A Protocol for a Systematic Review and Meta-Analysis of Hospital Readmissions Following Acute Upper Gastrointestinal Bleeding

This protocol outlines the planned methodology for a systematic review and meta-analysis. The primary objective of the review is to identify all-cause readmission rates for individuals hospitalized for an upper GI bleed (UGIB). Secondary objectives will include GI bleed-specific readmission rates, mortality (all-cause and GI bleed-specific), readmission diagnosis, and length of stay on readmission visit. High-risk subgroups will also be explored including age, sex, type of GI bleed (e.g., variceal or not), anti-coagulation status, and comorbidity status. Through this review, the research team aims to describe an important quality indicator, which has implications for both patient safety post-discharge after an UGIB and healthcare resource utilization.


Introduction
Acute upper gastrointestinal bleeding (AUGIB) has been previously defined as blood loss anywhere between the esophagus and the Ligament of Treitz (at the duodenojejunal flexure). In recent years UGIB has been redefined as bleeding above the ampulla of Vater within reach of upper endoscopy [1,2].
UGIB is one of the most common gastrointestinal emergencies, with an incidence of 50 to 160 per 100, 000 population per year and a 6-10% mortality [3,4]. Variceal and non-variceal bleeding are the two main categories of UGIB [5]. Non-variceal lesions account for 80-90% of UGIB cases. These include gastroduodenal peptic ulcers (20-50%), gastro-duodenal erosions, erosive esophagitis, Mallory-Weiss tears, as well as other conditions. Variceal bleeding largely is esophageal in nature, but occasionally originates from the stomach [1,6]. Varices are due to increased venous pressures, often from portal hypertension as a result of end-stage liver disease [7]. GI bleeding can be fatal and readmission within 30 days after the first episode of bleeding can pose a significant burden on the healthcare system. However, despite readmission rate being known as an important indicator and used in other morbid conditions, there is currently no summary data on this for upper GI bleeds. The purpose of this study is to systematically review and determine the readmission rate, and mortality for patients treated for an AUGIB.

Research question
What is the hospital readmission rate for adults discharged from the hospital following treatment for AUGIB?

Search Strategy
The online databases to be queried for the systematic review include MEDLINE (1946-Present), Embase (1976, Web of Science's Science Conference Proceedings section (1990 -present), and Cochrane Central Register of Controlled Trials (CENTRAL). Two researchers (CD, SK) will review the cited references of all included articles to identify other relevant studies.
It was decided to search all databases from inception based on a preliminary search, which revealed relatively few (less than 500) studies without any time limits imposed. Non-human studies will be excluded. All languages will be included. In the case that a foreign language publication makes it to abstract or fulltext screening and an English translation is unavailable, a translation service will be used.
Two key search concepts were identified from the research question. The researchers identified these themes and then identified common synonyms and alternative spelling that could be present in the literature. The results of this are in Table 2. Appropriate subject headings and keywords embedded in the respective databases will be used in combination with the search terms to capture any relevant studies. It was subsequently chosen by the researchers to not utilize "upper" in the search strategy and limit the results. This was decided as it was felt some articles may address GI bleeds in general and may stratify data by type within their results. Also, "non-variceal" was not used in the formal search strategy as it was felt that variceal and the versions of GI bleed would capture any of these articles. An example of the search strategy for MEDLINE is demonstrated in Table 3. A similar strategy will be employed for each database.  In addition to the electronic search, conference abstracts from North America's largest meetings in the fields of gastroenterology (American Gastroenterology Association and Canadian Association of Gastroenterology) and emergency medicine (Canadian Association of Emergency Physician (CAEP) and American College of Emergency Physicians (ACEP)) will be reviewed for the most recent five years (2016-21).
Based on their experience with gastroenterology and emergency medicine, and in discussion with their supervisors, no known experts were identified a priori by the researchers. However, this will be monitored during the abstract review process and if common authors are found, they will be contacted to see if they are aware of any ongoing or unpublished studies.

Identification of studies
The systematic review will follow the standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines study identification process [9]. This will involve a two-stage process. The first will consist of a review of the abstracts identified by the search. Subsequently, the full texts of the abstracts selected as potentially meeting inclusion criteria will be reviewed to determine the final included studies. Each review will be conducted by two researchers (SK, CD) independently and any disagreements will be resolved by discussion. In the case that consensus is unable to be reached via discussion, a third researcher (LB) will review the study to make the final decision. The initial agreement will be quantified for each review round utilizing Cohen's kappa. Reviewers will utilize Covidence to facilitate the screening process (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia).

Abstract Review
The initial review round will be to capture any studies remotely relevant to the research question and eliminate any clearly unrelated studies. To proceed to the second round, an abstract must: (i) be of an original research (see note below if reviews are identified in the search strategy); (ii) report data on GI bleeds, or GI-related complications; (iii) not be animal-based research.
To be clear, in this round the researchers will err on the side of inclusion. If an article's abstract does not clearly state it meets or does not meet a requirement but seems related to the overall theme (e.g., GI bleeds or GI disorders), it will be selected to proceed to the full-text review.
In the case that a literature review (e.g., systematic, scoping, or narrative) is identified by the search strategy and seems applicable to the research question, the researchers will read the review to determine if any cited studies that are not identified by the search strategy are potentially relevant to include.
The aim of the second review round will be to identify which studies meet all inclusion criteria. Researchers will utilize a standardized screening tool, adopted from Elzinga et al., to determine the inclusion eligibility of every study [10]. The tool consists of four questions, each addressing a specific inclusion/exclusion criterion.
The first question addresses the appropriate population and whether the study discusses adult (> 18 years old) patients who were hospitalized with a GI bleed. Articles investigating outpatients, pediatric populations, or only lower GI bleeds will be excluded. The second focuses on the outcome and asks whether the readmission rate is reported. Various forms of this (e.g., counts, proportions, ratios) will be accepted if the necessary data is available to combine them. One notable exclusion criterion will be studies that report readmission rates from all pathologies, not just GI bleeds. The third and fourth questions focus on methodology. The studies need to be original, human research (e.g., not animal or a review). Figure 1 displays the screening tool that will be utilized in a sequential manner by researchers.

Data Extraction and Synthesis
Data extraction and quality assessment will be undertaken in duplicate. Both researchers (SK, CD) will perform tasks independently, and then compare results. Any disagreements will be resolved by discussion. In the case that consensus is unable to be reached via discussion, a third researcher (LB) will review the article to make the final decision.

Data Extraction
A standardized data extraction tool will be utilized for all studies. Data will be extracted into Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). This is included in the Appendix. In general, it will incorporate four themes (study characteristics, patient characteristics, outcomes, and quality). Table 4 summarizes the four themes and sample questions within each.  will be contacted only once by email and have 30 days to respond. After this period, articles will be removed from the analysis.

Quality Assessment
Quality assessment will be conducted utilizing the Downs and Black Quality Assessment Scale [11]. This method was chosen due to its applicability to both randomized and non-randomized studies.

Data analysis
Summary measures for each included study and patient baseline characteristics will be reported along with associated 95% confidence intervals. For the entire population, the incidence of all-cause readmission will be pooled using a random-effects model, along with secondary outcomes (e.g., GI-specific readmission, mortality, readmission diagnosis, and length of stay), if feasible based on heterogeneity between studies and information reported in each included study.
In the situation where different timeframes are used to measure outcomes (e.g., seven-day versus 30-day readmission rate), there will be a check for a linear effect performed to see if outcomes can be extrapolated and combined to a similar time reference.
The degree of heterogeneity will be formally assessed by calculating I 2 .
Stratified analyses will also be conducted for various groups, including: Randomized control trials (RCTs) versus observational studies, interventional versus epidemiological studies, low versus high-risk UGIB (based on clinical scoring scales: Rockall > 1, Glasgow-Blatchford scores (GBS) > 0), high and low-quality studies, and time period. For specific subgroups, odds ratios (and 95% confidence interval) will also be calculated using a random-effects model to determine their overall impact on readmission (e.g., age, sex, degree of comorbidities, variceal, index treatment, and anticoagulation status).

Discussion
Although there have been advancements in treatment for UGIB, the mortality rate has remained relatively unchanged over the last 50 years [3]. Advances in endoscopic therapy and prevention of UGIB lesions, through treatment of Helicobacter pylori infection; use of proton pump inhibitors (PPIs); and use of selective cyclooxygenase-2 (COX-2) inhibitors, have affected incidence rates and morbidity. Conversely, risk factors of UGIB, including advancing age, renal failure, and exposure to antiplatelet therapy or systemic anticoagulation, have increased [12,13]. It is crucial to reassess the impact of UGIB on various outcomes because of changing epidemiology.
GI bleeding can be fatal and is one of the leading causes of readmission to hospital [3]. For certain diseases such as congestive heart failure, acute myocardial infarction, and pneumonia, 30-day hospital readmission is now a quality indicator [14]. Readmission within 30 days after the first episode of bleeding poses a significant burden on the healthcare system [15]. One study reported a 13% 30-day all-cause readmission rate, frequently due to recurrent bleeding [16]. It is seen that 30-day readmission led to an increase in health resource utilization, morbidity, and a double-fold increase in-hospital mortality when compared to patients who did not require readmission [16]. While in-hospital and 30-day mortality have been well studied in UGIB, there is limited data on 30-day all-cause hospital readmission of patients after discharge from hospital for a primary UGIB episode [14]. This study aims to address this important evidence gap.

Conclusions
This report describes the systematic review and meta-analysis protocol that will be utilized to determine the readmission rate of UGIB. It will highlight this for the general population, as well as certain high-risk subgroups. By addressing this current evidence gap, practitioners will be able to identify which patients are at greatest risk of decompensation post-discharge and this can inform future studies evaluating potential interventions to mitigate this risk. Table 5 is the data extraction tool that will be utilized by reviewers.

Title
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Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.