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1 November 1995 | Volume 123 Issue 9 | Pages 665-672
Objective: To compare the costs of alternative strategies for the treatment of duodenal ulcer.
Design: A cost comparison using decision analysis.
Methods: A decision model was used to compare the costs per cure of an endoscopically documented duodenal ulcer for three initial treatment strategies: 1) H2-receptor antagonist therapy for 8 weeks, 2) antibiotic therapy for Helicobacter pylori infection plus H2-receptor antagonist therapy, and 3) urease test-based treatment. For symptomatic recurrences, secondary treatment strategies included empiric retreatment with the same or other regimen, and treatment based on repeat endoscopy-guided urease test or biopsy, with an assumption of subsequent cure. The cohort modeled for this analysis consisted of patients at low risk for a malignant ulcer. Probability estimates were derived from published clinical trials, cohort studies, and expert opinion. Side effects from combination therapy with antibiotics and H2-receptor antagonists and resulting costs were included from the perspective of a group practice model health maintenance organization.
Results: For all secondary treatment strategies, initial therapy with antibiotics for H. pylori infection plus an H2-receptor antagonist resulted in the lowest average costs per symptomatic cure when the prevalence or likelihood of H. pylori infection exceeded 66% to 76%; the costs ranged from $284 for secondary (re)treatment with empiric antibiotic and H2-receptor antagonist therapy to $398 for endoscopy-guided secondary treatment. Initial treatment with an H2-receptor antagonist resulted in the highest costs, ranging from $372 for secondary treatment with empiric antibiotic and H2-receptor antagonist therapy to $679 for endoscopy-guided secondary treatment. The results were not sensitive to the rates of duodenal ulcer recurrence after either treatment, to the cost of either treatment, or to prevalence of H. pylori.
Conclusions: This cost analysis indicates that, regardless of the secondary treatment used for ulcer recurrence, initial therapy with antibiotics for H. pylori infection plus an H2-receptor antagonist provides the lowest costs per symptomatic cure. These cost savings and the lower recurrence rates associated with this treatment favor eradication of H. pylori as part of the initial treatment of duodenal ulcer.
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?
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. ARTICLE
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.
Methods
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Methods
Results
Discussion
Author & Article Info
References
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.
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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 x 17%) + (0.05 x 83%)]. Therefore, our baseline rate of long-term cure of 85% is conservative.
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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.
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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 who is cured but develops a recurrence. Repeat endoscopy is then done, showing an ulcer that is urease positive. The patient receives a course of antibiotic therapy for H. pylori plus an H2-receptor antagonist and is cured. The costs here include those for a course of H2-receptor antagonist therapy ($173), a course of omeprazole therapy ($109), an office visit for the persistent symptoms ($114), upper endoscopy with urease test ($604), and a course of antibiotic therapy for H. pylori plus an H2-receptor antagonist ($220).
Each cost is multiplied by its associated probability, and the dollar values are added, yielding the expected cost for that branch. The weighted combination of all branches after H2-receptor antagonist therapy yields the expected total direct costs for that strategy.
Analysis
Our analysis was limited to 1 year because of limitations of the published literature beyond this time frame regarding duodenal ulcer recurrence after treatment with an H2-receptor antagonist alone and after combination therapy. All calculations were done with SMLTRE decision software [30], which is used to construct decision trees, assign probability and cost values to each branch, and calculate the expected utility (in this case, cost per cure) by folding back the tree. One-, two-, and three-way sensitivity analyses were done with the most clinically relevant and potentially most influential probabilities and costs.
Results
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The $10 to $19 average cost difference between combination therapy for H. pylori infection and the urease test-based strategy does not include the difference of approximately $60 between upper endoscopy with and without biopsy. Adding this cost to the urease test-based strategy would make the true average cost difference $70 to $79.
For ulcer recurrence, empiric (re)treatment with an H2-receptor antagonist alone or with antibiotics for H. pylori infection (with repeat endoscopy only for persistent symptoms) is less costly than immediate repeat endoscopy. For example, the average cost of initial therapy with antibiotics for H. pylori infection plus an H2-receptor antagonist followed by repeat endoscopy for ulcer recurrence is $372, as opposed to (re)treatment with an H2-receptor antagonist alone or with combination therapy, the average costs of which are $284 and $287, respectively (Table 3).
The costs of secondary treatment with an H2-receptor antagonist alone and of secondary treatment with antibiotics plus an H2-receptor antagonist are nearly identical (an average cost difference of $3 to $7). This may be because of the limited time frame (1 year) of our analysis, which essentially limited the number of ulcer recurrences to one, and because of the conservative nature of the model.
Sensitivity Analyses
In one-way sensitivity analyses, no single variable affected the choice of initial strategy when considered within the ranges reported in the literature. However, several variables were explored in two- and three-way sensitivity analyses within plausible ranges to test the stability of the conclusions in several "what if" scenarios. Because our model for this problem consists of three initial strategies, three secondary strategies for recurrence, and many potential variables that could be explored, the number of possible two- and three-way analyses is substantial. We used clinical judgment and common sense to limit these exploratory analyses and present results for the two secondary strategies for recurrence that are the most likely to be used by clinicians: repeat endoscopy and empiric (re)treatment with antibiotics for H. pylori infection combined with an H2-receptor antagonist.
Prevalence
With endoscopy as the secondary strategy for ulcer recurrence, Figure 2 shows the cost per cure for each initial strategy as a function of the prevalence of H. pylori infection. Although cost differences are small, when the prevalence is very low (< 3%), initial treatment with an H2-receptor antagonist provides the lowest cost per cure. When the prevalence is greater than 66%, initial treatment with antibiotics plus an H2-receptor antagonist is the least costly strategy. Urease test-based treatment is the least costly strategy when the prevalence is more intermediate. This is consistent with the clinical axiom that a good diagnostic test provides the most benefit when the prevalence is intermediate (reflective of clinical uncertainty) [31].
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Long-Term Cure Rates
Within ranges reported in the literature, the results are not sensitive to long-term (1-year) cure rates with treatment with an H2-receptor antagonist alone or treatment with antibiotics for H. pylori infection plus an H2-receptor antagonist. For example, with repeat endoscopy as the secondary strategy for symptomatic recurrence, the long-term cure rate would have to be at least 80% for treatment with an H2-receptor antagonist alone, or less than 53% with combination therapy to make the alternative treatment less costly. Using (re)treatment with antibiotics for H. pylori infection plus an H2-receptor antagonist as the strategy for recurrence, the corresponding long-term cure rate would have to be at least 75% for treatment with an H2-receptor antagonist alone or less than 55% for combination therapy.
Varying prevalence along with long-term cure rates does not affect the choice of the initial strategy. Figure 3 is a three-way sensitivity analysis of the long-term cure rates for H2-receptor antagonist therapy alone, and for combination therapy with antibiotics for H. pylori infection and an H2-receptor antagonist when the prevalence of H. pylori infection is 70% to 100%. Points in areas above any prevalence line show that therapy with an H2-receptor antagonist is the less costly initial strategy while a point below any prevalence line would indicate that antibiotics for H. pylori infection plus an H2-receptor antagonist is the less costly strategy. Intersection of the two broken lines represents the base-case point, which is clearly below all prevalence lines, indicating that the combined therapy with antibiotics and an H2-receptor antagonist is the less costly strategy over this range of clinically plausible prevalences.
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Costs
Depending on the regimen, treatment with antibiotics for H. pylori infection plus an H2-receptor antagonist could be costly. In this analysis, because an H2-receptor antagonist is part of both treatments, costs are not independent. Assume, however, that the costs are independent—for instance, because a proton pump inhibitor is used instead of an H2-receptor antagonist as part of the strategy that includes antibiotics for eradication of H. pylori. In addition, if 20% or 30% of patients receiving therapy with antibiotics for H. pylori infection plus an H2-receptor antagonist had side effects that required an office visit as previously described (increasing the average cost of this strategy by $20 to $50), how would this affect the results? With repeat endoscopy as the secondary strategy for recurrence, the cost of combined antibiotic and H2-antagonist therapy would have to exceed $460 to $702, depending on which two initial strategies are compared, and assuming that the base cost estimate for treatment with an H2-receptor antagonist alone is $178 and the prevalence of H. pylori infection is 95%.
If the prevalence of H. pylori infection and costs of treatment are allowed to vary, does this affect the results, and if so, how? Figure 4 is a three-way sensitivity analysis that 1) examines thresholds for costs of both treatment with an H2-receptor antagonist alone and combined treatment with antibiotics plus an H2-receptor antagonist when the prevalence of H. pylori is 70% to 100%; 2) compares the initial strategies of urease test-based treatment and the combined therapy with antibiotics plus an H2-receptor antagonist; and 3) assumes (re)treatment with antibiotics for H. pylori infection plus an H2-receptor antagonist for symptomatic recurrences. In this figure, points in areas above any prevalence line indicate that the combination therapy is the less costly initial strategy. Intersection of the two broken lines represents the base-case point, which is clearly above all prevalence lines, indicating that the combined therapy with antibiotics and an H2-receptor antagonist is the less costly strategy. If, however, the cost of treatment with an H2-receptor antagonist alone were $50 and the cost of the combined therapy were $300, then the alternative initial strategy (in this example, urease test-based treatment) would be less costly, regardless of the range of prevalence.
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Discussion
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Several limitations of the analysis warrant discussion. Some of these limitations favor eradication of H. pylori as the initial treatment, whereas others favor initial treatment with an H2-receptor antagonist (Table 4). Overall, the model was designed to favor initial treatment with an H2-receptor antagonist—in particular because of our assumptions of 100% compliance and no significant toxicity. Noncompliance would presumably result in higher recurrence rates and increase the cost per symptomatic cure. Also, although H2-receptor antagonists are generally safe and well tolerated, adverse effects such as hepatitis [34, 35], central nervous system symptoms, and several drug interactions have been reported [36].
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We designed a simple, straightforward model to focus on the central issues and costs. The model does not consider cases of pseudomembranous colitis that might result from the regimen for H. pylori eradication. Depending on its frequency and severity, this complication could significantly increase the cost per cure of this strategy. Although, to our knowledge, no definite case of pseudomembranous colitis has been reported with metronidazole-based regimens, this complication is more likely to occur with more recently proven regimens that do not include metronidazole, such as that consisting only of amoxicillin and omeprazole.
The model does not consider reinfection with H. pylori. The estimated annual rate of reinfection of 3% is believed to be an overestimate [37]. Because the reinfection rate is relatively low and the natural history of reinfection (that is, when and how frequently reinfected persons become symptomatic from ulcer disease) is uncertain, we chose to ignore this variable.
Because this analysis was limited to 1 year, we did not consider the possibility of more than one symptomatic recurrence. If there were more than one recurrence, the cost of curing an ulcer with H2-receptor antagonists would be affected to a greater extent than would the cost of the regimen for H. pylori eradication because of the greater likelihood of multiple recurrences in patients receiving initial treatment with H2-receptor antagonists. More than one recurrence per year occurs in 20% of patients with duodenal ulcer disease. Had we included maintenance treatment with an H2-receptor antagonist after the recurrence, the cost per symptomatic cure also would have been increased. In addition, we assumed that all recurrences were uncomplicated, whereas 8% of initially uncomplicated ulcers result in complications such as hemorrhage, obstruction, or perforation when they recur [24].
This analysis considered only direct costs. The effects of considering indirect costs (for example, lost work time) are uncertain; the greater morbidity and increased need for evaluation attributable to the higher recurrence rates that are observed with initial treatment with an H2-receptor antagonist alone are partially offset by the morbidity and need for evaluation that result from antibiotic toxicity. We believe the indirect costs that result from the former would be greater, but this remains unproven.
The population to which the results are generalizable must be mentioned. The results are applicable to patients who, despite having duodenal ulcer disease, are relatively healthy and have no risk factors for serious underlying conditions such as inflammatory bowel disease or cancer. The results may not apply to patients who use nonsteroidal anti-inflammatory drugs in more than an episodic fashion or who have an ulcer with gastrointestinal blood loss. Because we assume in this model that duodenal ulcer disease is diagnosed by endoscopy, the results do not apply to patients with suspected ulcer disease or dyspepsia and may not apply to those with ulcer disease diagnosed by nonendoscopic methods.
Whether the results of the urease test should determine the initial treatment strategy depends on the assumed prevalence of H. pylori infection in duodenal ulcer disease. At the base-case prevalence of 95%, the urease test is more costly than empiric combination therapy. Although the cost difference is small, it does not include the cost of the initial endoscopy which, with biopsy, adds approximately $60 to the cost of the urease test-based strategy.
Because H. pylori is found in more than 95% of patients with duodenal ulcer disease, a urease test generally adds to the cost of a diagnosis both directly (by the added cost to the initial endoscopy and the cost of the urease test itself) and indirectly by false-negative test results with subsequent risk for ulcer recurrence. However, when clinical suspicion suggests an alternative cause for the duodenal ulcer (for example, unrecognized nonsteroidal anti-inflammatory drug use or the Zollinger-Ellison syndrome), which results in a more intermediate prevalence or probability of H. pylori infection, a urease test-based strategy may be less costly. This threshold for prevalence was 66% or 76%, depending on which secondary strategy for recurrence is considered. These prevalence thresholds are below the range reported in the literature. Thus, in the usual circumstance of high prevalence of H. pylori and when there are no identified confounding factors such as multiple duodenal ulcers or the use of nonsteroidal anti-inflammatory drugs, it is unlikely that initial urease testing will add anything but cost to the treatment of duodenal ulcer.
A consensus conference concluded that ulcer disease, whether first presentation or recurrence of the illness, requires treatment with antimicrobial agents in addition to antisecretory drugs [38]. Because it results in cost savings and is associated with lower recurrence rates, a strategy that includes eradication of H. pylori should be the first choice for the initial treatment of duodenal ulcer disease.
Presented at the 15th Annual Meeting of the Society for Medical Decision Making, 24 October 1993, Research Triangle Park, North Carolina.
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