Article Text
PDF
Abstract
Objective Clinical data comparing diagnostic strategies in the management of Helicobacter pylori-associated diseases are limited. Invasive and noninvasive diagnostic tests for detecting H. pylori infection are used in the clinical care of patients with dyspeptic symptoms. Modelling studies might help to identify the most cost-effective strategies. The objective of the study is to assess the cost-effectiveness of a ‘test-and-treat’ strategy with the urea breath test (UBT) compared with other strategies, in managing patients with H. pylori-associated dyspepsia and preventing peptic ulcer in the UK.
Design Cost-effectiveness models compared four strategies: ‘test-and-treat’ with either UBT or faecal antigen test (FAT), ‘endoscopy-based strategy’ and ‘symptomatic treatment’. A probabilistic cost-effectiveness analysis was performed using a simulation model in order to identify probabilities and costs associated with relief of dyspepsia symptoms (over a 4-week time horizon) and with prevention of peptic ulcers (over a 10-year time horizon). Clinical and cost inputs to the model were derived from routine medical practice in the UK.
Results For relief of dyspepsia symptoms, ‘test-and-treat’ strategies with either UBT (€526/success) and FAT (€518/success) were the most cost-effective strategies compared with ‘endoscopy-based strategy’ (€1317/success) and ‘symptomatic treatment’ (€1 029/success). For the prevention of peptic ulcers, ‘test-and-treat’ strategies with either UBT (€208/ulcer avoided/year) or FAT (€191/ulcer avoided/year) were the most cost-effective strategies compared with ‘endoscopy-based strategy’ (€717/ulcer avoided/year) and ‘symptomatic treatment’ (€651/ulcer avoided/year) (1 EUR=0,871487 GBP at the time of the study).
Conclusion ‘Test-and-treat’ strategies with either UBT or FAT are the most cost-effective medical approaches for the management of H. pylori-associated dyspepsia and the prevention of peptic ulcer in the UK. A ‘test-and-treat’ strategy with UBT has comparable cost-effectiveness outcomes to the current standard of care using FAT in the UK.
- dyspepsia
- 13c-urea breath test
- Helicobacter pylori
- cancer
- gastric and duodenal ulcers
Data availability statement
Data are available in a public, open access repository. This was a modelling study using only data that is available in the public domain and duly referenced in the Methods section.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Summary
What is already known about this subject?
Cost-effectiveness studies comparing strategies used for the management of Helicobacter pylori-associated diseases are limited.
Timely detection of H. pylori infections in individuals presenting with symptoms of dyspepsia is an important public health issue in order to prevent the development of serious long-term complications such as gastric cancer.
In the UK, faecal antigen test (FAT) is the most widely used noninvasive screening procedure for H. pylori, but no recent data about the relative cost-effectiveness of this strategy are available.
What are the new findings?
‘Test-and-treat’ strategies with either UBT or FAT are the most cost-effective medical approaches for the management of H. pylori-associated dyspepsia and the prevention of peptic ulcer in the UK.
‘Test-and-treat’ strategy with UBT has comparable cost-effectiveness outcomes to the strategy using FAT.
How might it impact on clinical practice in the foreseeable future?
Provide decision-makers with comparative data on the cost-effectiveness of noninvasive tests for testing and retesting for H. pylori infection.
Confirm that noninvasive tests such as UBT represent cost-effective and practical options for use in routine clinical practice in the UK.
Introduction
Between 20% to 30% of people in Western Europe are infected with Helicobacter pylori (H. pylori)1 and these infections play a causative role in the development of dyspepsia, peptic ulcers, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma.2–7 However, in most cases, H. pylori infections can be successfully eliminated with appropriate antibiotic treatment.8 For this reason, timely detection of H. pylori infections in individuals presenting with symptoms of dyspepsia is an important public health issue in order to prevent the development of serious long-term complications.9–11 Moreover, in spite of the initial cost, screening for H. pylori has been shown to generate significant reductions in total dyspepsia-related healthcare costs over the long term.12 Such screening programmes may also be cost-effective for the prevention of gastric carcinoma.13 14
Historically, H. pylori infections were typically diagnosed by analysis of biopsy samples taken from the stomach during endoscopy. However, this is an invasive procedure requiring hospital attendance and is resource consuming in terms of endoscopists’ time and laboratory testing. For this reason, alternative diagnostic methods that are simpler to use and can be performed in the community are of interest. In this respect, two types of noninvasive tests have been developed. The faecal antigen test (FAT) involves collecting a faecal sample that is sent for assay of H. pylori-specific antigens using enzyme immunoassay or immunochromatography.15 16 The urea breath test (UBT) involves ingestion of [13C]-urea, which is broken down in the stomach by urease produced by H. pylori to ammonia and carbon dioxide. The presence of [13C]-CO2 in exhaled air is then detected by mass spectroscopy or infrared technologies.
Individual patient meta-analysis has demonstrated that test-and-treat strategies using FAT or UBT provide comparable effectiveness at relieving symptoms of dyspepsia as first-line endoscopy, but at a greatly reduced cost.17 Similar, although less robust, conclusions may be drawn for noninvasive test-and-treat strategies compared with empirical symptomatic treatment.18 19 For this reason, noninvasive H. pylori screening is now recommended in young patients with dyspepsia who do not have alarm symptoms.8 19 In England and Wales, practice guidelines produced by the National Institute for Health and Clinical Excellence (NICE) recommend that clinicians offer patients with dyspepsia under 55 years and who do not have alarm symptoms noninvasive H. pylori testing using UBT, FAT or laboratory-based serology where its performance has been locally validated.20
We have recently performed a cost-effectiveness modelling study comparing a ‘test-and-treat’ strategy with UBT, ‘test-and-treat’ using endoscopy and empirical symptomatic treatment in the Spanish treatment setting.21 This study demonstrated that the UBT ‘test-and-treat’ strategy was the most cost-effective medical approach for management of dyspepsia and for the prevention of peptic ulcers and gastric cancer. However, this modelling study did not compare UBT with FAT, which is not widely used in Spain. In contrast, in the UK, FAT is the most widely used noninvasive screening procedure for H. pylori,22 but no recent data about the relative cost-effectiveness of these different strategies are available. For these reasons, we undertook a second modelling study based on practices and costs in the UK. The objective of this study was to compare the cost-effectiveness of four different management strategies (UBT, FAT, endoscopy and empirical symptomatic treatment) in the context of the British healthcare system.
Materials and methods
Study design
This medicoeconomic modelling study estimated the cost-effectiveness of the ‘test-and treat’ strategy using UBT in the diagnosis of H. pylori infection and in the subsequent prevention of H. pylori-related complications. The ‘test-and treat’ strategy using UBT for primary detection of H. pylori was compared with three other diagnostic strategies, namely, ‘test-and treat’ using FAT, an ‘endoscopy-based strategy’ and a ‘strategy starting directly with empirical symptomatic treatment’. Two therapeutic outcomes were evaluated, relief of symptoms of dyspepsia and prevention of peptic ulcers. Values and costs were estimated from a decision tree model simulating the four strategies. The management pathways modelled correspond to those used in routine clinical practice in the UK, and transition probabilities were based on British data whenever available. Due to uncertainty associated with the estimates of several model inputs, probabilistic simulations were used to derive estimates of costs and outcomes. The analysis was performed from a public health insurance perspective, taking into account direct medical costs only. No cost discounting was applied.
Description of the model
The decision tree model used in the study consisted of a succession of decision nodes identifying decisions to test for H. pylori, to undertake endoscopy, to initiate symptomatic treatment or antibiotic treatment for H. pylori eradication and to evaluate effectiveness. A corresponding set of event nodes identify the possible outcomes of these decisions. Each branch of the decision tree ends in a terminal node defined by the therapeutic outcome (success or failure). Independent decision trees were constructed for each of the four management strategies evaluated. These decision tree models used in the study are illustrated schematically in online supplemental material.
Supplemental material
UBT and FAT strategies
These two strategies follow an identical management pathway. The first step is testing for H. pylori with one of the two methods. If the pathogen is detected, first-line antibiotic therapy with clarithromycin-based triple therapy is initiated to eradicate it (according to the reference guide published by Public Health England).23 If a switch to other first-line therapies would become necessary (ie, clarithromycin resistance >15%), costs of therapy will remain similar. At the end of the prescribed treatment course, the patient is retested by UBT or FAT. In case of persistence of the infection, a second-line eradication treatment is initiated and the patient then tested again. Therapeutic outcomes are modelled after first-line therapy in the case of successful eradication or after second-line therapy regardless of whether eradication had been achieved.
In the case of a negative H. pylori test, symptomatic treatment, including mainly a proton pump inhibitor (PPI), is initiated for 4 weeks, and therapeutic outcome is evaluated at the end of this period. If symptoms have been relieved, the treatment is considered successful. If not, the patient undergoes endoscopy to identify any potential lesion (peptic ulcer or other macroscopic pathology).
Endoscopy-based strategy
In this strategy, the first step is to perform an endoscopy to detect any lesion and to take biopsies for H. pylori assay. If the assay result is negative, a 4-week symptomatic treatment is initiated after which outcome (symptom relief) is evaluated. If the result is positive, the patient undergoes first-line, and, if a retest is again positive, second-line, antibiotic treatment to eradicate the pathogen. As in the UBT and FAT strategies, therapeutic outcomes are modelled after first-line therapy in the case of successful eradication or after second-line therapy regardless of whether eradication had been achieved.
Empirical symptomatic treatment strategy
In this strategy, the first step is to start empirical symptomatic treatment with a PPI for 4 weeks. If symptoms have been relieved, the treatment is considered successful. If not, the patient undergoes endoscopy and follows the endoscopy strategy described above.
End states
For each management strategy, two end states were modelled. The first was the relief of dyspepsia symptoms at 4 weeks after initiation of symptomatic treatment (either following a negative H. pylori test in the two ‘test and treat’ and the ‘endoscopy-based’ strategies or during the first stage of the model in the ‘treat-and-test’ symptomatic treatment strategy). The second endpoint was prevention of occurrence (or recurrence) of a peptic ulcer over 10 years following a negative H. pylori test. Both end states were considered as binary variables (symptom relief vs no symptom relief and ulcer prevented vs ulcer not prevented). A payoff of 1 was assigned if the treatment objective was achieved and a payoff of 0 if it was not achieved.
Model inputs
Analysis population
The analysis population modelled corresponded to patients consulting a gastroenterologist for symptoms of dyspepsia.
Transition probabilities
Transition probabilities for the different chance nodes of the decision tree are listed in table 1.
Model inputs: transition probabilities
Cost inputs
For certain items, a fixed cost was applied when this was known. For others, a cost range was applied, corresponding to the different treatment options available (eg, for antibiotic treatment for elimination of H. pylori), differences in laboratory costs for test assays or to expert opinion when the exact cost was unknown (eg, for the management of peptic ulcer). All costs used in the model are presented in euros (1 EUR=0,871487 GBP) and are listed in table 2.
Model inputs: costs
For the UBT and FAT, costs include kit acquisition and test analysis. For endoscopy, two possible costs were applied. In the case when endoscopy revealed no suspect lesions, the cost applied was the procedure cost of endoscopy along with a rapid urease test. If suspect lesions were identified and biopsy samples were taken, the cost of histological testing for H. pylori was also included. It was assumed that five biopsy samples would be analysed by histology and one rapid urease test. These procedures were costed according to NHS National tariffs. If an ulcer was detected by endoscopy, then the cost of management was included.
Acquisition costs for symptomatic treatment of dyspepsia and for antibiotic treatment for elimination of H. pylori were taken from the recommended retail price listed in the NHS National tariff.
Model outputs
Values
For each treatment strategy, the expected value of each outcome of interest was computed as the product of the transition probabilities at each node of the relevant branch of the tree. Monte Carlo simulations were performed with 10 000 iterations, each using a randomly selected transition probability within the prespecified range. Expected values are presented as the mean and SD of the results of the individual Monte Carlo iterations.
Costs
For each treatment strategy, the total cost of each outcome of interest was computed according to the probabilities at each node of the tree. Monte Carlo simulations were performed with 10 000 iterations, each using a randomly selected value within the prespecified cost range. Total costs are presented as the mean and SD of the results of the individual Monte Carlo iterations.
Cost-effectiveness
Cost-effectiveness ratios were calculated for each strategy and each outcome. In the case of dyspepsia relief, costs of the symptomatic treatment course were divided by the value (probability of symptom relief by the treatment course). In the case of ulcer prevention, the cost over 10 years was divided by the value (1—probability of developing an ulcer) and divided by 10 to generate an annual cost/outcome. Monte Carlo simulations were performed with 10 000 iterations, each using randomly selected values for values and costs within the ranges used in the previous step. These ratios are presented as the mean and SD of the results of the individual Monte Carlo iterations.
Results
Value outcomes
For dyspepsia relief, the expected value of the treatment strategy ranged from 0.38 for endoscopy to 0.58 for the FAT (table 3). For prevention of peptic ulcer occurrence/recurrence, the expected value of the treatment strategy ranged from 0.10 for symptomatic treatment to 0.15 for the UBT and for the FAT (table 3).
Model outputs: costs and values according to management strategy
Cost outcomes
For dyspepsia relief, the total cost of the treatment strategy ranged from €298 for the FAT to €497 for endoscopy (table 3). For prevention of peptic ulcer occurrence/recurrence, the total 10-year cost of the treatment strategy ranged from €1595 for the FAT to €6105 for endoscopy (table 3).
Cost-effectiveness
Costs and values for each treatment strategy are displayed on a cost-effectiveness plane in figure 1. For both outcomes (dyspepsia relief and ulcer prevention), the FAT and the UBT dominated endoscopy and symptomatic treatment, being more effective and cheaper. The cost-effectiveness ratio for FAT and for UBT was very similar, €518±397 per event and €526±400 per event, respectively, for dyspepsia relief and €191±371 per event and €208±368 per event, respectively, for ulcer prevention.
Cost-effectiveness ratio for each strategy. Filled symbols: dyspepsia relief; open symbols: prevention of peptic ulcer occurrence/recurrence. Endo, endoscopy (♦,◊); FAT, faecal antigen test (■,□); ST, symptomatic treatment (▲,△); UBT, urea breath test (●,○).
Discussion
This modelling study indicates that a test-and-treat strategy in patients with dyspepsia using FAT or UBT for H. pylori offers a probability of relief of dyspepsia or of ulcer prevention at least as high as that offered by endoscopy or by an empirical symptomatic treatment. However, the cost of the strategy per patient successfully treated is over three times lower for dyspepsia relief and over two times lower for ulcer prevention with the noninvasive strategies compared with endoscopy or empirical symptomatic treatment. Compared with FAT, UBT shows a very similar cost-effectiveness profile. These findings are consistent with current recommendations from NICE,20 the Scottish Intercollegiate Guidelines Network24 and other international professional bodies,8 which recommend a noninvasive test-and-treat strategy for diagnosis of H. pylori infections and management of H. pylori-related disease.
The UK is considered a low-prevalence country for H. pylori,25 and the proportion of patients with dyspepsia who are tested positive for this organism is likely to be around 15%.23 It should be noted that the actual prevalence of H. pylori infection in dyspeptic patients in the UK has not recently been comprehensively assessed and that any estimate higher than 15% in H. pylori prevalence would benefit test-and-treat strategy cost-effectiveness outcomes. In addition, diagnostic tests need to have high performance rates and to be cheap, in order to be cost effective. The UBT fulfils both these conditions, with sensitivity, specificity, positive predictive value and negative predictive value all being >95%,26 comparable to the performance of the FAT.16
In spite of the fact that UBT is the most accurate noninvasive test for H. pylori27 28 and is recommended by NICE,20 it remains relatively underused compared with FAT in the UK. A survey of all accredited microbiology laboratories in England, conducted in 2015, found that >90% of laboratories proposed FAT as the first-line diagnostic test compared with <5% who proposed the UBT.22 Since UBT, unlike FAT, requires prescription of the labelled reagent, the authors of this study speculated that physicians were not encouraged to prescribe by their local funding body.
Compared with our previous cost-effectiveness modelling study in the Spanish setting,21 and despite the differences between healthcare systems and the prevalence of H. pylori, the results were similar. In both Spanish and British settings, the cost per treatment success was higher for the endoscopy and empirical treatment strategies than for the UBT strategy.
The currently available noninvasive strategies for H. pylori assessment do not provide information about antibiotic susceptibility. However, real-time PCR tests have been developed that permit assessment of clarithromycin susceptibility using faecal samples.29 These may be helpful in the future, but at present are not readily available in the UK and elsewhere. If these tests are used for additional characterisation of H. pylori-positive patients in the future, this would potentially increase the cost of a stool-based testing strategy but will comply with the demands for a proper antibiotic stewardship in management of H.pylori infection.
The study has a number of limitations. In particular, the transition probabilities and certain costs used in the model are not known with precision for the UK context, and a range of values has been tested for most variables using a probabilistic approach. In consequence, the model outputs (costs and values) are also limited in their precision. Second, the model assumes that all patients offered FAT, UBT or endoscopy will actually undertake them. Any differences in test acceptability and patient uptake will not be reflected in the model.
In conclusion, this health economic modelling study predicts that ‘test-and-treat’ strategies with either UBT or FAT are the most cost-effective medical approaches for the management of H. pylori-associated dyspepsia and the prevention of peptic ulcer in the UK. The ‘test-and-treat’ strategy with UBT has comparable cost-effectiveness outcomes to the current standard of care using FAT in the UK.
Data availability statement
Data are available in a public, open access repository. This was a modelling study using only data that is available in the public domain and duly referenced in the Methods section.
Ethics statements
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @gastrolivuni
Contributors HS and AB conceived and initiated the experiments. DMP, JB, IB, PM, HS and AB designed the models and the analysis plan. DMP, JB, IB and PM provided clinical advice and healthcare-related costs. AB performed the calculations and simulations. DMP, JB, IB, PM, HS and AB prepared the analysis report. HS drafted the manuscript in consultation with DMP, JB, IB, PM ad AB. All authors provided critical feedback and helped shape the research, analysis and the manuscript.
Funding This study was initiated and funded by Mayoly Spindler Laboratories.
Competing interests DMP, JB, IB and PM have received honoraria from Mayoly Spindler Laboratories for their contribution to the study. HS is an employee of Mayoly Spindler Laboratories. AB has received honoraria from Mayoly Spindler Laboratories for data management and data analyses. DMP has received honoraria for consultancy from Ipsen and Advanced Accelerator Applications. PM has received honoraria for consultancy from Bayer, Danone and speaker honoraria from Alfasigma, Bayer, Dr Falk and Malesci.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.