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

Stress-related gastrointestinal (GI) mucosal damage (also known as stress ulcers) can bedetected endoscopically in the majority of critically ill patients; however, the incidence of clinicallysignificant gastrointestinal bleeding as a result of this damage is approximately 1.5% to4%.

1,2Patients who develop gastrointestinal bleeding have an increased risk of death and longer

lengths of stay in the intensive care unit (ICU).PathophysiologyGastrointestinal mucosal damage in critically ill patients is believed to be due to a number offactors, and is not completely understood. However, hypoperfusion of the gastrointestinal tract isbelieved to be a primary cause of injury.

2,3The hypoperfusion may reduce the synthesis of the

protective mucus layer which is also eroded by toxins or refluxed bile salts that are not rapidlyremoved due to decreased gastrointestinal motility. The acidic environment of the stomachcontributes to the damage. Continued hypoperfusion impairs mucosal healing while reperfusionalso contributes by enhancing the inflammatory response.Risk Factors

A 1994 study by Cook and colleagues identified 2 primary risk factors for clinically relevantgastrointestinal bleeding in critically ill patients: greater than 48 hours of mechanical ventilationand coagulopathy.

1Other 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 ofgastrointestinal bleeding.

2,3

ProphylaxisAntacids, 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 ofexperience with these agents, and numerous clinical trials, the optimal prophylactic agent remainsunknown.In 1999, the American Society of Health-System Pharmacists (ASHP) developed a clinical practiceguideline for stress ulcer prophylaxis.

4They recommended prophylaxis for patients who are

mechanically ventilated for more than 48 hours, those with a history of gastrointestinal bleeding orulcer within the past year, and in patients with 2 or more of the following: sepsis, ICU stay longerthan 1 week, occult bleeding lasting 6 or more days, or use of high-dose corticosteroids. Therecommended 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 withan anticipated release date later this year.

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In 2008, the Eastern Association for the Surgery of Trauma (EAST) published clinical practiceguidelines for stress ulcer prophylaxis.

6They recommended prophylaxis for all patients who are

mechanically ventilated, have coagulopathy, traumatic brain injury, or major burn injury. Inaddition, 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-dosecorticosteroids. The authors considered the efficacy of H2RAs, PPIs, and sucralfate to beequivalent.The 2008 Surviving Sepsis Campaign guidelines also included a statement on stress ulcerprophylaxis.

7They 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 in2012.Generally, antacids are no longer used for stress ulcer prophylaxis. A 1996 meta-analysisdetermined that antacids did reduce the risk of bleeding compared with no therapy but thisdifference was not significant.

8In addition, antacids were significantly inferior to H2RAs. The

relative lack of efficacy coupled with an undesirable safety profile has eliminated antacids asuseful agents for stress ulcer prophylaxis in critically ill patients.

2,3In that same meta-analysis,

sucralfate did significantly reduce bleeding compared with no therapy.7

It also lowered the risk ofpneumonia and improved mortality. However, sucralfate is not commonly used for stress ulcerprophylaxis. In fact, a 2004 survey of critical care physicians indicated that 87% prescribe eitheran H2RA or PPI for stress ulcer prophylaxis.

9

Differentiating the efficacy and safety of the H2RAs and PPIs has been attempted in numerousclinical trials and meta-analyses. Two large recent meta-analyses have been published.

10,11Both

meta-analyses showed a lower incidence of upper GI bleeding with PPIs compared with H2 RAs;however, in the 2010 meta-analysis this difference was not statistically significant while it was

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significant in the 2012 analysis. Characteristics of these meta-analyses are shown in the tablebelow.Table. Recent meta-analyses evaluating PPIs and H2RAs for stress ulcer prophylaxis.

Barkun 201210

Lin 201011

Study inclusion criteria Randomized controlled trials in

adult, critically ill patients at riskfor GI bleeding

PPIs versus H2RAs Clinically relevant outcomes(studies that only evaluatedgastric pH were excluded)

Randomized controlled trials in

adult, critically ill patientsPPIs versus H2RAs Clinically relevant outcomes(studies that only evaluatedgastric pH were excluded) Studies that did not explicitlystate whether the patients werein the ICU were excluded

Number of studies 13 7*

Number of patients 1587 936

Primary outcome Clinically significant upper GIbleeding

Patients with upper GI bleeding

Other outcomes Nosocomial pneumonia All-cause mortality

ICU days

Pneumonia

ICU mortality

Results The incidence of GI bleedingwas reduced with PPIscompared to H2RAs (OR 0.30;95% CI 0.17 to 0.54; NNT 39) The incidence of nosocomialpneumonia was similar withPPIs 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 ICUwas similar with PPIs andH2RAs (WMD=-0.12 days; 95%CI -1.90 to 1.66)

The incidence of GI bleedingwas 11/540 (2.04%) with PPIsand 31/396 (7.83%) with H2RAs(pooled risk difference -0.04(95% CI -0.09 to 0.01; p=0.08) The incidence of pneumoniawas similar between groups;10.8% with PPIs versus 10.4%with H2RAs (pooled risk

difference 0.0; 95% CI -0.04 to0.05; p=0.86) ICU mortality was also similarbetween groups 16.7% withPPIs versus 15% with H2RAs(pooled risk difference 0.02;95% CI -0.04 to 0.08; p=0.5)

Conclusion PPIs reduce the incidence ofstress-related mucosal bleedingcompared with H2RAs incritically ill patients with similarincidence of nosocomial

pneumonia and mortality.

PPIs and H2RAs have similarincidence of stress-relatedmucosal bleeding, pneumonia,and ICU mortality.

*All 7 studies were included in the 2012 meta-analysis.

Abbreviations: CI=confidence interval, GI=gastrointestinal, H2RAs=histamine-2 receptorantagonists, ICU=intensive care unit, NNT=number needed to treat, OR=odds ratio, PPIs=protonpump inhibitors, WMD=weighted mean difference.There were a number of different PPIs evaluated in the studies, but the most common PPIs wereintravenous pantoprazole or omeprazole (intravenous or oral).

10,11Intravenous cimetidine or

ranitidine were the most commonly used H2RAs. It appears clear from these meta-analyses thatthere 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 associationwith 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 astrong association between PPI use andClostridium difficile-associated diarrhea.

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SummaryStress ulcer prophylaxis with PPIs or H2RAs is commonly provided to critically ill patients at risk forgastrointestinal bleeding. A recent meta-analysis of 13 studies found a significant reduction instress ulcer bleeding with PPIs in critically ill patients compared with H2RAs. However, PPIs didnot reduce the length of stay in the ICU or improve mortality compared with H2RAs. The primarylimitation 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 factorsfor 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? CurrOpin 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 Website.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 stressulcer prophylaxis. Eastern Association for the Surgery ofTrauma.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 guidelinesfor 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 incritical care. Crit Care Med. 2004;32(10):2008-2013.10. Barkun AN, Bardou M, Martel M. Proton pump inhibitors vs. histamine 2 receptor antagonistsfor stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis.Am JGastroenterol. 2012;107(4):507-520.

11. Lin PC, Chang CH, Hsu PI, Tseng PL, Huang YB. The efficacy and safety of proton pumpinhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among criticalcare 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 andproton pump inhibitor therapy: a meta-analysis.Am J Gastroenterol. 2012;107(7):1001-1010.

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