Mini-CAT

Matt Lemieszewski
PA Portfolio II – Summer 2022
Mini-CAT

Clinical Scenario:
A patient is being transferred to your subacute rehab facility from a local hospital following bilateral ORIF on the tibias. While completing your initial provider assessment, your attending starts them on Omeprazole 20mg QD prophylaxis despite any clinical indications or history of GERD or PUD.

Search Question:
Does the long-term use of a proton pump inhibitor as prophylaxis actually prevent the occurrence of PUD or upper GI bleeds?

PICO Table:

PopulationInterventionComparisonOutcome(s)
Geriatric patientsProton pump inhibitorsNo treatmentIncidence of ulcers
SNF residentsPPIsPlaceboIncidence of GI bleed
Subacute rehab patientsOmeprazole Rebound acid hypersecretion
Critically ill patients‘-azole’ Increased infection rates
ICU patients   

Search Strategy and Databases Used:

  • PubMed:
    • PPI Overuse: 7
    • PPI prophylaxis and GI Bleed: 4
    • Proton pump inhibitors AND stress ulcer prophylaxis: 32

  • JAMA:
    • PPI prophylaxis and GI Bleed: 2
    • Stress ulcer prophylaxis and proton pump inhibitors: 1

  • NEJM:
    • Stress ulcer prophylaxis and proton pump inhibitors: 9
    • PPI prophylaxis adverse effects: 2

  • Science Direct:
    • Proton pump inhibitors AND stress ulcer prophylaxis: 91
    • PPI prophylaxis causing ulcers: 66

I narrowed down the initial list of of articles by choosing the studies that were most relevant to my clinical scenario and question. Because my search question included both patient prognosis and potential harms, I screened for articles that were either meta-analyses, systematic reviews, randomized control trials, and cohort studies if neither of the first two were available. A randomized controlled trial (RCT) can give evidence of efficacy and efficiency while minimizing or eliminating bias. A major advantage of the cohort study design is the ability to study multiple outcomes that can be associated with a single exposure or multiple exposures in a single study. Even the combined effect of multiple exposures on the outcome can be determined.

Research Used:

CitationVilcu, Ana-Maria, et al. “Association between Acute Gastroenteritis and Continuous Use of Proton Pump Inhibitors during Winter Periods of Highest Circulation of Enteric Viruses.” JAMA Network Open, vol. 2, no. 11, 2019, https://doi.org/10.1001/jamanetworkopen.2019.16205.
AbstractIMPORTANCE: An increased risk of acute bacterial enteric infections has been reported among patients receiving proton pump inhibitor (PPI) therapy. The risk of acute gastroenteritis (AGE) of viral origin associated with continuous PPI exposure has been less studied.   OBJECTIVE: To investigate the association between continuous PPI therapy and AGE occurrence during winter epidemic periods when the circulation of enteric viruses is the highest.   DESIGN, SETTING, AND PARTICIPANTS: A matched cohort study was performed using a prospectively collected drug dispensing database from a large panel of community pharmacies in continental France. All patients recorded in the database during the 2015 to 2016 winter season, with documented age, sex, and use of an identifiable regular panel pharmacy, were eligible for the study. Each patient exposed to continuous PPI therapy was matched to 3 unexposed patients, according to year of birth, sex, and identifiable regular panel pharmacy. Analyses were performed between January 2017 and December 2018.   EXPOSURE: Continuous PPI use during the 2015 to 2016 AGE winter epidemic.   MAIN OUTCOMES AND MEASURES: The occurrence of at least 1 AGE episode during the 2015 to 2016 AGE winter epidemic was the main outcome. Episodes of AGE were identified using a previously validated algorithm based on drug dispensing data. Relative risks of AGE were estimated using a multivariable log-binomial model adjusted for age, sex, and treatments for chronic conditions.   RESULTS: There were 233 596 patients receiving PPI therapy (median [interquartile range] age, 71 [62-81] years; 55.8% female) and 626 887 matched patients not receiving PPI therapy (median [interquartile range] age, 70 [61-80] years; 56.3%female) included in the analyses. At least 1 AGE epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy. The adjusted relative risk of AGE for those receiving PPI therapy was 1.81 (95%CI, 1.72-1.90) for all ages considered, 1.66 (95%CI, 1.54-1.80) among those aged 45 to 64 years, 2.19 (95%CI, 1.98-2.42) among those aged 65 to 74 years, and 1.98 (95%CI, 1.82-2.15) among those aged 75 years and older.   CONCLUSIONS AND RELEVANCE: Continuous PPI therapy was associated with an increased risk of developing AGE during periods of highest circulation of enteric viruses. These findings support the hypothesis that PPI use is associated with an increased risk of enteric viral infections.
Link:https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2755852
CitationOrelio, Claudia C., et al. “Reducing Inappropriate Proton Pump Inhibitors Use for Stress Ulcer Prophylaxis in Hospitalized Patients: Systematic Review of De-Implementation Studies.” Journal of General Internal Medicine, 2 Feb. 2021, https://doi.org/10.1007/s11606-020-06425-6.
AbstractBackground A large proportion of proton pump inhibitor (PPI) prescriptions, including those for stress ulcer prophylaxis (SUP), are inappropriate. Our study purpose was to systematically review the effectiveness of de-implementation strategies aimed at reducing inappropriate PPI use for SUP in hospitalized, non-intensive care unit (non-ICU) patients.   Methods We searched MEDLINE and Embase databases (from inception to January 2020). Two authors independently screened references, performed data extraction, and critical appraisal. Randomized trials and comparative observational studies were eligible for inclusion. Criteria developed by the Cochrane Effective Practice and Organisation of Care (EPOC) group were used for critical appraisal. Besides the primary outcome (inappropriate PPI prescription or use), secondary outcomes included (adverse) pharmaceutical effects and healthcare use.   Results We included ten studies in this review. Most de-implementation strategies contained an educational component (meetings and/or materials), combined with either clinical guideline implementation (n = 5), audit feedback (n = 3), organizational culture (n = 4), or reminders (n = 1). One study evaluating the de-implementation strategy effectiveness showed a significant reduction (RR 0.14; 95% CI 0.03–0.55) of new inappropriate PPI prescriptions. Out of five studies evaluating the effectiveness of de-implementing inappropriate PPI use, four found a significant reduction (RR 0.21; 95% CI 0.18–0.26 to RR 0.76; 95% CI 0.68–0.86). No significant differences in the occurrence of pharmaceutical effects (n = 1) and in length of stay (n = 3) were observed. Adverse pharmaceutical effects were reported in two studies and five studies reported on PPI or total drug costs. No pooled effect estimates were calculated because of large statistical heterogeneity between studies.   Discussion All identified studies reported mainly educational interventions in combination with one or multiple other intervention strategies and all interventions were targeted at providers. Most studies found a small to moderate reduction of (inappropriate) PPI prescriptions or use.
Link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298652/
CitationAlhazzani, Waleed, et al. “Efficacy and Safety of Stress Ulcer Prophylaxis in Critically Ill Patients: A Network Meta-Analysis of Randomized Trials.” Intensive Care Medicine, vol. 44, no. 1, 4 Dec. 2017, pp. 1–11., https://doi.org/10.1007/s00134-017-5005-8.
AbstractPurpose Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients.   Methods We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers.   Results Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies.   Conclusions Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question.
Link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770505/
CitationZhou, Xiaoyang, et al. “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.” BMC Gastroenterology, vol. 19, no. 1, 21 Nov. 2019, https://doi.org/10.1186/s12876-019-1105-y.
AbstractBackground: Proton 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.   Methods: Literature 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.   Results: Twenty-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).   Conclusions: SUP 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.
Link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873751/
CitationKrag, Mette, et al. “Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU.” New England Journal of Medicine, vol. 379, no. 23, 6 Dec. 2018, pp. 2199–2208., https://doi.org/10.1056/nejmoa1714919.
AbstractBACKGROUND Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear.   METHODS In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization.   RESULTS A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.   CONCLUSIONS Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621. opens in new tab.)
Link:https://www.nejm.org/doi/full/10.1056/NEJMoa1714919

Summary of Evidence:

Author (Date)Level of EvidenceSample/Setting (# of subjects/ studies, cohort definition etc. )Outcomes StudiedKey FindingsLimitations and Biases
Vilcu, Ana-Maria, et al. (2019)Cohort StudyThere were 233,596 patients receiving PPI therapy and 626,887 matched patients not receiving PPI therapy included in the analysis.    The outcome of interest was the occurrence of at least 1 AGE episode during the epidemic period. It was coded as a binary variable (≥ 1 AGE case vs none).At least 1 acute gastroenteritis (AGE) epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy.   Patients aged 45 years and older receiving continuous PPI therapy had a significantly higher risk of developing AGE during periods of circulation of enteric viruses compared with those not using PPI therapy.   One-half of continuous PPI prescriptions are inappropriate. As regions head into enteric viral infection season, this would be the time to reassess the ongoing need for PPI therapy in patients, especially older adults, and potentially deprescribe.First, diagnoses were not available, and ascertainment of the AGE status relied solely on drug dispensing data.   Second, the actual PPI doses were unavailable, and a dose-response relationship could not be investigated.

Third, there is a risk of incomplete follow-up, which may result in misclassification of outcome or exposure status.
Orelio, Claudia C., et al. (2021)Systematic Review10 studies of adult, hospitalized patients in non-ICU settings, in which an intervention to reduce the use of inappropriate PPI was evaluated.   RCTs and comparative observational studies reported in English, Dutch, or German were eligible for inclusion.   Studies that addressed both PPI and H2RA medication as stress ulcer prophylaxis (SUP) were included if data on PPI use could be extracted separately.   Studies combining inpatient and outpatient data were included when inpatient data could be extracted separately.The primary outcome studied was inappropriate PPI prescription or use   Secondary outcomes included adverse pharmaceutical effects and healthcare use.In 2013, the Choosing Wisely campaign has identified PPI and H2RA acid-suppressive therapy for SUP as low-value care that should be avoided.   Among ten studies aimed at reducing inappropriate PPI use for SUP, all used mainly educational intervention strategies targeted at providers.   There was not an observed correlation between the effect size of inappropriate PPI use or prescription and the amount or types of de-implementation interventions in the studies.   Secondary outcomes were scarcely and inconsistently reported.None of the studies included provided sufficient intervention details to allow knowledge transfer of effective intervention strategies.
Alhazzani, Waleed, et al. (2017)Meta-analysis57 RCTs were included in this study.   18 trials compared PPIs with H2RAs; 2 PPIs with sucralfate; 4 PPIs with placebo; 18 H2RAs with sucralfate; 21 H2RAs with placebo; and 6 sucralfate with placebo.   Trial sample size ranged from 28 to 1200 patients. Different doses, routes of administration, and durations of prophylaxis were used for PPIs and H2RAs across the trialsThe primary outcome studied was the incidence of clinically important GI bleeding.   Secondary outcomes studied were incidences of pneumonia, mortality, C. difficile infections, and overt GI bleeding.PPIs ranked first in their effectiveness in preventing clinically important GI bleeds and overt GI bleeds, but dead last when compared to H2Ras and placebo in the incidence rate of developing pneumonia.   The universal use of SUP should be reconsidered in the light of uncertain net benefit.Estimates of baseline risk vary considerably across the included trials.   Only one trial addressed C. difficile infection, which is important given a recent 30,000-patient retrospective observational study suggesting that PPIs may increase the risk of Clostridium difficile colitis.   Majority of trials did not report on nutritional management, which limited the ability to examine the effect of enteral nutrition as an effect modifier.
Zhou, Xiaoyang, et al. (2019)Meta-analysis29 RCTs were included in this analysis.   Seven trials were multi-center, and twenty-two trials were single-center.   The discrepancy in the number of subjects between trials were large and it varied from 25 to 3298.Primary outcomes included clinically important and overt GI bleeding.   The secondary outcome studied was for all-cause mortalityUse of PPIs in stress ulcer prophylaxis (SUP) was associated with a reduced incident of clinically important GI bleeding and overt GI bleeding, but had no effects on the all-cause mortality   SUP was not associated with a lower mortality compared with the control group, regardless of the trials quality, the type of SUP used, and whether EN was used.   One of the included trials revealed a higher incidence of pneumonia in patients received H2RA, while other observational studies also found an increased risk of infectious complications, including pneumonia and CDI, in critically ill patients receiving SUP.There was significant statistical heterogeneity in the analysis for the overt GI bleeding,   There was also clinical heterogeneity between studies in the dosage, route of administration, and infusion duration of drug used.  
Krag, Mette, et al. (2018)RCTA total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group.The primary outcome was death by 90 days after randomization.   The secondary outcomes were clinically important events in the ICU (defined as clinically important gastrointestinal bleeding, new-onset pneumonia, C. difficile infection, or acute myocardial ischemiaIn predefined subgroup analyses, there was no heterogeneity in the effect of pantoprazole as compared with placebo on mortality at 90 days between patients with and patients without a history of liver disease, a history of or ongoing coagulopathy, shock, or mechanical ventilation.   A total of 360 (21.9%) of 1644 patients in the pantoprazole group and 372 (22.6%) of 1647 in the placebo group had one or more clinically important events in the ICU.   In the pantoprazole group, 41 patients (2.5%) had clinically important gastrointestinal bleeding, as compared with 69 (4.2%) in the placebo group.   In this trial of patients who were admitted to the ICU for an acute condition and were at risk for gastrointestinal bleeding, there was no significant differences between pantoprazole and placebo with regard to either 90-day mortality or the number of patients with a composite outcome of four clinically important events.  At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died, so there was immediately a group that could not be included in follow-up.   There was not mandate diagnostic endoscopy to assess the source of bleeding and was therefore unable to differentiate between stress ulcers and other causes of gastrointestinal bleeding.

Conclusions: (Briefly summarize the conclusions of each article then provide overarching conclusion)

Article 1 (Vilcu et al.): Individuals 45 years of age and older who receive PPI therapy on a regular basis have a higher risk of getting acute gastroenteritis when enteric viruses are most prevalent. The findings of this study support the hypothesis that persistent PPI use is linked to an increased risk of infections with enteric viruses and highlight the need for additional research to confirm this link and look into the pathophysiological mechanisms. However, there are limitations related to exposure and outcome ascertainment as well as potential residual confounding.

Article 2 (Orelio et al.): Ten studies used primarily educational intervention strategies aimed at providers to decrease inappropriate PPI use for stress ulcer prophylaxis in adult hospitalized, non-ICU patients. In some studies, the number of inappropriate PPI prescriptions or uses was reduced slightly to moderately. There was no one de-implementation strategy that was found to be superior. Due to variations in study populations, settings, reported outcome measures, and combination of interventions, the studies were heterogeneous. Poor implementation and reporting design was prevalent.

Article 3 (Alhazzani et al.): PPIs have the lowest absolute risk of clinically significant GI bleeding compared to no prophylaxis, making them the most effective preventative measure for stress ulcers. However, the benefit of PPIs must be weighed against the possibility of pneumonia and Clostridium difficile infection. The best estimate of the increase in pneumonia with PPIs compared to no prophylaxis is over 3%, according to moderate-quality evidence. These figures cast doubt on SUP’s overall net benefit and widespread adoption.

Article 4 (Zhou et al.): Critically ill patients in the ICU constantly experience various hemodynamic changes, such as hypoxia and hypotension, which can reduce GI mucosal blood flow and cause a breakdown of the GI mucosa’s defense mechanisms, leading to stress-related ulcers and subsequent GI bleeding. According to this meta-analysis, using PPI or H2RA to prevent stress ulcers was linked to a lower incidence of clinically significant GI bleeding and overt GI bleeding, but had no impact on all-cause mortality, pneumonia incidence, or C. diff infections.

Article 5 (Krag et al.): The 90-day mortality, percentage of days alive without the use of life support, and number of patients experiencing clinically significant events, infectious adverse events, or serious adverse reactions were comparable between pantoprazole-treated patients and placebo-treated patients among adult ICU patients who were at risk for gastrointestinal bleeding. Clinically significant gastrointestinal bleeding in the ICU occurred less frequently in patients taking pantoprazole compared to those taking a placebo.

Weight of the Evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)

  1. Article 3 (Alhazzani et al.): This 2018 meta-analysis included 57 trials, enrolling over 7,000 critically-ill patients looked to my question regarding the efficacy of PPIs as stress ulcer prophylaxis when compared to an array of other treatment options.

  2. Article 4 (Zhou et al.): Another meta-analysis, this study was also extremely strong, including 29 RCTs. The large difference between this article and the one above, was that this study only looked at the primary outcome of clinically important and overt GI bleeding, along with the secondary outcome of all-cause mortality. Additionally, this study only looked at patients using PPI therapy vs. placebo as opposed to other treatment options included in the study above.

  3. Article 1 (Vilcu et al.): While only a cohort study, I find this study stronger than the remaining two due to the size of the population studied. Over one year, this study analyzed data from over 800,000 patients, results that are capable of being applied to a larger, national scale.

  4. Article 5 (Krag et al.): A single RCT, this study looked at the effects of a single drug in the PPI compared to a placebo group. An additional limitation of this study was by looking at patients strictly in a critical care ICU setting, there was a slight drop (0.5%) in patients available for 90-day due to passing away.

  5. Article 2 (Orelio et al.): Although a systematic review, this study’s main focus was to compare approaches de-implementation and reducing inappropriate prescriptions. This study did not show what benefits the de-implementation had on any specific patient population, only showing why it is important to do so.

Magnitude of Effect

  1. (Vilcu et al.): At least 1 acute gastroenteritis epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy. The adjusted relative risk of AGE for those receiving PPI therapy was 1.81 (95%CI, 1.72-1.90) for all ages considered, 1.66 (95%CI, 1.54-1.80) among those aged 45 to 64 years, 2.19 (95%CI, 1.98-2.42) among those aged 65 to 74 years, and 1.98 (95%CI, 1.82-2.15) among those aged 75 years and older.

  2. (Orelio et al.): One study evaluating the de-implementation strategy effectiveness showed a significant reduction (RR 0.14; 95% CI 0.03–0.55) of new inappropriate PPI prescriptions. Out of five studies evaluating the effectiveness of de-implementing inappropriate PPI use, four found a significant reduction (RR 0.21; 95% CI 0.18–0.26 to RR 0.76; 95% CI 0.68–0.86). No significant differences in the occurrence of pharmaceutical effects (n= 1) and in length of stay (n = 3) were observed.

  3. (Alhazzani et al.): PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence).

    There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality).

  4. (Zhou et al.): 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)

  5. (Krag et al.): During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group.

Clinical Bottom Line and Significance:

Given the results of these studies, it would be my clinical opinion that PPIs are the most effective prophylactic strategy for stress ulcer prophylaxis when compared to other agents or no treatment at all. However, the benefit of PPIs must be balanced against the danger of pneumonia and, perhaps, Clostridium difficile infection. When the patient is no longer at risk for stress ulceration, the prophylaxis should be stopped. However, today, there are not any standards or tools that specify when it’s okay to stop using prophylaxis. Nevertheless, unless risk factors continue, this research supports that prophylaxis should be stopped after ICU discharge. This approach is supported by the argument that, despite prophylaxis’ ability to reduce nosocomial GI bleeding among non-critically ill patients compared to no prophylaxis, these patients’ overall risk of bleeding is low. Several studies have shown a persistently high rate of ongoing SUP among patients who are discharged from the ICU, despite the lower risk in hospitalized patients who are not critically ill. As mentioned in my strongest study, there was sufficient statistical evidence that supports an increased risk of pneumonia when PPIs were compared with H2 blockers (OR 1.27, 95% CI 0.96-1.68; moderate-quality evidence), sucralfate (OR 1.65, 95% CI 1.20-2.27), and placebo (OR 1.52, 95% CI 0.95-2.42; 3.1 percent absolute increase).These figures raise fundamental doubts about the net benefit of SUP and its widespread adoption.