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Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis |
Ford A C, Delaney B C, Forman D, Moayyedi P |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The use of eradication therapy in Helicobacter pylori (H. pylori)-positive peptic ulcer disease (PUD) was examined. Four strategies were compared:
no treatment;
an intermittent 1-month course of proton-pump inhibitor (PPI) therapy if the ulcer relapsed to a maximum of two courses;
maintenance PPI therapy with a doubling of the dose for 1 month if the ulcer relapsed; and
a 1-month course of PPI therapy and H. pylori eradication with a further month of PPI therapy if the ulcer relapsed.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised adults with PUD diagnosed at endoscopy or at barium meal.
Setting The setting was primary and secondary care. The economic study was conducted in Leeds, UK.
Dates to which data relate The effectiveness evidence was derived from literature published between 1990 and 2003. The costs were derived from a study published in 2002 and from actual data. The price year was not reported.
Source of effectiveness data The effectiveness data were derived from a review or synthesis of published studies.
Modelling A Markov model was developed, using Treeage Data Pro, to estimate the costs and benefits arising from the adoption of each of the four strategies evaluated. All strategies were evaluated over 1 year. Further details of the model were not reported.
Outcomes assessed in the review The outcomes assessed were:
the proportion of peptic ulcers healed,
the relapse rate,
the relative risk (RR) of an adverse event,
the RR of the ulcer persisting, and
the number-needed-to-treat (NNT).
Study designs and other criteria for inclusion in the review The data were derived from randomised clinical trials. The authors provided a list of predefined eligibility criteria. For example, eligible eradication therapies were PPI dual therapy, PPI/H2 receptor antagonist (H2RA) triple therapy, bismuth triple therapy, bismuth quadruple therapy, ranitidine bismuth citrate dual/triple therapy and clarithromycin monotherapy. Suitable comparative interventions were antisecretory therapy (PPI or H2RA), bismuth salts, sucralfate, antacid (regular or as required), placebo and no treatment.
Sources searched to identify primary studies The Cochrane Controlled Trials Register, MEDLINE, EMBASE and CINAHL were searched for primary studies. A recursive search of the retrieved articles' bibliographies was performed. Abstract books and conference proceedings were handsearched. Pharmaceutical companies and experts were also contacted.
Criteria used to ensure the validity of primary studies The methodological quality of the trials was assessed for adequacy of allocation of concealment.
Methods used to judge relevance and validity, and for extracting data The lead reviewer extracted the data on the basis of intention to treat analysis. A second reviewer conducted an unblinded check of this.
Number of primary studies included Fifty-two primary studies were included in the review.
Methods of combining primary studies The results of the primary studies were combined using a meta-analysis. A 95% confidence interval (CI) was calculated for each outcome. The data for gastric and duodenal ulcer (GU and DU, respectively) healing and recurrence were analysed separately whenever trial reporting allowed this. Comparison regimens were also analysed separately.
Investigation of differences between primary studies A random-effects model was used where significant heterogeneity between trial results was detected, and the reasons for the heterogeneity were explored using meta-regression. A post-hoc sub-group analysis was conducted to evaluate PPI triple therapy and bismuth salt quadruple therapy in preventing DU relapse, compared with no treatment. The result was compared with the main analysis, which included all regimens to evaluate the efficacy of optimum therapy.
Results of the review With no treatment, the healing rate of DU and GU was 25%.
With H2RA, the healing rate of DU was 85% (95% CI: 81 - 88) and that of GU was 89% (95% CI: 84 - 93).
With no treatment, the annual relapse rate of DU was 64% (95% CI: 57 - 70) and that of GU was 57% (95% CI: 34 - 57).
The RR of DU persisting after H. pylori eradication plus H2RA versus ulcer healing drug alone was 0.66 (95% CI: 0.58 - 0.76). The NNT was 14 (95% CI: 11 - 20).
The RR of DU persisting after H. pylori eradication plus H2RA versus no treatment was 0.37 (95% CI: 0.26 - 0.53). The NNT was 2.5 (95% CI: 2 - 4).
The RR of DU relapse after H. pylori eradication versus ulcer healing drug alone was 0.73 (95% CI: 0.42 - 1.25).
The RR of DU relapse after H. pylori eradication versus no treatment was 0.19 (95% CI: 0.15 - 0.26). The NNT was 2 (95% CI: 1.7 - 2.3).
In GU healing, H. pylori eradication therapy was not statistically superior to ulcer healing drug alone (RR 1.32, 95% CI: 0.92 - 1.90).
The RR of GU relapse after H. pylori eradication versus no treatment was 0.31 (95% CI: 0.19 - 0.48).
The RR of DU and GU relapse with maintenance H2RA versus H. pylori eradication was 1.37 (95% CI: 0.8 - 2.37).
The proportion of patients with adverse events was 22% on H. pylori eradication and 8% on H2RA.
The RR of an adverse event with H. pylori eradication was 2.28 (95% CI: 1.72 - 3.02).
Methods used to derive estimates of effectiveness Authors' assumptions were used to supplement the effectiveness evidence to feed into the model. These assumptions were based on a review of observational studies.
Estimates of effectiveness and key assumptions The authors assumed that 33% patients with healed ulcer would remain symptomatic and 50% of these would respond to maintenance PPI therapy.
Measure of benefits used in the economic analysis The main measure of health benefit used was the number of months free from dyspepsia. The benefits were not discounted.
Direct costs The direct costs included were those of the health service. These included the costs of medications, visits to the gastroenterologist and general practitioner, and endoscopy. The unit costs of these cost elements were reported, while the resources required were provided for some of them (based on authors' assumptions). The unit costs were derived from published sources. The total costs for optimal treatment were derived using modelling. All the costs were estimated for a 1-year time horizon, therefore discounting was not necessary and was not carried out. The price year was not reported.
Statistical analysis of costs The costs were treated deterministically. No statistical analysis of the costs was undertaken.
Indirect Costs The indirect costs were not included in the analysis.
Sensitivity analysis A sensitivity analysis was carried out to investigate the robustness of the results to variation in the input parameters used in the model. All model input parameters were tested in one-way sensitivity analyses. In addition, a probabilistic sensitivity analysis, in which a Monte Carlo simulation of 1,000 was used to vary all input parameters simultaneously, was undertaken. A 2-year follow-up was evaluated for GU disease. The upper and lower bounds of the 95% CIs around each estimate, as reported in the literature, were used for health outcomes, while a plausible range of values was used for costs.
Estimated benefits used in the economic analysis In patients with DU disease, the number of months free from dyspepsia was 1.9 with no treatment, 7.2 with intermittent PPI, 7.9 with maintenance PPI and 8.7 with H. pylori eradication.
H. pylori eradication resulted in an extra 1.5 months free from dyspepsia in comparison with intermittent PPI therapy.
In patients with GU disease, the number of months free from dyspepsia was 2.0 with no treatment, 8.3 with intermittent PPI, 8.5 with maintenance PPI and 8.6 with H. pylori eradication.
Cost results In patients with DU disease, the total cost was $580 with no treatment, $514 with intermittent PPI, $683 with maintenance PPI and $645 with H. pylori eradication.
H. pylori eradication cost, on average, an extra $131 in comparison with intermittent PPI therapy.
In patients with GU disease, the total cost was $3,031 with no treatment, $1,545 with intermittent PPI, $1,459 with maintenance PPI and $1,369 with H. pylori eradication.
Synthesis of costs and benefits The costs and benefits were combined in the form of incremental cost-effectiveness ratios (ICERs). A willingness-to-pay value of $182/month free from dyspepsia was taken from the literature (Kleinman et al. 2002, see 'Other Publications of Related Interest' below for bibliographic details) and was used as the threshold.
In patients with DU disease, intermittent PPI therapy dominated no treatment as it was less expensive and more effective. Similarly, H. pylori eradication therapy dominated maintenance PPI therapy.
In patients with DU disease, the ICER of H. pylori eradication therapy versus intermittent PPI therapy was $87 per month free from dyspepsia.
According to the probabilistic sensitivity analysis, there was greater than 95% certainty that H. pylori eradication was the most cost-effective strategy provided there was a willingness-to-pay of at least $112/month free from dyspepsia. At no willingness-to-pay value, there was any likelihood that maintenance PPI therapy was a cost-effective option. This result was robust to all sensitivity analyses except for the cost of H. pylori eradication. At a willingness-to-pay of $182/month free from dyspepsia, intermittent PPI therapy was likely to be more cost-effective if eradication therapy cost more than $393.
In patients with GU disease, H. pylori eradication therapy dominated the three other therapies. The average cost of H. pylori eradication therapy was $159 per month free from dyspepsia.
Considering a 2-year follow-up, there was greater than 95% certainty that H. pylori eradication was the most cost-effective strategy whatever the willingness-to-pay per month free from dyspepsia. This result was robust to all sensitivity analyses over 2 years.
The results of the one-way sensitivity analysis were not reported.
Authors' conclusions Helicobacter pylori (H. pylori) eradication is cost-effective for duodenal ulcer (DU) over 1 year and gastric ulcer (GU) over 2 years with over 95% confidence, despite the uncertainty present in the data.
CRD COMMENTARY - Selection of comparators The selection of the comparator was not explicitly justified. However, it was reported throughout the review of the literature that the treatment of PUD varied widely. The comparators represented alternative treatment strategies suggested by the review. You should consider whether any of the comparators represents widely adopted practice in your own setting.
Validity of estimate of measure of effectiveness Published studies were used to obtain the input parameters. The authors stated that a systematic review of the literature had been undertaken to identify all relevant research and minimise biases. The methods used to find and select the primary studies and to extract the data were clearly stated. In addition, the effectiveness data used were based on randomised clinical trials. The effectiveness data from different studies were combined using a meta-analysis. The impact of differences between the primary studies was considered. Uncertainty around the outcomes was evaluated in the model using a sensitivity analysis, and a justification for the values used in this analysis was provided. Therefore, the internal and external validity of the estimates should be high. However, where evidence of effectiveness was lacking, the data were derived from observational studies, hence introducing the possibility of confounding bias. However, the probabilistic sensitivity analysis suggested that the results were very robust.
Validity of estimate of measure of benefit The estimation of benefits was modelled. It is unclear whether the Markov model used for this purpose was appropriate since the model was not described (e.g. health states, duration of cycle, transition probabilities). In addition, a Markov model is specifically appropriate to estimate the associated benefits and costs over the lifetime of the patients. In the present study, the benefits and costs were assessed over a 1-year period. However, the model captured side effects that have been clearly established and were burdensome to the patients.
Validity of estimate of costs The authors stated that they adopted the perspective of a US third-party payer. All the categories of cost relevant to this perspective appear to have been included in the analysis. However, the costs associated with treating adverse events were not included in the analysis, and no justification for this exclusion was provided. Consequently, the cost-effectiveness of H. pylori eradication might have been overestimated. The unit costs were reported and the resources used were identified. A sensitivity analysis of the costs was undertaken, using ranges that appear to have been appropriate. The authors did not justify their assumptions about the frequency of outpatient visits and the frequency of endoscopies based on the literature. These assumptions might have biased the results. Discounting was not necessary, as the costs referred to a time period of 2 years at most, and was therefore not undertaken. The date to which the prices referred was not reported, which limits the reproducibility of the results.
Other issues The authors made appropriate comparisons of their findings with those from other studies. The issue of generalisability to other settings was not discussed. The results of the analysis were adequately reported and the authors' conclusions reflected the scope of the analysis. The authors reported one limitation of the cost-effectiveness analysis, the lack of data on the relief of symptoms from PUD following eradication therapy.
Implications of the study The authors suggested that an evaluation of symptom relief in the long term should be addressed in future trials.
Source of funding Supported by AstraZeneca, AxCan Pharma, the UK Medical Research Council, the UK National Health Service R&D Programme, Wyeth, Takeda, and Abbott Laboratories.
Bibliographic details Ford A C, Delaney B C, Forman D, Moayyedi P. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis. American Journal of Gastroenterology 2004; 99(9): 1833-1855 Other publications of related interest Briggs AH, Sculpher MJ, Logan RP, et al. Cost effectiveness of screening for and eradication of Helicobacter pylori in management of dyspeptic patients under 45 years of age. BMJ 1996;312:1321-5.
Fendrick AM, McCort JT, Chernew ME, et al. Immediate eradication of Helicobacter pylori in patients with previously documented peptic ulcer disease: clinical and economic effects. American Journal of Gastroenterology 1997;92:2017-24.
O'Brien B, Goeree R, Mohamed AH, Hunt R. Cost-effectiveness of Helicobacter pylori eradication for the long-term management of duodenal ulcer in Canada. Archives of Internal Medicine 1995;155:1958-64.
Kleinman L, McIntosh E, Ryan M, et al. Willingness to pay for complete symptom relief of gastroesophageal reflux disease. Archives of Internal Medicine 2002;162:1361-6.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Aged; Anti-Bacterial Agents /economics /therapeutic use; Anti-Ulcer Agents /economics /therapeutic use; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastric Mucosa /drug effects /pathology; Health Care Costs; Helicobacter Infections /diagnosis /drug therapy /economics; Helicobacter pylori /drug effects /isolation & Humans; Male; Middle Aged; Peptic Ulcer /drug therapy /economics /microbiology; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome; purification AccessionNumber 22004001206 Date bibliographic record published 31/12/2005 Date abstract record published 31/12/2005 |
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