A bleeding peptic ulcer is the most common cause of upper gastrointestinal bleeding (UGIB) [
About 25% to 30% of patients with bleeding peptic ulcers have major stigmata of ulcer hemorrhage, which is associated with a high-risk for rebleeding when treated by medical therapy alone [
Previous Asian studies reported that the use of oral PPIs is effective under certain circumstances in the treatment of bleeding peptic ulcers [
This was a two-center, prospective, randomized study to compare the effect of high-dose oral rabeprazole versus high-dose IV omeprazole on rebleeding after endoscopic treatment of bleeding peptic ulcers (ClinicalTrials.gov: NCT00838682). The study was conducted by investigators at Uijeongbu St. Mary’s Hospital and Bucheon St. Mary’s Hospital, The Catholic University of Korea, in accordance with the Declaration of Helsinki and the International Congress on Harmonisation Consolidated Guideline on Good Clinical Practice. The protocol was approved by the institutional review board of Uijeongbu St. Mary’s Hospital and Bucheon St. Mary’s Hospital. All subjects gave written informed consent and were enrolled from April 1, 2006, to April 19, 2007, and from October 1, 2007, to December 31, 2008.
Patients who presented with overt or suspected UGIB based on hematemesis and/or melena were eligible. These eligible patients were required to have a peptic ulcer with active bleeding (Forrest classification Ia: spurting or Ib: oozing) or a nonbleeding lesion (IIa: nonbleeding visible vessel or IIb: adherent clot) on emergency endoscopy performed within 24 hours after hospitalization. Patients aged 16 years or older who achieved primary hemostasis with endoscopic hemostatic treatment were eligible. Exclusion criteria were refusal of the endoscopic procedure, complications from a peptic ulcer that required operative treatment such as gastric outlet obstruction or peptic ulcer perforation, serious concurrent disease such as malignant tumors or end-stage diseases, pregnancy, history of gastrectomy or vagotomy, severe hepatic disease, known hypersensitivity to proton pump inhibitors, age under 16 years, and epilepsy.
Eligible patients who presented to the hospital because of overt or suspected UGIB and who were diagnosed with a bleeding peptic ulcer on emergency endoscopic finding were treated within 24 hours. Patients who achieved primary hemostasis with the endoscopic treatment were randomized into two groups using a random number table. All randomized patients were required to start a study drug within 24 hours of arrival at the emergency room. The IV omeprazole group received high-dose IV omeprazole for 72 hours, and the oral rabeprazole group received high-dose oral rabeprazole for 72 hours. Follow-up endoscopic examination was performed on days 1 and 3. If recurrent bleeding was suspected, repeat endoscopy was performed regardless of the prescheduled day. After the initial 72 hours, patients were discharged if they were stable without suspected rebleeding. Both groups received maintenance PPI therapy with rabeprazole 10 mg once daily from day 4 to week 6. The final follow-up endoscopic examination was performed in week 6.
The modality of endoscopic hemostasis was either monotherapy or combination therapy using one of the following treatment modalities: epinephrine injection (1 : 10,000 diluted in saline), heater probe, monopolar or bipolar electrocoagulation, argon plasma coagulation, or hemoclip. The hemostatic method considered the most effective was selected by the investigators based on the patient’s status, ulcer type, ulcer location, and bleeding pattern during the initial emergency endoscopy. The hemostatic treatment continued until active bleeding stopped and visible vessels disappeared.
In the oral rabeprazole group, rabeprazole 20 mg twice daily for 72 hours was given orally. In the IV omeprazole group, omeprazole 80 mg was injected intravenously as a bolus followed by continuous infusion at 8 mg/h for 72 hours.
The primary end point was the occurrence of rebleeding within 3 days after the successful initial endoscopic hemostasis. Clinical rebleeding was defined as the reoccurrence of hematemesis following the resolution after the initial endoscopic hemostasis and redevelopment of shock following stabilization of vital signs. Clinical rebleeding was confirmed immediately with emergency endoscopy. The secondary end points included rebleeding after day 3, death due to rebleeding or any cause, the need for surgery, and cure of ulcer by week 6.
Adverse events were recorded beginning from the time the study patients signed the study consent form and included all adverse events encountered during the study. Adverse events included any change from the pretreatment condition including symptoms, physical findings, or laboratory values.
A previous trial [
Student’s
Although the estimated sample size was not achieved, the study was terminated by the investigators because of slow enrollment. After termination of the study and completion of case report forms, the final analysis was performed. All results were analyzed on an intention-to-treat (ITT) basis.
A total of 106 patients, aged 19–87 years, with a bleeding peptic ulcer who met the inclusion criteria were enrolled in the study and received a treatment assignment. The ITT population comprised all 106 of the patients who received at least one dose of one of the study drugs; because all 106 patients received a study drug, none of the patients was excluded from the analysis. Fifty-four patients received high-dose oral rabeprazole, and 52 patients received high-dose IV omeprazole. Of the 106 patients, 62 patients completed the study, and 44 withdrew from the study (Figure
Demographics (ITT population).
Oral rabeprazole group ( |
IV omeprazole group ( |
|
|
---|---|---|---|
Age (yr) |
|
|
0.729 |
Age group | 0.496 | ||
<70 yr | 43 | 38 | |
≥70 yr | 11 | 14 | |
Sex (M/F) | 0.227 | ||
Male | 46 | 39 | |
Female | 8 | 13 | |
Symptoms at presentation | 0.356 | ||
Hematemesis | 11 | 7 | |
Melena | 27 | 27 | |
Hematochezia | 1 | 1 | |
Hematemesis + melena | 12 | 12 | |
Hematemesis + hematochezia | 2 | 0 | |
Other | 1 | 5 | |
Alcohol use | 30 | 31 | 0.698 |
Smoking | 25 | 24 | 1.000 |
NSAID use | 5 | 1 | 0.206 |
Pulse (beats/min) |
|
|
0.183 |
Blood pressure (mm Hg) | |||
Systolic |
|
|
0.111 |
Diastolic |
|
|
0.662 |
Hemoglobin (g/dL) |
|
|
0.569 |
Hematocrit (%) |
|
|
0.549 |
Comorbid illness | 34 | 36 | 0.543 |
ITT: intention-to-treat; IV: intravenous; NSAID: nonsteroidal anti-inflammatory drug.
Baseline characteristics (ITT population).
Oral rabeprazole group ( |
IV omeprazole group ( |
|
|
---|---|---|---|
Ulcer size (mm) | 13.7 ± 12.2 | 10.5 ± 11.1 | 0.173 |
Ulcer type | 0.415 | ||
GU | 30 | 27 | |
DU | 21 | 20 | |
GU and DU | 3 | 5 | |
|
0.653 | ||
Positive | 22 | 19 | |
Negative | 24 | 28 | |
Unknown | 8 | 5 | |
Stigmata of hemorrhage | 0.912 | ||
Active arterial spurting | 6 | 4 | |
Oozing | 15 | 14 | |
Nonbleeding visible vessel | 21 | 23 | |
Adherent clot | 12 | 11 | |
Endoscopic treatment | 0.254 | ||
Epi + hemoclip | 36 | 29 | |
Epi only | 7 | 8 | |
Hemoclip only | 6 | 5 | |
Epi + APC | 2 | 5 | |
Epi + mono | 0 | 2 | |
Epi + hemoclip + APC | 2 | 0 | |
Epi + hemoclip + mono | 1 | 0 | |
EBL | 0 | 2 | |
APC | 0 | 1 |
ITT: intention-to-treat; IV: intravenous; GU: gastric ulcer; DU: duodenal ulcer; Epi: epinephrine injection (1 : 10,000 dilution in saline); APC: argon plasma coagulation; mono: monopolar coagulation; EBL: endoscopic band ligation.
Flow chart. *For full details of patients who discontinued or dropped out, see Table
The results of ulcer rebleeding are shown in Table
Outcomes in the study patients with a bleeding peptic ulcer (ITT population).
Oral rabeprazole group ( |
IV omeprazole group ( |
|
|
---|---|---|---|
Rebleeding within 3 days | 2 | 1 | 1.000 |
Rebleeding after 3 days | 1 | 0 | 1.000 |
Total rebleeding | 3 | 1 | 0.618 |
Surgery | 2 | 0 | 0.495 |
Death | 1 | 0 | 1.000 |
Blood transfusion (units) |
|
|
0.582 |
Duration of hospitalization (days) |
|
|
0.124 |
ITT: intention-to-treat; IV: intravenous.
Two patients (3.7%) in the oral rabeprazole group and none in the IV omeprazole group underwent surgery
There were few adverse events reported. Two adverse events in the oral rabeprazole group were elevation of hepatic enzyme levels and generalized tonic seizure-like activity. The elevated hepatic enzyme levels were resolved within several days. The seizure-like activity, possibly caused by hyperventilation, was resolved within 15–20 seconds by conservative management; no sequela was seen during the 6-week follow-up period. The two adverse events in the IV omeprazole group were elevation of hepatic enzyme levels and premature ventricular beats. The elevated hepatic enzyme levels were resolved within several days. The patient with premature ventricular beats had a history of percutaneous coronary angioplasty because of angina and had no concomitant symptom. No severe adverse events resulted from withdrawal from the study in either group.
Table
Number (%) of patients who discontinued the study grouped by primary reason (ITT population).
Oral rabeprazole group ( |
IV omeprazole group ( |
|
---|---|---|
Loss to followup at 6 weeks | 21 (38.9%) | 14 (26.9%) |
Detection of exclusion criteria after enrollment* | 4 (7.4%) | 3 (5.8%) |
Patient request | 0 | 1 (1.9%) |
Protocol violation | 0 | 1 (1.9%) |
| ||
Total | 25 (46.3%) | 19 (36.5%) |
ITT: intention-to-treat; IV: intravenous.
*Detection of exclusion criteria after enrollment included lung cancer, stomach cancer at another site, bleeding of a gastric adenoma, Billroth II subtotal gastrectomy, and bleeding of a duodenal submucosal tumor.
The purpose of this prospective, randomized, controlled study was to compare the effect of high-dose oral rabeprazole versus high-dose IV PPI on rebleeding after endoscopic treatment of bleeding peptic ulcers with high-risk stigmata. Our study showed no significant differences in the effects of high-dose oral rabeprazole compared with high-dose IV omeprazole on rebleeding, the need for surgical intervention or blood transfusion, hospital stay duration, and mortality rate after endoscopic hemostasis in patients with a high-risk bleeding peptic ulcer. We note that our study had a small sample size.
This two-center trial was stopped by the investigators before the planned enrollment was completed. Recruitment in the study was slower than anticipated, and smaller than expected proportion of the patients with high-risk bleeding peptic ulcers qualified for the study. There are several reasons for this. First, the number of medical exclusions such as inpatient ulcer bleeding and recent PPI treatment decreased enrollment into this study. Second, the strict study design (e.g., starting a study drug within 24 hours of presentation to the emergency room) substantially reduced enrollment. Third, this trial was initiated by the investigators and not by the study sponsor.
High-dose IV PPI therapy in patients with a high-risk bleeding peptic ulcer who receive endoscopic hemostatic therapy reduces rebleeding, surgery, and mortality [
In our study, rebleeding rates in both the oral and IV PPI groups (3.7% versus 1.9% within 3 days and 5.6% versus 1.9% overall) were much lower than those of previous reported trials. There are several possible reasons for this difference. First, the method of endoscopic hemostasis in our study was not limited because we included any method that was successful in primary endoscopic hemostasis. Second, there was a very low prevalence of NSAID use in our study (5.7% of total enrolled patients), which was lower than in other studies on bleeding peptic ulcers. Third, our study enrolled Korean patients only. Previous studies showed that certain groups of Asian patients exhibit an increased pharmacodynamic effect of PPIs because of smaller parietal cell mass and a higher prevalence of either a slow-metabolizer phenotype for PPI or the presence of
Our study has several limitations. First, this was a two-center study and was stopped before enrollment was complete. The small sample size meant that the results of our study were statistically underpowered. Second, our study enrolled Korean patients only. Whether high-dose oral PPI therapy would have produced similar results in a Western population requires further investigation [
In conclusion, this two-center, prospective, randomized, controlled trial of patients with a bleeding peptic ulcer after endoscopic treatment has shown that the effect of high-dose oral rabeprazole did not differ significantly from that of high-dose IV omeprazole on rebleeding, the need for surgical intervention or blood transfusion, hospital stay duration, or mortality rate. Our data suggest that high-dose oral rabeprazole may be able to replace high-dose IV PPI as the treatment of choice after endoscopic hemostasis of bleeding peptic ulcers in certain circumstances. However, larger randomized, controlled trials to compare directly high-dose oral PPI with high-dose IV PPI are needed to document the efficacy of high-dose oral PPI in patients with a bleeding peptic ulcer.
No potential conflict of interests relevant to this paper was reported.
This study was supported by Janssen Korea Ltd. But, this trial was an investigator-initiated study, and Janssen Korea Ltd. was not involved in any aspect of the study (ClinicalTrials.gov: NCT00838682).