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

Abstract

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 important to patients.DesignSystematic review and network meta-analysis.Data sourcesMedline, PubMed, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature up to March 2019.Eligibility criteria for selecting studies and methodsWe included randomised controlled trials that compared gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided critical oversight of the systematic review, including identifying outcomes important to patients. We performed random-effects pairwise and network meta-analyses and used GRADE to assess certainty of evidence for each outcome. When results differed between low risk and high risk of bias studies, we used the former as best estimates.ResultsSeventy two trials including 12 660 patients proved eligible. For patients at highest risk (>8%) or high risk (4-8%) of bleeding, both PPIs and H2RAs probably reduce clinically important gastrointestinal bleeding compared with placebo or no prophylaxis (odds ratio for PPIs 0.61 (95% confidence interval 0.42 to 0.89), 3.3% fewer for highest risk and 2.3% fewer for high risk patients, moderate certainty; odds ratio for H2RAs 0.46 (0.27 to 0.79), 4.6% fewer for highest risk and 3.1% fewer for high risk patients, moderate certainty). Both may increase the risk of pneumonia compared with no prophylaxis (odds ratio for PPIs 1.39 (0.98 to 2.10), 5.0% more, low certainty; odds ratio for H2RAs 1.26 (0.89 to 1.85), 3.4% more, low certainty). It is likely that neither affect mortality (PPIs 1.06 (0.90 to 1.28), 1.3% more, moderate certainty; H2RAs 0.96 (0.79 to 1.19), 0.9% fewer, moderate certainty). Otherwise, results provided no support for any affect on mortality, Clostridium difficile infection, length of intensive care stay, length of hospital stay, or duration of mechanical ventilation (varying certainty of evidence).ConclusionsFor higher risk critically ill patients, PPIs and H2RAs likely result in important reductions in gastrointestinal bleeding compared with no prophylaxis; for patients at low risk, the reduction in bleeding may be unimportant. Both PPIs and H2RAs may result in important increases in pneumonia. Variable quality evidence suggested no important effects of interventions on mortality or other in-hospital morbidity outcomes.Systematic review registrationPROSPERO CRD42019126656.

Could stress ulcer prophylaxis increase mortality in high-acuity patients?

“…Based on the available evidence, we surmise that, although considerable uncertainty remains, the inferences from SUP-ICU and PEPTIC are consistent with the hypothesis that PPIs increase the risk of death in patients with higher illness severity. While, the overall evidence that PPIs reduce upper GI bleeding in the critically ill is unequivocal [5,15], it appears that most upper GI bleeds are not fatal, and the attributable mortality from such bleeds appears to be low [16]. Therefore, we suspect that most patients would exchange the small increased risk of upper GI bleeding to avoid a therapy that might increase their risk of death, despite the uncertainty.…”

“…However, because clinically important upper GI bleeding is very uncommon in some patient groups, there remains uncertainty about the ubiquity of benefit from prophylaxis. Moreover, although the risks of nosocomial pneumonia [2][3][4] and Clostridioides difficile infection [2] associated with exposure to proton pump inhibitors (PPIs) in observational studies have not been confirmed in RCTs [5], the potential for harm in some patient groups still exists. Overall, it remains highly plausible that the balance of risks and benefits for stress ulcer prophylaxis differs depending on the patient's circumstances.…”

Confronting COVID-19: Issues in Hemophilia and Congenital Bleeding Disorders

“…29 These risks, in additon to that of stress ulcer in this setting of critically-ill patients, highlight the role of prophylaxis with proton pump inhibitors or histamine-2 receptor antagonists. 30 Although a specific treatment for COVID-19 is currently unavailable, an increasing series of drugs, previously used for treating other viral diseases or investigational agents with antiviral targets or immunomodulatory effects, are being evaluated in clinical practice. 28 Many of these drugs may increase bleeding tendency because of toxicity at gastrointestinal (i.e., lopinavir/ritonavir, umfenovir) or hematologic (i.e., the interleukin-6 receptor inhibitor tocilizumab and the RNA-polymerase inhibitor favipiravir) level.…”

Stress ulcer prophylaxis: Is mortality a useful endpoint?

“…In this issue of Intensive Care Medicine, Wang and coworkers present the results from an update [6] of their previous systematic review and network meta-analysis [7]. In addition to another very small trial, the authors included the PEPTIC trial, a multi-centre cluster randomized trial including over 26.000 patients [8] and thus increasing the number of analysed patients from 12 660 to 39 569.…”

“…Although stress ulcer prophylaxis seems to be safe and efficient in patients at risk, not affecting mortality [5], Table 1 Proposal of bleedings risk categories and efficacy of stress ulcer prophylaxis according to Wang et al in their two studies [6,7]. Of note: a universally accepted definition of bleeding risk categories is still lacking *Risk factors identified in the trials included in the two cited meta-analyses: mechanical ventilation, neurosurgery, brain injury, respiratory failure, sepsis, burns, hypotension, postoperative complications, acute renal failure, multiple trauma, acid-base disorder, coagulopathy, multiple surgical procedures, circulatory failure, coma, preoperative GCS < 9, inappropriate secretion of antidiuretic hormone, major postoperative complications requiring reoperation, ≥ 60 years old, pyogenic central nervous system infection, marked jaundice, shock, stroke or head trauma with GCS < 10, corticotherapy, treatment with anticoagulants, hepatic failure, acute pancreatitis, major thoracic or abdominal surgery, renal replacement therapy, history of chronic liver disease, and major neurologic insult **Overt gastrointestinal bleeding = bleeding without the consequences of clinically important gastrointestinal bleeding such as haemodynamic changes, transfusion, haemoglobin decrease, or need for surgery uncertainty regarding other harmful effects remains.…”