Reviews/Evaluations

Anti-Ulcer Therapy Review

Background

The optimal cost-effective approach to the patient with uninvestigated dyspepsia has long been a matter of debate. First, it is important to recognize that the term dyspepsia represents a symptom, not a diagnosis. A single, universal definition of dyspepsia has not been established. Dyspepsia often is used to reflect a constellation of symptoms including recurring pain and discomfort in the upper abdomen and in some cases heartburn and reflux-like symptoms. Dyspepsia is a common complaint with estimates of 4-5% of patients naming dyspepsia as the primary reason for visiting their primary care provider (1). Furthermore, dyspepsia may indicate any one of several disease states (H.pylori infection, peptic or duodenal ulcer, gastroesophageal reflux, gastric motility disorders, non-ulcer dyspepsia, and malignancy). Symptoms are poor predictors of underlying etiology and there is a wide degree of symptom overlap among the disorders making diagnosis by history ineffective.

Endoscopy is considered the gold-standard for the diagnostic workup of dyspepsia. Upon endoscopy, up to 60% of patients with dyspepsia have no abnormal findings or definitive etiology (2). This is often termed functional dyspepsia or non-ulcer dyspepsia. The rates of peptic ulcer disease, GERD, and gastric malignancy are approximately 15-25%, 5-15%, and < 2% of patients respectively (2). The yield from upper endoscopy increases with age. Up to 95% of patients with duodenal ulcers and 70% of patients with gastric ulcers are associated with H.pylori infection, whereas 30-60% of patients with non-ulcer dyspepsia have H.pylori-induced gastritis. Classifying patients with uninvestigated dyspepsia according to symptom severity of symptom type (e.g. ulcer type, reflux type, etc.) have not shown to be effective in predicting the diagnosis because of the overlap of groupings. Regardless of the underlying etiology, if present, dyspepsia is often a relapsing condition. Symptomatic relapse rates range from 50-80%, necessitating the eed for maintenance therapy in many cases (3).

Evaluation Strategies

There are several initial management options for the patient presenting with new-onset dyspepsia: 1) empiric medical therapy with an acid suppressive or prokinetic drug with diagnostic evaluation reserved for therapeutic failures; 2) immediate diagnostic evaluation in all cases using endoscopy; and 3) H.pylori testing with subsequent eradication therapy in patients who test positive and acid suppressive therapy in patients who test negative (4). Each strategy is not without its limitations. Because resources are limited, efforts have been made to identify the most cost-effective approach. Few randomized trials exist comparing immediate diagnostic evaluation with empiric medical therapy, however, several decision-analyses have been performed (Tables 1 and 2). Yet, disparities that exist among symptoms and definitions of dyspepsia, the perspective of the analysis, the time frame considered, and the outcomes analyzed have produced conflicting conclusions and make clinical trial and decision analysis comparisons difficult.

Because the costs of endoscopy and other diagnostic evaluations are relatively high and the clinical yield is often low, many experts advocate the H.pylori test-and-treat strategy or empiric acid suppression therapy. The Cochrane Review concluded that early endoscopy was not more effective than initial prescribing, but may benefit some patients. Based upon the available literature, the American Gastroenterological Association (2), American Society for Gastrointestinal Endoscopy (5), American College of Gastroenterology (3), in addition to the Department of Veterans Affairs (6), numerous managed care plans and the University of WA (7), have endorsed similar recommendations including:

• Referral for prompt endoscopy is always indicated in patients > 45 years and in patients with alarm symptoms (e.g. weight loss, recurrent vomiting, dysphagia, evidence of bleeding, or anemia).
• If endoscopy has been competently performed once, there is no indication to repeat it unless new alarm symptoms have developed that require investigation.
• After endoscopy, treatment should be directed to the underlying diagnosis. Patients with nonsignificant findings (i.e. functional or non-ulcer dyspepsia), should receive reassurance and a course of acid suppression or prokinetic therapy if necessary.
• Patients < 45 years with no alarm symptoms should undergo H.pylori testing.
• All H.pylori (+) patients should receive eradication therapy. If these patients fail to respond to eradication after 4-8 weeks or alarm features develop, endoscopy is indicated. (It is unlikely that a gastric cancer not yet detected with test-and-treat, would progress to advanced cancer within this time frame).
• H.pylori (-) patients should receive a trial of acid suppression therapy (either H2 Antagonist or PPI) or a prokinetic for 4 weeks. If the patient does not respond by 4 weeks, therapy should be switched between classes for another 4 weeks. If the patient does not respond by 8 weeks, then endoscopy is indicated.

Choice of Empiric Acid Suppressive Therapy

Non-Ulcer Dyspepsia

In general, acid suppressive therapy is associated with marginal benefit over placebo. A meta-analysis of antisecretory agents for non-ulcer dyspepsia suggested a benefit of only 20% over placebo (8). A Cochrane meta-analysis comprised of studies evaluating the benefits of therapy on symptoms of non-ulcer dyspepsia (excluding patients with primarily GERD-like symptoms) suggested that H2 Antagonists are more effective than PPI therapy (RR=0.88; 95% CI = 0.76-1.01) (9). This finding was thought to be the result of lower methodological quality of the H2 Antagonist trials. There is no current evidence nevertheless that PPIs are more effective in treating non-ulcer dyspepsia.

Gastroesophageal Reflux Disease (GERD)

There is no debate as to the superiority of PPIs for the treatment of GERD. PPIs have been shown in numerous trials to be more effective in reducing symptoms, promoting healing, and preventing relapse in patients with GERD. A 1995 meta-analysis of 33 randomized controlled trials with more than 3000 patients demonstrated the following rates of symptom relief: placebo, 27%; H2 Antagonists, 60%; and PPIs, 83% (10). More recently, the Cochrane group summarized the evidence for the empiric treatment of uninvestigated GERD and endoscopy-negative GERD from 21 randomized controlled trials. They found the RR versus placebo for remission of uninvestigated GERD symptoms for H2 Antagonists was 0.77 (2 trials, 95% CI 0.60-0.99) and for PPIs was 0.35 (1 trial, 95% CI 0.26-0.46) for PPIs. Among 3 direct comparison trials, PPIs were found to be significantly more effective than H2 Antagonists (p<0.05). This advantage is particularly evident in patients with more severe GERD, erosive and Barrett's esophagitis, and hypersecretory conditions (e.g. Zollinger-Ellison).

Treatment Strategy: Step-Up and Step-Down Therapy

The wide variation in symptom and severity in patients with dyspepsia and GERD has led to a lack of consensus regarding the most appropriate approach to empiric drug therapy. Despite their obvious advantage, at least in patients with GERD, the universal use of PPIs is limited significantly by cost. In attempts to control escalating treatment costs, treatment strategies such as Step-Up and Step-Down therapy have been advocated. The most conventional, Step-Up therapy, begins empirically with lower cost alternatives such as lifestyle modifications, antacids, and H2 Antagonists reserving PPIs for treatment failures and patients with more severe forms of disease. Conversely, Step-Down therapy begins with a PPI for several weeks and then treatment is "stepped-down" to an H2 Antagonist if maintenance or continued treatment is necessary.

There are no clear data to support either treatment strategy as a universal approach to all patients (12). In its 1999 guidelines, the American College of Gastroenterology notes that although models constructed to evaluate the efficacy and cost-effectiveness of these approaches, neither has been proven superior, and they did not advocate either strategy. For the treatment of non-ulcer dyspepsia and mild to moderate GERD, step-up therapy may be a more cost-effective approach (13, 14). This approach is advocated by the Canadian Association of Gastroenterology (13). However, a recent cost-effective analysis demonstrated that a step-down strategy might be more cost-effective in patients with severe disease (15).

Table 1. Randomized Trials

Table 2. Decision Analysis

Acid Suppressive Therapy Cost Comparison

References

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