TITLE: Pre-Endoscopic Intravenous Proton Pump Inhibitors for … · Pre-Endoscopic Intravenous PPIs for Patients with Upper Gastrointestinal Bleeds 2 Response report12 13on pantoprazole

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TITLE: Pre-Endoscopic Intravenous Proton Pump Inhibitors for Emergency Department Patients with Upper Gastrointestinal Bleeds: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines

DATE: 05 February 2016

CONTEXT AND POLICY ISSUES

Upper gastrointestinal bleeding (UGIB) is a frequent cause of hospital admission.1 It is associated with substantial clinical and economic burden.2 UGIB is associated with morbidity and mortality. Mortality related to UGIB has been estimated to be 2% to 15%.3 The incidence of UGIB in the United States of America (USA) has been estimated as 48 to 160 events per 100,000 adults per year.3 UGIB results from various conditions and can be life-threatening.4 The causes for UGIB include peptic ulcer, arteriovenous malformation, Mallory-Weiss tear, aortoenteric fistula, esophageal varices, and malignancy.4,5 Peptic ulcer is the most common cause of UGIB in patients without known cirrhosis.4 Peptic ulcer is associated with risk factors such as advanced age; Helicobacter pylori infection; and use of nonsteroidal anti-inflammatory drugs and aspirin.4 It is estimated that 80% to 90% of all UGIB are non-variceal.6,7 Patients with UGIB typically present with symptoms of hematemesis (vomiting of blood or coffee-ground-like material) and/or, melena (dark, tarry stools).1,8 The initial management of patients with UGIB involves assessment of hemodynamic stability and the need for resuscitation.9 This information is used to assist in making decisions regarding triage, resuscitation, empiric medical therapy, and diagnostic procedures.8 Endoscopy is used with the aim of both diagnosis and when possible treatment.8 Drugs used for medical therapy include proton pump inhibitors (PPIs) and histamine receptor antagonist. PPIs include drugs such as esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. Proton pump inhibitors (PPIs) block the gastric enzyme, H2K-ATPase, and suppress gastric acid secretion.10 Inhibition of gastric acid secretion enhances healing of acid-related diseases such as peptic ulcer disease.10 It has been suggested that UGIB may be controlled by decreasing the amount of acid in the stomach.11 There is controversy regarding the usefulness of initial treatment with intravenous PPIs prior to endoscopy for managing patients with UGIB. It was apparent from a previous CADTH Rapid

Pre-Endoscopic Intravenous PPIs for Patients with Upper Gastrointestinal Bleeds 2

Response report12 on pantoprazole and a review13 on the management of patients with UGIB, that there were inconsistencies in the recommendations for the use of PPI prior to endoscopy. A Cochrane systematic review by Sreedharan et al.11 published in 2010, included six randomized controlled trials, and concluded that PPI administration prior to endoscopy in patients with UGIB significantly reduced the proportion of patients with stigmata of recent hemorrhage (SRH; active bleeding, adherent clot, or non-bleeding visible vessel). Though this pre-endoscopic PPI treatment reduces the requirement for endoscopic therapy during the index endoscopy there was no evidence that this early PPI treatment affects clinically important outcomes such as mortality, re-bleeding, and need for surgery.11 There remains a lack of definitive data to recommend the correct route of administration, best-practice dosing, as well as suggested timing of initiation of PPI treatment in UGIB.3,14 The purpose of this report is to review the clinical efficacy of pre-endoscopic intravenous proton pump inhibitors (PPI) for patients with UGIB and to review the evidence-based guidelines regarding the use of proton pump inhibitors before endoscopy in patients with UGIB. RESEARCH QUESTIONS

1. What is the clinical effectiveness of intravenous proton pump inhibitors initiated before

endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department?

2. What is the comparative clinical effectiveness of continuous versus intermittent dosing of

intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department?

3. What is the cost-effectiveness of intravenous proton pump inhibitors initiated before

endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department?

4. What are the evidence-based guidelines regarding the use of proton pump inhibitors

before endoscopy in patients with upper gastrointestinal bleeds? KEY FINDINGS

One observational study on patients with upper gastrointestinal bleeding who received either proton pump inhibitor infusion or saline infusion before endoscopy showed that overall there were no statistically significant differences between the two modalities with respect to endoscopic signs of bleeding, recurrent bleeding, emergency surgery, or mortality. No relevant studies, on the comparative clinical effectiveness of continuous versus intermittent dosing of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department, were identified. No relevant studies, on the cost-effectiveness of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department, were identified. Recommendations regarding the use of proton pump inhibitors before endoscopy in patients with upper gastrointestinal bleeding were inconsistent. Two guidelines recommended pre-


endoscopic PPI, one guideline recommended pre-endoscopic PPI in case of delayed endoscopy and one guideline did not recommend pre-endoscopic PPI. METHODS

Literature Search Methods

A limited literature search was conducted on key resources including Ovid Medline, Ovid Embase, PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit retrieval by publication type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and January 4, 2016. Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria Population Q1 to 3: Adult patients with an upper gastrointestinal bleed (e.g.,

peptic ulcer bleed) presenting to the emergency department, excluding patients with variceal bleeds

Q4: Same as above without restriction to emergency department setting

Intervention Q1, 3, and 4: Intravenous (IV) proton pump inhibitors (PPIs) (e.g., pantoprazole, omeprazole, rabeprazole, lansoprazole, esomeprazole) administered prior to endoscopy

Q2: Continuous IV PPI therapy (initial bolus + continuous infusion) Comparator Q1 and 3: Oral PPIs, H2RA, placebo, or no treatment pre-endoscopy;

Any of the above therapies provided post-endoscopy

Q2: Intermittent IV PPI therapy

Q4: No comparator required

Outcomes Q1 and 2: Clinical effectiveness and harms (e.g., rate of re-bleeding, need for transfusion, need for admission, length of hospital/ICU/emergency department stay, requirement for surgery, need for intervention, proportion of patients receiving endoscopy)

Q3: Cost-effectiveness outcomes

Q4: Evidence-based guidelines regarding the provision of pre-endoscopic intravenous proton pump inhibitors

Study Designs Health technology assessments (HTA), systematic reviews (SR), meta-analyses (MA), randomized controlled trials (RCT), observational studies, economic studies and evidence-based guidelines


Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2011. Guidelines which did not appear to be evidence based or had unclear methodology were excluded. Critical Appraisal of Individual Studies The included observational study was critically appraised using the Downs and Black checklist,15 and guidelines were assessed with the AGREE II instrument.16 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. SUMMARY OF EVIDENCE Quantity of Research Available

A total of 194 citations were identified in the literature search. Following screening of titles and abstracts, 170 citations were excluded and 24 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search. Of these 25 potentially relevant articles, 20 publications were excluded for various reasons, while five publications met the inclusion criteria and were included in this report. These were comprised of one observational study17 and four evidence-based guidelines.18-21 Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 7. Summary of Study Characteristics

Observational study Characteristics of the included observational study are summarized below and details are available in Appendix 2, Table A1. One relevant observational study17 was identified. It was published from Hungary in 2012. It was a retrospective study using data from medical records of patients with UGIB, who were admitted to the Emergency Department of a teaching hospital in Hungary. Of the 1369 patients admitted during April 2007 and July 2011, 1036 patients were excluded for various reasons and 333 patients, who were admitted during duty hours, were included in the analysis. PPI (pantoprazole) was compared with saline infusion. The age (mean or median not specified) of the patients was 63 years in the PPI group and 66 years in the saline group. The proportion of males was 72.9% in the PPI group and 63.4% in the saline group. Pantoprazole was administered as 80 mg bolus followed by 8 mg per hour continuous infusion. Outcomes reported were endoscopic signs of bleeding, urgent endoscopy, recurrent bleeding, emergency surgery and mortality. Guidelines A description of the included guidelines is summarized below and details are available in Appendix 2, Table A2 and Appendix 3, Table A3.


Four relevant guidelines18-21 were identified. One guideline18 was published from Europe in 2015 by the European Society of Gastrointestinal Endoscopy (ESGE). One guideline19 was published from United States of America (USA) in 2012. One guideline21 was published from the United Kingdom (UK) in 2012, by the National Institute of Health and Care Excellence (NICE). One guideline was a consensus statement20 published from Asia in 2011. All the guidelines were on the management of patients with UGIB and included a section on the use of PPI prior to endoscopy. Three guidelines19-21 provided explanations for the levels of evidence and one guideline18 did not. One guideline19 provided explanations for the strengths of recommendation and the other three guidelines18,20,21 did not. Details on the grading of evidence and strength of recommendation are provided in Appendix 3, Table A3. Summary of Critical Appraisal

Observational Study Critical appraisal of the included observational study is summarized below and details are available in Appendix 4, Tables A4. The included observational study17 specified the objective, and the inclusion and exclusion criteria and described the patient characteristics, intervention and outcomes. It was a retrospective study and potential for selection bias or performance bias cannot be ruled out. However, the characteristics of the patients in the PPI and saline groups appeared to be similar. The patients included in the analyses were those who had been admitted during duty hours; a large number of the patients were admitted during non-duty hours and were excluded from the analyses. No details regarding admissions during duty hours or non-duty hours were reported and the impact of this exclusion on the findings is unclear. Also, some patients were excluded from the analyses because of essential data missing in the records and the impact of these patients being excluded is unclear. A number of subgroup analyses were conducted but characteristics of the patients in these subgroups were not reported, hence comparability of the subgroups was unclear. It was also unclear if the subgroup analyses had been pre-planned or conducted after reviewing the data which could potentially introduce bias. In the light of these issues, the subgroup findings need to be viewed with caution. Sample size and power calculations were not mentioned. Disclosures of conflicts of interest were not mentioned. Generalizability is limited as the study was conducted at a single center and the patient population from different regions may be different and as policies and procedures across different hospitals may vary. Guidelines Critical appraisal of the guidelines are summarized below and details are available in Appendix 4, Table A5 The objectives were clearly stated in all the guidelines.18-21 The intended users of the guidelines were specified in three guidelines18,20,21 and not specified in one guideline.19 For three guidelines18,20,21 the guideline development group was comprised of individuals from relevant areas (such as gastroenterologists). One guideline19 was authored by two individuals and their areas of expertise were not specified. In two guidelines18,21 the methodology appeared to be rigorous; multiple databases were searched and a systematic review was conducted. In one guideline20 multiple databases were searched, in one guideline19 a single database was searched and in both guidelines details of methodology were sparse. In all guidelines the


evidence was graded. The strength of the recommendation was specified in two guidelines18,19 and not specified in two guidelines.20,21 In two guidelines18,20 it was mentioned that there were no competing interests. In one guideline,21 the guideline development group members was required to disclose their conflicts of interest and appropriate measures were taken in case of conflicts. In one guideline,19 the authors had associations with industry. One guideline20 was funded by industry. Summary of Findings

What is the clinical effectiveness of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department? Findings are summarized below and details are provided in Appendix 5, Tables A6. No relevant HTA, systematic review or RCT was identified. One relevant observational study17 based on data from medical records was identified. This included retrospective study17 compared outcomes in patients who were administered PPI prior to endoscopy with outcomes in patients who were administered saline prior to endoscopy. The study showed that the 30-day mortality rate was 6.3% in the PPI group and 4.3% in the saline group; the difference was not statistically significant (P = 0.49). The actively bleeding ulcers detected at endoscopic examination was in 19.2% patients in the PPI group compared to 24.7% patients in the saline group; the difference was not statistically significant (P = 0.29). The proportion of patients with clots detected at endoscopic examination was 21.7% in the PPI group and 12.9% in the saline group; the difference was not statistically significant (P = 0.50) No statistically significant differences were found between the two groups with respect to emergency surgery, urgent endoscopy, or recurrent bleeding. The authors also analyzed various subgroups. The different durations of PPI infusion did not appear to have significant differential effects on the outcomes. Mortality rates were 5.6%, 7.1% and 6.1% for the subgroups with PPI infusion of 0 to 4 hours, >4 hours and >6 hours, respectively; however the proportions were not statistically significantly different compared with the saline group (4.3%), (P values between 0.39 and 0.65). The proportions of patients with actively bleeding ulcers detected at endoscopic examination were 22.5%, 14.3% and 14.6% for the three subgroups with PPI infusion of 0 to 4 hours, >4 hours and >6 hours, respectively; however the proportions were not statistically significantly different compared with the saline group (24.7%), (P values between 0.07 and 0.69). The proportions of patients with clots detected at endoscopic examination were 25.3%, 16.3% and 27.1% for the three subgroups with PPI infusion of 0 to 4 hours, >4 hours and >6 hours, respectively; however the difference compared to the saline group (12.9%) was statistically significant for the 0 to 4 hour PPI group (P = 0.02) and not statistically significantly different for the > 4 hours PPI group or the > 6 hours PPI group; P = 0.50 and 0.44 respectively. In the subgroup of patients with duodenal ulcer bleeds there was no statistically significant difference in outcomes between the PPI group and the saline group (P values between 0.28 and 0.98). In the subgroup of patients with gastric ulcer bleeds there was no statistically significant difference in most outcomes between the PPI group and the saline group (P values between 0.11 and 0.82) except for clots. In the subgroup of patients with gastric ulcer bleeds, the proportion of patients with clots were 25.0% for the PPI group and 10.9% for the saline group (P = 0.04).


What is the comparative clinical effectiveness of continuous versus intermittent dosing of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department? No relevant studies on the comparative clinical effectiveness of continuous versus intermittent dosing of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department were identified What is the cost-effectiveness of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department? No relevant studies on the cost-effectiveness of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department were identified What are the evidence-based guidelines regarding the use of proton pump inhibitors before endoscopy in patients with upper gastrointestinal bleeds? The included guidelines are summarized below and details are available in Appendix 6, Table A7 Three guidelines18-20 used the clinical evidence from a Cochrane systematic review published by Sreedharan et al. in 2010. This Cochrane review mentioned that PPI administration prior to endoscopy in patients with UGIB, significantly reduced the proportion of patients with stigmata of recent hemorrhage (active bleeding, adherent clot, or non-bleeding visible vessel) .The Cochrane review also mentioned that though this pre-endoscopic PPI treatment reduces the requirement for endoscopic therapy during the index endoscopy there is no evidence that this early PPI treatment affects clinically important outcomes such as mortality, re-bleeding and need for surgery. Two guidelines18,20 also considered findings of one cost-effectiveness study which suggested that high dose PPI prior to endoscopy may be an effective and cost saving way to treat patients with UGIB. One guideline21 reviewed the findings from RCTs and concluded that with use of PPI prior to endoscopy there were no improvements in mortality, re-bleeding, or need for surgery and the quality of evidence was described as very low to low (Appendix 6, Table A7). In the light of conclusions from the clinical review, the guideline development group for this guideline did not think it was necessary to explore cost-effectiveness. The recommendations from the individual guidelines are presented in Table 2.


Table 2: Summary of Recommendationns

Guideline Author or Group, Year, Country

Recommendation

ESGE,18

2015, Europe

“ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80mg then 8mg/hour), in patients presenting with acute UGIH awaiting upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy (strong recommendation, high quality evidence).” Page: a1

Laine,19 2012, USA

“Pre-endoscopic intravenous proton pump inhibitor (PPI) (e.g., 80 mg bolus followed by 8 mg / h infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death (Conditional recommendation, high-quality evidence). If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce further bleeding (Conditional recommendation, moderate-quality evidence).” Page: 348

NICE,21 2012, UK “Do not offer acid-suppression drugs (proton pump inhibitors or H2-receptor antagonists) before endoscopy to patients with suspected non-variceal upper gastrointestinal bleeding.” Page: 160

Sung,20 2011, Asia “Pre-endoscopy proton pump inhibitor is recommended where early endoscopy or endoscopic expertise is not available within 24 h (agreement: 86.7%, level of evidence: low)” Page: 1172

ESGE = European Society of Gastrointestinal Endoscopy, H2-RA = histamine receptor antagonist, NICE = National Institute of Health and Care Excellence, UGIH = upper gastrointestinal hemorrhage, PPI = proton pump inhibitor, UK = United Kingdom, USA = United States of America

Limitations Clinical evidence was limited. No HTA, systematic review or RCT was identified; only one retrospective observational study was identified. Retrospective studies are prone to selection bias. Generalizability of the findings is limited as they pertain to an emergency department in one particular hospital. No relevant cost-effectiveness studies were identified. Neither the included study nor the guidelines were from Canada. Hence applicability in the Canadian setting is unclear. The recommendations in the guidelines did not specifically mention if they were for patients in the emergency department. Considering the variability in the recommendations from the different guidelines, a definitive conclusion is difficult.


CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

One relevant observational study and four relevant guidelines were identified. No relevant HTAs, systematic reviews, RCTs or economic studies were identified. One observational study, on patients with upper gastrointestinal bleeding who received either proton pump inhibitor infusion or saline infusion before endoscopy, showed no statistically significant differences between the two modalities with respect to endoscopic signs of bleeding, recurrent bleeding, emergency surgery or mortality. Recommendations regarding the use of proton pump inhibitors before endoscopy in patients with upper gastrointestinal bleeding were inconsistent. Two guidelines18,20 recommended pre-endoscopic PPI, one guideline19 recommended pre-endoscopic PPI in case of delayed endoscopy and one guideline21 did not recommend pre-endoscopic PPI. The variations in the recommendations appear to arise from the extent of importance given to certain outcomes. The three guidelines18-20 that were in favor of use of pre-endoscopic PPI considered the findings from the Cochrane review published in 2010. This Cochrane review mentioned that PPI administration prior to endoscopy in patients with UGIB, significantly reduced the proportion of patients with stigmata of recent hemorrhage, which reduced the need for endoscopic therapy, however this did not translate to reduction in re-bleeding, need for surgery, or mortality. The guideline21 that was not in favor of use of pre-endoscopic PPI, considered findings from a systematic review conducted by the guideline authors. This systematic review included four of the six RCTs included in the Cochrane review and also found no differences with respect to re-bleeding, need for surgery, or mortality for pre-endoscopic use of PPI compared to pre-endoscopic use of placebo or histamine 2 receptor antagonists. The authors did not assess the proportion of patients with stigmata of recent hemorrhage, likely because it was not considered an important outcome. There is controversy around the clinical significance of reduction in the proportion of patients with stigmata of recent hemorrhage as it does not translate to reduction in re-bleeding, need for surgery, or mortality.22,23 No relevant studies, on the comparative clinical effectiveness of continuous versus intermittent dosing of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department, were identified. No relevant studies, on the cost-effectiveness of intravenous proton pump inhibitors initiated before endoscopy in patients with upper gastrointestinal bleeds presenting to the emergency department, were identified. PREPARED BY:

Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


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11. Sreedharan A, Martin J, Leontiadis GI, Dorward S, Howden CW, Forman D, et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;(7):CD005415.

12. Continuous versus intermittent intravenous pantoprazole for acute gastrointestinal bleeding: a review of the clinical effectiveness and guidelines [Internet]. Ottawa: CADTH; 2015 May 1. [cited 2015 Jan 21]. (Rapid response report: summary with critical appraisal). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/may-2015/RC0653%20Pantoprazole%20for%20GI%20bleeds%20Final.pdf

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18. Gralnek IM, Dumonceau JM, Kuipers EJ, Lanas A, Sanders DS, Kurien M, et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy [Internet]. 2015 Oct [cited 2016 Jan 8];47(10):a1-46. Available from: https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0034-1393172.pdf

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ABBREVIATIONS

ESGE European Society of Gastrointestinal Endoscopy FU follow-up GRADE Grading of Recommendations Assessment, Development, and Evaluation H2-RA histamine receptor antagonist PPI proton pump inhibitor mg milligram NICE National Institute of Health and Care Excellence SD standard deviation SRH stigmata of recent hemorrhage UGIB upper gastrointestinal bleeding UK United Kingdom USA United States of America


APPENDIX 1: Selection of Included Studies

170 citations excluded

24 potentially relevant articles retrieved for scrutiny (full text, if

available)

1 potentially relevant report retrieved from other sources (grey

literature, hand search)

25 potentially relevant reports

20 reports excluded: - irrelevant population (1) - irrelevant interventions (5) - survey (1) - non-English publication (1) - guidelines with unclear methods (4) - other (review articles) (8)

5 reports included in review

194 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Clinical Studies

First

Author, Publication

Year,

Country

Study Design Patient

Characteristics

Intervention(s) Comparator(s) Clinical

Outcomes

Observational study Rácz,

17

2012,

Hungary

Retrospective (medical

records), single center (Gastroenterol

ogy Emergency Department of

teaching hospital in Győr) study.

Medical records of

UGIB patients admitted between April

2007 and July 2011. (In January

2009, preemptive PPI use was

included in the protocol for managing

UGIB patients arriving to the hospital during

the evening or night. Before that saline

infusion was used during the pre-

endoscopy period.)

Patients with UGIB

N = 333 (240 with bolus plus

infusion PPI [P], 93 with saline [S])

Age (years): 63.4 ± 15.2 in P,

66.0 ± 13.4 in S. % Male;

72.9% in P, 63.4% in S.

Hemoglobin (g/dL): 95.3 ± 30.2 in P,

96.8 ± 30.4 in S

PPI (pantaprazol, 80

mg bolus followed by continuous

infusion of 8 mg/hour) prior to endoscopy.

Duration of infusion before

endoscopy (hours) (mean ± SD): 6.9 ± 13.2

Saline prior to endoscopy.

Duration of infusion before

endoscopy (hours) (mean ± SD): 5.5 ± 12.9

Endoscopic signs of

bleeding, urgent endoscopy,

recurrent bleeding, emergency

surgery, mortality

N = total number of patients, P = PPI, PPI = proton pump inhibitor, S = saline, SD = standard deviation, UGIB = upper gastrointestinal bleeding


Table A2: Characteristics of Included Guidelines

Objectives Methodology

Gralnek (ESGE),18

2015, Europe

This guideline is on the diagnosis and management of

non-variceal upper gastrointestinal hemorrhage. It is to assist endoscopists in

providing care to patients.

Multiple databases (such as Medline, Embase, the Cochrane library, HEED) searched and systematic review conducted.

Evidence graded using GRADE Guideline was externally reviewed. Mechanism in place for updating guideline.

Laine,19

2012, USA

This guideline is on the management of patients with overt UGIB.

Medline database was searched. No additional details on methodology. Evidence graded using GRADE Guideline was externally reviewed.

No mention regarding updating of guidelines

NICE,21

2012, UK

This guideline is on the management of acute UGIB in adults and in young persons

(≥ 16 years). It is to assist healthcare professional in their practice.

Multiple databases (such as Medline, Embase, Cinahl, the Cochrane library, HEED) searched and systematic review conducted. Evidence graded using GRADE

Guideline was externally reviewed. Mechanism in place for updating guideline.

Sung,20

2011, Asia-Pacific

This is a consensus statement

on the management of non-variceal UGIB.

Multiple databases (such as Medline, Embase, Cochrane Register of

Controlled Trials) searched. Few details on methodology Evidence graded using GRADE Guideline was externally reviewed.

Mechanism for updating was unclear. It was mentioned that it was hoped that the consensus strategies would be updated regularly and adopted by health authorities.

ESGE = European Society of Gastrointestinal Endoscopy, GRADE = Grading of Recommendations assessment, development and Evaluation, NICE = National Institute of Health and Care Excellence, UK = United Kingdom, USA = United States of America


APPENDIX 3: Grading of Recommendations and Levels of Evidence

Table A3: Grading of Recommendations and Levels of Evidence Guideline Society

and/or Author, Year, Country,

Topic

Recommendation grade and Level of Evidence

Gralnek (ESGE),18 2015, Europe

Strength of Recommendations

Details not reported Levels of Evidence

GRADE used Details not reported

Laine,19 2012, USA

Strength of Recommendations

Strength Explanation

Strong Desirable effects of intervention clearly outweigh the undesirable effects

Conditional Uncertainty exists regarding trade-offs

Levels of Evidence using GRADE:

Level Explanation

High “Further research is very unlikely to change our confidence in the estimate of effect “ Page: 345

Moderate “Further research is likely to have an important impact on

our confidence in the estimate of effect and may change the estimate” Page: 345

Low “Further research is very likely to have an important impact on our confidence in the estimate of effect and is

likely to change the estimate” Page: 345

Very Low “Any estimate of effect is very uncertain” Page: 345

NICE,21

2012, UK Levels of Evidence using GRADE: Level Explanation

High “Further research is very unlikely to change our confidence in the estimate of effect” Page: 30





Very Low “Any estimate of effect is very uncertain” Page: 30


Table A3: Grading of Recommendations and Levels of Evidence

Guideline Society and/or Author, Year, Country,

Topic

Recommendation grade and Level of Evidence

Sung,20 2011, Asia-Pacific

Strength of Recommendations Details not reported

Levels of Evidence

Level Explanation

High “Further research is very unlikely to change our confidence in the estimate of effect” Page: 1171





Very Low “Any estimate of effect is uncertain” Page: 1171

ESGE = European Society of Gastrointestinal Endoscopy, GRADE = Grading of Recommendations assessment, development and

Evaluation, NICE = National Institute of Health and Care Excellence, UK = United Kingdom, USA = United States of America


APPENDIX 4: Critical Appraisal of Included Publications

Table A4: Strengths and Limitations of Observational Study using Downs and Black Checklist15

Strengths Limitations


17 2012, Hungary

Objectives were clearly stated.

Inclusion and exclusion criteria were stated

Patient characteristic, interventions and

outcomes were described.

P-values were provided

Not randomized; a retrospective study using medical records

Sample size calculation was not provided

Disclosure of conflicts of interest not provided

Generalizability limited to the study population (patients at one center in Hungary)

Table A5: Strengths and Limitations of Guidelines using AGREE II16 l


Gralnek (ESGE),18 2015, Europe

The scope and purpose were clearly stated.

The guideline development group comprised of individuals from relevant areas (such as gastroenterologist, gastrointestinal

endoscopist, interventional radiologist, surgeon)

The methods used for the development of the

guidelines appear to be rigorous (multiple database searched, and systematic review conducted)

Grading of evidence was done using the GRADE tool.

Strength of recommendation was stated

Cost implications were considered

It was mentioned that there were no competing interests

Unclear if patient input was sought

Unclear if organizational barriers were considered.

Laine,19 2012, USA

The scope was clearly stated.

Grading of evidence was done using the GRADE tool.

Strength of recommendation was stated

The intended users of the guidelines was not specified

The guideline was developed by two

individuals but their areas of expertise were not specified.

A single database was searched. Details of methodology were sparse.

Unclear if patient input was sought, however it was mentioned that patient preferences were considered.


Conflicts of interest were declared. Both authors were associated with industry

http://www.agreetrust.org/wp-content/uploads/2013/06/AGREE_II_Users_Manual_and_23-item_Instrument_ENGLISH.pdf


Table A5: Strengths and Limitations of Guidelines using AGREE II16 l


NICE,21 2012, UK

The scope and purpose were clearly stated.

The guideline development group comprised of individuals from relevant areas (such as gastroenterologist, hepatologist, surgeon,

interventional radiologist, nurse practitioner, economist, researcher and patient representative)

The methods used for the development of the guidelines appear to be rigorous (multiple database searched, and systematic review

conducted)

Patient input was sought

Cost implications were considered where appropriate. In the light of conclusions from the

clinical review regarding administration of PPI prior to endoscopy, the GDG did not think it was necessary to explore cost-effectiveness.

Grading of evidence was done using the GRADE tool

Guideline development group members were

required to disclose their conflicts of interest. Members were either required to withdraw completely or for the part of the discussion, if

their declared interest made it appropriate.


Strength of recommendations were not stated, however the evidence was graded

Sung,20 2011, Asia-Pacific The scope and purpose were clearly stated.

The guideline (consensus statement ) development group comprised of experts from 12 Asian countries in areas of acute UGIB, and

evidence-based medicine.

Multiple databases (such as Medline, Embase, Cochrane Register of Controlled Trials)

Grading of evidence was done using the

GRADE tool.

A modified Delphi process was used to make recommendations. The extent of agreement

was provided.

Cost implications were considered

It was mentioned that there were no competing interests

Details of methodology were sparse

Unclear if patient input was sought


Strength of the recommendation was not

stated.

Funded by pharmaceutical industry

ESGE = European Society of Gastrointestinal Endoscopy, GRADE = Grading of Recommendations Assessment, Development and Evaluation UK = United Kingdom, USA = United States of America

http://www.agreetrust.org/wp-content/uploads/2013/06/AGREE_II_Users_Manual_and_23-item_Instrument_ENGLISH.pdf


APPENDIX 5: Main Study Findings and Author’s Conclusions

Table A6: Summary of Findings of Included Clinical Studies

Main Study Findings and Author’s Conclusions


17 2012, Hungary

Main Findings: Outcomes with PPI (pantoprazole) infusion compared to saline infusion prior to endoscopy in UGIB patients

Outcome Number (%) of patients with outcome P value

Pantoprazole,

N = 240

Saline,

N = 93

Endoscopic signs of bleeding

Active bleeding 46 (19.2) 23 (24.7%) 0.26

Non bleeding visible vessel 49 (20.4%) 18 (19.3%) 0.83

Clot 52 (21.7%) 12 (12.9%) 0.50

Pigmented spot and clean base 93 (38.8%) 40 (43.0%) 0.48

Urgent endoscopy 19 (7.9%) 8 (8.6%) 0.89

Recurrent bleeding 40 (16.7%) 13 (13.9%) 0.55

Emergency surgery 21 (8.8%) 10 (10.7%) 0.57

Mortality 15 (6.3%) 4 (4.3%) 0.49 N = total number of patients in the group

Outcomes with PPI (pantoprazole) infusion of different durations compared to saline infusion prior to endoscopy in UGIB patients

Outcome Number (%) of patients with outcome

P value

Pantoprazole

subgroups (different infusion times)

Saline,

N = 93

Pantoprazol, 0 to 4 hours, N = 142

Endoscopic signs of bleeding - Active bleeding 32 (22.5%) 23 (24.7%) 0.69

Endoscopic signs of bleeding - Clot 36 (25.3%) 12 (12.9%) 0.02

Mortality 8 (5.6%) 4 (4.3%) 0.65

Pantoprazol, > 4 hours, N = 98



Mortality 7 (7.1) 4 (4.3%) 0.39

Pantoprazol, > 6 hours, N =82



Mortality 5 (6.1%) 4 (4.3%) 0.59 N = total number of patients in the group, , PPI = proton pump inhibitor, UGIB = upper gastrointestinal bleeding


Table A6: Summary of Findings of Included Clinical Studies

Main Study Findings and Author’s Conclusions

Outcomes with PPI (pantoprazole) infusion compared to saline infusion prior to endoscopy in UGIB patients (with duodenal ulcers)


Pantoprazole,

N = 128

Saline,

N = 47


Active bleeding 31 (24.2%) 14 (29.8%) 0.46


Clot 24 (18.7%) 7 (14.8%) 0.55





Mortality 7 (5.7%) 3 (6.3%) 0.76 N = total number of patients in the group, , PPI = proton pump inhibitor, UGIB = upper gastrointestinal bleeding

Outcomes with PPI (pantoprazole) infusion compared to saline infusion prior to endoscopy in UGIB patients (with gastric ulcers)


Pantoprazole,

N = 112

Saline,

N = 46


Active bleeding 15 (13.4%) 9 (19.5%) 0.32


Clot 28 (25.0%) 5 (10.9%) 0.04





Mortality 8 (7.1%) (2.2%) 0.22 N = total number of patients in the group, PPI = proton pump inhibitor, UGIB = upper gastrointestinal bleeding

Authors’ Conclusions: “In conclusion, according to our retrospective analysis profound acid suppression in gastroduodenal ulcer bleeding patients awaiting endoscopy did not decrease significantly the ratio of active bleeding and the

need for endoscopic therapy; however a trend of less active bleeding was seen with longer pantoprazole treatment. Preemptive administration of high-dose pantoprazole for longer than 4 hours decreased the severity of bleeding at first endoscopy in gastric ulcer patients but not in duodenal ulcer patients.”


APPENDIX 6: Guidelines and Recommendations

Table A7: Summary of Guidelines and Recommendations

Gralnek, European Society of Gastrointestinal Endoscopy (ESGE)18 2015, Europe Findings:

Clinical evidence from a Cochrane review by Sreedharan et al. published in 2010 was used for the

guideline report. This Cochrane review included six RCTs with 2223 patients with UGIB. PPI (oral or intravenous) was compared with H2-RA or placebo. This Cochrane review concluded that PPI administration prior to endoscopy in patients with UGIB, significantly reduced the proportion of patients

with SRH. Though this pre-endoscopic PPI treatment reduces the requirement for endoscopic therapy during the index endoscopy there is no evidence that this early PPI treatment affects clinically important outcomes such as mortality, re-bleeding and need for surgery.

Two cost-effectiveness studies (Tsoi et al.

24 and Al-Sabah et al.

25 both published in 2008) using

decision analytic models were included in the guideline report. The study by Tsoi concluded that use of

high dose PPI prior to endoscopy appeared to be an effective and cost -savings way to treat patients with UGIB. The study by Al-Sabah concluded that intravenous PPIs given prior to endoscopy were slightly more effective than no administration.

Recommendation: “ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80mg then 8mg/hour), in patients presenting with acute UGIH awaiting

upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy (strong recommendation, high quality evidence).” Page: a1

(H2-RA = histamine receptor antagonist, SRH = stigmata of recent hemorrhage , UGIH = upper gastrointestinal hemorrhage, PPI = proton pump inhibitor)

Laine,19 2012, USA Findings:

Clinical evidence from a Cochrane review by Sreedharan et al. published in 2010 was used for the guideline report. This Cochrane review included six RCTs with 2223 patients with UGIB. PPI (oral or intravenous) was compared with H2-RA or placebo. This Cochrane review concluded that PPI

administration prior to endoscopy in patients with UGIB, significantly reduced the proportion of patients with SRH. Though this pre-endoscopic PPI treatment reduces the requirement for endoscopic therapy during the index endoscopy there is no evidence that this early PPI treatment affects clinically

important outcomes such as mortality, re-bleeding and need for surgery.

Recommendation: “Pre-endoscopic intravenous proton pump inhibitor (PPI) (e.g., 80 mg bolus followed by 8 mg / h

infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death (Conditional recommendation, high-quality

evidence). If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce

further bleeding (Conditional recommendation, moderate-quality evidence).” Page: 348



NICE,21 2012, UK Findings:

Clinical studies: Outcomes with PPI treatment compared to placebo treatment in UGIB patients prior to endoscopy

Outcome No. of RCTs

No. of patients

Findings Quality of evidence

Mortality (≤30 days) 3 1983 No statistical or clinical difference in mortality rate

low

Re-bleeding (≤30

days)

3 1983 No statistical or clinical

improvement in re-bleeding rate

low

Surgery for continued or recurrent bleeding

(≤30 days)

3 1983 No statistical or clinical improvement in re-bleeding

rate

low

Blood transfusion requirement

1 631 No statistical or clinical improvement in the average unit of blood transfusions

moderate

Patients needing blood

transfusion

2 1352 No significant differences moderate

Length of hospital stay 1 631 No statistical or clinical improvement in the average length of hospital stay

moderate

FU = follow -up, PPI = proton pump inhibitor , RCTs = randomized controlled trials, UGIB = upper gastrointestinal bleeding

Outcomes with PPI treatment compared to H2-RA treatment in UGIB patients prior to endoscopy

Outcome No. of

RCTs No. of patients

Findings Quality of evidence

Mortality (≤30 days FU)

1 102 No statistical or clinical difference in mortality rate

Very low

Surgery for continued

or recurrent bleeding (≤30 days FU)

1 102 No statistical or clinical

difference in re-bleeding rate

Very low

Patients needing blood transfusion

1 102 No statistical or clinical difference in the rate of

patients needing blood transfusion

Very low

FU = follow -up, H2-RA = histamine 2 receptor antagonist , PPI = proton pump inhibitor , RCTs = randomized controlled trials, UGIB = upper gastrointestinal bleeding

Economic studies: “The GDG did not consider it necessary to explore the cost-effectiveness of PPIs versus H₂-RAs or placebo pre-endoscopy, as it had concluded from the clinical review that there was no benefit from these agents when given routinely pre-endoscopy.” Page: 154 (GDG = Guideline Development Group, H2-RA = histamine 2 receptor antogonist , PPI = proton pump inhibitor)



Recommendation:

“Do not offer acid-suppression drugs (proton pump inhibitors or H2-receptor antagonists) before endoscopy to patients with suspected non-variceal upper gastrointestinal bleeding.” Page: 160

Sung,20 2011, Asia Findings:

Clinical evidence from a Cochrane review by Sreedharan et al. published in 2010 was used for the guideline report. This Cochrane review included six RCTs with 2223 patients with UGIB. PPI (oral or

intravenous) was compared with H2-RA or placebo. This Cochrane review concluded that PPI administration prior to endoscopy in patients with UGIB, significantly reduced the proportion of patients with SRH. Though this pre-endoscopic PPI treatment reduces the requirement for endoscopic therapy

during the index endoscopy there is no evidence that this early PPI treatment affects clinically important outcomes such as mortality, re-bleeding and need for surgery.

One cost-effectiveness study by Tsoi et al.24

published in 2008 was considered. This study used a decision analysis based on the Hong Kong model. According to this study, the use of high dose PPI prior to endoscopy increases the upfront cost but reduces subsequent procedures and hence

decreases the duration of hospital stay, and thus is still cost-effective.

Recommendation:

“Pre-endoscopy proton pump inhibitor is recommended where early endoscopy or endoscopic expertise is not available within 24 h (agreement: 86.7%, level of evidence: low)” Page: 1172


APPENDIX 7: Additional References of Potential Interest

Guidelines (Unclear Methodology) Laursen SB, Jorgensen HS, Schaffalitzky de Muckadell OB. Management of bleeding gastroduodenal ulcers. Dan Med J [Internet]. 2012;59(7):C4473. Available from: http://www.danmedj.dk/portal/pls/portal/!PORTAL.wwpob_page.show?_docname=9102913.PDF Colle I, Wilmer A, Le Moine O, Debruyne R, Delwaide J, Dhondt E, et al. Upper gastrointestinal tract bleeding management: Belgian guidelines for adults and children. Acta Gastroenterol Belg. 2011;74(1):45-66. Economic Studies (Prior to Literature Search Period) Al-Sabah S, Barkun AN, Herba K, Adam V, Fallone C, Mayrand S, et al. Cost-effectiveness of proton-pump inhibition before endoscopy in upper gastrointestinal bleeding. Clin Gastroenterol Hepatol. 2008 Apr;6(4):418-25. Tsoi KK, Lau JY, Sung JJ. Cost-effectiveness analysis of high-dose omeprazole infusion before endoscopy for patients with upper-GI bleeding. Gastrointest Endosc. 2008 Jun;67(7):1056-63

http://www.danmedj.dk/portal/pls/portal/!PORTAL.wwpob_page.show?_docname=9102913.PDFhttp://www.danmedj.dk/portal/pls/portal/!PORTAL.wwpob_page.show?_docname=9102913.PDF

Context and policy issuesResearch questionSkey FindingsMethodsLiterature Search MethodsSelection Criteria and MethodsExclusion CriteriaCritical Appraisal of Individual Studies

Summary of EVIDENCEQuantity of Research AvailableSummary of Study CharacteristicsSummary of Critical AppraisalSummary of FindingsLimitations

Conclusions and implications for decision or policy makingReferencesABBREVIATIONS

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TITLE: Pre-Endoscopic Intravenous Proton Pump Inhibitors for … · Pre-Endoscopic Intravenous PPIs for Patients with Upper Gastrointestinal Bleeds 2 Response report12 13on pantoprazole