) for 2 weeks and his
symptoms resolved. Future treatment
options for Mark include:
a) Intermittent PPI or H2RA for recurrent
symptoms.
b) Diovol PRN.
c) Chronic acid suppression with H2RA
or PPI.
d) No treatment.
15. Which statement about therapy
with NSAIDs is TRUE?
a) COX-2 inhibitors have not been associated with risk of cardiovascular
events.
b) Standard dose H2RAs are effective in
reducing the risk of NSAID-induced
gastric ulcers.
c) Patients >65 starting on meloxicam
therapy should receive PPI or misoprostol co-therapy, or switch to celecoxib.
d) Low-dose ASA is not associated with
an increased risk of upper GI bleeding.
16. Which statement about prophylaxis
in patients treated with NSAIDs is
FALSE?
a) Co-therapy with a PPI has been
shown to reduce the incidence of
gastroduodenal ulcers.
b) Standard dose H2RAs (e.g. famotidine 20 mg bid) are not indicated in
the prevention of gastric ulcers.
c) Low-dose misoprostol (e.g. 200 mcg
bid) is as effective as a PPI with a
low incidence of side effects.
d) PPI therapy has been shown to be
effective for treating NSAID-associated GI ulcer complications.
17. Martha, a 47-year-old school
teacher, presents with a recent onset
12 | Update on the Management of Acid-Related Disorders: A Canadian Perspective
of heartburn, gnawing, abdominal pain
that has been causing discomfort. She
denies vomiting, blood in her stool or
recent weight loss. She takes HCTZ 25
mg daily for hypertension and recently
naproxen 550 mg intermittently for
lower back pain. What is the best initial treatment option?
a) Check H pylori serology status.
b) Stop intermittent naproxen use and
suggest acetaminophen.
c) Treat empirically with sulcrafate.
d) Refer to GI specialist for upper
endoscopy.
18. Burt is a 68-year-old retired engineer presenting with a recent history
of epigastric symptoms. He has experienced a 10-pound weight loss in the
past 3 months. Upon further examination, he is found to have a heme-positive stool. What is the best approach?
a) Check H pylori stool antigen.
b) Check H pylori serology.
c) Endoscopy
d) Empiric triple therapy with PPI + 2
antibiotics
19. For the prevention of DU recurrence after initial ulcer healing, which
statement below about H pylori eradication treatment is TRUE?
a) H pylori eradication treatment in
addition to acid suppressive therapy
is superior to acid suppressive therapy alone.
b) PPI therapy is superior to H pylori
eradication.
c) Neither strategy is very effective.
d) There is no significant difference
between the 2 treatment options.
20. Simon, a 32-year-old stockbroker,
presents to the clinic with burning
mid-epigastric discomfort that is
relieved with Tums, which he has been
using daily. H pylori testing is positive
by urea breath testing. Simon has no
known drug allergies. Treatment
options include:
a) PPI + amoxicillin + metronidazole x
10 days
b) PPI + levofloxacin + amoxicillin x 10
days
c) PPI + amoxicillin + clarithromycin x 7
days
d) Ranitidine HCl + amoxicillin + tetracycline x 14 days
March 2006
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