Important Gastrointestinal Bleeding Research Articles

Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis

BackgroundDuring the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies.ObjectiveTo describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring.MethodsREVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022.ResultsThe Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted.ConclusionProtocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Adjudication of a primary trial outcome: Results of a calibration exercise and protocol for a large international trial

BackgroundAscertainment of the severity of the primary outcome of upper gastrointestinal (GI) bleeding is integral to stress ulcer prophylaxis trials. This protocol outlines the adjudication process for GI bleeding events in an international trial comparing pantoprazole to placebo in critically ill patients (REVISE: Re-Evaluating the Inhibition of Stress Erosions). The primary objective of the adjudication process is to assess episodes submitted by participating sites to determine which fulfil the definition of the primary efficacy outcome of clinically important upper GI bleeding. Secondary objectives are to categorize the bleeding severity if deemed not clinically important, and adjudicate the bleeding site, timing, investigations, and treatments. MethodsResearch coordinators follow patients daily for any suspected clinically important upper GI bleeding, and submit case report forms, doctors' and nurses’ notes, laboratory, imaging, and procedural reports to the methods center. An international central adjudication committee reflecting diverse specialty backgrounds conducted an initial calibration exercise to delineate the scope of the adjudication process, review components of the definition, and agree on how each criterion will be considered fulfilled. Henceforth, bleeding events will be stratified by study drug, and randomly assigned to adjudicator pairs (blinded to treatment allocation, and study center). ResultsCrude agreement, chance-corrected agreement, or chance-independent agreement if data have a skewed distribution will be calculated. ConclusionsFocusing on consistency and accuracy, central independent blinded duplicate adjudication of suspected clinically important upper GI bleeding events will determine which events fulfil the definition of the primary efficacy outcome for this stress ulcer prophylaxis trial. RegistrationNCT03374800 (REVISE: Re-Evaluating the Inhibition of Stress Erosions)

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol

IntroductionThe Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding...

What counts as patient-important upper gastrointestinal bleeding in the ICU? A mixed-methods study protocol of patient and family perspectives

IntroductionClinically important upper gastrointestinal bleeding is conventionally defined as bleeding accompanied by haemodynamic changes, requiring red blood cell transfusions or other invasive interventions. However, it is unclear if this clinical...

The effects of pantoprazole vs. placebo on 1-year outcomes, resource use and employment status in ICU patients at risk for gastrointestinal bleeding: a secondary analysis of the SUP-ICU trial.

Patients in intensive care units (ICUs) are at risk of stress-related gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP), including proton pump inhibitors, is widely used in the attempt to prevent this. In this secondary analysis of Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, we assessed 1-year outcomes in the pantoprazole vs. placebo groups. In the SUP-ICU trial, 3298 acutely admitted ICU patients at risk of GI bleeding were randomly allocated, stratified for site, to pantoprazole or placebo. In this secondary analysis, we assessed clinically important GI bleedings in ICU and 1-year mortality, health care resource use (e.g. readmission with GI bleeding, use of home care and general practitioner), health care costs, and employment status for the Danish participants using registry data. Among the 2099 Danish participants, 2092 had data in the registries; 1045 allocated to pantoprazole and 1047 to placebo. The number of clinically important GI bleedings in ICU was 1.9 percentage points [95% CI 0.3-3.5] lower in the pantoprazole group vs. the placebo group, but none of the 1-year outcomes differed statistically significantly between groups, including total health care costs (€1954 [-2992 to 6899]), readmission with GI bleeding (-0.005 admissions [-0.016 to 0.005]), 1-year mortality (-0.013 percentage points [-0.051 to 0.026]), and employment (-0.178weeks [-0.390 to 0.034]). Among ICU patients at risk of GI bleeding, pantoprazole reduced clinically important GI bleeding in ICU, but this did not translate into a reduction in 1-year mortality, health care resource use or improvements in employment status.

Comparison of proton pump inhibitors and histamine 2 receptor antagonists for stress ulcer prophylaxis in the intensive care unit

Proton pump inhibitors (PPIs), followed by histamine 2 receptor antagonists (H2RAs), are the most commonly used drugs to prevent gastrointestinal bleeding in critically ill patients through stress ulcer prophylaxis. The relative efficacy and drug-related adverse events of PPIs and H2RAs remain unclear. In this retrospective, observational, comparative cohort study, PPIs and H2RAs for stress ulcer prophylaxis in critically ill patients were compared using a common data model. After propensity matching, 935 patients from each treatment group (PPI or H2RA) were selected. The PPI group had a significantly higher 90-day mortality than the H2RA group (relative risk: 1.28; P = 0.01). However, no significant inter-group differences in the risk of clinically important gastrointestinal bleeding were observed. Moreover, there were no significant differences between the groups concerning the risk of pneumonia or Clostridioides difficile infection, which are known potential adverse events related to these drugs. Subgroup analysis of patients with high disease severity were consistent with those of the total propensity score-matched population. These findings do not support the current recommendations, which prefer PPIs for gastrointestinal bleeding prophylaxis in the intensive care unit.

A pragmatic assessment of proton pump inhibitors vs. histamine type 2 receptor antagonists on clinically important gastrointestinal bleeding and mortality when used for stress ulcer prophylaxis in the ICU.

Approximately 1%-5% of critically ill patients experience clinically important gastrointestinal bleeding (CIGB). This study assessed the effectiveness and safety of proton pump inhibitors (PPIs) compared to histamine type 2 receptor antagonists (H2RAs) for prevention of CIGB in mechanically ventilated patients. This is a retrospective, single-center, pharmacoepidemiologic study. This study was carried out in six intensive care units (ICUs). Critically ill adults admitted between 9/1/14 and 9/1/19 who received PPIs or H2RAs within 24h of intubation and for ≥48h were included in this study. PPIs or H2RAs for stress ulcer prophylaxis. Primary outcomes were CIGB occurring 48h after ICU admission and hospital mortality. Secondary outcomes were pneumonia, Clostridioides difficile infection (CDI), acute kidney injury, myocardial infarction/ischemia, thrombocytopenia, and delirium. Outcomes were defined using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10)-codes with manual cross-reference for a hemoglobin drop, transfusion, or hemodynamic compromise to further define CIGB. Of 3873 patients, 2061 (53.2%) received PPIs. CIGB was rare but higher in the PPI group (0.34% vs. 0%, RR=1, 95% CI, 1-1; p=0.013); however, substantial group differences existed possibly predisposing the PPI group to CIGB. Hospital mortality was higher in the PPI group (42.1% vs. 29.1%, RR=1.23, 95% CI, 1.17-1.29; p<0.0001). PPIs remained an independent risk factor for mortality after multivariate adjustment (RR=1.61, 95% CI, 1.39-1.88; p<0.0001). Rates of secondary outcomes were similar between groups except thrombocytopenia (4.3% vs. 2.2%, RR=1.02, 95% CI, 1.01-1.03; p=0.0003) and delirium (83.7% vs. 78.1%, RR=1.34, 95% CI, 1.18-1.53; p<0.0001) that were higher in the PPI group. Proton pump inhibitors were associated with CIGB; however, the overall rate of CIGB was low. Compared to H2RAs, PPIs were associated with hospital mortality. Further identification of appropriate selection criteria for ulcer prophylaxis and comparisons of pharmacologic prevention strategies are warranted.

Predictors of gastrointestinal bleeding in adult ICU patients in the SUP-ICU trial.

In previous studies of predictors of gastrointestinal (GI) bleeding in the intensive care unit (ICU), most patients received pharmacological stress ulcer prophylaxis (SUP). We aimed to assess associations between potential predictors of clinically important GI bleeding (CIB) and overt GI bleeding in adult ICU patients, while considering the effect and potential interaction with use of SUP. We included 3291 acutely admitted adult ICU patients with risk factors for GI bleeding randomized to SUP (pantoprazole) or placebo in the SUP-ICU trial. We used logistic regression models adjusted for allocation to SUP to estimate associations between 23 potential predictors and CIB (primary outcome) and overt GI bleeding (secondary outcome). Furthermore, we assessed associations between potential predictors and both outcomes in each allocation group and assessed potential interaction with allocation to SUP. Increasing SAPS II and SOFA scores, use of circulatory support and renal replacement therapy were associated with increased risk of CIB and overt GI bleeding; chronic lung disease was associated with increased risk of overt GI bleeding. Results for the remaining potential predictors were compatible with both no difference or increased and decreased risks. We found no strong evidence for any interaction between treatment allocation and any potential predictors. In adult ICU patients at risk of GI bleeding, severity of illness, use of circulatory support and renal replacement therapy were associated with higher odds of CIB, with no strong evidence of interaction with SUP.

The efficacy and safety of acid suppressants for gastrointestinal bleeding prophylaxis in cardiac care unit patients.

Background and AimConcerns regarding adverse events associated with proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) for gastrointestinal bleeding (GIB) prophylaxis in the intensive care unit have increased in recent years. Few studies have focused on acid suppressant use in the cardiac care unit (CCU) setting exclusively. We performed a cohort study to determine the efficacy and safety of acid suppressants for GIB prophylaxis in CCU patients.MethodsThis retrospective cohort study included adults who were admitted directly to the CCU for more than 2 days from January 1, 2014, to April 30, 2019. The Crusade score was calculated to evaluate the risk of GIB. The primary outcomes were clinically important gastrointestinal bleeding (CIGIB), hospital‐acquired pneumonia (HAP), and in‐hospital mortality.ResultsOf the 3318 patients enrolled, 2284 (68.8%) patients received PPIs, 515 (15.5%) received H2RAs, and 519 (15.7%) received no acid suppressants. After adjusting for potential confounders, utilization of PPIs (2.69, 95% confidence interval [0.62–11.73]) and H2RAs (1.41, 95% confidence interval [0.19–10.36]) were not associated with a lower risk of CIGIB than the control. Sensitivity analyses revealed that PPI use was an independent risk factor for in‐hospital mortality in patients over 75 years old, with an adjusted odds ratio of 4.08 (1.14–14.63). PPIs increased the risk of HAP in patients over 75 years old and in those with heart failure, with adjusted odds ratios of 2.38 (1.06–5.34) and 2.88 (1.34–7.28), respectively.ConclusionsProton pump inhibitors and H2RAs for GIB prophylaxis in CCU patients were not associated with a lower risk of CIGIB than the controls. PPI therapy is associated with increased risks of HAP and in‐hospital mortality in patients over 75 years old. PPIs may increase the risk of HAP in patients with heart failure.

Prevention of gastrointestinal bleeding in critically ill patients.

This review focuses on the current literature on the epidemiology and prevention of stress-induced clinically important gastrointestinal bleeding in ICU patients. The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to be decreasing. Observational studies and an exploratory randomized controlled trial suggest that early enteral nutrition may be effective in preventing gastrointestinal bleeding in patients who are not at high risk. Recent systemic reviews and meta-analyses indicate that proton pump inhibitors and H2 receptor antagonists are more effective than placebo in preventing clinically important gastrointestinal bleeding, especially in high-risk and very high-risk patients, but do not reduce mortality. Although observational data suggested an association of proton pump inhibitors and H2 receptor antagonists with Clostridium difficile infection and pneumonia, this association was not confirmed in randomized controlled trials. The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to have decreased over time. Even though stress ulcer prophylaxis in critically ill patients has been a research focus for decades, many questions remain unanswered, such as which groups of patients are likely to benefit and what pharmacologic agent is associated with the best benefit-to-harm ratio.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48h), creatinine clearance < 60ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated systematic review and network meta-analysis of randomized trials.

Motivated by a new randomized trial (the PEPTIC trial) that raised the issue of an increase in mortality with proton pump inhibitors (PPIs) relative to histamine-2 receptor antagonists (H2RAs), we updated our prior systematic review and network meta-analysis (NMA) addressing the impact of pharmacological gastrointestinal bleeding prophylaxis in critically ill patients. We searched for randomized controlled trials that examined the efficacy and safety of gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. We performed Bayesian random-effects NMA and conducted analyses using all PEPTIC data as well as a restricted analysis using only PEPTIC data from high compliance centers. We used the GRADE approach to quantify absolute effects and assess the certainty of evidence. Seventy-four trials enrolling 39 569 patients proved eligible. Both PPIs (risk ratio (RR) 1.03, 95% credible interval 0.93 to 1.14, moderate certainty) and H2RAs (RR 0.98, 0.89 to 1.08, moderate certainty) probably have little or no impact on mortality compared with no prophylaxis. There may be no important difference between PPIs and H2RAs on mortality (RR 1.05, 0.97 to 1.14, low certainty), the 95% credible interval of the complete analysis has not excluded an important increase in mortality with PPIs. Both PPIs (RR 0.46, 0.29 to 0.66) and H2RAs (RR 0.67, 0.48 to 0.94) probably reduce clinically important gastrointestinal bleeding; the magnitude of reduction is probably greater in PPIs than H2RAs (RR 0.69, 0.45 to 0.93), and the difference may be important in higher, but not lower bleeding risk patients. PPIs (RR 1.08, 0.88 to 1.45, low certainty) and H2RAs (RR 1.07, 0.85 to 1.37, low certainty) may have no important impact on pneumonia compared with no prophylaxis. This updated NMA confirmed that PPIs and H2RAs are most likely to have a similar effect on mortality compared to each other and compared to no prophylaxis; however, the possibility that PPIs may slightly increase mortality cannot be excluded (low certainty evidence). PPIs and H2RAs probably achieve important reductions in clinically important gastrointestinal bleeding; for higher bleeding risk patients, the greater benefit of PPIs over H2RAs may be important. PPIs or H2RAs may not result in important increases in pneumonia but the certainty of evidence is low.

Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta-analysis and trial sequential analysis.

Acutely ill patients are at risk of stress-related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients. We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). The primary outcomes were all-cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials. We included 65 comparisons from 62 trials (n=9713); 43 comparisons were from intensive care units. Only three trials (n=3596) had overall low risk of bias. We did not find an effect on all-cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA-adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA-adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health-related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses. We did not observe a difference in all-cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive. PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.

Stress Ulcer Prophylaxis in Critically Ill Children: A Multicenter Observational Study.

To describe current stress ulcer prophylaxis practice in Canadian PICUs. Multicenter cohort study. We defined stress ulcer prophylaxis as the use of a proton-pump inhibitor, histamine-2 receptor antagonist, or sucralfate within the first 2 PICU days among children who had not been on these medications at home and had no evidence of gastrointestinal bleeding. Seven PICUs in Canada. Three hundred seventy-eight children requiring mechanical ventilation. None. Children were ventilated for a median (interquartile range) of 2 days (1-6 d) and stayed in the PICU for a median (interquartile range) of 4 days (2-10 d). The median (interquartile range) age was 1.3 years (0.3-6.7 yr). Seventy percent of all children received acid suppression during their PICU stay. One hundred sixty-seven (54%) of the 309 children eligible for stress ulcer prophylaxis received it. Histamine-2 receptor antagonists were the most frequently used class (66%), followed by proton-pump inhibitors (47%) and sucralfate (4%), and 20% received more than one class. Stress ulcer prophylaxis was continued on the PICU transfer orders for 34% of these children. Children who received prophylaxis were older and had a higher Pediatric Risk of Mortality III score, more often received nonsteroidal anti-inflammatory drugs and systemic corticosteroids and received less enteral nutrition. In multivariate analysis, age and invasive mechanical ventilation were independently associated with an increased likelihood of receiving stress ulcer prophylaxis and receiving feeds was independently associated with a decreased likelihood of receiving stress ulcer prophylaxis. Gastrointestinal bleeding was reported in 21 (6%) of 378 children; three (0.8%) were clinically important. Eighteen percent were treated for a new respiratory tract infection, and 1% developed Clostridium difficile-associated diarrhea. Stress ulcer prophylaxis is common in Canadian PICUs. Clinically important gastrointestinal bleeding and C. difficile-associated diarrhea are rare, and the utility of routine prophylaxis should be examined.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation

Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital. Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs). The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group. Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication. anzctr.org.au Identifier: ACTRN12616000481471.

Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial.

The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present. We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots. We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63). In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS. NCT02467621.

Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis

ObjectiveTo determine, in critically ill patients, the relative impact of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), sucralfate, or no gastrointestinal bleeding prophylaxis (or stress ulcer prophylaxis) on outcomes...

Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in critically ill adults - a meta-analysis of randomized controlled trials with trial sequential analysis

BackgroundProton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) have been widely used as stress ulcer prophylaxis (SUP) in critically ill patients, however, its efficacy and safety remain unclear. This study aimed to assess the effect of SUP on clinical outcomes in critically ill adults.MethodsLiterature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane database of clinical trials for randomized controlled trials (RCTs) that investigated SUP, with PPI or H2RA, versus placebo or no prophylaxis in critically ill patients from database inception through 1 June 2019. Study selection, data extraction and quality assessment were performed in duplicate. The primary outcomes were clinically important gastrointestinal (GI) bleeding and overt GI bleeding. Conventional meta-analysis with random-effects model and trial sequential analysis (TSA) were performed.ResultsTwenty-nine RCTs were identified, of which four RCTs were judged as low risk of bias. Overall, SUP could reduce the incident of clinically important GI bleeding [relative risk (RR) = 0.58; 95% confidence intervals (CI): 0.42–0.81] and overt GI bleeding (RR = 0.48; 95% CI: 0.36–0.63), these results were confirmed by the sub-analysis of trials with low risk of bias, TSA indicated a firm evidence on its beneficial effects on the overt GI bleeding (TSA-adjusted CI: 0.31–0.75), but lack of sufficient evidence on the clinically important GI bleeding (TSA-adjusted CI: 0.23–1.51). Among patients who received enteral nutrition (EN), SUP was associated with a decreased risk of clinically important GI bleeding (RR = 0.61; 95% CI: 0.44–0.85; TSA-adjusted CI: 0.16–2.38) and overt GI bleeding (RR = 0.64; 95% CI: 0.42–0.96; TSA-adjusted CI: 0.12–3.35), but these benefits disappeared after adjustment with TSA. Among patients who did not receive EN, SUP had only benefits in reducing the risk of overt GI bleeding (RR = 0.37; 95% CI: 0.25–0.55; TSA-adjusted CI: 0.22–0.63), but not the clinically important GI bleeding (RR = 0.27; 95% CI: 0.04–2.09).ConclusionsSUP has benefits on the overt GI bleeding in critically ill patients who did not receive EN, however, its benefits on clinically important GI bleeding still needs more evidence to confirm.

Time to onset of gastrointestinal bleeding in the SUP-ICU trial: A pre-planned substudy.

The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status. Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P=.37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); this significantly increased in the later period (to HR 0.85, 95% CI 0.53-1.37; P=.02). Patients with later compared to earlier CIB received more transfusions and had more diagnostic/therapeutic procedures for CIB. Clinically important gastrointestinal bleeding mostly occurred more than 2 days after randomization. University hospital admission was associated with significantly decreased risk of CIB in the earlier period only.

The effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in critically ill adults: a systematic review with meta-analysis.

To assess the effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in adult critically ill patients. We systematically reviewed randomised clinical trials comparing systemic corticosteroids administered for more than 24h with placebo/no treatment in adult critically ill patients. Trial selection, data abstraction and risk of bias assessments were performed in duplicate. We used trial sequential analysis (TSA) to assess the risk of random errors and the grading of recommendations, assessment, development, and evaluations (GRADE) approach to assess the quality of evidence. The primary outcome was the incidence of clinically important gastrointestinal bleeding within 90days. The secondary outcome was the incidence of gastrointestinal bleeding of any severity within 90days. Twenty-five trials (n = 14,615) reported data for the primary outcome and 55 trials (n = 21,792) for the secondary outcome. The pooled incidence of clinically important gastrointestinal bleeding was 2.3% in the corticosteroid group and 1.8% in the control group (RR, 1.26; 95% CI, 1.01-1.57; I2 = 0%, TSA-adjusted CI 0.51-3.14). We observed no difference in the risk of gastrointestinal bleeding of any severity (RR, 1.10; 95% CI, 0.92-1.32; I2 = 0%, TSA-adjusted CI 0.87-1.38). The GRADE quality of evidence was low (risk of bias and imprecision). We observed an overall low incidence of clinically important gastrointestinal bleeding among adult critically ill patients. Corticosteroids may slightly increase the incidence of clinically important gastrointestinal bleeding, but not bleeding of any severity. Rarity of events, infrequent trial reporting and high risk of bias reduced the quality of evidence.