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Esomeprazole for the treatment of peptic ulcer bleeding
Article in Expert Review of Gastroenterology and Hepatology · December 2010

DOI: 10.1586/egh.10.66 · Source: PubMed
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Esomeprazole for the

treatment of peptic
ulcer bleeding
Expert Rev. Gastroenterol. Hepatol. 4(6), 679–695 (2010)
Caroline M den Hoed1 Peptic ulcer bleeding is the most common cause of acute bleeding in the upper GI tract. The
and Ernst J Kuipers†1,2 incidence of peptic ulcer bleeding has slowly decreased and endoscopic treatment options have
improved; nevertheless, it remains a very common condition with a 7–15% mortality. Acidic
1
Departments of Gastroenterology and
Hepatology, Erasmus MC University environments have a negative effect on hemostasis. Therefore, acid inhibitors have been applied
Medical Center, Gravendijkwal 230, in the adjuvant treatment of peptic ulcer bleeding, both in preventing rebleeding and in treating
3015 CE, Rotterdam, The Netherlands the underlying cause. This requires profound acid suppressive therapy aiming for a rapid onset
2
Department of Internal Medicine,
Erasmus MC University Medical Center,
of effect and a persistent intragastric pH above 6. This can only be achieved by proton pump
Gravendijkwal 230, 3015 CE, inhibitors (PPIs). Esomeprazole is the S-isomer of omeprazole, and the first PPI to consist of only
Rotterdam, The Netherlands the active isomer. A number of studies have compared esomeprazole with other PPIs,
†
Author for correspondence: demonstrating a faster and more persistent increase in intragastric pH with the use of
[email protected]
esomeprazole than with other agents. Continuous high-dose intravenous treatment with
esomeprazole decreases rebleeding, surgery, transfusion rates and hospital days in peptic
ulcer bleeding.
KEYWORDS : ESOMEPRAZOLE s PEPTIC ULCER BLEEDING s PHARMACOLOGIC TREATMENT s PROTON PUMP INHIBITOR
Peptic ulcer bleeding is the most common cause Peptic ulcer rebleeding has an important
of acute hemorrhage in the upper GI tract, impact on mortality. The characteristics of the
accounting for approximately 50% of all cases [1] . ulcer at endoscopy are helpful in identifying
Reported incidences range from 48–160 cases those at high risk (i.e., most prone to rebleed
per 100,000 adults per year [2–5] . Approximately after primary endoscopic treatment). These, in
90% of peptic ulcer bleeds stop spontaneously, particular, include ulcers with an adherent clot,
but rebleeding occurs in 10–30% of cases [6] . ulcers with oozing from the ulcer bed, ulcers
Despite the progress in endoscopic interven- with a visible vessel and ulcers with spurting
tions and treatment options, the mortality of arteries. These lesions demonstrate a growing
peptic ulcer bleeding has been reported at a con- risk for rebleeding, which rises from 12% in the
stant rate of approximately 7–15% for the past first (ulcers with an adherent clot) to 90% in the
decades [7] . This stable rate, despite therapeutic latter group (ulcers with a spurting artery) [11,12] .
advances, can be partially explained by a change Management of the patient with peptic ulcer
in the underlying etiology of ulcer disease in bleeding starts with an assessment of the sever-
developed countries. 30 years ago, the primary ity of bleeding and the need for intervention as
etiologic agent was infection with Helicobacter can be determined on the basis of symptoms,
pylori, with many ulcers and ulcer complications age and comorbidities, hemodynamic stability
occurring in relatively younger adults without and assessment of basic laboratory para meters.
major comorbidities. In the past 10–15 years, A recent study from the UK demonstrated that
there has been a shift to low-dose acetylsalicylic ana lysis of these basic parameters leading to a
acid (ASA) and NSAIDs as the underlying cause cumulative ‘Blatchford’ score was highly effec-
of bleeding ulcers [8] . The fact that these medi- tive for the identification of cases at low risk for
cations are more commonly prescribed in the clinical intervention [13] .
elderly for musculoskeletal and cardiovascular Following current guidelines, diagnostic
conditions explains the shift over years to bleed- and therapeutic endoscopy should be per-
ing ulcers in the elderly with a higher prevalence formed within 24 h in most cases with upper
of significant comorbidities [7,9,10] . GI bleeding, with the exception of those at
www.expert-reviews.com 10.1586/EGH.10.66 © 2010 Expert Reviews Ltd ISSN 1747-4124 679

Drug Profile den Hoed & Kuipers
low risk of requiring clinical intervention, as well as selected the treatment of peptic ulcer bleeding. Although they all regulate
high-risk cases, for instance, those with active acute coronary acid secretion by receptor blockage, convincing evidence for the
syndrome [14] . beneficial effect of any of these drugs in peptic ulcer bleeding is
In case of low-risk stigmata – that is, ulcers with a clean base lacking [22] . The introduction of PPIs around 20 years ago allowed
or flat spots – no endoscopic hemostatic therapy is needed. more effective suppression of acid secretion. PPIs directly and irre-
However, in the presence of high-risk stigmata, therapy however, versibly block the acid pump instead of receptor blockage, and
is indicated [15,16] . In the event of an adherent clot, the decision have a higher antisecretory potential than the previously mentioned
to perform endoscopic treatment is somewhat controversial, but agents [12,23–30] . Since then, the benefit of high-dose PPI therapy
targeted irrigation is recommended to attempt clot dislodge- next to endoscopic therapy has been convincingly shown [24,29,31] .
ment and determine further endoscopic treatment depending In a large Cochrane collaboration meta-analysis on the use of PPIs
on the underlying stigmata. Endoscopic treatment can con- for peptic ulcer bleeding, a decrease in rebleeding rates, need for
sist of thermocoagulation, hemoclips, sclerosant or injection surgery and repeated endoscopic surgery was demonstrated, as well
(epinehrine) therapy, a combination of injection (epinehrine) as reduced mortality in Asian patients and all-ethnicity high-risk
therapy with either one or a combination of any of the treatment bleeders [26] .
options, with the latter option demonstrating the best results [14] .
Altogether, endoscopic therapy along with acid suppression is Overview of the market
currently the mainstay of treatment of patients with bleeding Since the development of omeprazole in the early 1980s, several
peptic ulcer. other PPIs have emerged on the market. Currently, there are five
PPIs registered on most markets – that is, omeprazole, pantoprazole,
Rationale of proton pump inhibitors lansoprazole, rabeprazole and esomeprazole. Omeprazole was the
An ex vivo study in 1953 noted that clot lysis increased in an first and most studied PPI. It possesses good antisecretory poten-
acidic environment [17] . The extent of lysis was inversely associ- tial [19,25] and can attain a pH above 6 for longer periods of time,
ated with the environmental pH; after 75 min, the clots in a pH for over 72 h [15,32] . Several studies demonstrated that omeprazole is
above 6 looked the same as at the beginning of the experiment, more effective than placebo in the treatment of peptic ulcer bleeding
which contrasted with the reduced size and roughened surface at in high-risk patients in terms of bleeding recurrence, hospital days
the lower levels of pH. In 1978, another study demonstrated that and the need for transfusion [23,27,33–37] . Other studies demonstrated
lowering of environmental pH increased prothrombin time and a positive effect of omeprazole on rebleeding, surgery, hospital stay
inhibited platelet aggregation. The same study concluded that the and death in patients with low-risk peptic ulcer bleeding [15,16] .
effect of pepsin on clot lysis increased with decreasing pH as a Lansoprazole was the second PPI to become available. It dif-
result of increased activation of pepsinogen [18–20] . More studies fers from omeprazole in pharmacokinetic characteristics, with
were conducted demonstrating that a pH value of at least 4 was a linear increase in plasma concentration in the dose range of
needed to maintain clot formation and prevent clot lysis [20] ; a pH 15–60 mg, and constant kinetics with either single or multiple
above 5 was demonstrated in another study to be associated with dosages [38] . Pantoprazole was the next agent to become avail-
reduced rebleeding of peptic ulcers [21] . Together, these data led to able. Similar to lansoprazole, pantoprazole demonstrates linear
the hypothesis that acid inhibition, and thus increase of intragastric pharmacokinetics and the bioavailability is independent of food
pH, could contribute to the treatment of patients with peptic ulcer intake [38,39] . High-dose continuous pantoprazole treatment has
bleeding. For that purpose, the histamine H2 receptor antagonists also been studied in peptic ulcer bleeding; however, these studies
(H2RA) somatostatin and octreotide were studied and used for did not yield a significant effect on the major parameters, when
comparing pantoprazole with H2RA [40,41] , except for a shorter
hospital stay and a decrease in units transfused in one study [42] .
O A study in healthy volunteers demonstrated that lansoprazole was
better than pantoprazole in increasing pH values with both oral
and intravenous (iv.) administration [43,44] .
O Rabeprazole differs from the other PPIs in that it is less metabo-
lized by CYP2C19 and CYP3A4. It demonstrates a better anti-
S
N N secretory effect on the first day of treatment [38] . A comparative study
demonstrated that there was no significant difference in raising pH
HN above 6 between rabeprazole, omeprazole and pantoprazole [6] .
Several meta-analyses have come to the conclusion that high-
O dose PPIs, particularly when given as a bolus plus continuous
infusion for 72 h, are effective in consistently increasing intra-
gastric pH to 6.0 and above and decreasing the rebleeding recur-
rence [12,45] . However, these conclusions were based on the results
Figure 1. Esomeprazole.
of studies conducted in Asian populations, which in this respect,
clearly differ from the Western population. Asian populations
680 Expert Rev. Gastroenterol. Hepatol. 4(6), (2010)

clinical efficacy [38] .
www.expert-reviews.com
Introduction to the drug
peptic ulcer treatment [38,47.48] .
namic properties, in both their influences

of esomeprazole in the treatment of
acid suppressive effects in Asians than
Western populations. High-dose PPI
in packets for a delayed-release oral sus-

its gastric acid production and provides
gitis and pH values than the other PPIs,
S-isomer of omeprazole, appeared to
in tablets, delayed-release capsules and

Differences between PPIs are reflected in
of peptic ulcer bleeding, no PPI, until
in European and US populations
therapy, thus, has more pronounced
PPIs, and they produce less acid than
pension; availability differs in different

Esomeprazole magnesium is supplied
pression, which subsequently affect their
other PPIs. Esomeprazole is the first PPI
gastric pH compared with other available
ease (GERD), peptic ulcers and, more
was developed with the aim of improving
tion. However, since esomeprazole, the
of high-dose iv. treatment with the
a smaller first-pass effect of most
strains, they have a higher prevalence
rates, in particular of cagA-positive
often have higher H. pylori prevalence
on speed and degree of gastric acid sup-

their pharmacokinetic and pharmacody-
UK) is the S-isomer of omeprazole and
with only the active isomer (S-isomer)

to be developed as a single optical iso-
acid-inhibiting agents, both H2RA and
the pharmacokinetic and pharmacody-
Esomeprazole (Nexium®; AstraZeneca,
the most rapid and constant rise of intra-

ulcer complications. Esomeprazole inhib-
recently, as additional treatment in peptic
patients with gastroesophageal reflux dis-
It is commonly used as a treatment for
namic profiles of racemic omeprazole [48] .
there was room for the administration
have a better effect on erosive esopha-
recently, was registered for this indica-
cies and the lack of a convincing effect
first generation of PPIs on outcome

[23,24,35,46] . Based on these discrepan-
morphisms, which is associated with
of low-metabolizing CYP2C19 poly-
mer with the rationale that treatment
will give better treatment outcomes.

Table 1. Effect of esomeprazole compared with other proton pump inhibitor agents on intragastric pH.
Study Area Study Patients n Treatment Results Study Ref.
(year) design period
Wilder- Europe Open RCT Healthy volunteers 25 Esomeprazole 40 mg vs pantoprazole Intragastric pH >4. Day 1: 8.3 vs 5.3 h (p < 0.0001). Day 5: 5 days [61]
Smith et al. (Helicobacter pylori 40 mg iv. for 5 days 13.9 vs 9.0 h (p < 0.0001). The first 4 h pH >4: 1.7 vs 0.6 h
(2004) negative) (p < 0.0001). A median pH >4 on day 5 only obtained
with esomeprazole
Hartmann Europe Open Healthy volunteers 28 Esomeprazole 40 mg iv. in 15 min or pH >4: 11.8 h vs 5.6 h (p < 0.001) and 7.2 h (p < 0.001) 24 h [56]
et al. randomized pantoprazole 40 mg iv. in 15 min or First 6 h, 3.4 vs 1.1 h (p < 0.000001) and 2.1 h (p < 0.001)
(2007) three-way pantoprazole bolus 40 mg i.v
cross-over
Rohss et al. Europe Open GERD patients 120 Esomeprazole 40 mg p.o. or Mean percentage of a 24 h period with pH >4 significantly 5 days [119]
(2002) randomized omeprazole 40 mg p.o. for 5 days greater on day 1: 48.6 vs 40.6% (p < 0.001) and day 5:
cross-over 68.4 vs 62.0%. Interpatient variability was significantly less
in esomeprazole
Miner et al. USA Open GERD patients 34 Oral esomeprazole 40 mg or Day 5, intragastric pH >4 for a mean 14.0 h with 5 days [57]
(2003) five-way lansoprazole 30 mg or omeprazole esomeprazole, 12.1 h with rabeprazole, 11.8 h with
cross-over 20 mg or pantoprazole 40 mg or omeprazole, 11.5 h with lansoprazole and 10.1 with
rabeprazole 20 mg once daily pantoprazole (p < 0.001). Esomeprazole significantly higher
percentage with pH >4 for more than 12 h (p > 0.05)
Miner et al. USA Open Healthy volunteers 42 Pantoprazole 40 mg iv. for 50 days + Day 5: percentage of time at pH >4 was 68.5 vs 53.3% 5 days [58]
(2006) cross-over esomeprazole 40 mg for 5 days p.o. (p < 0.001). Day 1: percentage of time pH >4 was 62.5 vs
or pantoprazole 40 mg p.o. for 5 days 51.0% (p < 0.001)
Andersson Europe Open Healthy males 12 Esomeprazole 5 mg p.o. or Area under curve of esomeprazole and omeprazole 5 days [72]
et al. cross-over esomeprazole 10 mg p.o. or increased from day 1–5. Mean inhibition values acid output:
(2001) esomeprazole 20 mg p.o. or 15, 29 and 46% in esomeprazole and 35% in omeprazole;
omeprazole 20 mg p.o. for 5 days day 5: 28 vs 62 vs 90% in esomeprazole and 79%
in omeprazole
Drug Profile
GERD: Gastroesophageal reflux disease; iv.: Intravenous; p.o.: Per oral; RCT: Randomized controlled trial.
681
Table 2. Proton pump inhibitors in upper gastrointestinal bleeding.
682
Jensen et al. USA RCT Peptic ulcer 153 Endoscopic treatment (thermal Stopped early because of slow enrollment. 30 days [40]
(2006) bleeding coagulation and/or epinephrine Rebleeding 6.9 vs 14.3%. Mortality 4 vs 4%.
(high risk) injection) and pantoprazole No significant differences
Drug Profile
80 + 8 mg/h iv. (72 h) or ranitidine

50 mg + 6.25 mg/h (72 h). After 72 h,
PPIs were given p.o. for 30 days
Sung et al. Asia RCT Peptic ulcer 156 Endoscopic therapy (thermal and Rebleeding 1.1 vs 11.6% (p = 0.009). Mortality 2.6 vs 5.1% 30 days [29]
(2003) bleeding epinephrine injection) and omeprazole (p > 0.2). Endoscopic therapy important
(high risk) 80 mg + 8 mg/h iv. (72 h) or only
omeprazole 80 + 8 mg/h iv. (72 h).
After 72 h, both groups were given
omeprazole 20 mg p.o. for 30 days
den Hoed & Kuipers
minimum
Zargar et al. Asia RCT Peptic ulcer 203 Endoscopic therapy (thermal and Rebleeding 7.8 vs 19.8% (p = 0.01). Fewer transfusions 30 days [42]
(2006) bleeding epinephrine injection) + pantoprazole (p = 0.003). Fewer days in hospital (p = 0.0003)
(high risk) 80 mg + 8 mg/h iv. (72 h) or placebo
(72 h). After 72 h, all patients were
given omeprazole 40 mg p.o. for
6 weeks
Lau et al. Asia RCT Peptic ulcer 240 Endoscopic therapy (thermal and Rebleeding 6.7 vs 22.5% (HR: 3.9). Mortality 4.2 vs 10% 30 days [76]
(2000) bleeding epinephrine injection) + omeprazole (p = 0.13)
(high risk) 80 mg + 8 mg/h iv.or placebo iv. for
72 h. After 72 h, all patients were
given omeprazole 20 mg p.o. for
2 months
Kaviani et al. Middle RCT Peptic ulcer 160 Endoscopic therapy (epinephrine Mean hospital stay 62.8 ± 28.6 vs 75 ± 35 h (p = 0.032). Mean 3 weeks [33]
(2003) East bleeding injection) + omeprazole 20 mg/6 h or transfusion 1.13 ± 1.36 vs 1.68 ± 1.68 bags (p = 0.029).
(high risk) placebo p.o. for 5 days Rebleeding 12 vs 26 patients (p = 0.022)
Schaffalitzky Europe RCT Peptic ulcer 274 Endoscopic therapy (epinephrine Overall outcome score difference in favor of omeprazole 21 days [36]
de bleeding injection and/or thermal) + (p = 0.004). Less blood transfusions (p = 0.01). Shorter degree
Muckadell (high risk) omeprazole 80 mg + 8 mg/h iv. or and duration of bleeding (p = 0.02). Less surgery (p = 0.003)
et al. (1997) placebo. After 72 h, both given or additional endoscopic therapy (p = 0.04)
omeprazole 20 mg p.o. untill day 21
Khuroo Asia RCT Peptic ulcer 220 Omeprazole 40 mg twice-daily for Further bleeding/rebleeding 10.9 vs 36.45 (p < 0.001). Surgery 30 days [34]
et al. (1997) bleeding 5 days or placebo 8 vs 26 patients (p < 0.001). Mortality 2 vs 6 patients.
(high risk) Transfusions 29.1 vs 70.9% (p < 0.001). Significant reduction
in patients with NBVV and adherent clots. No significant
reduction in patients with oozing or arterial spurting
HR: Hazard ratio; iv.: Intravenous; NBVV: Nonbleeding visible vessel; p.o.: Per oral; PPI: Proton pump inhibitor; RCT: Randomized controlled trial.
Expert Rev. Gastroenterol. Hepatol. 4(6), (2010)

Table 2. Proton pump inhibitors in upper gastrointestinal bleeding (cont.).
Lin et al. Asia RCT Peptic ulcer 200 Endoscopic therapy (epinephrine Rebleeding occured in the omeprazole 40 mg/6 h group; 9 vs 14 days [27]
(2006) bleeding injection) + omeprazole 40 mg/6 h iv. 32.8% in cimetidine in (p < 0.01). Volume of transfusion less in
(high risk) or omeprazole 40 mg/12 h or omeprazole 40 mg/6 h than omeprazole 40 mg/12 h and
cimetidine 400 mg/12 h iv. After 72 h, cimetidine (p < 0.001). No statistical difference in hospital stay,
omeprazole 20 mg p.o. was given for surgery and mortality
2 months
Lin et al. Asia RCT Peptic ulcer 100 Endoscopic therapy + omeprazole Intragastric pH >6, 84.4 ± 22.9% vs 53.5 ± 32.3% (p < 0.001). 14 days [28]
(1998) bleeding 40 mg + 160 mg/24 h iv. or cimetidine Rebleeding: 4 vs 24%, p = 0.004. Less transfusion median 0
(high risk) 300 mg + 1200 mg/24 h iv. If (0–2500 ml) vs median 0 (0–5000 ml; p = 0.08). No difference
necessary, a second look and repeated in mortality, hospital stay or surgery rate
endoscopic therapy was performed.
After 72 h, all patients were given
omeprazole 20 mg p.o. for 2 weeks
Hasselgren Europe RCT Peptic ulcer 333 Endoscopic therapy (not standardized) Overall outcome (scale): omeprazole was demonstrated to be 21 days [15]
et al. (1997) bleeding + omeprazole 80 mg + 8 mg/h iv. or better (p = 0.017). Need for surgery, omeprazole vs placebo
placebo. After 72 h, groups were (p = 0.003). Degree of bleeding (p = 0.003) and treatment
given omeprazole 20 mg p.o. for failure (p = 0.0009). Mortality identical. Subgroup oozing.
2 weeks Outcome of omeprazole was better (p = 0.01)
Sung et al. Worldwide RCT Peptic ulcer 767 Endoscopic therapy (not standardized) Recurrent bleeding 5.9 vs 10.3% (p = 0.026). Retreatment 6.4 30 days [37]
(2009) bleeding + esomeprazole 80 mg + 8 mg/h iv. or vs 11.6% (p = 0.012). Surgery 2.7 vs 5.4% and all-cause
(high risk) placebo for 72 h. After 72 h, all mortality 0.8 vs 2.1% (surgery plus all-cause mortality
patients were given esomeprazole not significant)
40 mg p.o. for 27 days
Li et al. Asia Retro- Peptic ulcer 607 Endoscopic therapy in oozing Surgery 3.8 vs 9.28% (p < 0.05), mortality rate 1.49 vs 2.66%, 30 days [19]
(2000) spective bleeding bleeding. Cimetidine 400 mg bolus iv. not significant. Transfusion not significantly different in
(excluding b.i.d for 5 days or omeprazole iv. number and volume
arterial 40 mg for 5 days
spurt)
HR: Hazard ratio; iv.: Intravenous; NBVV: Nonbleeding visible vessel; p.o.: Per oral; PPI: Proton pump inhibitor; RCT: Randomized controlled trial.
Drug Profile
683
countries. Each tablet or delayed-release capsule contains 20 or 6 seems to require a higher frequency of PPI administration as
40 mg of esomeprazole. The packets for oral suspension consist well as a high dosage. Furthermore, iv. administration provides
of 10, 20 or 40 mg of esomeprazole. Furthermore, an iv. form of faster acid suppression, as well as a prolonged higher pH than oral
esomeprazole is supplied and has become widely available over the administration [32,41,60,61] .
last few years, available in 40 mg vials [49] .
Pharmacokinetics & metabolism
Chemistry Absorption & distribution
The active ingredient in esomeprazole magnesium is bis(5- Following intake and passage through the stomach, esomepra-
methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] zole is rapidly absorbed in the proximal small bowel in healthy
sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate, an acid- volunteers as well as patients. After oral administration of 20 or
inhibiting compound. Esomeprazole is the S-isomer of omepra- 40 mg esomeprazole, Cmax varies between 0.78 and 3.32 after
zole, which is a mixture of S- and R-isomers. Its molecular for- 0.5–3.5 h [38,48] . Cmax increases with increasing dosage, as does the
mula is (C17H18N3O3S)2Mg 3H2O, with a molecular weight of area under curve (AUC), which shows a threefold increase in AUC
767.2 g/mol as a trihydrate and 731.1 g/mol on an anhydrous when increasing the dosage from 20 to 40 mg. Repeated daily
basis (FIGURE 1) [49] . administration of 40 mg esomeprazole improves the systemic
bioavailability to 90 compared with 64% after a single dose [49,53] .
Pharmacodynamics With the increase of the dose or frequency of administration of
Proton pumps are part of the super family of ion transporters esomeprazole there is a nonlinear increase in Cmax and AUC. This
using the ATP phosphorylation–dephosphorylation reaction, and may be due to the first-pass elimination and a decrease in systemic
are located on the cytoplasmic membrane of gastric parietal cell clearance (CL) [62] .
canaliculi. In the basal secretory state, proton pumps are located Intravenous administration demonstrates a higher Cmax of
within the cytoplasm. When activated by physiological digestive 2.51–5.5 µmol/l and a higher mean AUC with 20 and 40 mg
stimuli, they migrate to the lumen to exchange one H+ ion for one infusions compared with oral administration, firstly caused by
K+ ion. Chloride is excreted at the same time to form a hydrogen avoidance of the first-pass effect. After repeated dosing, these
chloride molecule [50] . differences become less pronounced [62,63] . The plasma elimina-
Esomeprazole inhibits gastric hydrochloric secretion by inhibit- tion half-life (t1/2 ) is comparable with that of the oral adminis-
ing the proton pump. This is achieved by accumulation in the tration, at 0.78 h after first administration rising to 1.15 h after
secretory canaliculus of the parietal cell when the cell is secreting the second. As is the case in oral administration, the systemic
hydrochloric acid. In this acidic environment, esomeprazole is clearance decreases with repeated infusion of esomeprazole. The
protonated and converted to the active inhibiting achiral sulfon- infusion rate used is of no influence on AUC, t1/2 or the systemic
amide form, which binds covalently to the sulfhydryl groups of clearance rate; it does, however, affect Cmax, which increases
the proton pump. This leads to the blocking of the final step in with shorter infusion periods [64] .
acid production and increasing intragastric pH [48,51,52] . Like omeprazole and other PPIs, 97% of esomeprazole is bound
This blockade remains during the lifecycle of the proton to plasma proteins. This binding remains constant within a con-
pump, which is 3 days on average [53] . However, proton pumps centration range of 2–20 µmol/l at a volume of distribution of
in parietal cells can not be blocked unless they are in an active around 16 l. Esomeprazole demonstrates a high degree of chiral
secreting stage [30] . This is due to the fact that protonation of the stability with an inversion rate of only 0.4% to the R-isomer [48,49] .
drug requires an acidic local environment with the drug acting
as a weak base. The restoration of acid secretion after treatment Metabolism
depends on protein turnover. As a result, despite the short plasma Esomeprazole is extensively metabolized by two cytochrome P450
half-life of 1–2 h, PPIs can be used on a daily basis [50] . isoenzymes, CYP2C19 and CYP3A4, into metabolites devoid of
antisecretory activity. Metabolization is primarily by CYP2C19
Acid suppression to hydroxy- and desmethyl-metabolites and to a lesser extent
The efficacy of gastric acid suppression for the treatment of pep- by CYP3A4 to sulfone metabolites. Sulfone metabolites inhibit
tic ulcer bleeding depends on the degree and duration of acid CYP2C19 which may appear to result in nonlinear dose-propor-
suppression over 24 h. For the optimization of hemostasis and tional pharmacokinetics. Following multiple dose administration
clot stability, a pH of at least 4 is needed, and some studies men- of 40 mg esomeprazole orally, CYP2C19 elimination decreases by
tion a pH of at least 6 [21,54] . H2RA demonstrated an increase 50%, while CYP3A4 elimination increases by 40%. This makes
in pH; however, this increase was neither prolonged nor high the metabolization less dependent on CYP2C19 [38,48] .
enough. In comparative studies between H2RAs and PPIs, PPIs CYP2C19 polymorphisms can influence the metabolization
generally demonstrate better and more prolonged acid suppres- of esomeprazole. Some specific populations should be taken into
sion and, therefore, pH increase [12,25,26,35,46,55] . Esomeprazole has account in the pharmacokinetics of esomeprazole. Individuals can
been tested against H2RAs and other PPIs in the doses currently be classified as either homozygous extensive metabolizers, heterozy-
marketed, and demonstrated a higher pH and maintained a pH gous extensive metabolizers or poor metabolizers according to met-
above 4 or 6 for a longer period [47,56–59] . Maintaining a pH above abolic rate. The frequencies of these three subgroups show a wide

Table 3. The effect of oral vs intravenous administration of proton pump inhibitors on intragastric pH and upper
gastrointestinal bleeding.
Study (year) Area Study Patients n Treatment Results Study Ref.
design period
Yilmaz et al. Turkey RCT Peptic ulcer 211 Omeprazole 80 mg iv. + 8 mg/h or Rebleeding 5 vs 4 patients. Surgery 3 vs 2 30 days [16]
(2006) bleeding omeprazole 80 mg/day p.o. patients. Mean length stay 4.6 ± 1.6 vs
(low risk) 4.5 ± 2.6 days. Transfusion 1.9 ± 1.1 units vs 2.1 ±
1.7. Mortality 2 vs 2 patients. All differences
between the two groups were nonsignificant
Wilder-Smith Europe Two random Healthy 40 + 24 Esomeprazole 40 mg iv. or esomeprazole Mean intragastric pH >4. Day 1: 10.1 vs 8.8 h and 5 days [63]
et al. (2005) two-way volunteers 40 mg p.o. for 5 days. day 5: 15.9 vs 15.3 h, no sign of difference.
cross-over Esomeprazole 20 mg iv. or 20 mg p.o. Day 1: 7.3 vs 6.6 h and day 5: 11.9 vs 12.3 h
studies for 5 days The area under curve differences between p.o.
and iv. were more pronounced on day 1 than on
day 5
Javid et al. Asia RCT Peptic ulcer 90 Endoscopic therapy (thermal coagulation Mean intragastric pH for omeprazole p.o. was 3 days [6]
(2009) bleeding and epinephrine injection) + 72 h of: 6.56 vs 6.93 for omeprazole iv. (p = 0.48). Mean
(high risk) omeprazole 80 mg iv. + 8 mg/h or intragastric pH for p.o. pantoprazole was 6.34 vs
80 mg p.o. + 40 mg twice-daily; 6.32 for pantoprazole iv. (p = 0.62). Mean
pantoprazole 80 mg iv. + 8 mg/h or intragastric pH for rabeprazole p.o. was 6.11 vs
pantoprazole p.o. 80 mg; 6.18 for rabeprazole iv. (p = 0.48). Mean
rabeprazole 80 mg iv. + 8 mg/h or intragastric pH without PPI treatment was 2.11
rabeprazole 80 mg p.o. + 40 mg
twice-daily
Laine et al. USA RCT Peptic ulcer 71 Endoscopic therapy + lansoprazole Intragastric pH >6, 67.8% of time with iv. vs 24 h [60]
(2008) bleeding 90 mg + 9 mg/h iv. or lansoprazole 64.8% p.o. pH >6, >60% in 22 patients iv. and
120 mg + 30 mg/3 h p.o. 22 patients p.o. At 1 h, mean pH iv.: 5.3 ± 0.4 vs
3.3 ± 0.4 p.o. (p = 0.001). Mean pH >6 in 2–3 h
iv. and 3–4 h p.o.
Bajaj et al. USA RCT Peptic ulcer 25 Endoscopic therapy (if necessary) + Rebleeding in 2 vs 0 patients (p = 0.46), organ 30 days [39]
(2007) bleeding pantoprazole 80 mg iv. + 8 mg/h or failure in 1 vs 0 patients (p = 0.99). Mortality was
pantoprazole 80 mg t p.o. twice daily for 0 in both groups. Transfusion 3.9 ± 3.7 vs
72 h. After 72 h all patients were given 3.6 ± 2.4 (p = 0.813). Hospitalization 6.8 ± 4.8 vs
40 mg pantoprazole p.o. twice daily for 5.2 ± 3.3 (p = 0.34)
30 days
Tsai et al. Asia RCT Peptic ulcer 156 Endoscopic injection therapy + Rebleeding 15.4 vs 16.7%. No differences in 14 days [75]
(2009) bleeding omeprazole 40 mg iv. every 12 h or hospital stay, transfusion volume, surgery or
(high risk) rabeprazole 20 mg p.o. twice-daily for mortality rate
72 h and esomeprazole 40 mg daily or
rabeprazole 20 mg p.o. twice-daily for
2 months
iv.: Intravenous; p.o.: Per oral; RCT: Randomized controlled trial.
Drug Profile
685
variation among ethnicities. The prevalence of poor metabolizers Inversely, inhibitors of CYP2C19 and CYP3A4 (fluconazole
ranges from 1.2 to 3.8% in Caucasians to 23% in Asians. Poor and fluvoxamin) can affect metabolism of esomeprazole and may
metabolizers demonstrate a three- to ten-fold and heterozygous double the systemic exposure. The AUC for esomeprazole is also
extensive metabolizers a two- to three-fold higher AUC compared doubled when coadministered with clarithromycin [49].
with homozygous extensive metabolizers [38] .
Despite these differences, in daily clinical practice, dosage adjust- Clinical efficacy
ment is not based on determination of CYP2C19 genotypes [48] . Several studies on the effect of esomeprazole on the intragastric
In patients with severe hepatic impairment (greater than pH have been conducted in healthy volunteers. An open-label
Child–Pugh class B) plasma levels of esomeprazole may be ele- cross-over study demonstrated that esomeprazole 40 mg per oral
vated and dosage should be kept low. Clinical data on the use of (p.o.) has a stronger acid-suppressive effect than pantoprazole
esomeprazole during pregnancy are insufficient [48] . 40 mg both when pantoprazole is administered orally and intra-
venously, with a p-value of less than 0.001 on day 1 and day 5 [58] .
Elimination These findings were confirmed in a more recent study [71] and an
The plasma elimination half-life is approximately 1–1.5 h. In total, earlier five-way cross-over study comparing orally administered
80% of esomeprazole is excreted as inactive metabolites in the standard doses [57] . Two other studies directly compared esome-
urine and the remainder is found as inactive metabolites in feces. prazole and omeprazole administered orally [72] or iv. [59] . Both
Less than 1% of the parent compound is found in urine [38,48,49] . demonstrated stronger acid suppression with esomeprazole. The
study by Andersson et al. demonstrated a 46–90% inhibition
Potential drug interactions of acid secretion on day 1–5 with esomeprazole 20 mg com-
Esomeprazole has a low potential for drug interaction with other pared with a 35–79% inhibition with 20 mg of omeprazole [72] .
drugs, and studies in vitro and in vivo have demonstrated that Rohss et al. demonstrated a mean acid output 5 h after dosing of
esomeprazole is unlikely to inhibit CYP isoenzymes other than 5.4 mmol/h with esomeprazole treatment versus 9.5 mmol/h with
CYP2C19 [48] . The inhibition of CYP2C19 has recently received omeprazole (p < 0.001) [59] . Two other cross-over studies demon-
much attention, as this same enzyme is required for the activation strated that iv. administration of esomeprazole had more effect
of clopidogrel, an inhibitor of platelet aggregation widely used for on intragastric pH than iv. pantoprazole at the same dose. The
the secondary prevention of cardiovascular events. Observational studies demonstrated that after 5 days of administering 40-mg
in vivo studies have repeatedly reported that the use of PPIs, in esomeprazole iv. or 40-mg pantoprazole iv., the administration
particular omeprazole and esomeprazole, impaired the preven- of esomeprazole had led to a pH above 4 in either 11.8 [56] or
tive effect of clopidogrel in patients at high risk for cardiovas- 13.9 [61] out of 24 h versus 5.6 [56] or 9.0 [61] out of 24 h during
cular complications, such as those with a coronary stent [65,66] . pantoprazole infusion (p < 0.001) (TABLE 1) .
However, these studies almost invariably suffer from confounding
by indication – that is, patients at higher risk are more likely to Low-risk bleeding
receive cardiovascular combination therapy including aspirin, and Several studies have focused on the effects of esomeprazole
thus also a PPI for gastroprotection [67] . By contrast, two prospec- treatment in patients with peptic ulcer bleeding in general, as
tive randomized controlled trials did not show any impairment in well as in the subgroup with low risk for recurrent bleeding. The
the effect of a PPI on the preventive efficacy of clopidogrel [68,69] . highest concern in these patients is treatment of the underlying
Nevertheless, the US FDA has issued a warning against come- cause as well as prevention of rebleeding. The risk of rebleed-
dication of clopidogrel and PPIs, in particular omeprazole and ing, however, is much lower than in the high-risk patients and
esomeprazole [201,202] . The potential downside of such a restrictive therapy, therefore, generally aims at an intragastric pH above 4.
approach is that these patients are at increased risk for upper GI Most studies conducted describe the use of oral administration
bleeding, and if this occurs, also for the dismal outcomes of such of omeprazole in a daily dose of 40 mg or higher. In a systematic
a bleeding episode. For this reason, international guidelines on the review comparing the available PPIs for their ability to keep
management of patients with such bleeding recommend proper intragastric pH above 4 when administered orally, the relative
gastroprotection with PPIs [14,67] . potency of esomeprazole on a mg-per-mg basis compared with
Other PPI-related drug interactions are related to the increase omeprazole was 1.6 [47] . In a randomized, open-label study,
of intragastric pH affecting the absorption of drugs such as esomeprazole 40 mg p.o. and omeprazole 40 mg p.o. were com-
ketoconazole and digoxin. Furthermore, there is the potential of pared with respect to intragastric acid inhibition, and the mean
inhibiting hepatic elimination of a wide range of drugs including percentage of time maintaining pH above 4 was significantly
diazepam, phenytoin and the R-isomer of warfarin [38] . However, greater in the patients using esomeprazole [73] .
these interactions are, generally not considered clinically signifi-
cant [51] . Systemic bioavailability of many antiretroviral agents is High-risk bleeding
reduced by gastric acid-reducing agents; in the case of atazanavir, In patients with a high risk for rebleeding, the first 3 days after
this has led to the advice not to coadminister atanazavir and PPIs; endoscopic therapy are crucial, since most recurrent bleeding occurs
however, other retroviral drugs can be coadministered with 20 mg within 72 h. It is generally accepted, based on the literature men-
esomeprazole [70] . tioned earlier, that the aim for these patients is to maintain the

Table 4. The effect of high-dose vs low-dose proton pump inhibitor treatment on intragastric pH or gastrointestinal bleeding.
Study Area Study Patients (n) Treatment Results Study Ref.
Udd et al. Europe RCT Peptic ulcer 142 Endoscopic therapy + omeprazole Rebleeding 11.6 vs 8.2%, surgery 7.2 vs 4.1%, mortality 30 days [83]
(2001) bleeding 20 mg/day iv. or omeprazole 2.9 vs 5.5%. No statistically significant differences
80 mg + 8 mg/h for 72 h iv.
Udd et al. Europe RCT Peptic ulcer 13 Endoscopic therapy + omeprazole Mean intragastric pH day 1: 4.9 ± 1.6 vs 6.3 ± 0.5 3 days [84]
(2005) bleeding 20 mg/day iv. or omeprazole (p = 0.035). Day 2: 4.9 ± 1.8 vs 6.7 ± 0.3 (p = 0.001).
80 mg + 8 mg/h for 72 h iv. Day 3: 5.7± 1.1 vs 6.7± 0.5 NS). Proportion of time
pH <4 on day 1 29.2 ± 34.1 vs 5.4 ± 5.7 (p = NS)
Netzer et al. Europe RCT Healthy 34 Omeprazole infusion 80 + 8 mg/h. Omeprazole vs ranitidine infusion: day 1 median pH 6.1 3 days [32]
(1999) volunteers Omeprazole injection 80 mg + vs 5.1 (p < 0.01), pH >4 95 vs 70% (p < 0.01). Day 2:
40 mg/6 h median pH 6.2 vs 3.2 (p < 0.01), 100 vs 38% of time
Ranitidine infusion 50 mg + pH >4. Injections significantly less effective than infusion
0.25 mg/kg/h. on day 1, on day 2 and 3 infusion and injection
Ranitidine injection 100 mg/6 h equally effective
Lin et al. Asia RCT Peptic ulcer 200 Endoscopic injection therapy + Rebleeding 6 vs 14 patients vs 22 patients (p = 0.0014). 14 days [27]
(2006) bleeding omeprazole 40 mg/6 h iv. (72 h) or Lower volume of blood transfusion in omeprazole
(high risk) omeprazole 40 mg/12 h iv. (72 h) or 40 mg/6 h vs omeprazole 40 mg/12 h (710 ml vs
cimetidine 400 mg/12 h iv. (72 h) and 1241 ml; p = 0.001) or those given cimetidine (710 ml vs
omeprazole 20 mg p.o. twice-daily or 1317 ml; p < 0.001)
cimetidine 400 mg p.o. twice-daily for
2 months
Andriulli Europe RCT Peptic ulcer 474 Endoscopic therapy (thermal coagulation Rebleeding 11.8 vs 8.1% (p = 0.18). Transfusion 1.7 ± 2.1 14 days [79]
et al. (2008) bleeding and/or epinephrine injection) + vs 1.5 ± 2.1 (p = 0.34). Hospitalization <5 days for 37 vs
(high risk) omeprazole/pantoprazole 80 mg 47% (p = 0.03). Mortality was equal in both groups
iv. + 8 mg/h or omeprazole/pantoprazole
40 mg daily iv. (72 h). After 72 h, all
patients 20 mg PPI p.o. twice daily till at
discharge
van Africa Open label Peptic ulcer 40 Endoscopic therapy + pantoprazole Median intragastric pH 0–24 h: 6.1 vs 6.1. 0–48 h: 48 h [41]
Rensburg bleeding 80 mg and 8 mg/h iv. or pantoprazole median pH 6.3 vs 5.9. Median percentage time pH >6,
et al. (2003) (high risk) 80 mg and 6 mg/h iv. 64 vs 47%. No significant differences
Simon- Europe Retro- Peptic ulcer 114 Endoscopic therapy + omeprazole iv. Poor outcome 12 vs 27% (p = 0.04). Rebleeding 7 vs 30 days [81]
Rudler et al. spective bleeding 80 mg + 8 mg/h (72 h) then omeprazole 24% (p = 0.01). Mortality due to hemorrhagic shock 0 vs
(2007) (high risk) 40 mg p.o. 1 week or omeprazole iv. 11% (p < 0.001) and need for surgery 1 vs 9% (p = 0.05)
40 mg till alimentation then p.o. for
1 week
iv.: Intravenous; NS: Not significant; PPI: Proton pump inhibitor; p.o.: Per oral; RCT: Randomized controlled trial.
Drug Profile
687
intragastric pH above 6 during those initial 3 days. This goal can A study with healthy volunteers demonstrated that oral
be approached by continuous high-dose iv. esomeprazole treatment, administration of lansoprazole in high-dose did not adequately
starting with a bolus of 80 mg followed by 8 mg/h continuously. maintain a pH above 6, and the authors concluded that is was
For that reason, a large multicenter trial was recently conducted possibly not an alternative for iv. high administration [44] . Metz
in which a multiethnic population of 764 adults with high-risk et al., however, demonstrated that iv. and oral administration
peptic ulcer bleeding were randomized to 80-mg bolus and 8 mg/h of lansoprazole when administered in a repeated high dosage,
esomeprazole or placebo after hemostatic endoscopic therapy. In a bolus of at least 90 mg and either 60 mg four-times daily p.o.
this study, a significant difference was found between the two or 9 mg/h iv., are close in the percentage of time maintaining a
groups with respect to the rates of recurrent bleeding, being 5.9 pH above 6 in H. pylori-negative volunteers [43] . A prospective
vs 10.3% (p = 0.026), and the need for endoscopic retreatment trial from the USA could not demonstrate a difference in the
(p = 0.01) [37] . A cost–effectiveness study published this year dem- effect of 80 mg orally twice daily or iv. pantoprazole 80-mg
onstrated that high-dose iv. administration of esomeprazole after bolus and 8 mg/h for 72 h on rebleeding after nonvariceal upper
successful endoscopic therapy improves patient outcomes at a GI bleeding. The study included only 25 patients and was thus
modest increase of costs (TABLE 2) [74] . too small to detect clinically relevant differences in outcome,
such as rebleeding [39] .
Oral versus intravenous Three Asian studies demonstrated that high-dose iv. admin-
Two studies by Wilder-Smith have compared the effects of iv. istration of PPI in peptic ulcer bleeding significantly reduced
and oral esomeprazole on gastric acid suppression and pharmaco- rebleeding, with a trend towards lower mortality in high-risk
kinetics, either in a dose of 20 or 40 mg. These studies both groups. The study by Lau et al. demonstrated a significant
demonstrated similar levels of intragastric acid control on day 1 difference between high-dose iv. omeprazole and placebo in
and day 5, with only a faster increase in intragastric pH in the iv. rebleeding rate (6.7 vs 22.5%), median hospital stay and a trend
group in the first few hours [63] . towards lower mortality (OR: 2.4 [0.87–6.60]) [76] . The stud-
The bioavailability of oral PPI is 65–80%, while by definition, ies by Lin et al. demonstrated that intravenously administered
the bioavailability of iv. PPI is 100% [54] . Intravenous adminis- omeprazole had a significantly better effect on increasing intra-
tration of PPI causes a faster increase in pH, mostly because of gastric pH and reducing rebleeding rates, as well as transfusion
circumventing the first-pass effect; this effect is less pronounced volumes, than intravenously administered cimetidine (TABLE 3)
after repeated dosage [62,63] . [28,77] . In a recent meta-ana lysis of seven studies comparing high
Current guidelines recommend treatment with an iv. bolus fol- and non-high-doses of PPIs in high- and low-risk peptic ulcer
lowed by continuous infusion of PPI in patients with high-risk bleeding, no significant differences were observed between oral
stigmata who have undergone successful endoscopic therapy [14] . and iv. andminstration [78] .
Since the proton pumps are continuously being regenerated, and
the half-life of PPI in the circulation is short, the rationale for this Low dose versus high dose
regimen is to first inactivate all actively secreting proton pumps A recent meta-analysis comparing oral and iv. non-high-dose with
with a bolus injection, then prevent further activation by the other high-dose PPI, administered after endoscopic treatment in low-
proton pumps with the continuous infusion [54] . and high-risk patients, did not demonstrate a further reduction
A prospective randomized controlled trial compared oral in rebleeding, surgery and mortality in the patients treated with
rabeprazole 40 mg daily with iv. omeprazole 80 mg/24 h in high-dose PPI [78] . In Italy, a multicenter study compared high-
high-risk ulcers. Both treatments were equally effective in these dose iv. administration of omeprazole or pantoprazole, whichever
subjects, with a H. pylori infection rate of 60% in both groups, was locally available, with low-dose iv. administration of these
with rebleeding rates of 15.4 and 16.7% respectively; however, drugs in patients with peptic ulcer bleeding and high-risk stigmata.
iv. dosages were very low and endoscopic treatment only con- In this randomized double-blind design, patients received either
sisted of epinephrine injection, which has been proven to be 80-mg bolus followed by 8 mg/h continuous infusion or a 40-mg
suboptimal treatment [75] . Another study compared the effect bolus daily. In this study, both regimens were equally effective,
of pantoprazole, omeprazole and rabeprazole in 72 h oral and with exception of a shorter hospital stay in the high-dose group
iv. administration on mean intragastric pH. Intravenous admin- (p = 0.03) [79] . The study design, however, contained several limita-
istration consisted of an 80-mg bolus and 8 mg/h continuous tions, with the incidence of rebleeding being remarkably high in
infusion, and oral administration consisted of 40 mg twice-daily the high-dose group (36%) and low in the low-dose group (0%),
for omeprazole and rabeprazole, and 80 mg twice-daily for pan- and with performance of a second-look endoscopy in 33% of cases,
toprazole. No differences were demonstrated in efficacy between in particular in the low-dose group [79] . An observational study
iv. administration and this relatively high oral dose [6] . In a suggested that treatment with any PPI administered p.o. or iv. in
study that compared omeprazole iv. 80-mg bolus and 8 mg/h a dose of above 100 mg/24 h reduced rebleeding, surgery, transfu-
with oral 80-mg bolus and 40 mg/6 h in healthy H. pylori- sion and probably mortality, compared with a standard dose of 20
negative volunteers and patients with high-risk bleeding, the iv. or 40 mg daily [80] . Although some studies suggest that there is
administration maintained a median intragastric pH above 6 no difference in the clinical efficacy of high- versus low-dose PPI,
significantly longer than oral treatment [32] . others demonstrate clear differences [81] . A double-blind cross-over

Esomeprazole for the treatment of peptic ulcer bleeding Drug Profile
study in H. pylori-positive patients first measured the intragastric demonstrated a faster and higher increase of intragastric pH in
pH with an 80-mg bolus and 8 mg/h of pantoprazole iv. and after H. pylori-positive patients during PPI treatment, related to the
a washout period in either 80-mg bolus and 4 mg/h iv. or 80-mg fact that H. pylori gastritis augments the acid-suppressive effect
bolus and 2 mg/h of pantoprazole iv. The mean intragastric pH of the PPI. This is one of the explanations for the difference
was maintained above 6 in all. However, the 8-mg/h infusion led between study outcomes of the effect of PPI dosages on peptic
to higher mean pH levels than the other treatment regimens [82] . ulcer bleeding in Asia, the USA and Europe, since the underlying
Another study with a two-step approach evaluated the intragastric etiology is mostly H. pylori infection in Asia, and NSAIDs and
pH in treatment with pantoprazole 80-mg bolus and 8 mg/h iv. low-dose ASA use in the USA and Europe [56] .
and 80-mg bolus and 6 mg/h iv. Both regimens demonstrated a Active bleeding as well as PPI therapy can cause false-negative
positive effect on rebleeding rate. However, the more intensive outcomes in H. pylori testing [93] . For this reason, guidelines
regimen demonstrated a lower intra-individual variability of the recommend to retest patients with a negative test result [14] .
intragastric pH and a greater proportion of time with an intra-
gastric pH above 6 [41] . A somewhat older prospective double-blind Safety & tolerability
study could not show a difference between an omeprazole 80-mg An excellent safety profile has been demonstrated for all available
bolus and 8 mg/h iv. regimen and a regimen of omeprazole 20 mg PPIs after approximately 20 years of clinical use in millions of
daily iv. in high-risk patients in rebleeding rate and percentage that patients for acid-related disorders [54] . The safety of esomeprazole
underwent surgery [83] . In this study involving high-risk patients, was evaluated in more than 89,000 patients in clinical trials of
40 patients were not given endoscopic treatment, either meaning 2 weeks to 5 years conducted worldwide [38,94] . In both long- and
they were not all high-risk patients, or researchers were not apply- short-term clinical trials, esomeprazole was well-tolerated [49] .
ing the best of care to all patients. A later study by the same authors Overall, in clinical trials, the tolerability was similar to that of
demonstrated a mean intragastric pH with low iv. dose regimens other PPIs, and the main adverse events associated with treat-
of omeprazole of above 4, while high iv. dose regimens obtained ment, which occurred in approximately 10%, were headache and
a mean intragastric pH above 6 [84] . A recent study conducted in diarrhea. Esomeprazole was not associated with any clinically
China compared iv. pantoprazole either administered continuously significant effect on laboratory parameters. In the literature, no
with 8 mg/h after a bolus of 80- or 40-mg every 6 h, and could major differences were found in the safety and tolerability of high
not demonstrate any differences in outcome [85] . dosage and iv. administration of esomeprazole, other than that
In low-risk patients, no differences were found in the outcomes high-dose continuous administration is associated with phlebitis
with either treatment with omeprazole 80-mg bolus and 8 mg/h around the iv. needle in a small number of patients [37,61,63,75] .
iv. or omeprazole 80 mg/day orally in rebleeding, surgery, trans-
fusion requirements and hospital stay, agreeing with the current Long-term effects
treatment protocol to treat low-risk patients with oral PPIs [16] . In the case of esomeprazole prescription for peptic ulcer bleeding,
Several cost–effectiveness studies have been performed con- the duration of treatment is dependent on the underlying cause, and
cerning high-dose iv. treatment. One study demonstrated that most patients will receive the drug for short-term use. However, in
treatment with a PPI in general after endoscopic therapy was cost the case of chronic low-dose ASA or NSAID use, long-term use can
effective in high-risk patients [86] . Another study confirmed that be necessary. There has been discussion in the literature concerning
high-dose iv. administration of PPI in patients with a peptic ulcer a potential association between long-term, and usually high-dose,
with high-risk stigmata was cost effective (TABLE 4) [87] . PPI therapy and community-acquired pneumonia [95–98] , an asso-
ciation with an increased risk of hip fractures [99–101] and a possible
NSAIDs & low-dose ASA users & H. pylori infection association with Clostridium difficile-associated diarrhea [102–106] .
It is important to realize that not all patients with peptic ulcer Only in the case of the increased risk for hip fractures has the FDA
bleeding caused by NSAIDs or low-dose ASA can cease their recently expressed a warning, based on the available data, stating
NSAID or ASA use. This means that long-term treatment with that a lower dose and shorter duration of PPI treatment should be
PPIs is necessary as prophylaxis in order to prevent ulcer recurrence. considered, especially in patients over 50 years of age, since there
Recent studies have demonstrated that the risk of rebleeding in is a possible increased risk of fractures of the hip, wrist and spine
these patients is lower with the combination of a COX- 2 inhibitor with the use of these medications.
and a PPI than with either a COX-2 inhibitor alone or the combi- Furthermore, long-term use of PPIs is associated with the devel-
nation of a conventional NSAID and a PPI [88–90] . For this reason, opment of fundic gland polyps; however, dysplastic lesions are very
international guidelines recommend the use of a combination of a rare despite the frequency of these polyps during PPI therapy [107] .
COX-2 inhibitor and a PPI for this indication [14] . PPI maintenance treatment is associated with the development of
Patients with peptic ulcer bleeding should be tested for H. pylori hypomagnesemia, sometimes with marked clinical symptoms [108] ,
infection and receive eradication therapy if H. pylori is present. as well as hypoacidity and hypergastrinemia [109] .
H. pylori eradication decreases the risk of recurrence of ulcers Finally, there is an interaction between profound acid-suppres-
more than PPI treatment. As the presence of H. pylori infection sive therapy and H. pylori infection. During profound acid sup-
has no effect on the early rebleeding rate, eradication therapy pression, H. pylori colonization expands from antral-predominant
can be scheduled after discharge [91,92] . In fact, some studies have to corpus-predominant pangastritis, which persists during PPI
www.expert-reviews.com 689
treatment. This is associated with accelerated progression towards frequent use of NSAIDs and aspirin, and the insufficient use
atrophic gastritis [110] . For this reason, European guidelines recom- of gastric prophylaxis [112] . As this concerns an elderly popula-
mend to consider H. pylori eradication in long-term PPI users [111] . tion with frequent comorbidities, the mortality of ulcer bleeding
Despite these precautions and potential side effects, it is clear remains substantial [9] . It is clear that endoscopy and endoscopic
that the benefits of PPI therapy largely outweigh the risks. therapy in high-risk patients within the first 24 h is the corner-
stone of therapy [113] . Importantly, endoscopic therapy should not
Regulatory affairs consist solely of epinephrine injection, but should be combined
In Europe and other markets, esomeprazole is approved for the with either clips or a thermal method. There is an important role
healing and prevention of ulcers associated with NSAID therapy, for the prevention of rebleeding, because this has a major impact
including COX-2 selective inhibitors. In the USA, esomepra- on mortality. Currently, PPIs are the best method to prevent
zole is approved for reducing the risk of gastric ulcers associated rebleeding after adequate endoscopic therapy; they have shown in
with continuous NSAID therapy in patients at risk of developing the majority of conducted studies to perform better than H2RA
gastric ulcers. Following treatment with esomeprazole iv., oral and other therapeutic agents. This in particular pertains so far
esomeprazole is approved in the EU and other markets for the to esomeprazole.
maintenance of hemostasis and prevention of rebleeding of gastric Since the development of esomeprazole, a PPI has reached
or duodenal ulcers. the market that consists solely of the active isomer, and several
Esomeprazole iv. has recently become the first PPI to be studies have proven the superiority of esomeprazole to other
approved for the iv. treatment of patients with peptic ulcer bleed- PPIs in maintaining high pH values, inhibiting acid secre-
ing. Until recently, no such approval existed for any PPI anywhere tion and healing of erosive esophagitis. Furthermore, a recent
in the world. Esomeprazole iv. is currently approved in the EU large multicenter study has demonstrated the positive effects
and other markets for the short-term maintenance of hemostasis of esomeprazole on high-risk peptic ulcer bleeding compared
and prevention of rebleeding in patients following therapeutic with placebo. Since no head-to-head comparisons have been
endoscopy for acute bleeding gastric or duodenal ulcers. conducted, no remarks can be made on the potential trans-
lation of the esomeprazole findings to other PPIs. The same
Conclusion issue holds for method and doses of administration. At this
There is a clear role for high-dose continuous iv. esomeprazole time, most evidence exists for high-dose iv. administration for
treatment in the treatment of peptic ulcer bleeding. For omepra- 72 h and this should be the option of choice. Most studies
zole and pantoprazole, such treatment has shown variable results conducted to compare high dose and low dose have impor-
in comparison with either placebo or H2RAs. In Asian studies, tant methodological flaws or included a very small number of
the results of such treatment with omeprazole consistently reduced patients. Considering the theoretical and in vitro background,
rebleeding rates and improved overall outcome. In most Western the high-dose bolus is needed to block the active PPIs and
studies, however, the same treatment did not reduce rebleed- the continuous infusion to block the proton pumps that are
ing, nor improve outcome. By contrast, high-dose continuous continuously activated afterwards. This could potentially be
iv. treatment with esomeprazole with the same dosing regimen obtained with repeated high oral dosage.
has been demonstrated to reduce rebleeding rates in both Asian Pre-endoscopy treatment with iv. PPIs has been reported to
and Caucasian patients who are at a high risk for rebleeding from reduce signs of active bleeding during endoscopy, and reduce
peptic ulcer disease [37] . This is in line with several comparative the need for second-look procedures. It has, however, no effect
studies in both healthy subjects and GERD patients demonstrat- on rebleeding rates or hospital duration [114–117] . For this reason,
ing a more pronounced acid-suppressive effect of esomeprazole in pre-endoscopy PPI treatment can be considered in patients pre-
comparison with other PPIs on a mg-per-mg basis. senting with signs of upper GI bleeding, but it should not result
As a result, high-dose continuous iv. esomeprazole is the first in endoscopy delay.
PPI regimen that has been approved for the treatment of high-
risk ulcer patients. Following adequate endoscopic therapy of Five-year view
these ulcers, this regimen is recommended for 72 h, based on the As mentioned earlier, future studies to compare different PPIs
repeated observation that the majority of rebleeds occur within head-to-head in peptic ulcer bleeding should be conducted,
this interval. Further studies need to show whether shortening as well as studies looking into the dose, method and optimal
of therapy and/or repeated bolus injection instead of continu- duration of administration. Given the need for solid end points
ous infusion can be as effective. The available studies on the such as rebleeding, these studies are difficult to perform as
latter topic are not convincing and are biased, among others, they require inclusion of large numbers of patients in multi-
by different treatment approaches to different treatment arms. center studies. Furthermore, the urgent character of the dis-
ease requires optimal organization of the study at individual
Expert commentary centers. Newer PPIs are under development, with the aim of
Peptic ulcer bleeding remains a common condition worldwide more rapid and more complete acid suppression by extended
despite a decrease in the prevalence of H. pylori infection in parts half-life. Furthermore, there is some progress in the develop-
of the developed world. This is at least, in part, explained by the ment of potassium competitive acid blockers, which is a broader

class of therapeutic agents that should reach faster and more Financial & competing interests disclosure
complete acid inhibition. However, concerns exist in the field Ernst J Kuipers has received research funding from Nycomed, AstraZeneca
of efficacy and safety of this drug class. Finally, gastrin and and Janssen Pharmaceutics and consulting fees from AstraZeneca. The
cholecystokinin (CCK) receptor antagonists are an interesting authors have no other relevant affiliations or financial involvement with
field of research; the receptor antagonist blocks somatostatin D any organization or entity with a financial interest in or financial conflict
release and thus inhibits acid secretion from parietal cells [118] . with the subject matter or materials discussed in the manuscript apart from
A larger role in prevention, especially in NSAID and low-dose those disclosed.
ASA-induced peptic ulcers, is a field that could achieve positive No writing assistance was utilized in the production of this
results in the decrease of peptic ulcer mortality. manuscript.
Key issues
s Esomeprazole decreases rebleeding, endoscopic retreatment and transfusion in high-risk peptic ulcer bleeding.
s Meta-analysis show that proton pump inhibitor adjuvant treatment in peptic ulcer bleeding decreases mortality and the need for
surgery analyses.
s Esomeprazole, compared with omeprazole, lansoprazole, pantoprazole and rabeprazole, provides better intragastric pH increase.
s Currently, patients with a peptic ulcer bleeding with high-risk stigmata should be treated with esomeprazole an 80-mg bolus and
8 mg/h intravenously for 72 h.
s All patients with peptic ulcer bleeding should be treated with 40-mg oral esomeprazole for a total of 30 days or more depending on
the underlying etiology.
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Esomeprazole for the treatment of peptic ulcer bleeding

Article in Expert Review of Gastroenterology and Hepatology · December 2010

Caroline M den Hoed Ernst J. Kuipers

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680 Expert Rev. Gastroenterol. Hepatol. 4(6), (2010)

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