Endoscopy 2016; 48(08): 699-700
DOI: 10.1055/s-0042-111001
Editorial
© Georg Thieme Verlag KG Stuttgart · New York

Prevention of rebleeding: high-dose PPIs, second-look endoscopy or both?

Angel Lanas
Service of Digestive Diseases, University Hospital, University of Zaragoza, CIBERehd. IIS Aragón, Zaragoza. Spain
› Author Affiliations
Further Information

Publication History

Publication Date:
26 July 2016 (online)

The main objective of medical and endoscopic therapy in patients with peptic ulcer bleeding (PUB) is to reduce mortality, need for surgery, and recurrence of bleeding. Endoscopic therapy in patients with high-risk stigmata (active bleeding, visible vessel or adherent clot) within the first 24 hours after hospital admission is probably the most determinant measure to reduce these three outcomes. This instrumental procedure followed by intravenous (I.V.) administration of high-dose proton pump inhibitor (PPI) for 3 days has become current standard therapy for this type of patient [1].

Peptic ulcer rebleeding after initial hemostasis is a serious complication that is directly related to the need for surgery and mortality. Different management approaches in patients with PUB are therefore tested to reduce rebleeding rates of PUB. It must be considered, however, that mortality associated with a PUB event is not always related to the bleeding event itself. Associated co-morbidities of patients who develop a PUB event are often the ultimate cause of death [2].

Routine second-look endoscopy, defined as an early (usually within 24 hours) scheduled endoscopic procedure to assess and treat, if needed, a previously diagnosed bleeding lesion is one of the strategies used to reduce the impact of rebleeding [3]. However, routine second-look endoscopy conducted regardless of the type of lesion or clinical signs of rebleeding is not recommended by the European Society of Gastrointestinal Endoscopy (ESGE) as part of the management of nonvariceal upper gastrointestinal hemorrhage [1]. The ESGE recommends second-look endoscopy in patients at high risk of rebleeding and in patients with clinical evidence of rebleeding following successful initial endoscopic hemostasis [1]. Available evidence indicates that although some meta-analyses of randomized clinical trials (RCTs) have shown that second-look endoscopy reduces the risk of rebleeding, this effect was present in the absence of cotherapy with high-dose PPI, and no additional benefit of second-look endoscopy was observed when combined with high-dose I.V. PPI [4]. These results can be explained by current evidence which shows that an 80 mg I.V. bolus followed by 8 mg/hour infusion of a PPI reduces rebleeding, surgery, and mortality in patients with high-risk peptic ulcers after successful endoscopic hemostasis [5]. This aspect is relevant and limits the impact of published studies concerning second-look endoscopy so far. In fact, the beneficial effect of second-look endoscopy in the meta-analysis was limited to studies that included high-risk patients [4].

Today, high-dose PPI is routine in the clinical management of patients with PUB [1] [5], but it is indicated in patients with PUB and high-risk stigmata at initial endoscopy. Therefore, in order to move forward, we should focus on patients at high risk of rebleeding. In this way, the study by Chiu et al. [6], published in this issue of Endoscopy, is a step in this direction. The authors compared the efficacy of a second endoscopy with high-dose PPI infusion to prevent ulcer rebleeding in patients who received endoscopic treatment for PUB. Randomization included one group of patients who received an I.V. bolus of 40 mg omeprazole/12 hours for 3 days and a second-look endoscopy within 16 – 24 hours; the second group received standard high-dose omeprazole infusion (a bolus of 80 mg plus 8 mg/hour) for 3 days. The primary outcome was recurrence of ulcer bleeding within 30 days. The study was designed as a noninferiority trial with an apparent small sample size linked to a single-center study. This design is always a matter of debate because, as the authors comment in their discussion, definition of the noninferiority margin is arbitrary and affects the sample size. The study showed no significant difference between groups: 6.5 % of patients in the high-dose I.V. PPI group and 7.9 % of patients in the second-look endoscopy (plus “low-dose” PPI) group developed rebleeding at 30 days. Mortality and the proportion of patients who required surgery for rebleeding was also not different between the groups. The study concluded that high-dose PPI infusion was not inferior to second-look endoscopy with bolus PPI in the prevention of peptic ulcer rebleeding. In some way, this conclusion would question the need for a second-look endoscopy when high-dose I.V. PPI is recommended.

However, although the study [6] increases our understanding of the best approach in the management of patients with PUB, the question of the added value of a second-look endoscopy in our therapeutic armamentarium to reduce rebleeding, surgery, and death in PUB is still an open question. In fact, we need studies that address whether high-dose PPI combined with second-look endoscopy is better than high-dose PPI alone in patients with PUB, high-risk stigmata, and successful initial endoscopy therapy. The timing for the second-look endoscopy may be also a question to debate. In the Chiu et al. study [6], there was a numerical trend towards a higher rate of rebleeding 24 hours after the first endoscopy, but not at 3 and 30 days, in the endoscopy group. This may be interpreted in two different ways. One way may question the clinical relevance of some of those initial rebleeding cases detected by endoscopy. The second interpretation suggests that, compared with clinical symptoms, early endoscopy detects rebleeding events earlier.

To make matters more complicated, the currently recommended regimen of continuous high-dose PPI infusion for 72 hours has been challenged recently in a meta-analysis of RCTs of bleeding ulcers with high-risk stigmata successfully treated with endoscopic hemostasis [7]. This study compared intermittent PPI treatment (variable dosage and timing of either oral or I.V. regimens) with the standard recommended therapy (80 mg I.V. bolus followed by 8 mg/hour continuous infusion) of a PPI [1] [5]. The effects of intermittent PPI therapy on rebleeding within 3 and 30 days, mortality, and urgent interventions were comparable to the standard continuous I.V. PPI regimen. As the only apparent reason for using antisecretory therapy in PUB patients is to increase the intragastric pH to stabilize the clot and prevent platelet disaggregation, the absence of differences between the continuous infusion and the intermittent PPI regimens should rely on their effect on gastric pH. Unfortunately, data on intragastric pH available in some of the studies included in Sachar’s meta-analysis [7] were heterogeneous and conducted in Asia, which cannot be extrapolated to Western countries; however, data suggested that an intragastric pH above 4 to 5 may be sufficient to prevent clot lysis [8]. High intragastric pH can also be achieved with oral PPI. An 80 mg dose of oral PPI followed by 40 – 80 mg orally/12 hours for 72 hours achieved a similar increase of intragastric pH to that obtained with continuous intravenous PPI infusion in high-risk peptic ulcers [9]. These data are in agreement with the results obtained in one study, also conducted in Hong Kong, where no differences in recurrent bleeding ulcers after endoscopic therapy were found in patients randomized to high-dose continuous infusion of esomeprazole vs. 40 mg of oral esomeprazole [10].

Based on the studies mentioned above, one may be inclined to consider that the study reported by Chiu et al. [6] supports the hypothesis that a second-look endoscopy is not necessary when high-dose PPI is administered after initial hemostasis. Unfortunately, intragastric pH was not measured in the study, and interpretation of results should be limited to the cautious conclusion of the authors. The value of the second-look endoscopy, combined with “high-dose” PPI treatment in the management of PUB with high-risk stigmata, should be tested in Western patients treated with a PPI dosage high enough to raise the intragastric pH above 6, or at least above 4. This will probably require a collaborative multicenter study. In the meantime, we need to adhere to current guidelines that recommend a second therapeutic endoscopy only in patients with clinical evidence of rebleeding or in patients at high risk of rebleeding.

 
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