By Dr. EJ Frech

Adapted from the original publication in Therapeutics and Clinical Risk Management 2009:5 65–73

This article reviews the medical therapy and prophylaxis of NSAID-associated gastrointestinal complications including peptic ulcer disease and non-ulcer dyspepsia.

Introduction
Over one hundred million prescriptions for non-steroidal anti-inflammatory drugs (NSAIDs) were written in the US in 2000, mostly for chronic pain syndromes and rheumatologic conditions. This likely represents only a fraction of NSAID used in the US due to readily available over the counter (OTC) forms of these drugs, including aspirin. Due to the aging population the use of aspirin for the chemoprevention of cardiovascular, cerebrovascular, peripheral vascular disease and metabolic syndrome is likely to continue to increase. The recent widely publicized concerns regarding increased cardiovascular risks associated with cyclo-oxygenase-2 (COX-2) selective inhibitors [i.e. Vioxx – Rofecoxib] has also contributed to increased use of non-selective NSAIDs. In spite of being among the most widely prescribed pharmaceuticals, NSAIDs have long been recognized as a major cause of gastrointestinal morbidity. NSAID-associated gastrointestinal complications range from dyspepsia without endoscopic findings to severe complications such as ulcer-related perforation, obstruction, or hemorrhage. The use of chronic NSAIDs increases the risk of peptic ulcer disease complications by 3- to 5-fold. Overall, 15%–35% of all peptic ulcer complications are reportedly related to chronic NSAID use. Major adverse gastrointestinal events attributed to NSAIDs are responsible for over 100,000 hospitalizations, US $2 billion in healthcare costs, and 17,000 deaths in the US each year.

Despite available medications to aid treatment of NSAID-associated complications, the number of hospitalizations and deaths has remained unchanged in the US. While clinically significant complications such as perforation, obstruction, or hemorrhage are relatively uncommon (1%–2% of all NSAID users, overall incidence of 2%–4% per year), gastrointestinal symptoms such as nausea, heartburn, dyspepsia, and abdominal pain are common and may occur in up to 40% patients taking chronic NSAIDs. Certain groups of persons are at increased risk for developing NSAID-related complications, including patients with a prior history of peptic ulcer disease, the elderly, patients taking high dose NSAIDs, and patients taking concurrent anticoagulation or corticosteroids. Therapeutic strategies to reduce NSAID-associated gastrointestinal complications have focused on treatment of acute events such as peptic ulcer disease and prevention of future events. Historically, the most widely employed prevention strategies involved either cyclo-oxygenase 2 (COX-2) selective inhibitors [i.e. Celebrex – Celecoxib] or administration of a nonselective NSAID with a proton pump inhibitor.

Pathogenesis of NSAID-associated peptic ulcer disease
NSAIDs and Helicobacter pylori are known to independently increase the risk for gastroduodenal ulcers and ulcer bleeding. This has important diagnostic and treatment implications as both ulcerogenic factors are highly prevalent. The relationship between H. pylori infection and NSAID use has important treatment implications. While it is generally thought that H. pylori infection and NSAIDs induce mucosal damage by different mechanisms, there is ongoing debate whether their coincidence is independent, additive, synergistic, or antagonistic. Whether eradication of H. pylori modifies the ulcer risk in patients on chronic NSAIDs remains a topic of debate. Mucosal injury caused by NSAIDs likely occurs by several different mechanisms and can be broadly divided into topical and systemic effects. Most NSAIDs including aspirin are readily absorbed across the gastric mucosa and temporarily trapped within the epithelial cells and cause damage to the gastrointestinal mucosa. The systemic effects play a more central role in the pathogenesis of NSAID-induced ulcers. NSAIDs exert their effects by interfering with prostaglandin production through the direct inhibition of cyclooxygenase activity. Most NSAIDs, including aspirin inhibit COX-1 and COX-2 equally. The ideal NSAID would inhibit COX-2, thereby reducing inflammation, without acting on COX-1 and its cytoprotective effects. The inhibition of COX-1 and loss of  protective gastrointestinal prostaglandins may cause a local ischemic injury by reduction in mucosal blood flow. While associated with less gastrointestinal toxicity, selective COX-2 inhibitors [Celebrex – celecoxib] are still associated with some risk for gastrointestinal toxicity particularly at higher doses and in high risk patients. Recently publicized concerns regarding the increased cardiovascular and thromboembolic risk in patients taking selective COX-2 inhibitors [i.e. Vioxx – Rofecoxib] and high doses of some nonselective NSAIDs has led to a global re-evaluation of the use of these drugs in clinical practice.

Medical therapy for NSAID-associated peptic ulcer disease
The treatment of peptic ulcer disease in H. pylori negative patients relies on prompt discontinuation of NSAIDs and the initiation of medical therapy to promote ulcer healing. Options for medical treatment include cytoprotective agents such as sucralafate [Carafate] and the prostaglandin analogue misoprostol [Cytotec]. The latter aims to restore the prostaglandins which become depleted by COX-1 inhibition. Acid-suppressive agents including histamine-2 antagonists (H2RAs) and proton pump inhibitors (PPIs) have also been employed as medical therapy.

Primary treatment of NSAID-associated peptic ulcer disease
Whenever possible, the primary treatment for NSAID-associated peptic ulcer disease should include discontinuing potential causative agents. In some instances this may not be possible due to concerns of the underlying chronic disease. This commonly occurs in patients with vascular diseases, especially coronary artery disease, which may pose high risk if antiplatelet therapy such as aspirin is discontinued. Numerous studies have evaluated endoscopic ulcer healing rates in the context of continued NSAID use. The extent of gastroduodenal mucosal damage caused by NSAIDs is highly dependent on the intraluminal gastric pH. Low intragastric pH enhances the diffusion of NSAIDs into the gastric mucosa and may facilitate local mucosal injury. While H2RAs have been associated with variations in 24-hour acid suppression, the profound and sustained acid suppressive effects exhibited by proton pump inhibitors have revolutionized the treatment of acid-related gastrointestinal diseases.  Multiple clinical trials have evaluated ulcer healing rates using proton pump inhibitors in chronic NSAID users. PPIs were in general superior to H2RAs, misoprostol, or sulcrafate; for study details, please refer to a detailed discussion in the original paper.

Secondary prophylaxis of NSAID-induced peptic ulcer disease
Once resolution of NSAID-associated peptic ulcer disease has been demonstrated, a careful assessment of risks and benefits of continued NSAID therapy should be undertaken before continuation of NSAID therapy. A number of risk factors have been identified that may be helpful in predicting an increased risk for NSAID-related complications. A history of complicated peptic ulcer disease and the use of multiple NSAIDs are major risk factors for recurrent complications. Therefore, prevention is recommended in high risk patients who are unable to discontinue NSAIDs or who have high risk medical comorbidities that favor continued NSAID therapy, i.e. patients with cardiovascular or cerebrovascular disease. It was concluded that for high risk patients, esomeprazole was well-tolerated and most effective in preventing peptic ulcer disease in those taking chronic NSAIDs – for details, please refer to a detailed discussion in the original paper. Combination treatment of a proton pump inhibitor and a selective COX-2 inhibitor has been suggested for optimal gastrointestinal protection in the highest risk patients, particularly those who have had complicated peptic ulcer disease.

Primary prophylaxis of NSAID-induced peptic ulcer disease
It is widely accepted that particularly proton pump inhibitors are effective in the treatment and prevention of recurrent NSAID-associated peptic ulcer disease. Primary prophylaxis against gastrointestinal complications in chronic NSAID users has been more controversial – for a more detailed discussion, please refer to the original paper. PPIs, H2RAs, misoprostol, or sulcrafate have all been studied and proven to be effective compared to no intervention. While most COX-2 inhibitors are no longer widely available, these drugs provided an alternative strategy in primary and secondary prophylaxis. Several large outcomes studies have demonstrated significantly fewer upper gastrointestinal events in patients treated with selective COX-2 inhibitors compared to non-selective NSAIDs. Whether aspirin negates the potentially protective benefits of selective COX-2 inhibitors remains controversial and patients receiving both aspirin and a selective COX-2 inhibitor may require prophylactic anti-ulcer therapy if they are at risk for gastroduodenal toxicity.

Secondary prophylaxis of NSAID-induced peptic ulcer disease using other antiplatelet agents

Aspirin has a known dose-related risk of gastrointestinal adverse events, particularly in elderly patients. Newer antiplatelet drugs, such as Plavix – clopidogrel have been proposed as an alternative in the prevention and treatment of vascular diseases. The 2000 American College of Cardiology – American Heart Association Guidelines recommended the use of clopidogrel for hospitalized patients with coronary syndromes who are unable to take aspirin because of major gastrointestinal intolerance. This has prompted investigators to evaluate the risk of recurrent ulcer bleeding using other antiplatelet medications. It was concluded that the risk of gastrointestinal bleeding in the aspirin plus esomeprazole group was significantly lower than the clopidogrel group and therefore superior in the prevention of recurrent ulcer bleeding. While the mechanism remains unknown, studies showed that clopidogrel poses a significant risk of peptic ulcer disease. This does not support the proposed 2000 ACC/AHA guidelines for use of clopidogrel in patients with previous gastrointestinal intolerance.

Potential protective effects of nitrovasodilators are of particular interest considering that concurrent use of aspirin and nitrates is common in patients with cardiovascular disease. Nitrates and nitric-oxide releasing drugs are believed to exert their protective effects by maintaining mucosal blood flow at the level of the gastroduodenal microcirculation, thereby counteracting one of the principal deleterious effects of COX-1 inhibition. Recent studies concluded that there was a benefit from co-administration of antisecretory drugs and nitrates in the prevention of upper GI peptic ulcer bleeding associated with NSAIDs, including aspirin.

Treatment of NSAID-associated gastrointestinal symptoms

As many as 40% patients treated with chronic NSAIDs experience upper gastrointestinal symptoms such as dyspepsia, abdominal pain, and heartburn. As many patients require NSAIDs to control their primary underlying chronic disease and cannot tolerate a dose reduction, interruption, or discontinuation of the drugs, studies have been conducted to address whether antisecretory agents are effective in controlling gastrointestinal symptoms related to NSAIDs despite the absence of endoscopic findings. It was concluded that esomeprazole improves upper gastrointestinal symptoms associated with chronic NSAID use, including selective COX-2 inhibitors.

Conclusion
High healing rates of peptic ulcers related to chronic NSAID use are achieved with medical therapy, particularly if the causative agent can be discontinued. The American Gastroenterological Association (AGA) recently released a consensus statement following a panel discussion of physicians in gastroenterology, rheumatology, cardiology, and internal medicine. The panel emphasized a careful review of treatment indications and risk factors, taking into consideration risks for both gastrointestinal and cardiovascular complications. If the causative agent cannot be discontinued, a reduced dose or switch to a more COX-2 selective NSAID in conjunction with co-administration of PPIs was suggested. Misoprostol was effective in reducing the risk of gastric ulcers in high risk patients such as the elderly and patients with previous history of peptic ulcer disease. Yet misoprostol has not been demonstrated to reduce the risk of duodenal ulcerations nor reduction in symptoms related to chronic NSAIDs. Moreover, misoprostol is often poorly tolerated due to gastrointestinal side effects. H2-receptor antagonist therapy is inadequate for patients receiving NSAIDs with risk factors for GI complications; moreover, they have been supplanted by the highly efficacious and well tolerated proton pump inhibitors. Lansoprazole has been shown to be effective in the primary treatment and secondary prophylaxis of NSAID-associated peptic ulcer disease, including maintenance therapy following resolution of duodenal ulcers. Esomeprazole is the only proton pump inhibitor effective in both primary and secondary prophylaxis of NSAID-associated peptic ulcer disease. Esomeprazole is highly effective in reducing non-ulcer related symptoms associated with chronic NSAID use and may help reduce the risk of bleeding from non-NSAID antiplatelet drugs. Clinical studies provide supportive evidence for the use of antisecretory medicine, especially PPIs, in the primary treatment of NSAID-associated peptic ulcer disease. Peptic ulcer disease and related complications may be prevented in chronic NSAID users with primary prophylactic use of adequate doses of misoprostol and anti-secretory medicines, especially PPIs. Aggressive prevention strategies should be undertaken in high-risk patients especially those with a history of peptic ulcer disease to prevent against recurrent peptic ulcer disease and its associated complications.