Role of proton pump inhibitors in the management of peptic ulcer bleeding

Abstract

Peptic ulcer bleeding is a serious medical problem with significant morbidity and mortality. Endoscopic therapy significantly reduces further bleeding, surgery and mortality in patients with bleeding peptic ulcers and is now recommended as the first hemostatic modality for these patients. The efficacy of large-dose proton pump inhibitor (PPI) therapy in reducing re-bleeding after endoscopic therapy has been supported by evidence derived from randomized controlled trials. It may be premature to recommend small-dose intravenous injection PPI after endoscopic hemostasis in patients with bleeding ulcers. An updated systematic review shows that PPI therapy before endoscopy significantly reduces the proportion with major stigmata and requirement for endoscopic therapy at index endoscopy. Some studies show that there is no significant difference between oral and intravenous PPIs in raising intragastric pH. However, clinical data is lacking in patients with peptic ulcer bleeding to date.

Peptic ulcer bleeding remains a serious medical problem with significant morbidity and mortality. Despite advance in management of this life-threatening condition, the mortality rate remains around 5%-10%. Endoscopic therapy significantly reduces further bleeding, surgery and mortality in patients with bleeding peptic ulcers and is now recommended as the first hemostatic modality for these patients[1,2].

Is adjuvant pharmacotherapy effective in reducing re-bleeding following successful endoscopic therapy? From a theoretical point of view, a stable blood clot in a peptic ulcer is crucial to hemostasis. However, in a low pH environment, platelet dysfunction has been observed[3,4]. In addition, pepsin can lyse the blood clots that plug vessels in the ulcer base and induce re-bleeding thereafter[4,5]. Thus, the hypothesis that by suppressing the intragastric acid, the use of proton pump inhibitor (PPI) might benefit patients at risk for further hemorrhage was proposed.

The efficacy of PPI therapy in reducing re-bleeding has been supported by evidence derived from randomized controlled trials[6]. Findings from meta-analyses suggest that histamine receptor 2 antagonists (H2RAs) might not be as effective as PPIs for this indication[6]. We have previously shown that pharmacological tolerance of H2RAs significantly limits their capability to sustain a high intragastric pH[7]. Therefore, we believe that PPIs should be the drug of choice for the prevention of peptic ulcer re-bleeding as far as therapeutic efficacy is concerned.

With regards to PPIs usage as an adjuvant pharmacotherapy in the management of peptic ulcer bleeding, the following questions should be answered: the dosage of optimal action, route of administration (oral or intravenous), mode of intravenous route (continuous infusion or bolus), use before or after endoscopic therapy and which is the choice PPI?

To sustain a high intragastric pH, a high dose of omeprazole has been used in previous studies concerning high-risk peptic ulcer bleeding. In our study, we used 40 mg omeprazole intravenous bolus followed by 160 mg/d continuously infusion for 3 d. The mean intragastric pH rose to 6.0 one hour after the initial bolus of omeprazole in the omeprazole group and it was maintained around this value for the rest of the 24 h[7]. The re-bleeding rates were much lower in the PPI group as compared with the H2RA group (Day 3: 0/50 vs 8/50, P < 0.01; Day 14: 2/50 vs 12/50, P < 0.01). In a similar study, Lau et al[8] used omeprazole 80 mg intravenous bolus followed by 8 mg/h for 3 d and the re-bleeding rates were also much lower in the PPI group as compared with the placebo group (Day 3: 5/120 vs 24/120 P < 0.001; Day 30: 8/120 vs 27/120, P < 0.001).

On the other hand, low dose PPI use was supported by some studies. A 2008 multicenter trial by Andriulli et al[9] demonstrated a similar efficacy of high dose PPI (80 mg bolus followed by 8 mg/h) and low dose PPI (40 mg bolus daily) in patients with peptic ulcer bleeding. They concluded that 40 mg omeprazole or pantoprazole daily was as effective as a high-dose regimen in reducing the risk of recurrent bleeding. Cheng et al[10] used 7-d low-dose omeprazole (3.3 mg/h) and 3-d high-dose omeprazole (8 mg/h) in patients with peptic ulcer bleeding combined with co-morbid illness. They concluded that prolonged low-dose PPI infusion for 7 d reduce re-bleeding during the first 28 d in these patients.

There are some points that deserve discussion in the Andriulli et al[9] and Cheng et al[10] studies. Dual endoscopic therapy has been proven significantly superior to epinephrine injection alone for bleeding high-risk peptic ulcers[11]. Epinephrine injection alone cannot seal the bleeding vessels immediately. Therefore, a high re-bleeding rate may occur after epinephrine injection alone[11]. This phenomenon has been observed in our previous studies[12]. Therefore, epinephrine injection is not recommended as the only therapeutic modality for these high-risk patients. Unfortunately, over 50% (50% in intensive regimen and 57.6% in standard regimen) of Andriulli et al’s[9] study and over one third of the patients (55/142, 38.7%) in Cheng et al’s[10] study received epinephrine injection alone. Under these conditions, results and conclusions may be misleading. Therefore, it may be premature to recommend low-dose intravenous PPI after endoscopic hemostasis in patients with bleeding ulcers[13].

How about the route of PPI usage? Which route (oral or intravenous) is the preferred route? Laine et al[14] used oral lansoprazole in patients with peptic ulcer bleeding. Patients were randomly assigned to intravenous lansoprazole (90 mg bolus followed by 9 mg/h infusion) or oral lansoprazole (120 mg bolus followed by 30 mg every 3 h). A pH was recorded for 24 h. Mean pH rose above 6 after 2-3 h of intravenous PPI and 3-4 h of oral PPI. They concluded that frequent oral PPI may be able to replace the currently recommended intravenous bolus plus infusion PPI therapy in patients with bleeding ulcers. In one recent article, Javid et al[15] also proved that there was no significant difference among various PPIs (omeprazole, pantoprazole and rabeprazole) given through different routes (intravenous and oral routes) on raising intragastric pH above 6 for 72 h after successful endoscopic hemostasis in bleeding peptic ulcer. In our recent study, we have proved that oral rabeprazole and intravenous omeprazole are equally effective in preventing re-bleeding (13/78 in rabeprazole vs 12/78 in omeprazole, P > 0.1) in high-risk bleeding peptic ulcers[16]. All secondary outcomes between the two groups were similar including the amount of blood transfusion, hospital stay, need for surgery and mortality.

Is it beneficial to use PPI before endoscopic therapy? Lau et al[17] concluded that infusion of high-dose omeprazole before endoscopy accelerated the resolution of signs of bleeding in ulcers (active bleeding: 12/187 in omeprazole group vs 28/190 in placebo group, P = 0.01) and reduced the need for endoscopic therapy (60/314 in omeprazole group vs 90/317 in placebo group, P = 0.007). An updated systematic review includes six trials of 2223 patients[18]. PPI therapy initiated before endoscopy in bleeding peptic ulcer patients significantly reduced the proportion with major stigmata (37.2% vs 46.5%, P = 0.005) and requirement for endoscopic therapy at index endoscopy (8.6% vs 11.7%, P = 0.02). However, there was no evidence that PPI therapy improves clinical outcomes.

How about the mode of intravenous administration? Should PPI be given as a bolus or continuous infusion? A pooled analysis of 16 randomized controlled trials (> 3800 patients) suggested that optimal effect is achieved with an intravenous 80 mg bolus, followed by continuous infusion of 8 mg/h for 3 d, after which therapy may be continued with an oral PPI. Intermittent bolus administration yielded a minimal benefit[18]. This observation is plausible because intermittent bolus of PPI may cause a big fluctuation of intragastric pH.

Is there any benefit in using PPIs for patients with high-risk patients? Recent meta-analyses showed that use of PPIs significantly decreased the risk of further bleeding [odds ratio: 0.4, 95% confidence interval (CI): 0.24-0.67], the need for urgent surgery (odds ratio: 0.5, 95% CI: 0.33-0.76) and the risk of death (odds ratio: 0.53, 95% CI: 0.31-0.91)[6,19,20].

What is the optimal large dose for intravenous PPI usage? It has been demonstrated that the benefit of PPI appears more pronounced in Oriental patients[21]. This phenomenon can be explained by the low gastric acid output, cytochrome P-450 2C19 genetic polymorphism and high prevalence of Helicobacter pylori in Asians. In our recent study, we compared two large doses of intravenous PPIs (160 mg/24 h, n = 60 mg/24 h and 192 mg/24 h, n = 60) in patients with high-risk peptic ulcer bleeding[22]. Bleeding recurred in a total of 11 (9.2%) patients, with six (10%) in the 192 mg/d group and five (8.3%) in the 160 mg/d group (P > 0.1). All secondary outcomes between the two groups were similar including the amount of blood transfusion (mean: 1179 mL vs 1203 mL, P > 0.1), hospital stay (mean: 9.5 d vs 9.9 d, P > 0.1), need for surgery (n = 1 vs n = 0, P > 0.1) and mortality (n = 1 vs n = 0, P > 0.1). Therefore, we believe that dosage of intravenous PPIs in Asians can be lower than that of Occidentals.

In conclusion, in patients with high-risk peptic ulcer bleeding after successful endoscopic therapy, a large intravenous dose of continuous infusion PPI for 3 d is recommended as the management of choice. Whether the oral route can replace the intravenous route in administering PPI remains to be determined.