NSAIDs and Helicobacter pylori

The authors provide an update on what is known about NSAIDs and Helicobacter pylori as factors in ulcerative gastrointestinal disease and the possibility of a synergistic risk effect between the two.

By M. Khalouck Abdrabbo, MD, and David A. Peura, MD, FACP

What is the clinical significance of nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori?

Nonsteroidal anti-inflammatory drugs and H. pylori are the most important pathogenic factors in the development of peptic ulcers and ulcer complications, but whether they interact additively or synergistically to increase ulcer risk remains controversial. Nonsteroidal anti-inflammatory drugs are prescribed more frequently than any other class of medication worldwide. Aspirin is widely used for cardiovascular prophylaxis, while prescription and over-the-counter (OTC) NSAIDs are frequently used for treatment of musculoskeletal discomfort, pain, and inflammation. More than 100 million prescriptions are written in the United States for NSAIDs, and another 30 billion OTC NSAID tablets are sold annually. One in five Americans is treated with an NSAID during the course of the year. About 70% of people over the age of 65 use NSAIDs weekly and 30% use them daily.
 

What are the most serious side effects associated with NSAIDs?

Nonsteroidal anti-inflammatory drugs are usually well tolerated, and their enormous use is a testimonial to the overall safety of this class of medication. However, side effects, when they do occur, can be quite serious. Gastrointestinal complications are the most commonly reported severe adverse events associated with NSAIDs. In the United States alone, more than 16,000 people die each year due to NSAID-related gastrointestinal side effects and an additional 100,000 people are hospitalized. This amounts to approximately 50 NSAID-related deaths and 300 hospitalizations daily, a situation of epidemic proportion that exceeds the morbidity and mortality from Hodgkin's disease, cervical cancer, and asthma combined.
 

What specific gastrointestinal complications can occur with NSAID use?

The serious gastrointestinal complications associated with NSAIDs include gastric and duodenal ulcers and ulcer complications such as bleeding or perforation. Up to 40% of chronic NSAID users develop endoscopic ulcers in the stomach and 15% in the duodenum. Most of these ulcers occur during the first 90 days of treatment. Although many ulcers are asymptomatic, some do cause significant symptoms or complications. Serious complications such as gastrointestinal bleeding reportedly occur in 1% to 2% of the general population of NSAID users, although as many as 15% of high-risk individuals develop problems each year if not appropriately managed. Also, NSAID-associated problems are not limited to the upper gastrointestinal tract; serious lower gastrointestinal tract events occur at a rate of 0.9% per year in rheumatoid arthritis patients who take naproxen.
 

Which patient populations are at highest risk for complications resulting from NSAID use?

Certain individuals who use NSAIDs are at particularly high risk for gastrointestinal complications. Previous ulcer disease, especially complicated ulcer, appears to increase the risk of subsequent serious NSAID-related gastrointestinal events 4- to 13-fold. In fact, ulcer rebleeding occurs in as many as 18% of patients with prior bleeding ulcers when they resume taking an NSAID or even low-dose aspirin.

Most chronic NSAID use is by the elderly, a population that often has associated comorbid illness, takes other medications, and self-medicates with OTC products, all of which increase susceptibility to and morbidity from drug-related adverse events. Old age by itself increases the risk of gastrointestinal complications three- to five-fold. Almost 3% of people older than 70 years of age experience a serious NSAID-associated complication. Since many of the elderly also take aspirin for cardiovascular protection, they are at even greater risk. The same holds true when they are prescribed anticoagulants or corticosteroids concomitantly with NSAIDs.
 

What is the role of H. pylori infection in ulcer disease?

A little more than 30 years ago, Drs. Barry Marshall and Robin Warren first cultured H. pylori and pointed out its relationship to ulcer disease. Subsequent reports from around the world suggested that ulcer disease was an infectious disease because more than 90% of patients with duodenal ulcer and 60% to 80% with gastric ulcer were infected with the bacterium. Studies confirmed that cure of infection accelerated ulcer healing, prevented ulcer recurrence, and in many instances obviated consequent ulcer complications.

More recent evidence, however, indicates that noninfectious ulcers are becoming more frequent, probably paralleling the declining prevalence of H. pylori in many parts of the world. As many as 60% of duodenal ulcers are now H. pylori negative, and 10% to 15% of ulcers recur after successful treatment of infection. Nevertheless, it is still important to test for and treat H. pylori in all ulcer patients since many can still be cured of their chronic disease.
 

By what mechanisms of action do NSAIDs and H. pylori cause ulcer disease?

Nonsteroidal anti-inflammatory drugs and H. pylori infection produce ulcers by different mechanisms. Prostaglandins are important substances responsible for gastrointestinal mucosal defense. Nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase (COX), the enzyme that controls prostaglandin synthesis, thereby weakening defense mechanisms and rendering the mucosa more susceptible to the ulcerogenic effects of acid and pepsin.

On the other hand, mucosal inflammation resulting from H. pylori infection not only disrupts mucosal defenses but also alters the physiology of gastric acid secretion. The robust acid secretion that accompanies infection in many individuals, coupled with impaired mucosal defenses, enhances susceptibility to ulcer disease. But even when acid production is not augmented by H. pylori infection, the severely inflamed mucosa is less able to defend itself against peptic injury and exogenous irritants.

Therefore, H. pylori and NSAIDs clearly should be viewed as independent risk factors for ulcer disease, but whether they interact additively or synergistically in ulcerogenesis remains an issue for debate. The confounding impact of concurrent low-dose aspirin in H. pylori-infected NSAID users is also a concern.

A recent meta-analysis examining the role of H. pylori infection and NSAID use in ulcer disease suggests a synergistic relationship. This analysis showed that uncomplicated ulcers were four times more commonly diagnosed in patients who took NSAIDs than in those who did not, irrespective of H. pylori status. Helicobacter pylori infection alone increased the risk of ulcers 3.5-fold. However, in those who were both infected with H. pylori and taking an NSAID, the ulcer risk was 60-fold greater compared to uninfected, non-NSAID users.

The synergy was similar with bleeding ulcers, although NSAIDs appeared to be the major determinant of complications. Infection was associated with a 1.79-fold increased bleeding risk, and NSAID use a 4.85-fold increase, while both factors together increased ulcer bleeding risk 6.13-fold. The authors concluded that H. pylori infection and NSAIDs significantly and independently increase the risk of ulcers and complications. For that reason, all patients with an ulcer should be treated for H. pylori, when present. However, even cure of infection does not obviate subsequent complications associated with NSAIDs, although it does significantly reduce the risk for complications associated with low-dose aspirin. In another report, most patients who experienced recurrent ulcer bleeding after resuming low-dose aspirin had persistent infection, again confirming the interaction between aspirin and H. pylori.
 

What about H. pylori infection in NSAID users who have not yet developed an ulcer?

A recent study of patients about to begin taking NSAIDs for the first time showed that H. pylori eradication could reduce the subsequent incidence of ulcers and complications. Whether patients who have been taking NSAIDs for a long time would benefit from H. pylori treatment remains to be determined. Until such data are available, there is no compelling reason to test NSAID users for H. pylori infection unless they have a history of ulcer disease.
 

What is the appropriate treatment regimen for NSAID-associated ulcers?

The therapeutic approach to an NSAID-associated ulcer is relatively straightforward. Healing the ulcer is the initial priority, followed by reducing the risk of ulcer recurrence. Treating H. pylori infection, if present, and reevaluating the need for an anti-inflammatory drug or an alternative analgesic, such as acetaminophen, may suffice. When NSAIDs are stopped, either histamine–2 receptor antagonists or proton pump inhibitors (PPIs) will effectively heal ulcers. (A PPI will heal an ulcer faster.) If NSAIDs are continued, then the lowest possible dose should be used and a PPI prescribed. Studies have shown that a PPI is the most efficient ulcer treatment for patients who continue taking NSAIDs. Because sucralfate is not as effective as acid suppression in this setting, it is not recommended for treatment of NSAID-associated ulcers.

Although the COX-2 inhibitors cause fewer gastrointestinal problems than traditional NSAIDs, they do not heal ulcers. Therefore, it is inappropriate to prescribe one of these drugs for a patient with an active ulcer without a concomitant PPI.
 

How can the risk for an initial or recurrent ulcer be minimized?

The key to the management of NSAID-related gastrointestinal problems is decreasing the risk for an initial or recurrent ulcer or subsequent complications. Consequently, individuals with the risk factors mentioned earlier are candidates for risk reduction strategies, such as using either misoprostol (a synthetic prostaglandin) or a PPI together with an NSAID or prescribing a COX-2 inhibitor. Misoprostol prevents ulcers and their complications, especially when taken at full dose (200 mcg three or four times daily), although at this dose side effects, particularly diarrhea, limit patient compliance. Lower doses of misoprostol, while better tolerated, are less effective. On the other hand, PPIs are well tolerated, prevent recurrent ulcers, and ulcer rebleeding even in high-risk NSAID users who are also taking low-dose aspirin. The COX-2 inhibitors also effectively lower the risk for NSAID-related ulcers and complications. However, it appears that concomitant aspirin use will diminish a COX-2 inhibitor's favorable gastrointestinal safety profile.

The data comparing a COX-2 inhibitor to combination therapy with an NSAID and PPI are limited but suggest both strategies are effective in reducing, but not completely eliminating, complications. Whether prescribing a COX-2 inhibitor and a PPI for high-risk patients, especially those who also take aspirin for cardiovascular reasons, can obviate almost all complications still needs to be determined.
 

How is H. pylori infection diagnosed and treated?

Tests available to diagnose H. pylori infection include those requiring endoscopy and biopsy and noninvasive techniques such as the urea breath test, stool antigen, and serology. Endoscopic techniques are highly sensitive and specific, but they are expensive, which limits their usefulness in an office setting. Many physicians still rely on serology to diagnose infection because it is widely available and inexpensive. But in areas with a low prevalence of H. pylori, the positive predictive value of serology is too low to recommend treatment based on a positive test result. Serology cannot reliably distinguish between current or prior infection. As a corollary, however, it has good negative predictive value, so a negative test result essentially excludes H. pylori infection.

Better noninvasive alternatives to serology are the stool antigen test and urea breath test. These techniques, now readily available to clinicians, are easy to perform and relatively inexpensive. Unlike serology, both are accurate before and after treatment, assuming no antibiotic use for four weeks or PPI use for one week prior to testing, which could lead to false negative results. A recent international consensus report identifies the urea breath test and stool antigen test as the tests of choice to diagnose H. pylori infection in the office setting.

A 10- to 14-day course of triple therapy (a PPI, amoxicillin 1000 mg, and clarithromycin 500 mg, all taken twice daily) can successfully cure infection in more than 80% of patients. Substituting metronidazole 500 mg for amoxicillin is appropriate only in penicillin-sensitive individuals due to the high rates of nitroimidazole-resistant organisms. Documented treatment failures—that is, patients with a positive stool, breath, or endoscopic test after treatment—have likely acquired macrolide resistance and thus should not be retreated with clarithromycin. Retreatment should be a two-week course of quadruple therapy: a PPI twice daily, plus two tablets of bismuth subsalicylate, tetracycline 500 mg, and metronidazole 500 mg, all four times daily. This higher metronidazole dose is helpful in overcoming antibiotic resistance. For particularly refractory cases, rifabutin- or furazolidone-based triple therapy has proved successful.
 

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