Comparison between esomeprazole 20 mg Vs 40 mg as stress ulcer prophylaxis (SUP) in critically ill patients: A retrospective cohort study

Abstract Critically ill patients admitted to intensive care units (ICUs) are at high risk of developing upper gastrointestinal bleeding due to GI stress ulceration (SU). The major independent risk factors for the development of GI bleeding in the ICUs include mechanical ventilation (MV) and coagulopathy. There is no enough evidence regarding the most appropriate dosing of esomeprazole as stress ulcer prophylaxis (SUP) in critically ill patients. This is a retrospective cohort study conducted at King Abdulaziz Medical City‐Riyadh between January and December 2018 to determine the efficacy and safety of two different regimens of esomeprazole (20 vs 40 mg) as SUP in critically ill patients with major risk factors of GI stress ulceration. A total of 1864 patients were reviewed, 387 patients meeting inclusion criteria were enrolled. The propensity score was used to adjust for clinically and statistically relevant variables. We considered a P value of <.05 as statistically significant. 49 patients (12.6%) had received Esomeprazole 20 mg during the study period. Compared with Esomeprazole 20 mg, Esomeprazole 40 mg was not superior in GI bleeding prevention (aOR 2.611, 95% CI 0.343‐20.247, P = .356). In addition, neither ICU C. difficle, ICU mortality within 30 days, ICU LOS, hospital LOS, ICU re‐admission within 6 months, RBCs transfusion, nor platelets transfusion requirements were significant. On the other hand, Esomeprazole 40 mg was statistically associated with Enterobacteriaceae, Pneumonia, and longer MV duration.


| INTRODUC TI ON
Critically ill patients admitted to intensive care units (ICUs) are at high risk of developing upper gastrointestinal bleeding (UGIB) due to GI stress ulceration (SU) leading to several consequences. 1 No specific definition for SU, nevertheless can be defined as an acute, erosive, inflammatory insult that causes mucosal injury which varies from superficial ulcers to deep bleeding lesions that occur after the first 24 hours of hospitalization. 1,2 The prevalence of gastrointestinal (GI) bleeding is different between studies because of mixed populations. 3 GI bleeding secondary to SU after mechanical ventilation in ICU Patients have been noted, as studies reported an incidence of SU and subepithelial hemorrhage within 24 hours of admission in ICU patients. 3 The major risk factors for the development of GI bleeding in the ICUs include mechanical ventilation, coagulopathy, and hepatic or kidney failure. 4 Observational studies showed that proton pump inhibitors (PPIs) are the most commonly used prophylactic agents in the ICU. 5 A meta-analysis provides moderate quality evidence for clinicians and guideline groups suggesting that PPIs, when compared to H2RAs, lower the risk of clinically important and overt GI bleeding among critically ill patients, without increasing the risk of pneumonia and mortality, or ICU length of stay. 5 A study of NSAID-associated GU healing was not statistically different when comparing different esomeprazole dosing regimen (20 vs 40 mg esomeprazole) after 8 weeks. 6 Another study by Plein et al compared 20 vs 40 mg pantoprazole, found that 20 mg pantoprazole was safe and effective in maintaining patients with healed reflux esophagitis in remission.
Additionally, 20 mg of pantoprazole provides good long-term therapeutic efficacy at less drug exposure and lower costs. 7 There is no enough evidence regarding the most appropriate dosing of esomeprazole as stress ulcer prophylaxis in critically ill patients.
This study aims to investigating the efficacy and safety for different regimens of esomeprazole (20 mg vs 40 mg) as stress ulcer prophylaxis in critically ill patients with major risk factors for stress ulceration.

| Eligibility criteria
Patients were enrolled in the study if they were critically ill aged 16 y/o or older with at least one major risk factors of stress ulceration (i.e. requiring MV > 24 hours and/or coagulopathy (INR>1.5 or platelets< 50,000/microliter)) and administered esomeprazole

| Availability of data and material
Data are available upon request due to privacy/ethical restrictions.

| Outcomes
The primary outcome was GI bleeding, pneumonia, bacteremia, significant urinary tract infection, ICU Clostridium difficile. GI bleeding determined with GI endoscopy and/or receiving PPI as a treatment dose with documentation of GI bleeding. Clostridium difficile confirmed with a positive polymerase chain reaction (PCR). The secondary outcomes were RBCs/platelets transfusion requirement, mechanical ventilation duration, ICU/hospital length of stay and ICU mortality.

| Data management and statistical analysis
Collected data were entered in Microsoft Excel after being coded.
There were two arms considered in this study, patients who received esomeprazole 20 vs 40 mg as stress ulcer prophylaxis. As expected in an observational study, differences in baseline characteristics between the two treatment groups may exist. To adjust for these differences, a propensity score for the use of Esomeprazole 20 mg was generated with Apache II scores. Baseline characteristics, baseline severity, and outcome variables were compared between the two groups.
Categorical variables were presented as percentages and numerical variables (continuous variables) as mean and standard deviation (SD). The normality assumptions were assessed for all numerical variables using a statistical test (ie Shapiro-Wilk test) and also using graphical representation (ie histograms and Q-Q plots). We compared categorical variables using the chi-square or Fisher exact test, normally distributed numerical variables with the t-test, and other quantitative variables with the Mann-Whitney U test.
Multivariate logistic regression was used to find out the relationship between treatments and the different outcomes considered in this study, adjusting for the generated propensity score.
We assessed model fit using the Hosmer-Lemeshow goodnessof-fit test. Generalized linear regression and multiple linear regression were also used to find out the relationship between treatments and the different outcomes considered in this study, adjusting for the generated propensity score. The odds ratios (OR) and estimates with the 95% confidence intervals (CI) were reported for the associations. We considered a P value of <.05 as statistically significant and used SAS version 9.4 for all statistical analyses.

| Ethical consideration
The study was approved by King Abdullah International Medical Research Center Institutional Review Board, Riyadh, Saudi Arabia.
Participants' confidentiality was strictly observed throughout the study by using anonymous unique serial number for each subject and restricting data only to the investigators. Informed consent was not required due to the research's method as per the policy of the governmental and local research center.

| Patient characteristics
The study included 387 patients, of which 49 (12.6%) had received Esomeprazole 20 mg during the study period. Table 1 Table 2 shows the severity illness baseline between Esomeprazole 20 mg and Esomeprazole 40 mg treatment groups. The severity illness baseline (APACHE II score, SOFA score) and nutrition risk (NUTRIC score) within 24 hours of ICU admission were not statistically significant.

| Outcomes
The association between Esomeprazole prophylaxis dose and GI bleeding using multivariate analysis adjusted for propensity score is summarized in Table 2. Compared with esomeprazole 20 mg, esomeprazole 40 mg was not superior in GI bleeding prevention (adjusted

| D ISCUSS I ON
In the practice, stress ulcer prophylaxis (SUP) continues to be the standard of care in patients admitted to intensive care units (ICU) and Proton pump inhibitors (PPIs), are the most used agents. 5 Our study aimed to study the efficacy as well as safety between two different regimens of esomeprazole as stress ulcer prophylaxis in a critically ill Note: Denominator of the percentage is the total number of patients. *T-Test/^Wilcoxon rank sum test is used to calculate the P-value. ^^Chi-square test is used to calculate the P-value. $*Propensity score adjusted Generalized linear model is used to calculate estimates and P-value. $**Propensity score adjusted multiple regression model is used to calculate estimates and P-value. $ propensity score adjusted Logistic regression is used to calculate Odds ratio and P-value. **Fisher Exact test is used to calculate the P-value. Note: Denominator of the percentage is the total number of patients. *T-Test/^Wilcoxon rank sum test is used to calculate the P-value. ^^Chi-square test is used to calculate the P-value. $*propensity score adjusted Generalized linear model is used to calculate estimates and P-value. $**propensity score adjusted multiple regression model is used to calculate estimates and P-value. $ propensity score adjusted Logistic regression is used to calculate Odds ratio and P-value. **Fisher Exact test is used to calculate the P-value.

| CON CLUS ION
In conclusion, our study found that Esomeprazole 40 was not superior to Esomeprazole 20 in terms of preventing GI bleeding in critically ill patients. On the other hand, pneumonia, Enterobacteriaceae infections, and MV duration were significantly higher with Esomeprazole 40. These data confirm the need for randomized controlled trials with a larger sample size to clarify and confirm our study findings.