Are proton pump inhibitors more effective than histamine-2 receptor antagonists for stress ulcer prophylaxis?

Stress-related gastrointestinal (GI) mucosal damage (also known as stress ulcers) can be detected endoscopically in the majority of critically ill patients; however, the incidence of clinically significant gastrointestinal bleeding as a result of this damage is approximately 1.5% to 1,2 4%. Patients who develop gastrointestinal bleeding have an increased risk of death and longer lengths of stay in the intensive care unit (ICU). Pathophysiology Gastrointestinal mucosal damage in critically ill patients is believed to be due to a number of factors, and is not completely understood. However, hypoperfusion of the gastrointestinal tract is 2,3 believed to be a primary cause of injury. The hypoperfusion may reduce the synthesis of the protective mucus layer which is also eroded by toxins or refluxed bile salts that are not rapidly removed due to decreased gastrointestinal motility. The acidic environment of the stomach contributes to the damage. Continued hypoperfusion impairs mucosal healing while reperfusion also contributes by enhancing the inflammatory response. Risk Factors A 1994 study by Cook and colleagues identified 2 primary risk factors for clinically relevant gastrointestinal bleeding in critically ill patients: greater than 48 hours of mechanical ventilation 1 and coagulopathy. Other risk factors include hypotension, renal or hepatic failure, sepsis, trauma (especially head or spinal cord injury), burns (>35% of body surface area), and a history of 2,3 gastrointestinal bleeding. Prophylaxis Antacids, sucralfate, histamine-2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) have been evaluated for the prevention of stress ulcers in critically ill patients. Despite years of experience with these agents, and numerous clinical trials, the optimal prophylactic agent remains unknown. In 1999, the American Society of Health-System Pharmacists (ASHP) developed a clinical practice 4 guideline for stress ulcer prophylaxis. They recommended prophylaxis for patients who are mechanically ventilated for more than 48 hours, those with a history of gastrointestinal bleeding or ulcer within the past year, and in patients with 2 or more of the following: sepsis, ICU stay longer than 1 week, occult bleeding lasting 6 or more days, or use of high-dose corticosteroids. The recommended prophylactic agents included sucralfate for patients with gastric access via the oral, nasogastric, or gastrostomy route, and H2RAs for other critically ill patients at risk for stress ulcers. At the time of this guideline, there was minimal information on PPIs for stress ulcer prophylaxis; thus, they are not a recommended therapy. The ASHP guidelines are currently being updated with 5 an anticipated release date later this year. In 2008, the Eastern Association for the Surgery of Trauma (EAST) published clinical practice 6 guidelines for stress ulcer prophylaxis. They recommended prophylaxis for all patients who are mechanically ventilated, have coagulopathy, traumatic brain injury, or major burn injury. In addition, prophylaxis for patients in the ICU was recommended for patients with multiple trauma, sepsis, acute renal failure, an Injury Severity Score greater than 15, or patients using high-dose corticosteroids. The authors considered the efficacy of H2RAs, PPIs, and sucralfate to be equivalent. The 2008 Surviving Sepsis Campaign guidelines also included a statement on stress ulcer 7 prophylaxis. They recommended the use of either an H 2RA or a PPI. However, H2RAs were given a higher evidence grade (1A versus 1B). An update to these guidelines is anticipated in 2012. Generally, antacids are no longer used for stress ulcer prophylaxis. A 1996 meta-analysis determined that antacids did reduce the risk of bleeding compared with no therapy but this 8 difference was not significant. In addition, antacids were significantly inferior to H2RAs. The relative lack of efficacy coupled with an undesirable safety profile has eliminated antacids as 2,3 useful agents for stress ulcer prophylaxis in critically ill patients. In that same meta-analysis, 7 sucralfate did significantly reduce bleeding compared with no therapy. It also lowered the risk of pneumonia and improved mortality. However, sucralfate is not commonly used for stress ulcer prophylaxis. In fact, a 2004 survey of critical care physicians indicated that 87% prescribe either 9 an H2RA or PPI for stress ulcer prophylaxis. Differentiating the efficacy and safety of the H2RAs and PPIs has been attempted in numerous 10,11 clinical trials and meta-analyses. Two large recent meta-analyses have been published. Both meta-analyses showed a lower incidence of upper GI bleeding with PPIs compared with H 2 RAs; however, in the 2010 meta-analysis this difference was not statistically significant while it was

significant in the 2012 analysis. Characteristics of these meta-analyses are shown in the table below. Table. Recent meta-analyses evaluating PPIs and H2RAs for stress ulcer prophylaxis. 10 11 Barkun 2012 Lin 2010 Study inclusion criteria Randomized controlled trials in adult, critically ill patients at risk for GI bleeding PPIs versus H2RAs Clinically relevant outcomes (studies that only evaluated gastric pH were excluded) Randomized controlled trials in adult, critically ill patients PPIs versus H2RAs Clinically relevant outcomes (studies that only evaluated gastric pH were excluded) Studies that did not explicitly state whether the patients were in the ICU were excluded 7* 936 Patients with upper GI bleeding Pneumonia ICU mortality The incidence of GI bleeding was 11/540 (2.04%) with PPIs and 31/396 (7.83%) with H2RAs (pooled risk difference -0.04 (95% CI -0.09 to 0.01; p=0.08) The incidence of pneumonia was similar between groups; 10.8% with PPIs versus 10.4% with H2RAs (pooled risk difference 0.0; 95% CI -0.04 to 0.05; p=0.86) ICU mortality was also similar between groups 16.7% with PPIs versus 15% with H2RAs (pooled risk difference 0.02; 95% CI -0.04 to 0.08; p=0.5) PPIs and H2RAs have similar incidence of stress-related mucosal bleeding, pneumonia, and ICU mortality.

Number of studies Number of patients Primary outcome Other outcomes Results

13 1587 Clinically significant upper GI bleeding Nosocomial pneumonia All-cause mortality ICU days

The incidence of GI bleeding was reduced with PPIs compared to H2RAs (OR 0.30; 95% CI 0.17 to 0.54; NNT 39) The incidence of nosocomial pneumonia was similar with PPIs and H2RAs (OR 1.05; 95% CI 0.69 to 1.62) All cause mortality was similar with PPIs and H2RAs (1.19; 95% CI 0.84 to 1.68) The number of days in the ICU was similar with PPIs and H2RAs (WMD=-0.12 days; 95% CI -1.90 to 1.66) PPIs reduce the incidence of stress-related mucosal bleeding compared with H2RAs in critically ill patients with similar incidence of nosocomial pneumonia and mortality.

Conclusion

*All 7 studies were included in the 2012 meta-analysis. Abbreviations: CI=confidence interval, GI=gastrointestinal, H 2RAs=histamine-2 receptor antagonists, ICU=intensive care unit, NNT=number needed to treat, OR=odds ratio, PPIs=proton pump inhibitors, WMD=weighted mean difference. There were a number of different PPIs evaluated in the studies, but the most common PPIs were 10,11 intravenous pantoprazole or omeprazole (intravenous or oral). Intravenous cimetidine or ranitidine were the most commonly used H2RAs. It appears clear from these meta-analyses that there is no significant difference between these classes of drugs in mortality or pneumonia; however, whether PPIs offer a significant advantage in reducing stress ulcer bleeding is unclear. Additional concerns with the use of PPIs in place of H2RAs are their cost and association with Clostridium difficile-associated diarrhea. Neither of these issues was addressed in the above meta-analyses; however, a recent meta-analysis of case-control or cohort studies suggests a 12 strong association between PPI use andClostridium difficile-associated diarrhea.

Summary Stress ulcer prophylaxis with PPIs or H2RAs is commonly provided to critically ill patients at risk for gastrointestinal bleeding. A recent meta-analysis of 13 studies found a significant reduction in stress ulcer bleeding with PPIs in critically ill patients compared with H 2RAs. However, PPIs did not reduce the length of stay in the ICU or improve mortality compared with H2RAs. The primary limitation to choosing PPIs over H2RAs are cost related. Updated clinical practice guidelines are anticipated in late 2012. References: 1. Cook DJ, Fuller HD, Guyatt GH, et al for the Canadian Critical Care Trials Group. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med. 1994;330(6):377-381. 2. Ali T, Harty RF. Stress-induced ulcer bleeding in critically ill patients. Gastroenterol Clin N Am. 2009;38(2):245-265. 3. Quenot JP, Thiery N, Barbar S. When should stress ulcer prophylaxis be used in the ICU? Curr Opin Crit Care. 2009;15(2):139-143. 4. ASHP. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm. 1999;56(4):347-379. 5. Therapeutic Guidelines. American Society of Health-System Pharmacists Web site.http://www.ashp.org/Import/PRACTICEANDPOLICY/ PolicyPositionsGuidelinesBestPractices/BrowsebyDocumentType/TherapeuticGuidelines.aspx. Accessed July 10, 2012. 6. Guillamondegui OD, Gunter OL, Bonadies JA, et al. Practice management guidelines for stress ulcer prophylaxis. Eastern Association for the Surgery of Trauma.http://www.east.org/tpg/stressulcer.pdf. Published 2008. Accessed June 30, 2012. 7. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. 8. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients.JAMA. 1996;275(4):308-314. 9. Daley RJ, Rebuck JA, Welage LS, Rogers FB. Prevention of stress ulceration: current trends in critical care. Crit Care Med. 2004;32(10):2008-2013. 10. Barkun AN, Bardou M, Martel M. Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012;107(4):507-520. 11. Lin PC, Chang CH, Hsu PI, Tseng PL, Huang YB. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med. 2010;38(4):1197-1205. 12. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107(7):1001-1010.