DOI: 10.15171/mejdd.2018.

116
236 Original Article

Comparison of Oral versus Intravenous Proton Pump Inhibitors

in Preventing Re-bleeding from Peptic Ulcer after
Successful Endoscopic Therapy
Seyed Mohammad Valizadeh Toosi 1, Ahmad Reza Elahi Vahed 2,
Iradj Maleki 3,*, Zohreh Bari 1

ABSTRACT
1. Assistant Professor of Gastroenterol-
BACKGROUND
ogy, Gut and Liver Research Center, Proton pump inhibitors (PPIs) are now widely prescribed for the management of patients with acute
Mazandaran University of Medical upper gastrointestinal bleeding; although its optimal dose and route of administration has remained a
Sciences, Sari, Iran controversial issue. The aim of this study was to assess the clinical effectiveness of high dose oral versus
2. Resident of Internal Medicine, Mazan- intravenous (IV) PPI after successful endoscopic therapy in patients with bleeding peptic ulcer disease.
daran University of Medical Sciences,
METHODS
Sari, Iran 178 patients with active upper gastrointestinal bleeding due to a peptic ulcer with stigmata
3. Associate Professor of Gastroenterol- of high risk for re-bleeding entered the study. After successful endoscopic hemostasis, they were
ogy, Gut and Liver Research Center, randomized to receive either high dose oral pantoprazole (80 mg stat and 80 mg twice daily for 3
Mazandaran University of Medical days) or high dose intravenous pantoprazole (80 mg IV infusion within 30 minutes and 8 mg per
hour for 3 days). After the 3rd day, the patients in both groups received oral pantoprazole 40 mg
Sciences, Sari, Iran
twice daily for one month. The end points were comparing the rate of re-bleeding or mortality, and
the need for blood transfusion or surgery during the first month between the two groups.

RESULTS
There were not significant statistical differences between the two groups in the volume of
blood transfusion, mean duration of hospital stay, need to surgery, or mortality rates. However, the
rates of re-bleeding were 2.3% (2:88) in the IV group and 3.3% (3:90) in the oral group (p = 0.6).

CONCLUSION
According to our findings, it seems that high dose oral PPI can be a good alternative to high
dose IV PPI in patients with bleeding peptic ulcer who are at high risk of re-bleeding. Due to the
lower cost and the availability of oral PPIs, their use can be economically much more affordable.

KEYWORDS:
Proton pump inhibitor, Peptic ulcer, Hemorrhage, Endoscopic therapy
Please cite this paper as:
Valizadeh Toosi SM, Elahi Vahed AR, Maleki I, Bari Z. Comparison of Oral versus Intravenous
Proton Pump Inhibitors in Preventing Re-bleeding from Peptic Ulcer after Successful En-
doscopic Therapy. Middle East J Dig Dis 2018;10:236-241. doi: 10.15171/mejdd.2018.116.

*
INTRODUCTION
Corresponding Author:
Peptic ulcer disease is the most common cause of upper gastrointestinal
Iradj Maleki, M.D
Associate Professor of Gastroenterology, bleeding (UGIB), accounting for about 50% of cases.1,2 In a recent review
Gut and Liver Research Center, Mazandaran article from Iran peptic ulcer disease was the most common cause of UGIB
University of Medical Sciences, Sari, Iran
Telefax: + 98 11 33377176
(30-65%) and erosive gastro-duodenopathy ranked the second (16-25%).3 It
Email: [email protected] remains a serious medical problem with significant morbidity and mortality.
Endoscopic therapy significantly reduces further bleeding, surgery, and mortal-
Received: 15 Mar. 2018
Accepted: 18 Jul. 2018 ity in patients with bleeding peptic ulcers and is now recommended as the
first hemostatic modality for these patients.4-6 However, there is a high risk of

© 2018 The Author(s). This work is published by Middle East Journal of Digestive Diseaes as an open access
article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.
org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited.

Middle East J Dig Dis/ Vol.10/ No.4/October 2018

 Valizadeh Toosi et al. 237

peptic ulcer re-bleeding in 14-36% of patients in spite of spurting bleeding (Forrest IA), oozing bleeding (Forrest
efficient endoscopic intervention.7,8 IB), non- bleeding visible vessel (Forrest IIA) or adherent
Gastric acid inhibits clot formation and promotes clot clots (Forrest IIB)] were enrolled in the study.18 On the
lyses and accordingly, disturbs hemostasis of ulcers in the other hand, patients with low risk of bleeding from ulcers
stomach and duodenum.9 Therefore, reduction of gastric (clean base ulcer, flat pigmented ulcers), suspicious ma-
acid secretion can prevent ulcer re-bleeding.8 Proton pump lignant ulcer, bleeding tendency, uremia, liver cirrhosis,
inhibitors (PPIs) are the drugs that are widely used to reduce and Mallory Weiss tear were excluded from the study.
gastric acid secretion. Intravenous (IV) and oral pantopra- Therapeutic endoscopy for patients with high risk
zole with equal dose have similar acid suppression effect.10 peptic ulcer for bleeding (Forrest IA-IIB) were done by
Compared to standard dose of oral PPI, high dose oral PPI injecting up to 40 mL of epinephrine (diluted 1:10000)
has faster acid suppression 11 and also high dose IV PPI around the ulcer crater to stop bleeding and electroco-
has faster adequate acid suppression effect (gastric acid agulation therapy by Argon Plasma Coagulation (APC)
PH > 6) than high dose oral PPI.11,12 However, the optimal for all patients. Also, a biopsy sample was taken from
route, dose, and duration of PPI therapy after endoscopic antrum for evaluating H. pylori infection. For patients
therapy of a bleeding peptic ulcer remain controversial. with unsuccessful endoscopic therapy, an immediate
Several controlled trials and meta-analyses have surgery consultation was performed.
shown the comparable efficacy of IV and oral PPIs in ul- The enrolled patients were randomly allocated into
cers at high risk of re-bleeding after endoscopic therapy. two groups using sealed envelopes containing a thera-
However, they mostly recommended further studies to peutic option (either IV or oral pantoprazole). In the oral
confirm the results.13-17 pantoprazole (Oral-Pan) group, the patients received
In this study, we attempted to evaluate and compare pantoprazole (Nolpaza, Iranian pharmaceutical company
the effects of IV and oral PPIs in preventing re-bleeding Actoverco) 80 mg orally early after endoscopy and then
from peptic ulcers after successful endoscopic therapy. twice daily for 72 hours. In the IV pantoprazole (IV-Pan)
group, the patients received injective pantoprazole (Pepti
MATERIALS AND METHODS care, Iranian Razak Drau Company) 80 mg, infused
Design and patients: during 30 minutes and then 8 mg/hour IV pantoprazole
This study was a single center, prospective, ran- for 72 hours. After the 3rd day, all the patients of both
domized trial conducted in a tertiary teaching hospital groups received oral pantoprazole 40 mg twice daily.
(Imam Khomeini Hospital, Sari) in Iran. The protocol During the hospital stay, the serum hemoglobin (Hb)
was approved by the Ethics Committee of Mazandaran was checked every 8 hours. Blood transfusions were
University of Medical Sciences and was also regis- performed if Hb was lower than 7 g/dL in young patients
tered in Iranian Registry of Clinical Trials (number: or lower than 9 gr/dL in patients older than 50 years or
IRCT2014082515510N2). Furthermore, a written informed in patients with history of ischemic heart disease (IHD)
consent was obtained from all subjects. or those being in shock. After endoscopic therapy, re-
From June 2014 to May 2015, all adult patients who bleeding was suspected if hematemesis reappeared or
were admitted to our Gastroenterology Department with the patient developed orthostatic hypotension, unstable
symptoms of UGIB, as documented by hematemesis, vital signs (systolic blood pressure < 90mmHg, pulse
melena, or hematochezia, were considered to be included rate > 120/min) or Hb drop > 2g/dL (despite blood trans-
in this study. They were evaluated by upper GI endoscopy fusion). Patients suspected to re-bleeding underwent ur-
during the first 24 hours of admission, after hemodynamic gent endoscopy and if active bleeding, fresh blood, or
stabilization. It should be mentioned that all patients blood clots were seen, epinephrine injection and APC
received IV pantoprazole (80 mg stat followed by 8 mg were performed. Then they again received pantoprazole
infusion per hour) before endoscopic assessment. according to their protocol group. Also, in case of definite
Patients older than 18 years with successful endoscopic cardiac or neurological indications for continuing Aspirin
therapy of high risk ulcers for re-bleeding [defined as intake, the drug was given to the patients after 24 hours

Middle East J Dig Dis/ Vol.10/ No.4/October 2018

 238 Oral vs. Intravenous PPI for Peptic Ulcer Re-bleeding

Table 1: Demographic and clinical variables of patients at entry to the study

Variable IV PPI group Oral PPI group P value
Number of patients (%) 88 (49.4%) 90 (50.6%) 0.9
Mean age (Years) 60.3 (25-89) 58.4 (18-100) 0.8
Sex: • Male 49 (55.7%) 63 (70%)
0.04
• Female 39 (44.3%) 27 (30%)
Smoking 22 (25%) 29 (32.2%) 0.3
History of PUD 14 (15.9%) 9 (10%) 0.2
Aspirin or NSAID 68 (77.2%) 63 (60%) 0.4
Clopidogrel 7 (8%) 4 (4.4%) 0.3
Warfarin 7 (8%) 2 (2.2%) 0.9
Melena 69 (77.3%) 77 (85.6%) 0.3
Hematemesis 51 (57.7%) 38 (42.2%) 0.5
Mean initial Hb (gr/dL) 9 8.7 0.8
Mean supine BP (mm Hg) 113/72 112/70 0.9
Mean sitting BP 111/71 109/69.5 0.8
NSAID: non-steroidal anti-inflammatory drug; Hb: Hemoglobin, BP: Blood pressure; PPI: proton pump inhibitor; PUD: peptic ulcer disease

Table 2: Endoscopic findings of the patients in the two groups

EGD Findings IV-Pan group Oral-Pan group P value
Gastric ulcer 39 36 0.5
Duodenal ulcer 57 59 0.9
Adherent clot 26 (29.5%) 18 (20%) 0.14
Oozing 23 (26.1%) 33 (36.7%) 0.13
Non-bleeding visible vessel 38 (42.2%) 38 (42.2%) 0.8
Spurting 1 (1.1%) 1 (1.1%) 0.9
EGD: Esophagogastroduodenoscopy

of endoscopic treatment. RESULTS

On the day of discharge, a standard H. pylori eradication From June 2014 to May 2015, 376 patients with clinical
regimen followed by oral PPI (pantoprazole 40mg twice evidence of UGIB were admitted to our hospital. Upper GI
daily) was prescribed for patients infected with H. pylori, endoscopy was performed for all patients. 178 patients had
but the rest of the patients were advised to continue just endoscopic evidence of high risk peptic ulcers for re-bleed-
oral PPI for one month. They were all asked to be visited ing (according to Forrest classification). They underwent
at the end of one month or sooner in case of any problem. therapeutic endoscopy, using diluted adrenaline injection
A questionnaire including demographic characteristics, and APC. Also, in two patients, clips were used to control
history of previous UGIB, non-steroidal anti-inflamma- bleeding. These high risk patients were enrolled in the
tory drugs (NSAIDs) or Aspirin use, volume of blood study; 88 patients were randomly allocated to the IV-Pan
transfusion at entry and during hospital stay, the days group and 90 patients were allocated to the oral-Pan group.
of hospital stay, endoscopic findings, and the need for The causes of GI bleeding in the remaining 198 patients
re-endoscopy, and surgery, and mortality rates up to one were esophageal varices, clean-base ulcers, esophageal
month after discharge were completed for all patients. cancer, Mallory Weiss tearing, gastric cancer, and Dieu-
Statistical analysis was performed using SPSS software lafoy’s lesion. They were excluded from the study.
(version 16, Chicago, IL, USA). The descriptive variables All the patients completed the study. 112 patients
such as mean, standard deviations, and frequency were used. were men (63%) and 66 patients (37%) were women.
Chi square (X2) and t tests were used as appropriate. P value Other demographic and also clinical and endoscopic
less than 0.05 was considered as statistically significant. data are shown in tables 1 and 2.

Middle East J Dig Dis/ Vol.10/ No.4/October 2018

 Valizadeh Toosi et al. 239

Table 3: Primary and secondary outcomes in the two groups

Outcome IV-Pan group Oral-Pan group P value
Mortality (%) 3(3.4%) 1 (1.1%) 0.3
Re-bleeding (%) 4 (4.5%) 3 (3.3%) 0.6
Surgery (%) 1 (1.1%) 1 (1.1%) 0.9
Volume of blood transfusion
113 117 0.8
(unit of packed cell)
Mean duration of hospital stay
3.7 3.4 0.8
(Days)
Repeated EGD 5 (5.6%) 3 (3.3%) 0.6
EGD: Esophagogastroduodenoscopy

Seven patients (3.9%) re-bled. Four patients were in DISCUSSION

the IV-Pan group and three were in the Oral-Pan group. According to the results of our study, there were no
Four of the re-bleedings happened during hospital stay significant differences between the two groups of IV-Pan
and three happened at the 8th, 8th, and 15th day after hospital and Oral-Pan in the rates of re-bleeding and re-endoscopy,
discharge, respectively. There were no significant differ- duration of hospital stay, the volume of blood transfusion,
ences between the two groups in the rate of re-bleeding, and rates of surgery and mortality during one month
neither during hospital stay, nor after discharge (table 3). of follow up. There are several other studies that have
Accordingly, eight patients needed second endoscopy; s h o w n almost the same results.
five were in the IV-Pan group and three were in the oral-Pan In 2008, Tsai and colleagues conducted a study in
group (p = 0.6). The reason for the repeated endoscopies which 156 patients with high risk peptic ulcers were
were re-bleeding in seven patients (as mentioned previ- divided into two groups to receive either IV PPI or oral
ously) and second-look endoscopy to assess the quality PPI for the first 72 hours after therapeutic endoscopy.
of the performed injection and APC in one patient. Afterwards, all the patients received standard doses of
Two patients underwent surgery during hospital stay. oral PPI. The outcomes of re-bleeding, need to transfusion,
One was in the IV-Pan group and the other was in the mortality, surgery, and duration of hospital stay were
Oral-Pan group. The first patient underwent surgery at similar in both groups.19
the first day of hospital admission and the second patient Also, in 2011, Mostaghni and co-workers showed no
underwent surgery at the second day due to re-bleeding. significant differences in the rate of re-bleeding, duration
The reason for surgery was the inability of therapeutic of hospital stay, and the volume of blood transfusion
endoscopy to control the bleeding. among 85 patients with high risk peptic ulcer disease
Four patients died; three patients were in the IV-Pan who had received either high dose oral omeprazole or IV
and one in the Oral-Pan group, respectively (table 3). pantoprazole during the first 72 hours after therapeutic
Three patients died at presentation due to massive GIB endoscopy.15
that could not be controlled endoscopically and they died In 2012, Yen and others evaluated the adverse outcomes
before undergoing surgery. But the 4th patient underwent of PUD bleeding in 100 patients who had been divided
surgery and died at the 11th day after surgery. All the into two groups of high dose IV and oral PPI after thera-
patients were older than 60 years. peutic endoscopy. They showed that duration of hospital
For all the patients oral feeding was started 24-48 stay was shorter in oral PPI group (1.8 days vs. 3.9 days,
hours after successful therapeutic endoscopy and they respectively), but the difference was not statistically
were discharged from hospital if they had stable vital significant. Also, other outcomes of GIB including the
signs and acceptable hemoglobin levels. After discharge, rates of re-bleeding, surgery, mortality, and volume of
all the patients were followed up by phone call contacts transfusion were similar in both groups.14
up to one month to ask about re-bleeding, hospital re- In another single-center, randomized, controlled,
admission, blood transfusion, surgery, and mortality. double-blind and double-dummy study in 2014, 244

Middle East J Dig Dis/ Vol.10/ No.4/October 2018

 240 Oral vs. Intravenous PPI for Peptic Ulcer Re-bleeding

patients with bleeding PUD, entered the study after ACKNOWLEDGEMENTS

therapeutic endoscopy. 118 patients received high dose The authors cheerfully acknowledge the financial
IV esomeprazole plus oral placebo, and 126 patients support of Mazandaran University of Medical Sciences.
received high dose oral esomeprazole plus placebo IV
infusion for 72 hours. The patients were followed up for ETHICAL APPROVAL
30 days after index bleeding. According to the results, no There is nothing to be declared.
difference existed between the two groups in outcomes
of re-bleeding, need to blood transfusion, days of hospi- CONFLICT OF INTEREST
tal stay, and re-endoscopy. However, this study stopped The authors declare no conflict of interest related
prematurely and therefore, the results of the study are not to this work.
conclusive for equivalency or non-inferiority of two treat-
ment regimens.16 REFERENCES
In 2013, Tsoi and colleagues performed a meta-analysis 1. Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK,
Persing J. The national ASGE survey on upper gastroin-
to compare the outcomes of administering oral versus IV testinal bleeding. I. Study design and baseline data. Gas-
PPI after therapeutic endoscopy in patients with high-risk trointest Endosc 1981;27:73-9.
PUDs. Six randomized clinical trials from 2006 to 2011, 2. Rockall TA, Logan RF, Devlin HB, Northfield TC. Inci-
including 615 patients, (302 patients in oral PPI and 313 dence of and mortality from acute upper gastrointestinal
haemorrhage in the United Kingdom. Steering Commit-
patients in IV PPI groups) were evaluated. The outcomes tee and members of the National Audit of Acute Upper
of re-bleeding, volume of blood transfusion, need for Gastrointestinal Haemorrhage. BMJ 1995;311:222-6.
surgery, days of hospital stay, and all-cause mortality doi:10.1136/bmj.311.6999.222.
showed no statistically significant differences between 3. Masoodi M, Saberifiroozi M. Etiology and outcome of
acute gastrointestinal bleeding in iran: a review article.
the two groups.17 Middle East J Dig Dis 2012;4:193-8.
Finally, according to two recent systematic reviews and
4. Cook DJ, Guyatt GH, Salena BJ, Laine LA. Endoscopic
meta-analyses, both oral and IV PPI can be effectively therapy for acute nonvariceal upper gastrointestinal hem-
used after endoscopic treatment of high risk ulcers.20,21 orrhage: a meta-analysis. Gastroenterology 1992;102:139-
48.
Although our results are almost similar to previous
studies, our study had a limitation. The endoscopies had 5. Hwang JH, Fisher DA, Ben-Menachem T, Chandrasekha-
ra V, Chathadi K, Decker GA, et al. The role of endoscopy
been performed by six gastroenterologists. This might in the management of acute non-variceal upper GI bleed-
have interfered with the same interpretation of the ulcers. ing. Gastrointest Endosc 2012;75:1132-8. doi:10.1016/j.
gie.2012.02.033.
However, we used Forrest classification in order to stan-
6. Laine L, McQuaid KR. Endoscopic therapy for bleeding
dardize the interpretation of the ulcers. On the other
ulcers: an evidence-based approach based on meta-anal-
hand, using Iranian brand of pantoprazole is a strong yses of randomized controlled trials. Clin Gastroenterol
point of our study. Hepatol 2009;7:33-47. doi: 10.1016/j.cgh.2008.08.016.
In conclusion, our study showed no statistically sig- 7. Marmo R, Rotondano G, Piscopo R, Bianco MA,
D’Angella R, Cipolletta L. Dual therapy versus mono-
nificant difference between the two groups of IV or oral therapy in the endoscopic treatment of high-risk bleed-
PPI in the outcomes of high risk peptic ulcers after ther- ing ulcers: a meta-analysis of controlled trials. Am J
apeutic endoscopy. Therefore, it seems that high dose Gastroenterol 2007;102:279-89. doi:10.1111/j.1572-
0241.2006.01023.x.
oral PPI can be a good alternative to high dose IV PPI in
8. Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect
ptients with bleeding peptic ulcer disease. Furthermore, of acid and pepsin on blood coagulation and platelet ag-
due to the lower cost (approximately 30 times) and avail- gregation. A possible contributor prolonged gastroduodenal
ability of oral PPI, its use can be economically much mucosal hemorrhage. Gastroenterology 1978;74:38-43.
more affordable. We suggest further studies to evaluate 9. Cheng HC, Sheu BS. Intravenous proton pump inhibi-
tors for peptic ulcer bleeding: Clinical benefits and limits.
the effects of different types of oral PPIs on the outcomes World J Gastrointest Endosc 2011;3:49-56. doi:10.4253/
of high risk peptic ulcers after therapeutic endoscopy. wjge.v3.i3.49.

Middle East J Dig Dis/ Vol.10/ No.4/October 2018

 Valizadeh Toosi et al. 241

10. Hartmann M, Ehrlich A, Fuder H, Luhmann R, Emekli-

bas S, Timmer W, et al. Equipotent inhibition of gastric
acid secretion by equal doses of oral or intravenous pan-
toprazole. Aliment Pharmacol Ther 1998;12:1027-32.
doi:10.1046/j.1365-2036.1998.00406.x.
11. Sachs G, Shin JM, Howden CW. Review article: the
clinical pharmacology of proton pump inhibitors. Aliment
Pharmacol Ther 2006;23 Suppl 2:2-8. doi:10.1111/j.1365-
2036.2006.02943.x.
12. Laine L, Shah A, Bemanian S. Intragastric pH with oral
vs intravenous bolus plus infusion proton-pump inhibitor
therapy in patients with bleeding ulcers. Gastroenterology
2008;134:1836-41. doi:10.1053/j.gastro.2008.03.006.
13. Phulpoto JA, Bhatti ZA, shaikh A. Comparison of oral and
intravenous proton pump inhibitor in patients with high risk
bleeding peptic ulcers. Rawal Med J 2013;38:7-10.
14. Yen HH, Yang CW, Su WW, Soon MS, Wu SS, Lin HJ.
Oral versus intravenous proton pump inhibitors in pre-
venting re-bleeding for patients with peptic ulcer bleeding
after successful endoscopic therapy. BMC Gastroenterol
2012;12:66. doi:10.1186/1471-230X-12-66.
15. Mostaghni AA, Hashemi SA, Heydari ST. Comparison
of oral and intravenous proton pump inhibitor on patients
with high risk bleeding peptic ulcers: a prospective, ran-
domized, controlled clinical trial. Iran Red Crescent Med
J 2011;13:458-63.
16. Sung JJ, Suen BY, Wu JC, Lau JY, Ching JY, Lee VW,
et al. Effects of intravenous and oral esomeprazole in the
prevention of recurrent bleeding from peptic ulcers after
endoscopic therapy. Am J Gastroenterol 2014;109:1005-
10. doi:10.1038/ajg.2014.105.
17. Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison
of oral vs. intravenous proton pump inhibitors in patients
with peptic ulcer bleeding. Aliment Pharmacol Ther
2013;38:721-8. doi:10.1111/apt.12441.
18. Heldwein W, Schreiner J, Pedrazzoli J, Lehnert P. Is the
Forrest classification a useful tool for planning endo-
scopic therapy of bleeding peptic ulcers? Endoscopy
1989;21:258-62. doi:10.1055/s-2007-1010729.
19. Tsai JJ, Hsu YC, Perng CL, Lin HJ. Oral or intravenous
proton pump inhibitor in patients with peptic ulcer bleed-
ing after successful endoscopic epinephrine injection. Br
J Clin Pharmacol 2009;67:326-32. doi:10.1111/j.1365-
2125.2008.03359.x.
20. Siau K, Chapman W, Sharma N, Tripathi D, Iqbal T, Bhala
N. Management of acute upper gastrointestinal bleeding:
an update for the general physician. J R Coll Physicians
Edinb 2017;47:218-30. doi:10.4997/JRCPE.2017.303.
21. Jiang M, Chen P, Gao Q. Systematic Review and Net-
Work Meta-Analysis of Upper Gastrointestinal Hemor-
rhage Interventions. Cell Physiol Biochem 2016;39:2477-
91. doi:10.1159/000452515.

Middle East J Dig Dis/ Vol.10/ No.4/October 2018