Initial Steps to Prevent Nonsteroidal Anti-Inflammatory Drug- or Aspirin-Induced Enteropathy: Long-Term Outcome Data.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin are among the most frequently prescribed and used medications.1 With the development of video capsule endoscopy, the frequency and severity of NSAID enteropathy has become more evident.2 NSAID-induced enteropathy has a different pathological mechanism from gastroduodenal mucosal injury, so different treatments and preventative strategies are needed.

NSAID-induced enteropathy is common. Approximately 70% of regular NSAID users develop injury in the small intestine, which is more common than gastroduodenal mucosal injuries.2 Endo et al.3 reported small-bowel mucosal breaks in 57.6% of patients receiving NSAIDs. There is a poor correlation between NSAID-induced damage and symptoms in the small intestine. NSAID-induced enteropathy is usually asymptomatic or has nonspecific symptoms, such as iron-deficiency anemia, occult blood, diarrhea, hypoalbuminemia, and malabsorption of vitamin B12. Endo et al.4 studied patients on low-dose aspirin with obscure gastrointestinal (GI) bleeding with capsule endoscopy and found that more than 95% of the patients had some mucosal injury in the small bowel. The enteropathy was characterized by multiple petechiae and loss of villi. It revealed that even low doses of NSAIDs could lead to the generation of erosions and ulcerations in the small intestine.5 Maiden et al.6 reported mucosal injury in the small bowel in 68% to 75% of volunteers after 2 weeks of therapy with 75 mg slow-release diclofenac taken twice daily.

Recent studies have reported unwanted and more dangerous adverse effects in the small intestine if proton pump inhibitors (PPIs) are combined with NSAIDs.7 PPIs, by suppressing gastric acid secretion, are very effective for reducing NSAID-induced damage in the stomach but are without proven benefit in preventing NSAID-related damage in the rest of the GI tract.7 Moreover, PPIs alter the microbiome in the small intestine.8 Capsule endoscopy studies have revealed that adding PPIs to NSAIDs results in a higher frequency of mucosal lesions in the small intestine than the frequency observed in patients taking NSAIDs alone.9,10 Some investigators have reported that all patients taking both NSAIDs and PPIs have ulcerations in the small intestine.9 Most patients (80% to 100%) taking low-dose NSAIDs and PPI therapy have active mucosal lesions in the small bowel after 2 weeks of therapy.10 A recent prospective capsule endoscopy study found that enteric-coated aspirin and PPI were the two most important risk factors for the development of mucosal breaks in the small intestine.3 However, it should be considered that it was an observational cross-sectional study, and PPI use is a well-known marker of comorbidity that might not have been properly controlled for in the analysis.11 No human clinical trial has shown that the combination of a PPI and aspirin is associated with an increased risk of lower GI bleeding.

Strategies to prevent aspirin- or NSAID-induced enteropathy include the identification and modification of associated risk factors and co-prescription of a protective agent.12 Shim et al.13 showed outcomes and long-term follow-up data in a nationwide multicenter study in Korea and reported that recurrence of NSAID-induced small bowel injury was not frequent (4.6%). Conservative management was also sufficient in most recurrent cases. The risk factors for recurrence were old age and hypertension. However, that study did not present accurate information of coadministered drugs after the initial episode of bleeding because of its retrospective design. However, after or during the first episode of small bowel bleeding, 64% of patients received PPIs. These patients might have added or continued to take PPIs for treatment of enteropathy alone as well as to lower the risk of upper GI bleeding. Six patients showed recurrence. There were no comparative data on PPI use between the recurrent and nonrecurrent cases. If it is supposed that all recurred cases were taking PPIs, the maximum possible recurrence rate for NSAID-PPI coadministration would be 6 of 61 (10%). The study did not analyze which type of aspirin the patients had used. However, in Korea, most of the aspirin prescribed for cardiovascular prevention is the enteric coated form. In the initial episode of bleeding, the most prominent capsule endoscopic findings were multiple ulcerations (59%) and erosions or aphthae (23%). However, the diagnosis of recurrence depended on clinical findings without a repeated capsule endoscopy. Lesions in the small intestine might tend to persist whether NSAID therapy is continued or not.

NSAID- or low-dose aspirin-induced enteropathy is common but can be asymptomatic.11 Moreover, because of the difficulty in diagnosing it, as well as the lack of any proven-effective treatment for NSAID-induced enteropathy, the clinical relevance may be underestimated. Shim et al.13 showed a clinically benign course of enteropathy in long-term follow-up data. Further studies of drug interactions and risk factor analyses are required to determine an effective preventive strategy.