Medicolegal Issues

Stress Ulcer Agents


 

An article published this year in the American Journal of Health-Systems Pharmacy defined stress ulcers as “acute superficial inflammatory lesions of the gastric mucosa induced when an individual is subjected to abnormally high physiologic demands.”1

These stress ulcers are believed to be caused by an imbalance between gastric acid production and the normal physiologic protective mucosal mechanisms in the gastrointestinal (GI) tract. Reduction of blood flow to the gastric mucosa may also lead to ischemic damage to the GI mucosa.

New and Pipeline Drugs

Thrombin-JMI Epistaxis Kit. Although most likely to be used in emergency departments (EDs) and trauma centers, the new Thrombin-JMI Epistaxis Kit (topical bovine thrombin, King) may find its way to hospitals and physician offices.

This new intranasal spray delivery device for hemostatic treatment of oozing blood and minor bleeding of accessible capillaries or small venules, was recently FDA approved. Some high-risk groups require rapid intervention to curb epistaxis (e.g., the elderly) to prevent complications or life-threatening events. The Thrombin-JMI intranasal spray delivery device works directly by clotting fibrinogen. It should not to be used on large blood vessels or injected. The kit is supplied in a package that includes a 20,000 IU vial of thrombin with 20 mL diluent, a spray pump, and actuator. It is expected to be available in EDs and trauma centers by year’s end.

Selzentry (maraviroc, Pfizer). FDA-approved on Aug. 6, it is the first agent in a new class of anti-HIV drugs known as HIV entry blockers. This agent holds promise for HIV-positive patients who no longer respond to other anti-HIV drugs (e.g., protease inhibitors, reverse transcriptase inhibitors). Maraviroc is effective against a specific strain of HIV known as CCR5-tropic HIV-1. Maraviroc binds to CCR5, blocking HIV from binding to this receptor. When CCR5 is unavailable, CCR5-tropic HIV cannot engage a CD4 cell to infect it. In clinical trials, patients were tested for the presence of CCR5-tropic HIV-1 using a co-receptor tropism assay, Trofile (MonogramBiosciences Inc.), which predicts a patient’s likelihood for response to maraviroc. Maraviroc received a priority review at the FDA and a priority review in the European Union. Monogram Biosciences released Trofile on Aug. 6 to coincide with the commercial availability of maraviroc. SCH-D (vicriviroc, Schering-Plough) is another entry blocker. It is in Phase III clinical trials.

The development of stress ulcers, or stress-related mucosal disease (SRMD), occurs in 75% to 100% of critically ill patients within 24 hours of intensive care unit (ICU) admission. Although bleeding risk has decreased over the years, mortality from stress-related bleeding nears 50%. According a peer-reviewed guideline from the American Society of Health-System Pharmacists (ASHP), indications for SRMD in the ICU setting include:2

  • Coagulopathy;
  • Mechanical ventilation longer than 48 hours;
  • History of GI ulceration or bleeding within one year of the current admission;
  • Glasgow Coma score of 10 or less (or if unable to obey simple commands);
  • Thermal injury to more than 35% of the body surface area;
  • Partial hepatectomy;
  • Multiple trauma;
  • Transplantation perioperatively in the ICU;
  • Spinal cord injury;
  • Hepatic failure; and
  • Two or more of the following risk factors: sepsis, ICU stay of a week or longer, occult bleeding for more than six days, or high-dose corticosteroids (more than 250 mg a day of hydrocortisone or the equivalent).

Other risk factors for SRMD in ICU patients include multiorgan failure, chronic renal failure, major surgical procedures, shock, and tetraplegia.3,4

Recommended SRMD prophylaxis agents should be institution-based, taking into account the administration route (e.g., functioning GI tract), daily dosing regimens, adverse effect profile, drug interactions, and total costs. Classes that can be used include sucralfate, antacids, H2 receptor antagonists (H2RA), and proton-pump inhibitors (PPIs).

Some patients may prefer the oral route. Some agents can be given in solution or suspension and administered via a nasogastric tube—but be aware of drug interactions. There are limited comparative data for preventing SRMD with these classes. The H2RA and PPI classes of agents are available in intravenous forms, which may be preferable in critically ill patients. However, none of the PPIs are FDA-approved for SRMD prophylaxis.

In the general patient population, SRMD prophylaxis with H2RAs or PPIs is common in 30% to 50% of patients without clear evidence of benefit. Qadeer, et al., identified a 0.4% bleeding rate in their retrospective case-control study of nearly 18,000 patients over a four-year period. In their study, the key risk factor for development of nosocomial GI bleeding was treatment with full-dose anticoagulation or clopidogrel.

Another concern they identified is that when a patient commences an SRMD prophylaxis agent in the hospital, they continue on it post-discharge when it is not needed. This creates an unnecessary cost burden and risks adverse drug interactions.

Todd Janicki, MD, and Scott Stewart, MD, both with the department of medicine at the State University of New York at Buffalo, this year reported on a review of evidence for SRMD prophylaxis in general medicine patients from the peer-reviewed literature.5 They found limited data, identifying only five citations meeting their evaluation criteria. Two of these studies noted only a 3% to 6% reduction in clinically significant bleeding utilizing SRMD prophylaxis. TH

Michele Kaufman is a clinical/managed care consultant and medical writer based in New York City.

New Indications

The two oldest low molecular heparin (LMWH) injection products, Fragmin (dalteparin, Pfizer) and Lovenox (enoxaparin, Sanofi-Aventis) have each added new indications to their U.S. labels. Fragmin is now indicated for extended treatment of symptomatic venous thromboembolism (VTE) including both proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) to reduce VTE recurrence in patients with cancer.

Its other FDA-approved uses:

  • Prophylaxis of DVT (which may lead to PE) in patients undergoing hip replacement surgery;
  • Prophylaxis of DVT in patients undergoing abdominal surgery who are at risk for thromboembolic (TE) complications;
  • Prophylaxis of DVT in patients who are at-risk for TE complications due to severely restricted mobility during acute illness; and
  • Prophylaxis of ischemic complications due to unstable angina and non-Q-wave myocardial infarction (MI) when used along with aspirin.

Lovenox is now also indicated for treatment of patients with acute ST-segment elevation MI (STEMI), managed medically or with subsequent percutaneous coronary intervention (PCI).

Its other FDA-approved uses:

  • Prophylaxis of DVT in abdominal surgery;
  • Prophylaxis of DVT in hip replacement surgery;
  • Prophylaxis of DVT in knee replacement surgery;
  • Prophylaxis of DVT in medical patients with severely restricted mobility during acute illness;
  • Inpatient treatment of acute DVT with or without PE;
  • Outpatient treatment of acute DVT without PE; and
  • Prophylaxis of ischemic complication of unstable angina and non-Q-wave STEMI managed medically or with subsequent PCI.

References

  1. Grube RRA, May DB. Stress ulcer prophylaxis in hospitalized patients not in intensive care units. Am J Health-Syst Pharm. 2007;64:1396-400.
  2. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm. 1999;56:347-379.
  3. Qadeer MA, Richter JE, Brotman DJ. Hospital-acquired gastrointestinal bleeding outside the critical care unit: risk factors, role of acid suppression, and endoscopy findings. J Hosp Med. 2006;1(1):13-20.
  4. Weinhouse GL, Manaker S. Stress ulcer prophylaxis in the intensive care unit. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Mass. 2007.
  5. Janicki T, Stewart S. Stress-ulcer prophylaxis for general medical patients: a review of the evidence. J Hosp Med. 2007;2(2):86-92.

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