Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy

A bleeding peptic ulcer remains a serious medical problem with significant morbidity and mortality. Endoscopic therapy significantly reduces further bleeding, surgery, and mortality in patients with bleeding peptic ulcers [1] and is now recommended as the first hemostatic modality for these patients [1, 2].

Following endoscopic therapy, proton pump inhibitor (PPI) can reduce re-bleeding and surgery [3, 4]. The therapeutic efficacy of PPI is related to its potent inhibition of gastric acid [5], because acid and acid dependent protease activity impairs blood clotting [6, 7]. However, the optimal route, dose and duration of PPI therapy after endoscopic therapy remain controversial.

Oral PPI has been found to be effective in preventing re-bleeding in previous studies [8‐13]. For cost effectiveness, it is worth evaluating the benefits of oral PPI and intravenous (IV) PPI in patients with peptic ulcer bleeding [14]. Recently, Laine et al [15] and Javid et al [16] proved that oral PPI can achieve a similar intragastric pH with that receiving IV PPI. Following up on these evidences, we have observed a similar preventing capability of oral PPI clinically [17]. Therefore, oral PPI may be able to replace IV PPI after successful endoscopic therapy.

In this study, we attempted to evaluate two different routes, using high dose PPIs to prevent re-bleeding for bleeding peptic ulcer patients after successful endoscopic therapy.

From January 2010 to Feb 2011, 126 patients were found to have the high-risk stigmata of active bleeding, or NBVV at Changhua Christian Hospital. Twenty six patients were excluded from the study for the following reasons: lack of informed consent (n = 3), bleeding tendency (n = 8), gastric malignancy (n = 5), and prior use of PPI (n = 10) (Figure 1). Finally, 100 patients were enrolled in this study (50 in the ESO group and 50 in the LAN group). Four patients in this study (n = 2 for each group) received hemoclip placement and others received heater probe thermocoagulation. The two groups were well matched for the factors affecting outcome (Table1).

Table2 shows the clinical outcomes of this study. In the LAN group, 25 patients were allowed to stay at home due to absence of shock and initial hemoglobin greater than 10 g/dL. Re-bleeding occurred in 2 (4%) patients in the ESO group and 2 patients (4%) in the LAN group within 14 days (p = 1). All re-bleeding episodes occurred on the second day of enrolment. All these four patients received a second heater probe thermocoagulation and obtained ultimate hemostasis. The mean duration of hospital stay was 3.9 days in the ESO group and 1.8 days in the LAN group (p > 0.01). There was no patient with mortality or surgical intervention in both groups. The volumes of blood transfusion were comparable between both groups (mean, ESO: 781 ml, LAN: 520 ml, p > 0.1).

Our study suggests that patients with oral and intravenous proton pump inhibitors have a similar clinical outcome, including recurrent bleeding, blood transfusion, surgery and mortality after endoscopic therapy for high-risk bleeding peptic ulcers. In addition, we find that oral route PPIs can decrease hospital stay and therefore decrease medical expenses associated with peptic ulcer bleeding in this trial. This is, to our knowledge, the first randomized controlled trial to compare the clinical outcome (including re-bleeding rate, blood transfusion, surgery, hospital and mortality rate) of high dose oral and IV PPIs following endoscopic therapy for patients with bleeding peptic ulcer.

The use of PPIs following endoscopic therapy for bleeding peptic ulcers can help to stabilize blood clots, promote platelet aggregation and prevent fibrinolysis [18, 19]. In our previous study and recent meta-analysis, PPIs have been found to be superior to H2 blockers or placebo in preventing re-bleeding following endoscopic therapy for peptic ulcers [20, 21]. Current guidelines suggest a high dose PPI followed by continues infusion as standard adjuvant pharmacotherapy for bleeding peptic ulcers especially in the Western countries [20, 21]. This recommendation was based on previous studies that show that high doses of PPI followed by continuous infusion are able to sustain a higher intragastric pH [22, 23].

Although high doses intravenous PPI are demonstrated to be superior to placebo [24], there is no evidence showing high doses of intravenous PPIs are superior to oral PPIs with regards to the clinical outcome of bleeding peptic ulcer patients following endoscopic therapy. As compared with the intravenous route administration of PPI, oral PPI is more attractive because of its availability and cost-effectiveness. In our previous study, we found that both oral and intravenous administration of regular doses of PPIs have a similar re-bleeding rate (16.7% vs. 15.4% for IV omeprazole vs. oral rabeprazole) following endoscopic therapy for bleeding peptic ulcers [17]. Banerjee et al found that oral buffered esomeprazole (40 mg po) is superior to IV pantoprazole (40 mg IV every 12 h) to achieve intragastric pH > 6 in healthy volunteers [25]. Laine et al conducted the first study to compare the acid suppression effect of oral and intravenous lansoprazole in bleeding peptic ulcer patients [15]. They randomized patients into two groups: (a) intravenous lansoprazole (90 mg bolus followed by 9 mg/h) and (b) intermittent high dose oral lansoprazole (120 mg bolus followed by 30 mg every three hours). Patients were monitored with a 24-hour pH monitor. They found that a mean pH above 6 was achieved 1 hour earlier ( 2–3 hours vs. 3–4 hours) in the intravenous compared with oral group. They concluded that frequent oral PPI can replace currently recommended intravenous PPI. Javid et al from India found there is no difference among different PPIs and different routes of these PPIs (omeprazole, pantoprazole and rabeprazole ) in intragastric pH above 6 for 72 hours after endoscopic therapy for bleeding peptic ulcers [16]. A pilot study from Bajaj et al suggests oral pantoprazole is similar to IV pantoprazole on 30-day re-bleeding rate [26]. Based on these studies, we conducted this study to clarify the clinical efficacy of high dose oral and intravenous PPIs after successful endoscopic therapy for patients with bleeding peptic ulcers.

In this randomized comparative trial, we found patients with oral and intravenous PPI have a similar clinical outcome, including recurrent bleeding, blood transfusion, surgery and mortality. Interestingly, we found that patients in the oral PPI group have a shorter hospital stay compared with the IV group (1.8 days vs. 3.9 days). This is the first study to suggest the finding of similar intragastric pH via different routes of administration may suggest for similar clinical outcomes [15, 16]. The low rebleeding rate of 4% in both groups is lower than our previous study of regular dose PPIs but is comparable to a multicenter study with high dose intravenous esomeprazole [24]. This suggests that high doses rather than regular doses of PPI via the oral route may achieve comparable clinical outcomes with high dose intravenous PPI.

This is important in two ways. First, the cost associated with the pharmacotherapy can be reduced. The cost of oral PPI is one tenth the cost of the intravenous PPI in Taiwan. In addition, a patient with oral PPI can be discharged earlier in our study. Taking both together, approaches with high dose oral PPI can be more economical than high dose intravenous PPI. Second, the oral route administration of PPI is easy and dose not require frequent monitoring for the infusion site reactions (such as edema, thrombophlebitis, and so on). In addition, the use of oral disintegrating lansoprazole can be taken without water and repeated endoscopy can be performed without waiting for gastric emptying [27].

The result of this study suggests a similar clinical outcome between oral and intravenous large dose PPIs as adjuvant therapy to prevent re-bleeding for patients with high-risk bleeding peptic ulcers after successful endoscopic therapy. Patients with oral PPIs have a shorter hospital stay. However, the study was not powered to prove equivalence or non-inferiority. A larger trial is required to further clarify the role of oral PPIs in patients with high-risk bleeding ulcers.

H-HY, MD, C-W Y, MD, W-WS, MD, M-SS, MD, S-SW, MD Participated in the study, drafting, read and final approval of the manuscript. H-HY, MD, C-W Y, MD contributed equally to the writing of the manuscript. H-JL, MD Design the study, participate the study, analysis of the data and final approval of the manuscript.