British Journal of Clinical Pharmacology. Zhixiang Jian 1,HuiLi 2, Nicholas S. Race 3,TingtingMa 4,HaoshengJin 1 and Zi Yin 1

British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016) 82 880 889 880 META-ANALYSIS Is the era of intravenous proton pump inhibitors coming to an end in patients with bleeding peptic ulcers? Meta-analysis of the published literature Correspondence Professor Yin Z or Professor Jin HS, General Surgery Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510080, China. Tel.: +86 134 1634 3575; Fax: +86 20 8376 9487; E-mail: yinzi@outlook.com Received 9 July 2015; revised 27 November 2015; accepted 15 December 2015 Zhixiang Jian 1,HuiLi 2, Nicholas S. Race 3,TingtingMa 4,HaoshengJin 1 and Zi Yin 1 1 General Surgery Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China, 2 Neurological Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China, 3 Purdue University Weldon School of Biomedical Engineering, Indiana University School of Medicine, B.S. Biomedical Engineering, Rose-Hulman Institute of Technology, Terre Haute, IN USA and 4 Gynaecology and Obstetrics Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China Keywords bleeding peptic ulcers, intravenous, oral, proton pump inhibitors AIMS Oral and intravenous proton pump inhibitors (PPIs) are equipotent in raising gastric ph. However, it is not known whether oral PPIs can replace intravenous PPIs in patients with bleeding peptic ulcers. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials to compare oral and intravenous PPIs among patients with peptic ulcer bleeding. A search of all major databases and relevant journals from inception to April 2015, without a restriction on languages, was performed. RESULTS A total of 859 patients from seven randomized controlled trials were included in the meta-analysis. Similar pooled outcome measures were demonstrated between the two groups in terms of oral PPIs vs. intravenous PPIs in the rate of recurrent bleeding within the 30-day follow-up period [risk ratio = 0.90; 95% confidence interval (CI): 0.58, 1.39; P =0.62;I 2 =0%).Intermsofthe rate of mortality, both oral and intravenous PPIs showed similar outcomes, and the pooled risk ratio was 0.88 (95% CI: 0.29, 2.71; P =0.82;I 2 = 0%). Likewise, no significant difference was detected in the need for blood transfusion and length of hospital stay; the pooled mean differences were 0.14 (95% CI: 0.39, 0.12; P = 0.29; I 2 = 32%) and 0.60 (95% CI: 1.42, 0.23; P =0.16; I 2 = 79%), respectively. CONCLUSIONS Our results suggest that oral PPIs are a feasible, safe alternative to intravenous PPIs in patients with bleeding peptic ulcers, and may be able to replace intravenous PPIs as the treatment of choice in these patients. DOI:10.1111/bcp.12866 2016 The British Pharmacological Society

Oral vs. intravenous PPI in bleeding peptic ulcers Introduction Acute upper gastrointestinal bleeding is a potentially lifethreatening condition which remains among the most common reasons for emergency hospital admission. It has an annual incidence ranging from approximately 50 to 150 per 100 000 of the population. With significant morbidity and mortality, peptic ulcer disease is the most common cause of acute upper gastrointestinal bleeding, accounting for about half of episodes [1 5]. Recurrent bleeding occurs in 14 36% of patients and could lead to end-organ dysfunction and even death, which presents significant challenges for gastroenterologists after initial bleeding control by resuscitation and endoscopic therapy [6 8]. Gastric acid disturbs the homeostasis of ulcers in the stomach and duodenum by inhibiting clot formation and promoting clot lysis; thus, the use of high-dose intravenous proton pump inhibitors (PPIs) has become standard practice in the management of upper gastrointestinal bleeding [9]. Several studies have established the efficacy of the adjuvant use of both intravenous and oral PPIs in high-risk bleeding ulcers after endoscopic therapy [10 16]. However, the relative effectiveness of oral and intravenous routes of administration remains controversial. Studies have shown that the risk of rebleeding and continued bleeding from an ulcer is strongly associated with the stigmata seen at endoscopic examinations (major stigmata include spurting, oozing vessels, nonbleeding visible vessels or fresh adherent clots; old adherent clots were considered minor stigmata, and all adherent clots were considered as low-risk stigmata) [10, 11, 17]. It has been reported that the administration of oral PPIs can be appropriate and adequate for most patients who present with ulcer bleeding and have low-risk stigmata with no requirement for intravenous PPI treatment [18]. Overuse of intravenous PPIs in acute upper gastrointestinal bleeding is a common practice worldwide [10, 17]. It is worth noting that, although the use of high-dose intravenous PPIs is widely accepted, the efficacy of high-dose oral PPIs in treating acute peptic ulcer bleeding has remained a topic of dispute [19]. Due to the cost-effectiveness of oral PPIs with respect to intravenous PPIs, the era of widespread oral PPI use for patients with high-risk peptic ulcer bleeding may have arrived. Recently, a meta-analysis demonstrated a similar effectiveness between oral and intravenous PPIs but the results were limited by the fact that the trials were open label and the relatively small sample size. Meanwhile, the trial of Sung et al., which included the largest patient sample size among the published studies, was published in 2014 [19, 20]. Furthermore, the previous studies came from South Asia, and the use of endoscopic therapy was not standardized. The present meta-analysis was the most up to date, and comparedthesafetyandefficacy of oral vs. intravenous PPI in high-risk peptic ulcer bleeding when given with or without endoscopic intervention. Methods The methods of literature search, inclusion and exclusion criteria, outcome measures and methods of statistical analysis were defined in a protocol according to the Preferred Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations for study reporting (see Supporting Information) [21]. Information sources and search strategy The primary sources of the reviewed studies up to April 2015, without restriction on the languages of publication, were Pubmed, Embase, Cancerlit, Cochrane and ISI Web of Science. We combined the database-specific search terms of proton pump inhibitors and PPI (pantoprazole, omeprazole, lansoprazole, esomeprazole, rabeprazole, dexlansoprazole) and intravenous and oral, as well as truncated search terms utilizing the wildcard ( * ) character for patients with bleeding peptic ulcers after endoscopic haemostasis. The related articles function was also used to broaden the search, and the computer search was supplemented with manual searches of reference lists for all retrieved original articles and review articles, primary studies and abstracts from meetings, to identify other studies not found in the computer search. Finally, only randomized controlled trials (RCTs) were given full consideration for analysis. Authors of relevant abstracts were contacted to obtain any unpublished data (if available). When the results of a single study were reported in more than one publication, only the most recent and complete data were included. Eligibility criteria All included clinical RCTs assessed the clinical effectiveness of oral PPIs vs. intravenous PPIs in patients older than 18 years with symptoms and signs of upper gastrointestinal bleeding, such as haematemesis, melena or the presence of blood in the nasogastric tube lavage. High-risk peptic ulcer bleeding was defined as active bleeding (Forrest IA, IB) or having a nonbleeding protuberant vessel (Forrest IIA) [22]. Haemostasis interventions by endoscopic therapy, haemoclips or heater probe were performed within 24 h of admission, with or without endoscopic injection. Exclusion criteria varied between studies but included the following: patients who were pregnant; did not obtain initial haemostasis with endoscopic therapy; had a history of chronic liver disease and portal hypertension; had a gastroduodenal malignancy; had undergone gastric surgery; had known adverse drug reactions to the trial drugs or were currently using antisecretory drugs, histamine type 2 receptor antagonists or PPIs; did not give written informed consent; had bleeding tendency; or had used PPIs within 14 days of enrolment. In addition, nonhuman studies, non-experimental trials, review articles, editorials, letters/case reports and articles not reporting the outcomes of interest were excluded from the current meta-analysis. Data extraction and quality assessment Two reviewers (JZX and JHS) independently considered the eligibility of potential abstracts and titles. Retrieval strategies were refined with a smaller set of reports. When there was a disagreement about a study or a lack of information for an accurate assessment of eligibility, the study was carried to the full-text stage for evaluation. To ensure homogeneity of data collection and to rule out any subjective influence in data Br J Clin Pharmacol (2016) 82 880 889 881

Z. Jian et al. gathering and entry, data were extracted independently and in duplicate by another two reviewers (MTT and YZ), and discrepancies were resolved by iteration, discussion and reaching a consensus. For each RCT, the following data were extracted: the baseline characteristics of number of patients, age, gender ratio, ulcer size, successful endoscopic therapy history, Forrest classification [stigmata of haemorrhage, a classification of upper gastrointestinal haemorrhage used for the purposes of comparison and in selecting patients for endoscopic treatment: Forrest I: acute haemorrhage (Forrest IA, spurting haemorrhage; Forrest IB, oozing haemorrhage); Forrest II: signs of recent haemorrhage (Forrest IIA, visible vessel; Forrest IIB, adherent clot; Forrest IIC, flatpigmentedhaematinonulcer base); Forrest III: lesions without active bleeding (lesions without signs of recent haemorrhage or fibrin-covered clean ulcer base)] and medication [22]. The qualities of the included RCTs were assessed by the Cochrane Risk of Bias Tool [23]. We reached complete concordance for all variables assessed. Moreover, authors of included published studies were contacted whenever we found that data essential for the meta-analysis were missing or unclear. The effects of oral PPIs vs. intravenous PPI on rebleeding, transfusion requirements, length of hospital stay and mortality within 30 days of bleeding peptic ulcers were pooled from included RCTs. Data synthesis and analysis We performed the meta-analysis using standard methods to evaluate the overall effect of oral and intravenous PPIs on recurrent bleeding, mortality, the need for blood transfusion and length of hospital stay according to an intent-to-treat (ITT) principle [23]. The reported risk ratio (RR) and 95% confidence interval (CI) were used in the analysis. Medians were converted to means using the technique described by Hozo et al. [24] The fixed-effect model (by the application of the generalized inverse variance method) was first used to pool the results; this assumes that all the studies share the same common (fixed or nonrandom) effect size. Variance was used to calculate the weight of each study. The standard heterogeneity test statistic, I 2, was used to assess the consistency of the effect sizes, which indicates the percentage of the variability in effect estimates that is due to true between-study variance rather than within-study variance. Heterogeneity was considered not to be statistically significant when the Cochrane Q test P value was more than 0.1. In cases of heterogeneity, a meta-analysis was performed, applying the random-effects model, which assumes that studies do not have the same effect size and assigns a weight to each study, taking into account both within- and between-study variance based on the method of DerSimonian and Laird [25]. In addition, an I 2 valueoflessthan25%wasdefined as representing low heterogeneity, a value between 25% and 50% was defined as moderate heterogeneity and a value of greater than 50% was defined as high heterogeneity [23]. Subgroup analyses, which considered more homogeneous studies, were performed to identify subsets of patients more likely to benefit from this treatment and to assess the efficacy of different studies. To determine the extent to which the combined risk estimate might be affected by individual studies, sensitivity analysis was performed by consecutively omitting every study from the meta-analysis (leave-one-out procedure). The mixed-effect model was applied to obtain summary effects within and across subgroups, whereas subgroups were also compared by means of the I 2 statistic [26]. Funnel plots were used to screen for publication bias [27]. Meta-analysis was conducted using the Review Manager (RevMan) Meta-Analysis software, version 5.1.6, and 95% CIs were calculated as estimates of precision for RR. The statistical tests were two sided, and P values <0.05 were considered to be statistically significant [28]. Results Study characteristics Table 1 lists the baseline characteristics of the seven included RCTs (a flowchart of publication search and selection is presented in Figure 1). All were single-centre studies [19, 29 34], with no significant difference between the groups in demographic information. The total number of patients per study ranged from 25 to 244. The majority of the patients were male and were randomized to receive oral or intravenous PPIs using a random number table or a computer-generated sequence, or based on even and odd days of the month [33]. Initial endoscopic haemostasis was defined as no visible haemorrhage with observation for 3 min. Ultimate haemostasis was defined as no rebleeding within 14 days after endoscopic therapy. Rebleeding was concluded if active bleeding, fresh blood or blood clots were found by emergent endoscopy, or if unstable vital signs, continuous tarry, bloody stool or a drop in haemoglobin level > 20 g l 1 within 24 h were noted. Severity of bleeding was assessed by the Rockall scoring system in both groups [35]. A blood transfusion was given if the haemoglobin level decreased to lower than 90 g l 1 or if the patient s vital signs deteriorated. If a state of shock occurred, blood was transfused independently of haemoglobin levels. The patient s clinical status was monitored after discharge by telephone conversation if any rebleeding or death occurred within 30 days. It should be emphasized that most physicians do not prefer to administer intravenous PPIs in patients with low-risk ulcers, as reported in the study by Yilmaz et al. [30]. The other included RCTs all involved enrolled patients with high-risk bleeding peptic ulcers after successful endoscopic interventions. Study quality assessment Figure 2 summarizes the possible risks of bias of the trials included in the meta-analysis. Selective reporting, baseline imbalance and sources of finding bias were avoided in all RCTs. Generation of adequate sequence was not reported in two studies [29, 31], and concealment of allocation was not fully implemented in another two trials [33, 34]. Sample size estimation was performed in three studies [19, 32, 34]. Yilmaz et al. conducted the RCT in a double-blind manner as all treatment assignments were revealed at the end of the study. In that study, a person outside the study staff placed the two drug formulations into sealed, opaque envelopes and coded them based on random table numbers. In the trial by Sung et al., study medications were placed in sealed, consecutively numbered packages which would only be opened after informed consent was obtained by an endoscopist or research 882 Br J Clin Pharmacol (2016) 82 880 889

Oral vs. intravenous PPI in bleeding peptic ulcers Table 1 Baseline characteristics of the included RCTs Authors/ country Comparison No. of patients (male%) Age (years, SD) Ulcer size (cm, SD) Successful endoscopic therapy history* Forrest classification IA/IB IIA/IIB/IIC III Medication Jae et al. [29] ORP 19(NA) NA NA Yes 6 13 0 Pantoprazole 40 mg, po, bid for 5 days /South Korea (2006) IVP 19(NA) NA NA Yes 4 15 0 Pantoprazole 80 mg, IV drip, qid for 3 days + pantoprazole 40 mg, po, qid for 8 weeks Yilmaz et al. [30] ORP 99(67) 52.8(19.6) 1.06(0.6) No 0 37 62 Omeprazole 40 mg, po, bid for 3 days + omeprazole 40 mg, po, qid for 6 weeks /Turkey (2006) IVP 112(71) 52.7(17.1) 1.05(0.4) No 0 30 82 Omeprazole 80 mg, IV drip, qid for 3 d + omeprazole 40 mg, po, qid for 6 weeks Bajaj et al. [31] ORP 12(50) 59.5(19.4) NA Yes 3 5 4 Pantoprazole 80 mg, po, bid for 3 d + pantoprazole 40 mg, po, bid for 30 days /United States (2007) IVP 13(77) 66.2(6.2) NA Yes 4 4 5 Pantoprazole 80 mg, IV drip, qid for 3 d + pantoprazole 40 mg, po, bid for 30 days Tsai et al. [32] ORP 78(74) 67.9(15.2) 1.12(0.4) Yes 33 44 0 Rabeprazole 20 mg, po, bid for 3days + rabeprazole 20 mg, po, qid for 2 months /Taiwan (2008) IVP 78(71) 69.4(15.0) 1.06(0.4) Yes 31 47 0 Omeprazole 40 mg, IV drip, bid for 3 days + rabeprazole 20 mg, po, qid for 2 months/esomeprazole 40 mg, po, qid for 2 months Mostaghni et al. [33] ORP 44(75) 57.3(16.5) NA Yes 14 30 0 Omeprazole 40 mg, po, bid for 3 days + omeprazole 20 mg, po, qid for 30 days Iran (2011) IVP 41(73) 61.7(17.2) NA Yes 12 29 0 Pantoprazole 80 mg, IV drip, qid for 2 3 days + omeprazole 20 mg, po, qid for 30 days Yen et al. [34] ORP 50(68) 62.7(16.3) 1.60(1.4) Yes 22 28 0 Lansoprazole 30 mg, po, qid for 3 days + lansoprazole 30 mg, po, qid for 2 months Taiwan (2012) IVP 50(74) 65.0(15.6) 1.40(1.4) Yes 21 29 0 Esomeprazole 40 mg, IV drip, qid for 3 days + esomeprazole 40 mg, po, qid for 2 months Sung et al. [19] ORP 126(76) 63.8(17.0) 2.00(12.7) Yes 55 71 0 Placebo, IV drip, qid for 3 days + esomeprazole 40 mg, po, bid for 27 days Hong Kong (2014) IVP 118(72) 64.3(15.5) 2.00(13.6) Yes 51 67 0 Esomeprazole 80 mg, IV drip, qid*3 days + placebo, po, bid for 27 days *Endoscopic successful haematemesis is considered successful when active bleeding (Forrest IA and IB) was stopped. For nonbleeding patients (Forrest IIA and IIB), the end point of endoscopy haematemesis was the successful application of haemoclips or a heater probe on the bleeding vessel after the removal of blood clot at the ulcer base. Stigmata of haemorrhage, a classification of upper gastrointestinal haemorrhage used for purposes of comparison and in selecting patients for endoscopic treatment: Forrest I: acute haemorrhage (Forrest IA, spurting haemorrhage; Forrest IB, oozing haemorrhage); Forrest II: signs of recent haemorrhage (Forrest IIA, visible vessel; Forrest IIB, adherent clot; Forrest IIC, flat pigmented haematin on ulcer base); Forrest III: lesions without active bleeding (lesions without signs of recent haemorrhage or fibrin-covered clean ulcer base). Ulcer size >2 cm (with its percentage in each group in parentheses). Bid, twice daily; IV, intravenous; IVP, intravenous proton pump inhibitor; NA, not available; ORP, oral proton pump inhibitor; po, orally; qid, four times daily; SD, standard deviation. Br J Clin Pharmacol (2016) 82 880 889 883

Z. Jian et al. Figure 1 Flowchart of publication search and selection nurse [19]. Other studies did not specify the blinding manner. In addition, ITT analysis was only applied by Sung et al.; however, their study was terminated prematurely owing to recruitment difficulties. Meta-analysis As shown in Figure 3, similar pooled outcome measures were demonstrated between the two groups in terms of oral PPIs vs. intravenous PPIs in the rate of recurrent bleeding within a 30- day follow-up period (RR = 0.90; 95% CI: 0.58, 1.39; P = 0.62; I 2 = 0%). In subgroup analysis, there was no significant difference between the oral and intravenous PPI groups in the rate of recurrent bleeding within 72 h (2.4% vs. 5.1%,P =0.26) and 7 days (5.6% vs.6.8%,p = 0.68) [19]. Two studies reported the 15-day rebleeding result, and a nonsignificant difference pooled outcome was also demonstrated (RR = 1.07; 95% CI: 0.55, 2.10; P =0.84;I 2 = 0%) [32, 34]. In terms of the rate of mortality, both oral and intravenous PPIs showed similar outcomes, and the pooled RR was 0.88 (95% CI: 0.29, 2.71; P = 0.82), with a null heterogeneity (I 2 =0%)(Figure4).Likewise, no significant difference was detected in the need for blood transfusion or length of hospital stay, and the pooled mean differences were 0.14 (95% CI: 0.39, 0.12; P =0.29; I 2 = 32%) and 0.60 (95% CI: 1.42, 0.23; P = 0.16; I 2 = 79%), respectively (Figures 5, 6). Additionally, with only seven studies, it is difficult to interpret publication bias for the present meta-analysis. However, potential missing studies appeared to be those with statistically significant results, which is highly unlikely. Therefore, publication bias is unlikely to have been a concern in the present review (Figure 7). Sensitivity analysis also confirmed the stability of the pooled results. Discussion Based on these studies, we conducted the present metaanalysis to clarify the clinical efficacy of high-dose oral and intravenous PPIs after successful endoscopic therapy for patients with bleeding peptic ulcers. The most important finding in the present study was that adjuvant pharmacotherapy of oral administration of PPI was as effective as that of intravenous PPI in controlling bleeding peptic ulcers. Both oral and intravenous PPIs achieved similar success in inducing haemostasis in recurrent bleeding at 72 h, 7 days, 15 days and 30 days of follow-up after the administration of standard endoscopic therapy. Other clinical outcomes, including the need for blood transfusion, surgery, length of hospital stay and mortality, were all comparable. Rebleeding after initial control of acute nonvariceal upper gastrointestinal bleeding is an important clinical issue that continues to be a significant problem, requiring resuscitative and endoscopic therapy, and possibly resulting in end-organ dysfunction and death [36, 37]. Endoscopic therapy 884 Br J Clin Pharmacol (2016) 82 880 889

Oral vs. intravenous PPI in bleeding peptic ulcers Figure 2 Risks of bias in the trials included in the meta-analysis decreases, but does not eliminate, the risk of adverse outcomes for peptic ulcer bleeding. In addition, maintenance of an intragastric ph of > 6 has been considered to result in a lower rebleeding rate, so the use of PPIs following endoscopic therapy for bleeding peptic ulcers can help to promote platelet aggregation, stabilize blood clots and prevent fibrinolysis [7, 9, 38]. In spite of this evidence, the optimal route and dosage of administration has remained controversial, although several recent studies have demonstrated the efficacy of intravenous PPIs in reducing the adverse outcome of peptic ulcer bleeding [39, 40]. The administration of intravenous PPIs requires nursing supervision and hospital admission, leading to high costs, while oral administration is attractive due to widespread availability, ease of implementation and cost-effectiveness. With this in mind, it would be reasonable to prescribe an oral PPI to patients with high-risk bleeding ulcers, provided that it is as effective as its intravenous counterpart. Gastric ph was used as a marker for the effectiveness of both oral and intravenous PPIs in the included RCTs. Based on previous studies showing that high doses of intravenous PPI followed by continuous infusion are able to sustain a higher intragastric ph, current guidelines suggest this clinical pathway as standard adjuvant pharmacotherapy for bleeding Figure 3 Oral proton pump inhibitor (PPI) vs. intravenous PPI in the rate of recurrent bleeding within a 30-day follow-up period. CI, confidence interval; IVP, intravenous PPI; ORP, oral PPI; M-H, Mantel-Haenszel method Br J Clin Pharmacol (2016) 82 880 889 885

Z. Jian et al. Figure 4 Oral proton pump inhibitor (PPI) vs. intravenous PPI in the rate of mortality within a 30-day follow-up period. CI, confidence interval; IVP, intravenous PPIs; ORP, oral PPIs; M-H, Mantel-Haenszel method Figure 5 Oral proton pump inhibitor (PPI) vs. intravenous PPI in blood transfusion within a 30-day follow-up period. CI, confidence interval; IV, intravenous; IVP, intravenous PPI; ORP, oral PPI Figure 6 Oral proton pump inhibitor (PPI) vs. intravenous PPI in length of hospital stay. CI, confidence interval; IV, intravenous; IVP, intravenous PPI; ORP, oral PPI peptic ulcers, especially in Western countries [28, 41]. Although high doses of intravenous PPI have been demonstrated to be superior to placebo [42], currently available evidence does not indicate that oral administration is inferior to intravenous administration with regard to the clinical outcome of bleeding peptic ulcers in patients following endoscopic therapy. The benefits of PPIs appear to be independent of the route of administration and dose, as reported by Andriulli et al., who evaluated 35 RCTs comparing PPI vs. placebo or histamine type 2 receptor antagonist [16]. In addition, there is no evidence to indicate that bleeding, surgery or mortality would be influenced by the route of PPI administration, as reported in the meta-analysis of Leontiadis et al. [43]. More recently, Javid et al. demonstrated that there is no significant difference among various PPIs, administered via different routes, on raising gastric ph above 6 for 72 h after successful endoscopic haemostasis, and high doses of various oral and intravenous PPIs are equivalent in their ability to suppress gastric acid secretion [44]. Furthermore, a similar effectiveness between oral and intravenous PPIs in raising intragastric ph has been demonstrated. After ingestion, the effect of an oral PPI would initiate 1 h, with the maximum plasma concentration achieved 2 3 h later; thus, oral administration is associated with high bioavailability [45]. It seems that oral PPIs have substantially equivalent efficacy to intravenous PPIs in decreasing the adverse outcomes of highrisk bleeding ulcers, especially rebleeding. It has also been shown that high-dose oral PPI following endoscopic treatment significantly decreases rebleeding, and probably mortality, when compared with placebo [39]. From the included studies, the overall rebleeding rate reported by Tsai et al. [32]appeared to be higher in those receiving PPIs alone than in those receiving endoscopic intervention and PPIs; this may be because they adopted epinephrine injection as the primary haemostatic 886 Br J Clin Pharmacol (2016) 82 880 889

Oral vs. intravenous PPI in bleeding peptic ulcers Figure 7 Symmetry of Funnel plot depicted little publication bias in trials included in the meta-analysis measure, which may be considered suboptimal for high-risk bleeders [46]. Tsai et al. had not expected to find that epinephrine injection was the best available therapy [32]. However, their study revealed that oral and intravenous PPIs were similarly effective as adjuvant pharmacotherapy, even if the endoscopic therapy was limited to epinephrine injection. Notably, they conducted a head-to-head trial comparing a high dose of oral rabeprazole with a regular dose of intravenous omeprazole (40 mg intravenous infusion every 12 h), the latter being considered (in spite of controversial results) to be more effective [32]. Therefore, Mostaghi et al. carried out a study to compare oral and intravenous PPIs directly [33]. In the latter research, they not only achieved a lower rate of rebleeding in the omeprazole group, but also revealed that high-dose oral omeprazole (40 mg twice daily) is equally effective as high-dose intravenous pantoprazole (8 mg every hour) in reducing recurrent bleeding, the need for blood transfusion, length of hospital stay and mortality after successful endoscopic haemostasis. Similar intragastric ph, in spite of different routes of administration, may suggest similar clinical outcomes. Yen et al. suggested that high doses of PPI (rather than regular doses) via the oral route may achieve comparable clinical outcomes to those found with high-dose intravenous PPIs [34]. Nevertheless, PPI dosage effects as they relate to clinical efficacy are another unsettled issue in the management of patients with peptic ulcer bleeding. The focus of the present study was to investigate the effects of route rather than the dosage. Hopefully, well-designed future studies will help to resolve the PPI dosage controversy. A previous meta-analysis reported that PPI therapy was effective only in patients with high-risk stigmata for rebleeding, which led Yilmaz et al. to design their study to make a comparison between oral and intravenous omeprazole in patients with bleeding peptic ulcers without high-risk stigmata [30, 47]. In doing so, they added stronger studysupported evidence to the literature that patients with bleeding ulcers and low-risk stigmata can be treated effectively with oral omeprazole. The present meta-analysis showed that, compared with intravenous PPIs, the oral route of administration of PPIs is less challenging to implement, does not require frequent monitoring for infusion site reactions and can be more economical, as demonstrated by the lower cost of the oral administration method and the earlier discharge of patients receiving oral PPIs reported in the study by Yen et al. [34]. There were several limitations to the present study. First, some of the included RCTs were not designed as equivalence or non-inferiority studies, which in retrospect would have been a more favourable study design. Second, the difficulty of planned patient enrolment led some studies to stop prematurely. Third, a large number of patients dropped out owing to the strict exclusion criteria which were imposed on various factors, resulting in the fact that the predefinedsamplesizeineachstudymightnot have been large enough for detecting small differences. In conclusion, the present results suggest that oral PPIs are a feasible, safe and effective alternative to intravenous PPIs in terms of rebleeding, the need for emergency surgery, transfusion requirements, length of hospital stay and mortality in patients with bleeding peptic ulcers. Oral PPIs may be able to replace intravenous PPIs as the treatment of choice in peptic ulcer bleeding. Acknowledgements This study was supported by grants from the 2015 Guangdong Medical Science and Technology Research Fund (A2015476) and the 2015 Guangdong General Hospital, Guangdong Academy of Medical Sciences Doctoral Fund. Competing Interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: YZ had support from 2015 Guangdong Medical Science and Technology Research Fund (A2015476) and 2015 Guangdong General Hospital, Guangdong Academy of Medical Sciences Doctoral Fund for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. References 1 Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc 1981; 27: 80 93. 2 RockallTA,LoganRFA,DevlinHB,Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995; 311: 222 6. 3 Cook DJ, Guyatt GH, Salena BJ, Laine LA. Endoscopic therapy for acute nonvariceal upper gastrointestinal hemorrhage: a metaanalysis. Gastroenterology 1992; 102: 139 48. Br J Clin Pharmacol (2016) 82 880 889 887

Z. Jian et al. 4 British Society of Gastroenterology Endoscopy Committee. Nonvariceal upper gastrointestinal haemorrhage: guidelines. Gut 2002; 51 (Suppl. 4): iv1 6. 5 Christensen A, Bousfield R, Christiansen J. Incidence of perforated and bleeding peptic ulcers before and after the introduction of H2- receptor antagonists. Ann Surg 1988; 207: 4 6. 6 Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol 2009; 7: 33 47. 7 Marmo R, Rotondano G, Piscopo R, Bianco MA, D Angella R, Cipolletta L. Dual therapy versus monotherapy in the endoscopic treatment of highrisk bleeding ulcers: a meta-analysis of controlled trials. Am J Gastroenterol 2007; 102: 279 89. 8 Chung IK, Kim EJ, Lee MS, Kim HS, Park SH, Lee MH, Kim SJ, Cho MS, Hwang KY. Endoscopic factors predisposing to rebleeding following endoscopic hemostasis in bleeding peptic ulcers. Endoscopy 2001; 33: 969 75. 9 Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effects of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor to prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74: 38 43. 10 Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, Chan FK, Ng EK, You JH, Lee CW, Chan AC, Chung SC. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343: 310 6. 11 LinHJ,LoWC,LeeFY,PerngCL,TsengGY.Aprospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998; 158: 54 8. 12 Palmer K Non-variceal upper gastrointestinal haemorrhage: guideline. Gut 2002; 51 (Suppl. 4): 1 6. 13 Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003; 139: 843 57. 14 Khuroo MS, Yattoo G, NJavid G, Khan BA, Shah AA, Gulzar GM, Sodi JS. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997; 336: 1054 8. 15 Javid G, Masoodi I, Zargar SA, Khan BA, Yatoo GN, Shah AH, Gulzar GM, Sodhi JS. Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am J Med 2001; 111: 280 4. 16 Andriulli A, Annese V, Caruso N, Pilotto A, Accadia L, Niro AG, Quitadamo M, Merla A, Fiorella S, Leandro G. Proton-pump inhibitors and outcome of endoscopic hemostasis in bleeding peptic ulcers: a series of meta-analyses. Am J Gastroenterol 2005; 100: 207 19. 17 Lin HJ, Lo WC, Cheng YC, Perng CL. Role of intravenous omeprazole in patients with high-risk peptic ulcer bleeding after successful endoscopic epinephrine injection: a prospective randomized comparative trial. Am J Gastroenterol 2006; 101: 500 5. 18 Triadafilopoulos G Review article: the role of antisecretory therapy in the management of non-variceal upper gastrointestinal bleeding. Aliment Pharmacol Ther 2005; 22 (Suppl. 3): 53 8. 19 Sung JJ, Suen BY, Wu JC, Lau JY, Ching JY, Lee VW, Chiu PW, Tsoi KK, Chan FK. 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. 20 Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Alimentary Pharmacol Ther 2013; 7: 721 8. 21 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: W65 94. 22 Heldwein W, Schreiner J, Pedrazzoli J, Lehnert P. Is the Forrest classification a useful tool for planning endoscopic therapy of bleeding peptic ulcers? Endoscopy 1989; 21: 258 62. 23 Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011 [online]. Available at at: http:// www.cochrane-handbook.org (last accessed 26 December 2014). 24 Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005; 5: 13. 25 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177 88. 26 Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Subgroup analyses. In: Introduction to Meta-analysis. Chichester: Wiley, 2009; 149 86. 27 Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991; 337: 867 72. 28 Barkun AN, Bardou M, Kuipers EJ, Sung J, Hunt RH, Martel M, Sinclair P; International Consensus Upper Gastrointestinal Bleeding Conference Group. International consensus recommendations on the management of patients with nonvaricealupper gastrointestinal bleeding. Ann Intern Med 2010; 152: 101 13. 29 Jae YJ, Kwang RJ, Young H. A comparison of the effect of highdose oral and intravenous proton pump inhibitor on the prevention of rebleeding after endoscopic treatment of bleeding peptic ulcers. Korean J Gastrointest Endosc 2006; 22: 6 11. 30 Yilmaz S, Bayan K, Tuzun Y, Dursun M, Canoruc F. A head to head comparison of oral vs. intravenous omeprazole for patients with bleeding peptic ulcers with a clean base, flat spots and adherent clots. World J Gastroenterol 2006; 12: 7837 43. 31 Bajaj JS, Dua KS, Hanson K, Presberg K. Prospective, randomized trial comparing effect of oral versus intravenous pantoprazole on rebleeding after nonvariceal upper gastrointestinal bleeding: a pilot study. Dig Dis Sci 2007; 52: 2190 4. 32 TsaiJJ,HsuYC,PerngCL,LinHJ.Oralorintravenousproton pump inhibitor in patients with peptic ulcer bleeding after successful endoscopic epinephrine injection. Br J Clin Pharmacol 2008; 67: 326 32. 33 Mostaghi AA, Hashemi SA, Heydari ST. Comparison of oral and intravenous proton pump inhibitor on patients with high risk bleeding peptic ulcers: a prospective, randomized, controlled clinical trial. Iran Red Crescent Med J 2011; 13: 458 63. 34 Yen HH, Yang CW, Su WW, Soon MS, Wu SS, Lin HJ. Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy. BMC Gastroenterol 2012; 12: 66. 35 Rockall TA, Logan RFA, Devlin HB. Risk assessment following acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316 21. 36 LauJY,SungJJ,LamYH,ChanAC,NgEK,LeeDW,ChanFKSRC, Chung SC. Endoscopic retreatment compared with surgery in 888 Br J Clin Pharmacol (2016) 82 880 889

Oral vs. intravenous PPI in bleeding peptic ulcers patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999; 340: 751 6. 37 Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1995; 90: 206 10. 38 Cheng HC, Sheu BS. Intravenous proton pump inhibitors for peptic ulcerbleeding: clinical benefits and limits. World J Gastrointest Endosc 2011; 3: 49 56. 39 Bardou M, Toubouti Y, Benhaberou-Brun D, Rahme E, Barkun AN. Meta-analysis proton pump inhibition in high-risk patients with acute peptic ulcer bleeding. Aliment Pharmacol Ther 2005; 21: 677 86. 40 Leontiadis GI, Howden CW. The role of proton pump inhibitors in the management of upper gastrointestinal bleeding. Gastroenterol Clin North Am 2009; 38: 199 213. 41 SungJJ,ChanFK,ChenM,ChingJY,HoKY,KachintornU,Kim N,LauJY,MenonJ,RaniAA,ReddyN,SollanoJ,SuganoK,Tsoi KK, Wu CY, Yeomans N, Vakil N, Goh KL; Asia-Pacific Working Group. Asia-Pacific Working Group consensus on non-variceal upper gastrointestinal bleeding. Gut 2011; 60: 1170 7. 42 Sung JJ, Barkun A, Kuipers EJ, Mössner J, Jensen DM, Stuart R, Lau JY, Ahlbom H, Kilhamn J, Lind T; Peptic Ulcer Bleed Study Group. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding: a randomized trial. Ann Intern Med 2009; 150: 455 64. 43 GI L, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2006; 1: CD002094. 44 Javid G, Zargar SA, U-Saif R, Khan BA, GN Y, AH S, Gulzar GM, JS S, MA K. Comparison of p.o. or i.v. proton pump inhibitors on 72-h intragastric ph in bleeding peptic ulcer. J Gastroenterol Hepatol 2009; 24: 1236 43. 45 LaineL,ShahA,BemanianS.IntragastricPHwithoralvs. intravenous bolus plus infusion proton pump inhibitor therapy in patients with bleeding ulcers. Gastroenterology 2008; 134: 1836 41. 46 Calvet X, Vergara M, Brullet E, Gisbert JP, Campo R. Addition of a second endoscopic treatment following epinephrine injection improves outcome in high-risk bleeding ulcers. Gastroenterology 2004; 126: 441 50. 47 Khuroo MS, Khuroo MS, Farahat KL, Kagevi IE. Treatment with proton pump inhibitors in acute non-variceal upper gastrointestinal bleeding: a meta-analysis. J Gastroenterol Hepatol 2005; 20: 11 25. Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher s web-site: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12866/suppinfo. S1 PRISMA 2009 Checklist Br J Clin Pharmacol (2016) 82 880 889 889