A Cost Analysis of Alternative Treatments for Duodenal Ulcer

Duodenal ulcer disease is an important clinical problem primarily because of its frequency. Approximately 500 000 new cases and four million recurrences occur annually in the United States [1]. Although mortality due to duodenal ulcer disease is relatively low, this disease is associated with considerable morbidity and cost. The direct costs of diagnosis and treatment and the indirect costs of time lost from work total between three and four billion dollars per year [2]. Excess production of acid was long believed to cause this condition, but the exact pathogenesis and optimal treatment of duodenal ulcer disease remain areas of ongoing clinical interest and controversy. Helicobacter pylori, a gram-negative, urease-producing organism first isolated from gastric mucosa in 1982 by Marshall and Warren [3], is now considered the major cause of chronic active gastritis and is an integral part of the pathogenesis of peptic ulcer disease. Because H. pylori is present in 90% to 100% of patients with duodenal ulcer [4-6], it has become accepted management to detect and eradicate the organism, resulting in decreased ulcer recurrence. Currently, the most popular method of detection is with a test for urease in an antral biopsy specimen obtained during upper endoscopy. The urease test has a reported sensitivity of 89% to 98% and a specificity of 93% to 98% [7]. We did this cost analysis to determine the answers to several questions: Are there cost savings associated with the initial eradication of H. pylori as compared with traditional acid suppression? Given the high association of H. pylori with duodenal ulcer disease, is a urease test necessary, and what effect does this test have on cost? Do factors such as the prevalence of H. pylori infection in duodenal ulcer disease and the cost and side effects of treatment affect the optimal treatment strategy? Methods We used decision analysis, a quantitative method for determining the optimal management strategy under conditions of uncertainty. Decision analysis allows for the integration of information from the published literature and other sources. A cost-focused decision analysis consists of essentially four steps. The first is to create a decision tree that identifies decision alternatives and their clinical outcomes. The second step is to assign probabilities to each outcome and costs to each treatment strategy. The third step is to determine the best strategy under baseline assumptions of probability and cost (in this case, the lowest cost per cure). The fourth step is to test the stability of the baseline conclusions over a range of plausible probabilities and costs, a process known as sensitivity analysis. Design of the Decision Tree Decision analysis was used to compare the direct costs per symptomatic cure of an endoscopically documented duodenal ulcer for three initial treatment strategies: 1) therapy with an H2-receptor antagonist for 8 weeks; 2) therapy with antibiotics for H. pylori infection plus therapy with an H2-receptor antagonist [combination therapy]; and 3) urease test-based treatment with an H2-receptor antagonist alone or with antibiotics for H. pylori infection plus an H2-receptor antagonist for negative and positive results, respectively. Figure 1 is a decision tree showing the major choices that can be made and the chance events that can occur during the treatment of duodenal ulcer disease: the initial treatment choices as described above; the subsequent course, including initial healing and symptomatic recurrences; and the secondary strategies for evaluation and treatment of symptomatic ulcer recurrence. Figure 1. Decision tree for the treatment of duodenal ulcer. Helicobacter pylori Helicobacter pylori After completion of the initial treatment, patients with persistent symptoms at the end of 8 weeks receive a 4-week course of omeprazole and are assumed to be cured of symptoms after 12 weeks (Figure 1). Patients who later develop a symptomatic recurrence receive one of three secondary strategies: 1) endoscopy-guided treatment with either combination therapy for H. pylori infection; omeprazole; or antacids, based on the results of a diagnostic test [urease test or histologic stains], with an assumption of subsequent symptomatic cure; 2) empiric [that is, nonendoscopic] treatment with the same regimen; or 3) empiric treatment with the other regimen, with repeat endoscopy done only for persistent symptoms and then followed by definitive treatment. Of the three secondary strategies, repeat endoscopy and empiric treatment (or retreatment) with combination therapy are the two that are most likely to be used by practitioners. Empiric treatment (or retreatment) with an H2-receptor antagonist alone is much less likely to be used in practice today but was included in our analysis for completeness and for its former utility. A fundamental assumption of this cost analysis is that all members of the cohort are eventually cured. Patient Population The target population for this analysis is a patient cohort with endoscopically documented duodenal ulcer disease and no risk factors for serious underlying conditions such as cancer or inflammatory bowel disease. Such patients would be younger than age 60 years, would show no weight loss, would not have a history of continuous use of nonsteroidal anti-inflammatory drugs, and would have no evidence of gastrointestinal blood loss. The more recent literature suggests that the prevalence of H. pylori infection in such a cohort would be close to 100% [5]. We assumed that this low-risk patient population would be similar to populations in the cohort studies and clinical trials from which probability values were derived. Further Assumptions of the Model In addition to the assumptions already mentioned, other assumptions were incorporated into the model. Regarding compliance with the treatment for H. pylori, we assumed, in accordance with the published literature [8], that 50% of patients would take less than 60% of the prescribed treatment. Although it would be assumed that this would lower the eradication rate and subsequent long-term cure rate, recent data suggest that reducing the duration of treatment from 2 weeks to 1 week may not significantly affect the efficacy of treatment [9]. We also assumed that 10% of patients receiving antibiotic treatment for H. pylori infection plus an H2-receptor antagonist would require an office visit for adverse effects from the antibiotics. Half of these adverse effects would be rash, the other half would be diarrhea or upper gastrointestinal upset or both. The costs associated with such adverse effects were incorporated into the base cost for H. pylori treatment. The regimen used for H. pylori eradication consisted of ranitidine, 300 mg nightly for 8 weeks; amoxicillin, 750 mg three times daily; metronidazole, 500 mg three times daily; and bismuth subsalicylate, 120 mg four times daily, all for 12 days. This regimen was modified from that used by Hentschel and colleagues [10], who observed an eradication rate of 89%. We added bismuth subsalicylate to justify extrapolation of the published data on the efficacy and compliance with bismuth-containing regimens. Substitution of amoxicillin with tetracycline, 500 mg four times daily, results in no appreciable difference in the efficacy or cost of treatment. Finally, we assumed that any endoscopy done for recurrence of symptoms after attempted H. pylori eradication as the initial treatment would include the cost of histologic stains (hematoxylin-eosin and Giemsa) for the detection of H. pylori, provided that an ulcer is visualized during the repeat endoscopy. For repeat endoscopy for symptomatic recurrences after initial treatment with an H2-receptor antagonist alone, we assumed that only an antral biopsy specimen for urease testing would be obtained. Probabilities and Costs Baseline probability values and ranges used in sensitivity analysis were derived from both the medical literature and expert opinion (Table 1). Average healing and recurrence rates for duodenal ulcer were calculated from previous reports of either cohort studies or randomized clinical trials. Rates from each study were used to calculate an overall weighted average. For the H. pylori eradication rate, the calculated weighted average of 83% agrees with the results of a published meta-analysis [27]. Assuming that 55% of H. pylori-positive duodenal ulcers and 5% of H. pylori-negative ulcers recur symptomatically within 1 year [28], the recurrence rate would be 14% [(0.55 17%) + (0.05 83%)]. Therefore, our baseline rate of long-term cure of 85% is conservative. Table 1. Baseline Probabilities and Ranges Used in the Analysis* To provide cost estimates for economic analyses, the perspective simulated was that of a group practice model health maintenance organization. For all medications shown in Table 2, costs were estimated based on average wholesale prices from the 1994 Red Book [29]. Direct medical costs for diagnostic tests, for the technical component of upper endoscopy, and for an office consultation with a gastroenterologist were determined by using the costs for labor and materials assigned by the cost accounting system at a 742-bed teaching hospital. Costs for physician services were based on allowable Medicare reimbursement. Baseline cost estimates for diagnosis, treatment, and management of complications are summarized in Table 2, along with the ranges over which sensitivity analyses were conducted. All costs exclude the cost of the initial upper endoscopy but include all subsequent costs. Table 2. Baseline Direct Costs and Ranges Used in the Analysis* Costs along each branch of the decision tree were weighted by their probabilities and added, resulting in the expected total direct cost for that particular branch (Figure 1). For example, consider a patient who receives initial treatment with an H2-receptor antagonist followed by omeprazole for persistent symptoms and w