Risk factors for stress ulcers and stress ulcer prophylaxis

Stress ulcer prophylaxis is a topic that comes up frequently on the internal medicine service but is not frequently given more than a moment of consideration.  Numerous studies have identified how acid-suppressive therapies (eg. namely proton pump inhibitors and histamine-2 receptor antagonists) are widely prescribed and often lacking an indication.  Studies of various designs have revealed that 46-73% of patients who receive acid-suppressive therapy while hospitalized do not have an indication.^1-3 

The most robust guideline to date for the use of acid-suppressive therapy for stress ulcer prophylaxis was published in 1999 and was comprised of data almost entirely from patients in the intensive care unit (ICU).⁴  At that time, there was only one randomized control trial addressing stress ulcer prophylaxis in the non-ICU setting.  These guidelines identified and determined the weight of various risk factors for the development of stress ulcers and these values are continued to be used today.  The presence or absence or risk factors should be used to determine the need for stress ulcer prophylaxis, not just admission to the ICU.  The summary of recommendations follows below.

Major risk factors:

• Mechanical ventilation (for ≥48 hours)
• Coagulopathy (platelet <50,000/mm³, INR >1.5, aPTT >2x control)

Each of these is an independent predictor of clinically important bleeding and prophylaxis is recommended if either of these risk factors is present (Strength of evidence = C).  To give you an idea of the scale of this problem, if one or both of these major risk factors are present, clinically important bleeding rates were 3.7%.  If neither were present, they were 0.1%.

• Additionally, history of GI bleed or ulcer in the past year before admission is considered a risk factor justifying prophylaxis (Strength of evidence = D)

Minor risk factors:

• Sepsis
• Renal insufficiency
• Hepatic failure
• Enteral feeding
• High dose glucocorticoids [>250 mg hydrocortisone or equivalent (~60 mg prednisone, ~50 mg methylprednisolone, ~9 mg dexamethasone)]
• Heparin
• Warfarin
• ICU stay > 1 week
• Occult bleeding for ≥6 days

None of these are independent predictors of clinically important bleeding and prophylaxis is recommended only if ≥2 are present (Strength of evidence = D)

Risk factors in special patient populations (in the ICU plus):

• Head/spinal injury (with Glasgow Coma Scale ≤10)
• Thermal injuries (involving >35% of body surface area)
• Undergoing hepatic or renal transplant
• Hepatic failure

Prophylaxis is recommended for patients in the ICU with any of these risk factors

Choice of agent

In the original AJHP guideline, proton pump inhibitors (PPIs) were not recommended due to lack of evidence.  Since then, PPIs have overtaken histamine-2 receptor antagonists in popularity and are widely used for stress ulcer prophylaxis, with good reason.  PPIs are able to sustain the gastric pH >6, do not need to be dose adjusted for renal dysfunction, and have been shown to reduce clinically important upper GI bleeding compared to histamine-2 receptor antagonists in a recent meta-analysis of randomized controlled trials.⁵ 

As far as efficacy is concerned, choice in PPI is irrelevant as all are considered equivalent at equivalent doses.  The dose recommended for stress ulcer prophylaxis is:⁴

• Omeprazole 20 mg daily or twice daily

Drug	Approximate dose equivalent
Omeprazole (Prilosec) Pantoprazole (Protonix) Rabeprazole (Aciphex) Lansoprazole (Prevacid) Esomeprazole (Nexium) Dexlansoprazole (Dexilant)	20 mg 40 mg (so 40 mg once or twice daily per our formulary) 20 mg 30 mg 20 or 40 mg 60 mg

Lastly, acid-suppressive therapy is not without risks.  PPIs have been associated (not causality) with the development of:

• Community-acquired pneumonia
• Hospital-acquired pneumonia
• Clostridium difficile-associated diarrhea and recurrence
• Osteoporosis
• Increased cost to the institution and eventually patient if continued on discharge
• Multiple vitamin deficiencies, thrombocytopenia, acute interstitial nephritis, drug interactions
• Rebound gastric acid hypersecretion

Take home points:

• Decide whether to start stress ulcer prophylaxis based on the above risk factors and reevaluate need for therapy if risk factors resolve
• Pantoprazole 40 mg daily or twice daily is an appropriate dose
• Proton pump inhibitors, though very effective, are not a side effect free class

References:

1.  Nardino RJ, Vender RJ, Herbert PN.  Overuse of acid-suppressive therapy in hospitalized patients.  Am J Gastroenterol  2000;95(11):3118-22.

2.  Hughes GJ, Belgeri MT, Perry HM.  The impact of pharmacist interventions on the inappropriate use of acid-suppression therapy.  Consult Pharm  2011;26:485-90.

3.  Reid M, Keniston A, Heller JC, et al.  Inappropriate prescribing of proton pump inhibitors in hospitalized patients.  J Hosp Med  2012;7(5):421-5.

4.  ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm. 1999; 56:347-79.

5.  Alhazzani W, Alenezi F, Jaeschke RZ, et al.  Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis.  Crit Care Med  2013;41(3):693-705.

photo by cygnus921