Page | 1
Section17.1: Antiulcer medicines
Review for section update
Submitted for WHO Secretariat by
Grigorios I. Leontiadis, MD, PhD
Assistant Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton ON,
Canada
Joint Coordinating Editor, Upper Gastrointestinal and Pancreatic Diseases Group, The Cochrane
Collaboration
Yuhong Yuan MD, PhD, MSc
Research Associate, Division of Gastroenterology, McMaster University, Hamilton ON, Canada
Potential conflicts of interest
Dr. Leontiadis has acted as consultant for and received research grants from AstraZeneca (a
pharmaceutical company producing PPIs)
Dr. Yuan has no COI
Date: January 10, 2013
Page | 2
Background
The 18th Expert Committee on The Selection and Use of Essential Medicines requested a review for
possible deletion of ranitidine class of medicines and another review to answer the question ‘should
adults and children with gastro-oesophageal reflux or non-ulcer dyspepsia be treated with H2
antagonists compared to proton pump inhibitors’
This review answers the following specific questions, in adults:
Use of H2 antagonists compared to proton pump inhibitors for gastro-oesophageal reflux or non-
ulcer dyspepsia
Should Ranitidine be deleted from EML
Is there need for parenteral preparation of omeprazole
Summary of review
After reviewing the available evidence (as shown below; please note that the major body of work has
been done by mid-2000 and there have been only minor updates thereafter) we concluded that:
1. Ranitidine (and other H2RAs) should not be deleted. PPIs are more effective than H2RAs in the
management of gastro-oesophageal reflux disease (GERD) and or non-ulcer dyspepsia (NUD).
However, H2RAs have advantages (some of which are particularly important for patients in
developing countries): faster onset of action, no need to time administration before meals,
lower cost, no fear of interaction with clopidogrel, probably safer in pregnancy. Furthermore
they can be used in patients who cannot tolerate PPIs because of side effects.
2. There is a need for parenteral (intravenous) preparation of omeprazole (or another PPI) for
patients experiencing acute bleeding from a peptic ulcer or patients who need potent acid
suppression treatment but are unable to take oral PPIs.
Page | 3
1. H2 RECEPTOR ANTAGONISTS (H2RAS) VERSUS PROTON PUMP INHIBITORS
(PPIS) FOR GASTROESOPHAGEAL REFLUX DISEASE (GERD)i
According to the most recent AGA (American Gastroenterological Association) Medical Position
Statement on the management of GERD “for the treatment of patients with esophageal GERD
syndromes (healing esophagitis and symptomatic relief) [...] PPIs are more effective than H2RAs, which
are more effective than placebo” 1. All other recent consensus guidelines are in agreement among them
with regards to the above statement 2, 3.
However, consensus guidelines acknowledge that H2RAs maintain a position in the treatment of GERD:
In the most recent Asia-Pacific consensus on the management of gastroesophageal reflux
disease 2, statement #30 reads that “H2RAs and antacids are useful in treating episodic
heartburn”. According to this document: “H2RAs and antacids are commonly used for episodic
heartburn, primarily for postprandial heartburn. The perception of heartburn serves as a trigger
for medication use, and the expectation is an immediate symptom relief that PPIs are unlikely to
provide. The onset of action of antacids on esophageal acid concentration is 30 min after dosing
and inhibition persists for 1 h.65 However, studies reported that meaningful heartburn relief can
already be achieved 19 min after consumption. In contrast, H2RAs have been shown to provide
symptom relief within 30 min of dosing that can last up to 12 h. When consumed 30 min prior to
a meal, H2RAs are effective in completely or partially preventing postprandial heartburn. There is
some evidence to suggest that simultaneous consumption of both an H2RA and an antacid
provides better control of esophageal acid exposure and heartburn symptoms, when compared
to the clinical effect of each one of these products alone. On-demand treatment with H2RAs has
been shown to be safe and effective in GERD patients.”2
According to the ACG (American College of Gastroenterology) Updated guidelines for the
diagnosis and treatment of gastroesophageal reflux disease: “The OTC [over the counter] H2RAs
are particularly useful when taken prior to an activity that may potentially result in reflux
symptoms (heavy meal or exercise in some patients). Many patients can predict when they are
going to suffer from reflux and can premedicate with the OTC H2RAs. Comparisons between OTC
H2RAs and antacids are limited. It has been suggested that antacids provide a more rapid
i The acronym in UK English spelling is GORD (gastro-oesophageal reflux disease)
Page | 4
response, but gastric pH begins to rise less than 30 min after taking a dose of H2RA so this does
not seem to be a major factor. The peak potency of OTC H2RAs and antacids are similar, but the
H2RAs have a much longer duration of action (up to 10 h).” 3
It is important to note that the latest major guidelines were published in 2008. The issue of publications
a few years prior to the latest guidelines (since there is usually a 2-5 year lag, between the publication of
evidence and the publication of guidelines) and after the latest guidelines has been dealt methodically
at the end of this section. This approach was followed for the other sections as well.
Below, we examine the evidence from individual randomized controlled trials (RCTs) and systematic
reviews and meta-analyses of RCTs.
1.1. SHORT TERM MANAGEMENT OF REFLUX ESOPHAGITIS
PPIs have been consistently shown to be superior to H2RAs in healing esophagitis or resolving symptoms
in patients with reflux esophagitis (as defined by endoscopy).
Moayyedi et al conducted a Cochrane systematic review and meta-analysis of RCTs on short-term
treatment of reflux esophagitis (one to three months) that had been published until December 2004 4:
The results were as follows:
PPIs were effective in healing esophagitis compared to placebo (5 RCTs, 965 participants,
relative risk, RR 0.22; 95% confidence interval, CI 0.15 to 0.31).
H2RAs were also effective in healing esophagitis compared to placebo (10 RCTs, 1241
participants, RR 0.74, 95% CI 0.66 to 0.84).
However, PPIs were more effective than H2RAs in healing esophagitis at 4 weeks (26 RCTs that
compared PPIs vs. H2RAs or H2RAs plus prokinetics, 4032 participants, RR 0.50, 95% CI 0.45 to
0.560; PPIs were also more effective in symptom relief compared to H2RAs at 4 weeks (15 RCTs,
2941 participants, 0.57, 95% CI 0.48 to 0.68).
We conducted an updated MEDLINE literature search on December 20, 2012 for relevant RCTs that had
been published after the conduction of the search by Moayyedi et al (December 2004). We identified
only one relevant RCT that had compared a PPI with an H2RA in the short term management of reflux
esophagitis 5. This RCT was a small trial (110 participants) and the results were in the same direction
with the results from the Cochrane review by Moayyedi et al. Therefore we can confidently conclude
Page | 5
that it is very unlikely that the conclusions of the above mentioned Cochrane review would change
substantially if it was updated today.
1.2. SHORT TERM MANAGEMENT OF ENDOSCOPIC NEGATIVE REFLUX DISEASE AND SHORT TERM
EMPIRICAL MANAGEMENT OF GERD
PPIs are more effective than H2RAs in symptom relief in patients with endoscopic negative reflux disease
(ENRDii; GERD-like symptoms but no erosive esophagitis on endoscopy) and in patients receiving
empirical treatment for GERD-like symptoms (no endoscopy performed or endoscopy results not used in
allocating treatment).
van Pinxteren et al conducted a recent Cochrane systematic review and meta-analysis of RCTs on short-
term treatment of NERD or short-term empirical treatment for GERD that had been published until
November 2008 (short-term treatment was defined as treatment that lasted 1 to 12 weeks) 6. The
results were as follows:
With regards to heartburn remission by short term management ENRD:
PPIs were more effective than placebo (8 RCTs, RR 0.73, 95% CI 0.67 to 0.78)
H2RAs were also better than placebo (2 RCTs, RR 0.84, 95% CI 0.74 to 0.95)
PPIs were more effective than H2RAs (4 RCTs, 960 participants, RR 0.78, 95% CI 0.62 to 0.97).
With regards to empirical treatment of patients with GORD-like symptoms, the results were similar as
above:
PPIs were better than placebo (2 RCTs, RR 0.37 95% CI 0.32 to 0.44).
H2RAs also better than placebo (2 RCTs, RR 0.77, 95% CI 0.60 to 0.99).
PPIs were more effective than H2RAs (7 RCTs, 3147 participants, RR 0.66, 95% CI 0.60 to 0.73).
We conducted an updated MEDLINE literature search on December 21, 2012 for relevant RCTs that had
been published after the conduct of the search by van Pinxteren et al (November 2008). We identified
only one relevant RCT that had compared a PPI with an H2RA in the short term management of NERD 7.
This RCT was a very small trial (only 33 participants); although the difference between the two
treatments was non-significant, the study was underpowered. Even if it is included in the existing meta-
analysis the results of the meta-analysis are not likely to change. However, it should be noted that the
ii Another acronym for ENRD is NERD (non erosive reflux disease)
Page | 6
results of the pooled analysis on ENRD patients had a 95% CI whose upper boundary was close to the
line of no-effect 6, therefore the results could theoretically become non-significant if a large “negative”
RCT appears in the future.
1.3. MAINTENANCE THERAPY OF REFLUX ESOPHAGITIS AND ENRD
In 2005 Donnellan et al published a Cochrane systematic review and meta-analysis of RCTs that assessed
treatments for the maintenance therapy of reflux esophagitis and ENRD 8. The results were as follows:
For patients with ENRD there were very limited data available, with only one RCT that showed that PPIs
were superior to placebo.
For patients with healed erosive esophagitis:
Both PPIs and H2RAs were more effective than placebo in maintaining a remission of esophagitis
and in maintaining symptom relief.
However, PPIs were more effective than H2RAs in maintaining a remission of esophagitis (6 RCTs,
1156 participants, RR of relapse 0.57; 95% CI 0.47 to 0.69 and in maintaining symptom relief (4
RCTs, 831 participants, RR of relapse 0.55; 95% CI 0.47 to 0.65).
On the other hand, one RCT found a statistically significant increase in headache with PPIs
compare with H2RAs 9.
The Cochrane review concluded that “Healing doses of PPIs are more effective than all other therapies,
although there is an increase in overall adverse effects compared to placebo, and headache occurrence
compared to H2RAs. H2RAs prevent relapse more effectively than placebo, demonstrating a role for PPI-
intolerant patients.” 8
We conducted an updated MEDLINE literature search on December 22, 2012 for relevant RCTs that had
compared H2RAs and PPIs and had been published after the date Donnellan et al conducted their search
(2003). We identified 5 new RCTs 10, 11 ,12, 13, 14. Each one of these new RCTs found that PPIs were
significantly more efficacious than H2RAs in maintenance treatment of erosive esophagitis. Therefore, it
is very unlikely that the conclusions of the above mentioned Cochrane review would change
substantially if it was updated today.
Page | 7
2. H2RAS VERSUS PPIS FOR NONULCER DYSPEPSIA (NUD)
There is limited evidence on the efficacy of H2RAs and PPIs in patients with non-ulcer dyspepsia iii.
In 2006 Moayyedi et al published a Cochrane systematic review and meta-analysis of RCTs on
pharmacological interventions for NUD 15. Both H2RAs and PPIs were more effective than placebo, and
there was no evidence of a difference between H2RAs and PPIs. More specifically:
Twelve RCTs (2183 participants) compared H2RAs with placebo: pooled relative risk reduction,
RRR 23%, 95% CI 8% to 35%.
Ten RCTs (3347 participants) compared PPIs with placebo: RRR 13%, 95% CI 4% to 20%.
There was only one RCT (Blum 2000) 16 that compared H2RAs with PPI therapy in 588
participants: the difference was not statistically significant (RRR 7%; 95% CI 16% to -3%).
We conducted an updated MEDLINE literature search on December 22, 2012 for relevant RCTs that had
compared H2RAs and PPIs and had been published after the conduction of the search by Moayyedi et al
(January 2006). We found no additional RCTs.
Recent consensus guidelines on the management of NUD acknowledge the presence of the above
mentioned RCTs, but note that the evidence derived from these studies (especially the ones that
compared H2RAs with placebo) is undermined by methodological limitations 17, 18,19.
3. OTHER DIFFERENCES BETWEEN H2RAS AND PPIS
3.1. H2RAS VS. PPIS: SPEED OF ONSET OF ACTION
As discussed above, PPIs are superior to H2RAs regarding the time required to achieve complete
resolution of symptoms in GERD and NUD and regarding the time required to achieve healing of
esophagitis. These time periods are in the order of days or weeks.
iii Dyspepsia is defined as chronic or recurrent pain or discomfort centered in the upper abdomen.
Non-ulcer dyspepsia (another synonym is functional dyspepsia (FD)) is diagnosed when a patient with dyspepsia has “negative
or insignificant findings on their endoscopy or barium studies and have had other organic (pancreato-biliary disease,
esophagitis, peptic ulcer disease and neoplastic disease) and drug-induced (non-steroidal anti-inflammatory drugs) and
metabolic disorders excluded by appropriate investigations (blood tests, abdominal ultrasound or 24 hour pH
studies/manometry etc)”15
.
Page | 8
However, H2RAs have a faster onset of effect on the symptoms of GERD and NYD, compared to PPIs. This
time period is in the order of minutes or 1-2 hours. Of note, “onset of effect”(when a patient has a
noticeable improvement in his/her symptoms) is different from “complete resolution of symptoms”
(when a patient is completely symptom free, even from mild, not-bothersome symptoms).
Khury et al showed in a RCT in healthy volunteers that postprandial oral ranitidine (75 or 150 mg)
provided more rapid increase in gastric pH to > 3 and > 4 compared to postprandial oral
omeprazole (10 or 20 mg)20.
Dettmar et al showed in a RCT studying 4-hour pH in GERD patients that oral ranitidine was
superior to oral omeprazole in reducing the acidity in the stomach and the esophagus 21.
Hedenstrom et al in a RCT that assessed 4-hour pH in healthy volunteers, found that oral
ranitidine and famotidine resulted in a fast and significant raise in the intragastric pH while oral
omeprazole had no effect in the intragastric pH during the study period (4-h) 22.
Pipkin et al showed that, in GERD patients , oral ranitidine or famotidine had a faster onset of
action compared to oral omeprazole or a lansoprazole: the H2RAs achieved a significantly
greater and more rapid rise in intragastric pH in the hour immediately after dosing and offered a
faster relief of symptoms 23.
This suggests that H2RAs may be more effective than PPIs for on-demand treatment for episodic
heartburn or episodic dyspepsia.
3.2. H2RAS VS. PPIS: TIMING OF ADMINISTRATION IN RELATION TO MEALS
PPIs are more effective when administered before a meal 24,25,26.
As Howden & Chey have stated “PPIs are best absorbed in the absence of food. Ingestion of food after a
PPI stimulates parietal cell activity when blood levels of the PPI are increasing; this promotes uptake of
the PPI by the parietal cells. Therefore, patients should be advised to take their PPI between 30 and 60
minutes before eating. For patients on a once-daily PPI, the best time to take it is about 30 to 60 minutes
before breakfast.”27
On the other hand, H2RAs can be administered at any time in relation to the meals:
Orr et al, in a RCT in healthy volunteers, showed that the timing of oral ranitidine administration
in relation to a meal did not result in differences in pharmacokinetics (peak ranitidine
concentrations, time to peak concentration, area under the serum-concentration time curve or
Page | 9
elimination half-life) or pharmacodynamics (median intragastric pH or mean hydrogen-ion
activity over the 23-h study interval)28.
Pounder et al, in a RCT in healthy volunteers, showed the exact timing of oral cimetidine
administration in relation to meals was not critical29.
This difference between H2RAs and PPIs, may offer an advantage to the H2RAs as on-demand treatment
for episodic postprandial dyspepsia or episodic postprandial heartburn (a patient who has already had a
meal and developed postprandial symptoms, can only treat this episode with a medication that can be
administered postprandially).
Of note, most of our knowledge on the pharmacokinetics of PPIs and H2RAs in relation to meals is
derived from trials on healthy volunteers. However, we have no reason to expect that the results will be
different in ambulatory patients.
3.3. H2RAS VS. PPIS: SAFETY IN PREGNANCY
An additional argument in favor of retaining H2RAs in the WHO List of Essential Medicines , is their
proven safety during pregnancy (interestingly there is an even higher need for acid suppression during
pregnancy, because the prevalence of GERD is higher during pregnancy 30,31). According to the FDA
labeling system for drugs in pregnancy 32 (Table 1), all H2RAs (ranitidine, cimetidine, famotidine and
nizatidine) are “relatively safe” in pregnancy and are classified as category B drugs 33. Of the PPIs,
lansoprazole, rabeprazole, pantoprazole and esomeprazole are also “relatively safe” in pregnancy and
are also classified as category B drugs 33. However there have been safety concerns about omeprazole in
pregnancy (animal studies that showed that omeprazole in doses about 5.5 to 56 times the human dose
was associated with dose-related embryo-lethality and fetal toxicity and postnatal developmental
toxicity), therefore it is classified as category C drug 33. Epidemiological studies of pregnant women have
revealed no evidence of adverse events of omeprazole on pregnancy or an increased risk of congenital
malformations, but there these studies may have methodological limitations 34,35.
Table 1.
Definitions and management strategies from the US Food and Drug Administration categories for drugs taken during pregnancy 32
CATEGORY DEFINITION MANAGEMENT STRATEGY
A Adequate and well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus in the first trimester of pregnancy.
Because studies are not able to rule out the possibility
of harm, (name of drug) should be used during
Page | 10
CATEGORY DEFINITION MANAGEMENT STRATEGY
pregnancy only if clearly indicated.
B
Animal reproduction studies have failed to demonstrate a risk to the fetus,
but there are no adequate and well-controlled studies of pregnant women.
Or animal studies demonstrate a risk, and adequate and well-controlled
studies in pregnant women have not been done during the first trimester.
Because the studies of humans cannot rule out the
possibility of harm, (name of drug) should be used
during pregnancy only if clearly needed.
C
Animal reproduction studies have shown an adverse effect on the fetus,
but there are no adequate and well-controlled studies of humans. The
benefits from the use of the drug in pregnant women might be acceptable
despite its potential risks. Or animal studies have not been conducted and
there are no adequate and well-controlled studies of humans.
(Name of drug) should be given to pregnant women
only if clearly needed.
D
There is positive evidence of human fetal risk based on adverse reaction
data from investigational or marketing experience or studies of humans,
but the potential benefits from the use of the drug in pregnant women
might be acceptable despite its potential risks.
If this drug is used during pregnancy, or if the patient
becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus.
X
Studies in animals or humans have demonstrated fetal abnormalities or
there is positive evidence of fetal risk based on adverse reaction reports
from investigational or marketing experience, or both. The risk involved in
the use of the drug in pregnant women clearly outweighs any possible
benefits.
(Name of drug) is contraindicated in women who are or
might become pregnant. If this drug is used during
pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the
potential hazard to the fetus.
3.4. H2RAS VS. PPIS: COST
H2RAs cost less than PPIs in North America (Table 2 and 3). Although PPIs are more effective than H2RAs,
some patients can be switched to H2RAs are remain satisfied with their treatment 36. This is particularly
important for low and middle income countries. However, it is important to note that internationally the
range of the price for omeprazole (a PPI) is much higher than for ranitidine (an H2RA). Therefore, it is
possible that omeprazole may be purchased at a lower price than ranitidine in some countries.
According to the International Drug Price Indicator Guide 37 the cost of omeprazole and ranitidine is as
follows:
Ranitidine:
Median Price 0.0235$/tab-cap
Lowest Price 0.0161$/tab-cap
High/Low Ratio 3.42
Page | 11
Highest Price 0.0551$/tab-cap
Omeprazole:
Median Price 0.0255$/tab-cap
Lowest Price 0.0114$/tab-cap
High/Low Ratio 12.54
Highest Price 0.1429$/tab-cap
Table 2 38
Page | 12
Table 3 39
4. PPI PARENTERAL PREPARATION
The vast majority of patients that require PPI treatment can be treated with oral PPIs. However, there
are some situations were intravenous (IV) PPI treatment is either preferable or is the only possible route
of administration 40.
The official FDA-approved indication for IV Nexium (esomeprazole) in the US, reads: “NEXIUM I.V. is a
proton pump inhibitor indicated for the treatment of Gastroesophageal Reflux Disease (GERD) with
erosive esophagitis (EE) in adults and pediatric patients greater than one month of age, when oral
therapy is not possible or appropriate.”
The official indication for IV Nexium (esomeprazole) in the Wales, is wider: “Esomeprazole (Nexium® IV)
is recommended as an option for use within NHS Wales for gastric antisecretory treatment when the oral
route is not possible, such as gastro-oesophageal reflux disease (GORD) in patients with erosive reflux
oesophagitis and/or severe symptoms of reflux for children and adolescents aged 1–18 years of age.”
The UK Summary of Product Characteristics for IV Nexium (esomeprazole) as provided by AstraZeneca
states 41:
“Nexium for injection and infusion is indicated for:
Adults
Page | 13
gastric antisecretory treatment when the oral route is not possible, such as:
gastro-oesophageal reflux disease (GORD) in patients with oesophagitis and/or severe
symptoms of reflux
healing of gastric ulcers associated with NSAID therapy
prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.
prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or
duodenal ulcers.
Children and adolescents aged 1-18 years
• gastric antisecretory treatment when the oral route is not possible, such as:
- gastro-oesophageal reflux disease (GORD) in patients with erosive reflux oesophagitis and/or severe
symptoms of reflux.”
IV PPIs can be used in patients who require potent acid suppression therapy but:
cannot swallow oral medications because of severe stricturizing GERD, or
have gastric outlet obstruction due to peptic ulcer disease.
Less often, patients with an obstruction of the oro-pharynx or the upper GI tract (due to malignancy, or
trauma) may need short-term IV PPI treatment.
However, the most important and most common indication for IV PPIs is peptic ulcer bleeding. IV
esomeprazole has already approved for this indication in Europe, and a relevant application to the FDA
is pending. This is based mainly on the results of a large high-quality multi-center RCT that was
published in 2009 42, but even older Cochrane systematic reviews and meta-analyses of RCTs had found
that there is strong evidence supporting the efficacy of high-dose IV PPI treatment in such patients
(while the evidence for the efficacy of oral PPI treatment in such patients is not very strong, especially
regarding the effects on mortality) 43. With the exception of the UK NICE guidelines, where the guideline
development group “did not feel able to make a firm recommendation on the preferred route of
administration”44, all other consensus guidelines (for example, American College of Gastroenterology
guidelines45, International Consensus Guidelines46, Asia-Pacific Guidelines47) have recommended the use
of high-dose IV PPIs in patients with peptic ulcer bleeding following appropriate endoscopic treatment.
Page | 14
REFERENCES
1 Kahrilas PJ, Shaheen NJ, Vaezi MF, et al; American Gastroenterological Association. American
Gastroenterological Association Medical Position Statement on the management of gastroesophageal
reflux disease. Gastroenterology. 2008;135(4):1383-91.
2 Fock KM, Talley NJ, Fass R, et al. Asia-Pacific consensus on the management of gastroesophageal reflux
disease: Update. J Gastroenterol Hepatol. 2008; 23(1):8-22.
3 DeVault K.R., Castell D.O. Updated guidelines for the diagnosis and treatment of gastroesophageal
reflux disease. Am J Gastroenterol. 2005; 100(1):190-200.
4 Moayyedi P, Santana J, Khan M, Preston C, Donnellan C. Medical treatments in the short term
management of reflux oesophagitis. Cochrane Database of Systematic Reviews 2007; Issue 2: CD003244
5 Jeong HY, Lee BS, Sung JK, et al. [A randomized, prospective, comparative, multicenter study of
rabeprazole and ranitidine in the treatment of reflux esophagitis]. [Korean] Korean Journal of
Gastroenterology/Taehan Sohwagi Hakhoe Chi. 2006; 47:15-21.
6 van Pinxteren B, Sigterman KE, Bonis P, et al. Short-term treatment with proton pump inhibitors, H2-
receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and
endoscopy negative reflux disease. Cochrane Database Syst Rev. 2010; Issue 11:CD002095.
7 Nakamura K, Akiho H, Ochiai T, et al. Randomized controlled trial: roxatidine vs omeprazole for non-
erosive reflux disease. Hepatogastroenterology. 2010;57: 497-500.
8 Donnellan C, Preston C, Moayyedi P, Sharma N. Medical treatments for the maintenance therapy of
reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database of Systematic Reviews
2005, Issue 2: CD003245.
9 Metz DC, Bochenek WJ, Pantoprazole US GERD Study Group. Pantoprazole maintenance therapy
prevents relapse of erosive oesophagitis. Aliment Pharmacol Ther. 2003; 17: 155-64.
10 Richter JE, Fraga P, Mack M, et al. Pantoprazole US GERD Study Group. Prevention of erosive
oesophagitis relapse with pantoprazole. Aliment Pharmacol Ther. 2004; 20: 567-75.
Page | 15
11 Norman Hansen A, Bergheim R, Fagertun H, et al. A randomised prospective study comparing the
effectiveness of esomeprazole treatment strategies in clinical practice for 6 months in the management
of patients with symptoms of gastroesophageal reflux disease. Int J Clin Pract. 2005; 59: 665-71.
12 Hansen AN, Bergheim R, Fagertun H, et al. Long-term management of patients with symptoms of
gastro-oesophageal reflux disease - a Norwegian randomised prospective study comparing the effects of
esomeprazole and ranitidine treatment strategies on health-related quality of life in a general
practitioners setting. Int J Clin Pract. 2006; 60:15-22.
13 Jee SR, Seol SY, Kim do H, et al. [A randomized, comparative study of rabeprazole vs. ranitidine
maintenance therapies for reflux esophagitis--multicenter study]. [Korean] Korean Journal of
Gastroenterology/Taehan Sohwagi Hakhoe Chi. 2005; 45:321-7.
14 Peura DA, Freston JW, Haber MM, et al. Lansoprazole for long-term maintenance therapy of erosive
esophagitis: double-blind comparison with ranitidine. Dig Dis Sci. 2009; 54: 955-63.
15 Moayyedi P, Shelly S, Deeks JJ, et al. Pharmacological interventions for nonulcer dyspepsia. Cochrane
Database Syst Rev. 2006; Issue 4: CD001960.
16 Blum AL, Arnold R, Stolte M, et al. Short course acid suppressive treatment for patients with functional
dyspepsia: results depend on Helicobacter pylori status. Gut. 2000; 47:473-80.
17 Miwa H, Ghoshal UC, Fock KM, et al. Asian consensus report on functional dyspepsia. J Gastroenterol
Hepatol. 2012;27: 626-41.
18 Talley NJ, Vakil N; Practice Parameters Committee of the American College of Gastroenterology.
Guidelines for the management of dyspepsia. Am J Gastroenterol. 2005;100:2324-37.
19 Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the
evaluation of dyspepsia. Gastroenterology. 2005;129: 756-80.
20 Khoury RM, Katz PO, Castell DO. Post-prandial ranitidine is superior to post-prandial omeprazole in
control of gastric acidity in healthy volunteers. Aliment Pharmacol Ther. 1999;13:1211-4.
Page | 16
21 Dettmar PW, Sykes J, Little SL, et al. Rapid onset of effect of sodium alginate on gastro-oesophageal
reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux
episodes. Int J Clin Pract. 2006; 60:275-83.
22 Hedenstrom H, Alm C, Kraft M, et al. Intragastric pH after oral administration of single doses of
ranitidine effervescent tablets, omeprazole capsules and famotidine fast-dissolving tablets to fasting
healthy volunteers. Aliment Pharmacol Ther. 1997;11: 1137-41
23 Pipkin GA, Mills JG. Onset of action of antisecretory drugs: beneficial effects of a rapid increase in
intragastric pH in acid reflux disease. Scand J Gastroenterol Suppl. 1999; 230: 3-8.
24 Delhotal-Landes B, Cournot A, Vermerie N, et al. The effect of food and antacids on lansoprazole
absorption and disposition. Eur J Drug Metab Pharmacokinet. 1991;Spec No 3:315-20.
25 Wilder-Smith C, Röhss K, Bokelund Singh S, et al. The effects of dose and timing of esomeprazole
administration on 24-h, daytime and night-time acid inhibition in healthy volunteers. Aliment Pharmacol
Ther. 2010;32: 1249-56.
26 Hatlebakk, JG, Katz, PO, Camacho-Lobato, L, et al. Proton pump inhibitors: Better acid suppression
when taken before a meal than without a meal. Aliment Pharmacol Ther. 2000; 14: 1267-72.
27 Howden CW, Chey WD. Gastroesophageal reflux disease. J Fam Pract. 2003;52:240-7.
28 Orr WC, Finn AL, Allen M, et al. The timing of evening meal and ranitidine administration--effects on
patterns of 24 hour intragastric acidity. Aliment Pharmacol Ther. 1988; 2: 541-9.
29 Pounder R.E., Williams J.G., Hunt R.H. The effects of oral cimetidine on food stimulated gastric acid
secretion and 24 hour intragastric acidity. Cimetidine: proceedings of the second international
symposium on histamine h2-receptor antagonists. Excerpta Medica, 1977; Amsterdam - ICS no. 416; pp
189-204. Date of publication: 1977. [book]
30 Richter JE. Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin North Am. 2003; 32:
235-61.
31 Borum ML. Gastrointestinal diseases in women. Med Clin North Am. 1998; 82: 21-50.
Page | 17
32 Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmacother. 2001;
35:1485-9.
33 Thukral C, Wolf JL. Therapy insight: drugs for gastrointestinal disorders in pregnant women. Nat Clin
Pract Gastroenterol Hepatol. 2006 ;3: 256-66.
34 Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N
Engl J Med. 2010; 363: 2114-23.
35 Gill SK, O'Brien L, Einarson TR, et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-
analysis. Am J Gastroenterol. 2009;104:1541-5.
36 Lucas LM, Gerrity MS, Anderson T. A practice-based approach for converting from proton pump
inhibitors to less costly therapy. Eff Clin Pract. 2001;4 :263-70.
37 International Drug Price Indicator Guide, Management Sciences for Health (MSH).
http://erc.msh.org/mainpage.cfm?file=1.0.htm&module=dmp&language=english. Assessed jan 10, 2012.
38 How Do You Prescribe PPIs? Education for Quality Improvement in Patient Care. University of Victoria.
December 2011. http://web.uvic.ca/~eqip/sites/default/files/EQIP_PPI_Methods_2011_Web.pdf
39 Navigating acid suppression options. Considerations for optimal PPI therapy. RxFiles Academic
Detailing Program. September 2007.
http://www.rxfiles.ca/rxfiles/modules/druginfoindex/druginfo.aspx
40 Pang SH, Graham DY. A clinical guide to using intravenous proton-pump inhibitors in reflux and peptic
ulcers. Therap Adv Gastroenterol 2010;3:11-22.
41 Electronic Medicines Compendium (eMC)
http://www.medicines.org.uk/emc/medicine/14054/SPC/Nexium+I.V.+40mg+Powder+for+solution+for+
injection+infusion Assessed Jan 10, 2012.
42 Sung JJ, Barkun A, Kuipers EJ, et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer
bleeding: a randomized trial. Ann Intern Med 2009;150:455-64.
Page | 18
43 Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer
bleeding. Cochrane Database Syst Rev 2006;(1):CD002094.
44 CG141 Acute upper GI bleeding: NICE guideline. 13 June 2012
http://guidance.nice.org.uk/CG141/NICEGuidance/pdf
45 Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol 2012;107:345-
60.
46 Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the
management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med
2010;152:101-13.
47 Sung JJ, Chan FK, Chen M, et al. Asia-Pacific Working Group consensus on non-variceal upper
gastrointestinal bleeding. Gut 2011;60:1170-7.