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Aim: Present meta-analysis aims to evaluate studies of low dose vs high-dose PPI post-endoscopic hemostasis, additionally including the newly published RCTs and to conclude if low-dose PPI can generate the comparable results as high-dose PPI.
Methods: In keeping with identification of suitable trials, the electronic databases Pubmed, Medline, Cochrane Library, and the Embase. All randomized control trials concerning low versus high dose PPI administration post-endoscopy haemostasispublished until 12/2014 were identified. Primary outcomes were rebleeding rates, need for surgical intervention and mortality.
Results: Studies includeda total of 1651 participants. There were significantly less cases of rebleeding in the low-dose PPI treatment arm (p=0.003). All but one study provided data concerning need for Surgical Intervention and Mortality. The respective effect sizes were [OR, 95% CI: 1.35, 0.72-2.53] and [OR, 95% CI: 1.20, 0.70-2.05]. Both treatment arms were comparable considering the aforementioned outcomes (p=0.35 and p=0.51 respectively). Meta-regression analysis likewise unveiled comparable outcomes between studies using pantoprazole versus lansoprazole concerning all three outcomes [Rebleeding (p= 0.944), Surgical intervention (p= 0.884) and Mortality (p=0.961).
Conclusions: A low-dose PPI treatment is equally effective as a high-dose PPI treatment succeeding endoscopic seizing of bleeding. We anticipate the completion of more high quality RCT’s that will embrace distinct ethnicities, standardized endoscopic diagnosis and management, double-blind strategies, and appraisal of results working specific standards over clear-cut follow-up periods.
Keywords: High dose PPI, Low dose PPI, evidence based medicine; systematic review; meta-analysis; ulcer rebleeding.
Emergency upper gastrointestinal hemorrhage is a frequent and a substantial situation in clinical practice (1). The fundamental management entails resuscitation and endoscopic therapy, but recurrence yet happens following primary control of hemorrhage (2). At present, proton pump inhibitors (PPIs) for endoscopic hemostasis is the customary treatment regimen, and convincing guidelines, consensus-generated, have endorsed the use of a high-dose PPI regimen (80 mg bolus followed by IV administration of 8 mg/h for 72 h) after arrest of bleeding for enhanced-risk upper gastrointestinal recurrence of hemorrhage (3, 4). The conceivable clinical advantage of the high-dose regimen is to progress clot firmness by maintaining the gastric pH more than 6 (5, 6). Nevertheless, when high-dose PPI is contrasted to a low-dose PPI administration after initial control of hemorrhage is accomplished, certain clinical trials (7, 8) and two older meta-analyses (9, 10) conveyed comparable results in recurrent hemorrhage rate and the demand for surgical management between the high- and low-dose PPI treatments.
Three adequately powered RCTs have been released (11-13) after the publication of the aforementioned meta-analyses. This meta-analysis aims to evaluate RCT’s of low dose vs high-dose PPI after endoscopic bleeding arrest by additionally including the newly published RCTs and to conclude if low-dose PPI regimen can generate comparable results as the high-dose regimen after initial hemostasis by endoscopists.
All RCT’s regarding low versus high dose PPI administration post-endoscopy haemostasis were identified (2, 7, 8, 11-17). In keeping with identification of suitable studies, the electronic databases Medline, Embase, Pubmed and the Cochrane Library were utilized to identify articles from 2000 to 2014 in the English language literature that encompassed the succeeding terms and/or amalgamations in their keyword lists, abstracts or titles: RCT, double-blind, dexlansoprazole, omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, high dose PPI, low dose PPI, PPI, and bleeding. The last search was done in December 2014.
Where it was appropriate the afore-mentioned terms were inserted in “[MESH]” (Pubmed and the Cochrane Library) or else the terms were joint with “AND/OR” and asterisks.
The outline for this cyclic search is depicted in Figure 1.
Study was approved by the Ethics committee of Comenius University, Bratislava and was conducted in conformity with the ethics of ‘Good Clinical Practice’.
Two authors (G.CH, G.S) autonomously chose studies to include and exclude and reached consensus when they did not come to an agreement in the original assignment. The following variables concerning studies were collected: journal and year of publication, country of derivation, authors, duration of trial, participant characteristics and data in regard with rebleeding, need for surgery and mortality.
Trials were encompassed under the subsequent criteria: a) RCT, b) contrasting high-dose versus low-dose PPI for post-endoscopy hemostasis for acute ulcer bleeding and c) disposal of satisfactory data (rebleeding, need for surgery and mortality). Successively, studies were excluded if the PPI treatment was commenced before endoscopic engagement and in case they had not been published (conference presentations). Duplicate publications were excluded, and when a study had material overlay with another, the more recent study was integrated to the analysis. High-dose PPI was taken into consideration if at minimum twice the low-dose of any of the PPIs administered during the 72 h succeeding post-endoscopy hemostasis.
Interventions and outcome definition
There was a noteworthy discrepancy in the definition of rebleeding. The difference between failed haemostasis and rebleeding was not distinctly defined. Four studies (2, 14, 15, 17) excluded patients from registration if they did not have spontaneous hemostasis or bleeding was not fostered via endoscopic methods. Consequently, haemorrhage after the primary endoscopic intervention could be considered as rebleeding. Actively bleeding patients were excluded in one study (16). Two studies (7, 8) did not explicitly dismiss patients with bleeding ulcer and in whom it could not be ceased by endoscopy. Udd et al (8) outlined rebleeding as recurrence of bleeding endoscopically documented or continuing haemorrhage requiring an emergency surgical procedure and excluded patients whom endoscopic therapy and operation failed to cure. Bajaj et al (7) excluded patients with copious bleeding causing unrelenting shock who were incapable of resuscitation without interventional radiology or surgery. Rebleeding was substantiated by endoscopy. Andriulli et al (14) performed selective sequential endoscopy in high-risk patients presented with ≥ 6 points graded by the Rockall scoring system.
Indication for surgery was failure to stop bleeding despite repeated endoscopy or radiologic intervention. Only Yüksel et al (17) stated that surgery was contemplated in cases of failure of the second endoscopic treatment. Whether radiologic intervention was considered as a surgical intervention was not evidently specified in studies.
Of 9 studies providing data for mortality, four studies (2, 11, 12, 17) did not declare the timing of assessment. Hsu et al (13) reported mortality within 14 days. Three studies (7, 8, 16) reported a 30-days mortality while Andriulli et al (14) reported only in-hospital mortality.
A meta-analysis (adhered to the QUOROM statement) (18, 19) was done for all RCTs comparing low dose versus high dose PPI after post-endoscopy hemostasis. The primary outcomes used for this study were: a) rebleeding b) need for surgery and c) mortality.
In order to protect analysis against false positive conclusions we pre-specified the use of pantoprazole versus lansoprazole as a covariate to be investigated by subgroup analysis or meta-regression
The reviewer level of agreement was assessed by the Maxwell test statistic and the generalized McNemar statistic. A fixed-effects model was used to calculate pooled estimates of outcomes though a randomized-effects model was used conferring the level of heterogeneity. Individual studies binary outcomes were gathered to calculate individual odds ratios with 95% confidence intervals using the Mantel-Haenszel test. To each total or subtotal the test for overall effect and the test for heterogeneity were provided. Cochrane Q tests and I2 statistics, correspondingly, were operated to assess statistical heterogeneity and inconsistency of treatment effects across trials (20). For Cochrane Q test statistical significance was specified at 0.10. To investigate the extent of inconsistency among outcomes of the studies I2 statistics were measured. The results were stated as a portion of total variation across studies owed by statistical heterogeneity noticeably than chance. A level of 0% designates that all variability in effect estimates is attributed to chance instead of statistical heterogeneity. A level beyond 50% designates considerable statistical heterogeneity.
Kendall’s Tau and Spearman Rank-Order Correlation tests were employed to ascertain the symmetry of the funnel plot (Effect vs. Variance) and detect any publication bias. The standardized effect size was drawn compared to the normal quantile values for visual inspection of possible publication bias in the normal quantile plot.
The magnitude of the publication bias was assessed by the Fail-Safe tests.
The effect of covariates on management outcomes was assessed by Metaregression.
Study quality assessment
the Jadad composite scale scored the quality assessment of the methodology of the studies integrated in the meta-analysis (24). Corresponding to this 5-point scale (0 point for “No”, 1 point for “Yes” for the succeeding factors: randomized study; randomization designated; double blind trial; double blinding designated; reference to withdrawals and dropouts) low-quality studies are attributed a score of ≤2 while the respective scores for high-quality studies are ≥3.
Maxwell test statistic was insignificant (p =0.851) demonstrating that reviewers did not differ significantly. The generalized McNemar test (p =0.57) showed that the concordance was spread evenly.
The baseline participant characteristics in the analyzed studies are synopsized in Table 1. The results of the included trials are depicted on Table 2. All ten studies provided data for rebleeding [OR, 95% CI: 1.55, 1.16-2.07]. There were significantly less cases of rebleeding in the low-dose PPI treatment arm (p=0.003) (Table 3, Figure 2). All but the study of Cheng et al (15) provided data concerning need for Surgical intervention and Mortality. The respective effect sizes were [OR, 95% CI: 1.35, 0.72-2.53] and [OR, 95% CI: 1.20, 0.70-2.05]. Both treatment arms were comparable considering the aforementioned outcomes (p=0.35 and p=0.51 respectively) (Table 3, Figure 2).
There was not Heterogeneity among studies considering all three outcomes. Normal quantile plots did not detect any obvious publication bias concerning all outcomes (Figure 3).
We utilized the fail-safe method (Rosenthal’s or Orwin’s Method) to calculate the number of future trials with a zero-mean effect size, essential to reduce the combined significance to a level (0.05). These tests disclosed that 9 studies to be needed to change our results concerning rebleeding, and 5 studies concerning need for Surgery. Considering the fact that there have been no further than 10 studies released over the past 14 years, it is extremely unlikely that such a bulky number of relevant trials would have gone unpublished or have been unexploited by our search approach.
Metaregression analysis also revealed that studies using pantoprazole versus lansoprazole were comparable to all three outcomes [Rebleeding (p= 0.944), Surgical intervention (p= 0.884) and Mortality (p=0.961) Table 4.
Summary of main results: High-dose PPIs do not deliver a greater efficiency to non–high-dose PPIs in decreasing the rates of rebleeding, surgical intervention, or mortality after post-endoscopic bleeding arrest. These outcomes did not change with the use of either pantoprazole or lansoprazole.
Overall completeness and applicability of evidence: Subsidiary evidence implies that PPI administration outcome may not be straightforwardly associated with intragastric pH. Udd et al (8) contrasted the influences of high- dose and low-dose omeprazole on gastric acidity in bleeding peptic ulcer managed via endoscopy. Authors discovered a significant difference in gastric pH comparing the two treatment arms on the initial two days of administration. Nevertheless, the difference recurrent haemorrhage rates between the two treatment arms was not statistically significant. Consequently, if gastric pH can operate as a consistent surrogate marker for satisfactory management is uncertain.
This analysis with fail-safe tests disclosed that 9 studies to be compulsory to change our results concerning rebleeding, and 5 studies concerning need for Surgery. Bearing in mind the fact that there have been no more than 10 RCTs published over the past 14 years, it is highly unlikely that such a large number of analogous studies would have been missed by our search.
Considering the quality of the evidence:Our study encompasses 10 RCTs. Seven out of 10 are of high quality (≥3) according to the Jadad classification (24). All but one study (7) were sufficiently powered to validate their results. There was notheterogeneity among studies with regard to each of the three outcomes. Normal quantile plots for inspection of publication bias concerning all three outcomes were normal. The distribution of effect sizes was similar to the distribution of normal quantiles.
Agreements and disagreements with other studies or reviews: A meta-analysis by Leontiadis et al (25) analyzed 24 RCT’s in which participants were provided with high-dose and non-high-dose PPIs. Rebleeding percentages and surgical management were significantly lessened in the high-dose and non-high-dose PPI arms in contrasted to participants who were administered placebo or H2-receptor antagonists. Nevertheless, meta-regression analysis revealed no association of PPI dose with treatment effects. Two meta-analyses (9, 10) have been published comparing low versus high PPI doses (administered after endoscopic hemostasis) in terms of rebleeding, need for surgery and mortality. In the meta-analysis of Wu et al (10) three of the included 9 studies were abstracts enhancing the possibility of selection bias. The meta-analysis by Wang et al (9) included 7 RCTs but the risk of bias was not provided for visual inspection in terms of funnel plots. Our results are in accordance with those of the aforementioned meta-analyses given the inclusion of additional three sufficiently powered RCTs. Besides the risk of bias is extensively analyzed both by statistical tests and visual inspection through normal quantile plots.
Potential biases in the review process: a)The time frame for recurrence of haemorrhage rates should be considered, since one study stated re-bleeding within the initial 72 h (17), one study stated re-bleeding within seven days (14), one study reported in-hospital only re-bleeding (8), one study stated re-bleeding within 14 days (13), and six studies stated re-bleeding within a month (2, 7, 11, 12, 15, 16). Results for re-bleeding should be unraveled with thoughtfulness, and additional subgroup analyses were not conducted in the present meta-analysis, b) Studies analyzed in the present meta-analysis were accomplished with diverging doses of PPI, various ethnicities with distinct preponderance of re-bleeding and fluctuating extent of related comorbidities and c) Analysis in the present meta-analysis was not completed in accordance to the intent-to-treat principle, with violations of this principle in four studies (2, 8, 14, 17). Yet, detailed data were deficient, and postulations were problematic to make.
In conclusion, a low-dose PPI is equally effective as a high-dose PPI administration succeeding endoscopic bleeding arrest in bleeding peptic ulcer patients. We anticipate the completion of more high quality RCT’s that will embrace distinct ethnicities, standardized endoscopic diagnosis and management, double-blind strategies, and appraisal of results working specific standards over clear-cut follow-up periods.
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