Clinical Question:

During my Internal Medicine rotation, I have seen many critically ill patients who were prescribed Protonix or Prilosec (which are proton pump inhibitors) for stress ulcers prophylaxis to combat against any future gastrointestinal bleeding. That got me thinking about Histamine 2 receptor antagonists and why I have not seen any prescribed for the same indication. Are H2RAs subtherapeutic against PPIs, or are they seen as more harmful?

Search Question:

In critically ill patients who are prescribed stress ulcer prophylaxis, how do histamine 2 receptor antagonists compare with proton pump inhibitors in reducing gastrointestinal bleeding and reducing other possible adverse events like pneumonia and Clostridium difficile?

PICO Question:

P	I	C	O
Stress ulcer prophylaxis	Histamine 2 receptor antagonists	Proton pump inhibitors	Reducing gastrointestinal bleeding
Critically ill patients prescribed stress ulcer prophylaxis	H2RAs	PPIs	Reducing pneumonia
Patients prescribed stress ulcer prophylaxis			Reducing Clostridium difficile

Search Strategy:

PubMed

• Stress ulcer prophylaxis AND Histamine 2 receptor antagonists – 82 articles
  • Filters: last 10 years
• Stress ulcer prophylaxis AND Histamine 2 receptor antagonists AND Proton pump inhibitors – 71 articles
  • Filters: last 10 years

TRIP Database

• (Stress ulcer prophylaxis) (Histamine 2 receptor antagonists) – 16 articles
  • Filter: last 10 years
• (Stress ulcer prophylaxis) (Histamine 2 receptor antagonists) (Proton pump inhibitors) – 5 articles
  • Filter: last 10 years

Cochrane Library

• (Stress ulcer prophylaxis) (Histamine 2 receptor antagonists) – 21 articles
  • Filter: Last 10 years
• (Stress ulcer prophylaxis) (Histamine 2 receptor antagonists) (Proton pump inhibitors) – 2 articles
  • Filter: Last 10 years

For the article selection of my critically appraised topic (CAT) I wanted to find articles that were of the highest level of evidence available, which were either a systematic review or a meta-analysis. I looked for studies that were within that last ten years, which all were.

I searched through 3 different databases and I ended up choosing my six articles from PubMed and Trip Database. I included two systematic reviews/meta-analysis, one meta-analysis, and three retrospective cohort studies (where one of them was a retrospective, single-center, pharmacoepidemiologic study). Many of the articles I found talked about the cost analysis between using PPIs or H2RAs for stress ulcer prophylaxis, which did not correlate with what I was looking for. Other articles had comparisons for stress ulcer prophylaxis between H2RAs, sucralfate, and placebos.

Articles Chosen (6 or more) for Inclusion:

1) Wang, Y., Ge, L., Ye, Z. et al. Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated systematic review and network meta-analysis of randomized trials. Intensive Care Med 46, 1987–2000 (2020). https://doi-org.york.ezproxy.cuny.edu/10.1007/s00134-020-06209-w

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

https://link-springer-com.york.ezproxy.cuny.edu/article/10.1007/s00134-020-06209-w

2) Zhou, X., Fang, H., Xu, J., Chen, P., Hu, X., Chen, B., . . . Xu, Z. (2019). 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, 19, 1-14. https://doi.org/10.1186/s12876-019-1105-y

Abstract

Background: 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 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.

https://www.proquest.com/docview/2328444504/fulltextPDF/EA46E9B44AE34C58PQ/1?accountid=15180&sourcetype=Scholarly%20Journals

3) Liu, Y., Li, D., & Wen. A. (2020). Pharmacologic Prophylaxis of Stress Ulcer in Non-ICU Patients: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Clinical Therapeutics, 42(3), 488-498.e8. https://doi.org/10.1016/j.clinthera.2020.01.008

Abstract

Purpose: Acid-suppressive medications are widely used in non–intensive care unit (non-ICU) patients for stress ulcer (SU) prophylaxis. However, SU prophylaxis in this population is still controversial. The purpose of this study was to systematically evaluate the efficacy and tolerability of these agents for SU prophylaxis in non-ICU patients.

Methods: Electronic databases including Cochrane, ClinicalTrials.gov, Ovid-Medline, Embase, Chinese CNKI, and Wanfang Data were systematically searched on July 10, 2019, for randomized controlled trials (RCTs) that evaluated acid-suppressive medications in non-ICU patients. Network meta-analysis and pairwise meta-analysis were performed to calculate odds ratios (ORs) and 95% CIs. A random-effects model was used for generating pooled estimates. The primary outcome was occurrence of SU bleeding, and the adverse drug events (ADEs) were described as the secondary outcome.

Findings: A total of 17 RCTs involving 1985 patients were eligible. Meta-analysis results indicated that the occurrence of SU bleeding was significantly decreased with all acid-suppressive medications compared with placebos (gastric mucosa protectants, OR = 0.29 [95% CI, 0.14–0.61]; H2-receptor antagonists, OR = 0.3 [95% CI, 0.18–0.50]; proton pump inhibitors [PPIs]: OR = 0.08 [95% CI, 0.04–0.16]). The occurrence of SU bleeding was significantly decreased with PPIs compared with gastric mucosa protectants (OR = 0.29; 95% CI, 0.12–0.72) and H2-receptor antagonists (OR = 0.28; 95% CI, 0.16–0.48). There was no significant difference between any 2 classes of PPIs on SU bleeding or any 2 acid-suppressive medications on ADEs.

Implications: PPIs could significantly decrease SU bleeding risk without increasing ADEs than other acid-suppressive medications for SU prophylaxis in non-ICU patients. However, RCTs of high quality were required to confirm the findings of this investigation.

https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S0149291820300436

4) Lilly, C. M., Aljawadi, M., Badawi, O., Onukwugha, E., Tom, S. E., Magder, L. S., & Harris, I. (2018). Comparative Effectiveness of Proton Pump Inhibitors vs Histamine Type 2 Receptor Blockers for Preventing Clinically Important Gastrointestinal Bleeding During Intensive Care: A Population-Based Study. Chest, 154(3), 557–566. https://doi.org/10.1016/j.chest.2018.05.015

Abstract

Background: Proton pump inhibitors (PPIs) and histamine type 2 receptor blockers (H2Bs) are used for stress ulcer prophylaxis. Although the PPIs have greater potency for acid suppression, their relative effectiveness for preventing clinically important GI bleeding (CIGIB) has not been established. The goal of this study was to determine whether prophylactic PPIs were associated with lower risk of CIGIB than H2Bs among critically ill adults.

Methods: This retrospective cohort study included adults with critical illness from January 1, 2008, to June 30, 2012, who had at least one stress ulcer risk factor and received a PPI or H2B for ≥ 3 days. Cox proportional hazards regression propensity score matching and instrumental variable analyses were used to control for selection bias and confounding by unmeasured factors. The Acute Physiology and Chronic Health Evaluation Score version IV score was used to adjust for differences of acuity. The main outcome and exposure was CIGIB.

Results: Among 70,093 patients at risk, 49,576 (70.7%) received prophylaxis for at least 3 days, and 424 patients (0.6%) met the definition for experiencing CIGIB. The hazard for CIGIB was two times greater for PPI users compared with H2B users (adjusted hazard ratio, 1.82 [95% CI, 1.19-2.78]; hazard ratio, 2.37 [95% CI, 1.61-3.5]). Sensitivity analyses failed to detect any plausible scenario in which PPIs were superior to H2Bs for the prevention of CIGIB.

Conclusions: H2Bs were robustly and consistently associated with significantly lower CIGIB risk compared with PPIs in this population.

https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S0012369218307955?via%3Dihub

5) Song, M. J., Kim, S., Boo, D., Park, C., Yoo, S., Yoon, H. I., & Cho, Y. J. (2021). Comparison of proton pump inhibitors and histamine 2 receptor antagonists for stress ulcer prophylaxis in the intensive care unit. Scientific reports, 11(1), 18467. https://doi.org/10.1038/s41598-021-98069-7

Abstract

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446063

6) Boyd C, Hassig T, MacLaren R. 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. Pharmacotherapy. 2021; 41: 820–827. https://doi-org.york.ezproxy.cuny.edu/10.1002/phar.2621

Abstract

Objective: 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.

Design: This is a retrospective, single-center, pharmacoepidemiologic study.

Setting: This study was carried out in six intensive care units (ICUs).

Patients: Critically ill adults admitted between 9/1/14 and 9/1/19 who received PPIs or H2RAs within 24 h of intubation and for ≥48 h were included in this study.

Intervention: PPIs or H2RAs for stress ulcer prophylaxis.

Measurements and Main Results: Primary outcomes were CIGB occurring 48 h 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.

Conclusion: 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.

https://accpjournals-onlinelibrary-wiley-com.york.ezproxy.cuny.edu/doi/full/10.1002/phar.2621

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc)	Outcome(s) studied	Key Findings	Limitations and Biases
Wang, Y.; Ge, L.; Ye, Z.; Siemieniuk, R.A.; Blaser, A.R.; Wang, X.; Perner, A.; Moller, M.; Alhazzani, W.; Cook, D.; Guyatt, G. (2020)	Systematic Review and Meta-Analysis	– 74 randomized controlled trials enrolled 39,569 patients that were looked at	– Outcomes included mortality at the longest follow-up reported, clinically important bleeding, pneumonia, and Clostridioides difficile infection   – Statistical analysis was preformed using RevMan version 3.4.3 and Stata version 15.1	– PPIs had little to no impact in regards to mortality, while H2RAs had no impact   – Regarding clinically important bleeding, both PPIs and H2RAs had reduced risks of bleeding (RR = 0.65 vs. 0.67)   – There were no differences in patients who developed pneumonia who were taking PPIs or H2RAs (RR = 1.08 vs. 1.07)   – The risk of the patients getting C. diff were similar in both cohorts (RR = 1.05)	– The limitations that were discussed included lack of blinding in some of the RCTs, lack of allocation sequence concealment, and excessive loss to follow up on some patients
Zhou, X.; Fang, H.; Xu, J.; Chen, P.; Hu, X.; Chen, B; Wang, H.; Hu, C.; Xu, Z. (2019)	Meta-Analysis	– 29 randomized controlled studies were included in this meta-analysis which included six RCTs, seven multi-center retrospective cohort studies, and twenty-two single center retrospective cohort studies   – The number of participants varied between each study. The numbers ranged from 25 patients to 3,298 patients.	– The primary outcome looked at clinically important GI bleeding and overt GI bleeding   – Secondary outcomes looked at incidences of pneumonia and Clostridium difficile infection (CDI)   Statistical analysis was preformed using Stata/SE version 11.0 software and trial sequential analysis was preformed using TSA program version 0.9.5.10 beta	– Regarding the primary outcomes, usage of PPIs or H2RAs led to a decreased risk of clinically important bleeding (RR = 0.58) and a significant reduction in the incident of overt GI bleeding was seen with the use of either PPIs or H2RAs   – Regarding secondary outcomes, administration of either PPIs or H2RAs did not lead to increased risk of developing pneumonia nor did it lead to increased risk of developing a C. diff infection.	– The widely varied number of subjects between trials could have thrown off effect sizes between smaller studies and much larger ones   – The definition of overt GI bleeding and clinically important bleeding varied between different studies that may cause statistical heterogeneity
Liu, Y.; Li, D.; Wen, A. (2020).	Systematic Review and Meta-Analysis	– This systematic review and network meta-analysis had a total of 17 randomized controlled trials involving 1,985 patients   – The number of patients in each study ranged from 40 to 320	– The primary outcome was the prevalence of stress ulcer bleeding with the use of different acid-suppressive medications   – Secondary outcomes included overall adverse events during prophylactic treatment, including death, infection, headache, diarrhea, nausea, myalgia, dermatitis, and abnormal vision   – Statistical analysis was preformed using Stata version 13.1 and Review Manager version 5.1	– The primary outcome of the time saw that patients that were on PPIs were associated with a significantly lower occurrence of stress ulcer bleeding than patients who were on H2RAs (OR = 0.28)   – Additional primary outcomes showed there were no statistically significant differences in what type of PPI was used as a stress ulcer prophylaxis   – Regarding secondary outcomes, the prevalences of overall adverse drug events were 1.9% with PPIs and 3.1%–34.6% with H2RAs	– There was a higher bias for random sequence generation in 10 trials, allocation concealment in 17 trials, blinding of participants and personnel in 12 trials, and blinding of outcome assessment in 17 trials
Lilly, C.; Aljawadi, M.; Badawi, O.; Onukwugha, E.; Tom, S.; Magder, L.; Harris, I. (2018)	Retrospective Cohort Study	– This retrospective cohort study was a multicenter study that took place in various ICUs throughout Maryland   – 49,576 patients who were critically ill and needed stress ulcer prophylaxis (SUP)   – Half the patients were on PPI prophylaxis and the other half were on H2RAs. Each cohort were on SUP for at least three days	– The primary outcome this study looked at was incidence of clinically important GI bleeding (CIGIB)   – Statistical analysis was performed using SAS, version 9.3 and Stata version 11	– The risk of CIGIB was nearly twofold higher among the PPI group compared with the H2RA group (HR = 1.97)   – There was also a higher risk of CIGIB in the PPI cohort among male patients (HR = 1.27) and patients who had acute renal failure (HR = 1.59)	– Some patients in the study might not have met the criteria of what clinically important GI bleeding was   – The patients were not completely randomized in which cohort they would be assigned to
Song, M.J.; Kim, S.; Boo, D.; Park, C.; Yoo, S.; Yoon, H.; Cho, Y. (2021)	Retrospective Cohort Study	– In this single-center retrospective cohort study, 1,870 critically ill patients were given stress ulcer prophylaxis to combat against GI bleeding   – The cohorts were split into equal halves, with 935 patients in the PPI cohort and 935 patients in the H2RA cohort	– The primary outcome was looking at the hospital mortality up to 90 days   – Secondary outcomes included instances of clinically important GI bleeding, pneumonia, and C. difficile infection   – Statistical analysis was performed using the Cyclops package from OHDSI	– The primary outcome saw 242 patients (25.9%) die in the PPI cohort vs. 204 patients (21.8%) die in the H2RA cohort, which was a 28% increase between the groups   – There were no statistically significant differences between the two cohorts in the risk of clinically important GI bleeding, which occurred in 1.6% of the PPI group and 1.7% of the H2RA group   – There were also no significant differences between the PPI and H2RA groups concerning the risk of pneumonia (RR 1.08) and C. difficile infection (RR 1.47)	– Only data from indexed hospitalizations was included, so the mortality rate may have been underestimated   – Incidences of pneumonia and C. difficile may also have been underestimated due to hospital indexing
Boyd, C.; Hassig, T.; MacLaren, R. (2021)	Retrospective, Single-center, Pharmaco-Epidemiologic Study	– In this retrospective, single-center, pharmaco-epidemiologic study, there were 3,873 patients at the UCHealth University of Colorado Hospital   – 2,061 patients were part of the PPI cohort (where the most common PPI administered was pantoprazole once daily)   – 1,812 patients part of the H2RA cohort (where the most common H2RA administered was famotidine once to twice daily)	– The primary outcomes were looking at clinically important GIB and mortality   – Secondary outcomes included instances of infectious complications of pneumonia and CDI, kidney injury, myocardial dysfunction, thrombocytopenia, and delirium with a special look at risk factors for mortality   – Statistical analysis was performed using the JMP Pro statistical analysis software, v.10.0.2 (SAS Institute Inc.)	– The overall occurrence of any GIB was not different between PPIs and H2RAs (0.58% vs. 0.44%, respectively; RR = 1.32), seven (0.34%) patients in the PPI group and no patients in the H2RA group (p = 0.013) experienced the primary outcome of clinically important GIB at least 48 h from ICU admission   – Four from those seven patients from the PPI cohort who had CIGIB died between 3-7 days after admission   – There were also no significant differences between the PPI and H2RA groups concerning incidence of pneumonia, CDI, acute kidney injury, and myocardial infarction/ischemia   – In-hospital mortality remained significantly more likely to occur with PPI therapy compared to H2RA therapy	– Retrospective cohort studies rely on hospital records, so some extraction errors may have occurred   – Thirty-two patients were still a part of the study even though they received both agents. They may have been started on one group and then switched to another

Conclusion(s):

Article 1 concluded by saying critically ill patients who were treated with either a PPI or an H2RA had similar effects on mortality compared to each other, but PPIs had a slightly higher increase in mortality (with lower certainty of evidence). The incidences of pneumonia or C. diff were not statistically significant in either cohort.

Article 2 concluded by saying usage of either stress ulcer prophylaxis (PPIs or H2RAs) were a benefit in reducing the risk of clinically important GI bleeding in critically ill patients. Patients who were given enteral nutrition fared a lot better with SUP than without enteral nutrition. Administration of either PPIs or H2RAs did not lead to increased risk of developing pneumonia nor did it lead to increased risk of developing a C. diff infection.

Article 3 concluded by saying PPIs were more effective in reducing stress ulcers in non-ICU patients than H2RAs. PPIs also did not increase any adverse drug events during prophylactic treatment, including death, infection, headache, diarrhea, nausea, myalgia, dermatitis, or abnormal vision.

Article 4 concluded by saying H2RAs were associated with fewer episodes of clinically important GI bleeding and risk of CIGIB was nearly twofold higher among the PPI group compared with the H2RA group.

Article 5 concluded by saying the patients who received PPIs for their stress ulcer prophylaxis had a significantly higher 90-day mortality than the patients who received H2RAs. There were no statistically significant differences in either cohort regarding the risk of pneumonia or C. diff.

Article 6 concluded by saying PPIs were associated with greater risks of clinically important GI bleeding and in-hospital mortality over H2RA usage. Secondary outcomes like pneumonia and C. diff were not statistically significant in either cohort.

My overall conclusion based off these 6 studies is that real world studies showed that usage of histamine 2 receptor antagonists had much lower clinically important GI bleeding and in-hospital mortality in critically ill patients over the usage of proton pump inhibitor. Taking into consideration that neither drug gave rise to increased risks of either pneumonia or C. diff infections, I would prescribe H2RAs over PPIs in patients of this population.

Clinical Bottom Line:

I will weigh my studies in the following order: Article 1, Article 2, Article 4, Article 5, Article 6 and lastly Article 3.

I weighed article 1 the highest of all my articles. This article was my first systematic review and meta-analysis and it had close to 40,000 participants. The PEPTIC trial was the largest clinical trial ever conducted in intensive care medicine and it looked at the effects of PPI vs. H2RA administration for stress ulcer prophylaxis with patients in the ICU. Both PPIs and H2RAs had reduced risks of bleeding (RR = 0.65 vs. 0.67), and there were no differences in either cohort with secondary outcomes like risks of the patient acquiring pneumonia or C. difficile.

I weighed article 2 the next highest because it was also a systemic review and meta-analysis with over 6,000 participants. This study showed that the usage of either drug led to a decreased risk of clinically important GI bleeding (RR = 0.58) as well as overt GI bleeding. Enteral nutrition seemed to also decrease mortality when it was administered with either stress ulcer prophylaxis. Administration of either PPIs or H2RAs did not lead to increased risk of developing pneumonia nor did it lead to increased risk of developing a C. diff infection

Next for me is article 4. Even though this was a multi-center retrospective cohort study, there were close to 50,000 participants in the study that received either PPIs or H2RAs for their SUP. CIGIB was seen as two times greater for PPI users compared with H2RA users (AHR = 1.82). Even though this study did not go into whether there were any increased risks of pneumonia or C. diff infections, the sheer number of participants that were seen could not go unnoticed.

Next was article 5 for me. This article had a clear delineation of participants in each cohort (935 per group). The primary outcome, although different from looking at whether the drug caused clinically important GI bleeding, looked at the 90-day in-hospital mortality rate which was significantly higher for the patients who were on the PPIs than those who were on the H2RAs (RR = 1.28). As the other articles have already mentioned, there were no statistically significant differences in either cohort regarding risks of acquiring pneumonia or C. diff.

Second to last for me was article 6. This was another retrospective cohort study that was done through a pharmaco-epidemiological lens. This study showed us that CIGIB was a rare occurrence, but it did happen more often in the PPI group than the H2RA group (0.34% vs. 0.00%). Hospital mortality was higher in the PPI group than in the H2RA group (42.1% vs. 29.1%, RR = 1.23). Seven participants from the PPI group had CIGIB, and four of those seven died within a week after admission. There were no significant differences in either cohort in the risk of acquiring pneumonia or C. diff.

Lastly for me is article 3. Even though this article was a systematic review/meta-analysis, the patients in the study were not in the ICU setting. The study also did not look at any of the secondary outcomes like risks of developing pneumonia or a C. diff infection. Many limitations plagued this article including a higher bias for random sequence generation and blinding of participants and personnel in more than half of the trials, and bias in allocation concealment and blinding of outcome assessment in every single one of the trials.

Clinical significance (not just statistical significance)

The systematic reviews/meta-analysis showed us that neither drug had increased risks of clinically important GI bleeding nor any increased risks of developing secondary adverse drug events like pneumonia or a C. difficile infection. The retrospective studies, where real world patients in metropolitan cities were looked at, showed us that H2RAs were indelibly better for ICU patients in terms of reducing in-hospital mortalities and reducing CIGIB against PPIs and did not have risks of secondary adverse outcomes. In that sense, since H2RAs were non-harmful and helped patients in every study that was presented, I would choose histamine 2 receptor agonists over proton pump inhibitors as my stress ulcer prophylaxis of choice in critically ill patients.

Any other considerations important in weighing this evidence to guide practice 

Many of my articles mentioned that the usage of proton pump inhibitors over histamine 2 receptor antagonists came from flawed guidelines from over two decades ago, with many providers and clinicians raising concerns over their usage. The PEPTIC trial showed many of those guideline’s flaws, and many other studies came after it to show that H2RAs were more therapeutic and led to less mortalities than PPIs. There need to be more recent studies done to further identify the most appropriate selection of stress ulcer prophylaxis, and more studies that show how much more cost-effective it is to use one type of drug over the other.