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A Second-Order Simulation Model of the Cost-Effectiveness of Managing Dyspepsia in the United States Pelham M. Barton, Paul Moayyedi, Nicholas J. Talley, Nimish B. Vakil and Brendan C. Delaney Med Decis Making 2008; 28; 44 originally published online Dec 5, 2007; DOI: 10.1177/0272989X07309644 The online version of this article can be found at: http://mdm.sagepub.com/cgi/content/abstract/28/1/44

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COST-EFFECTIVENESS ANALYSIS: APPLICATIONS

A Second-Order Simulation Model of the Cost-Effectiveness of Managing Dyspepsia in the United States Pelham M. Barton, PhD, Paul Moayyedi, PhD, Nicholas J. Talley, MD, Nimish B. Vakil, MD, Brendan C. Delaney, MD

Background. The ‘‘gold-standard’’ evidence of effectiveness for a clinical practice guideline is the randomized controlled trial (RCT), although RCTs have a limited ability to explore potential management strategies for a chronic disease where these interact over time. Modeling can be used to fill this gap, and models have become increasingly complex, with both dynamic sampling and representation of second-order uncertainty to provide more precise estimates. However, both simulation modeling and probabilistic sensitivity analysis are rarely used together. The objective of this study was to explore uncertainty in controversial areas of the 2005 American Gastroenterology Association position statement on the management of dyspepsia. Methods. Individual sampling model, incorporating a second-order probabilistic sensitivity analysis. Population. US adult patients presenting in primary care with dyspepsia. Interventions compared:

empirical acid suppression, test and treat for Helicobacter pylori, initial endoscopy, acid suppression then endoscopy, test and treat then proton pump inhibitor (PPI) then endoscopy. Outcomes. Cost-effectiveness, quality-adjusted life years, and costs in US dollars from a societal perspective, measured over a 5-year period. Data sources: mainly Cochrane meta-analyses. Results. Endoscopy was dominated at all ages by other strategies. PPI therapy was the most cost-effective strategy in 30-year-olds with a low prevalence of H. pylori. In 60-year-olds, H. pylori test and treat was the most cost-effective option. Conclusions. Acid suppression alone was more cost-effective than either endoscopy or H. pylori test and treat in younger dyspepsia patients with a low prevalence of infection. Key words: computer simulation; dyspepsia; cost-benefit analysis. (Med Decis Making 2008;28:44–55)

T

strategy for guidelines,1 they are usually unable to compare multiple strategies, and long-term follow-up is problematic, subject attrition erodes internal validity, and sample sizes are often unrealistic. Furthermore, representativeness of subjects, a concentration on effect as the outcome with costs ‘‘added alongside,’’ and simplistic frequentist analyses ignoring prior evidence may make RCTs a poor guide for policy. Detailed evaluation of the consequences of the many ‘‘downstream’’ management options and determination of the effect of a decision on the frequency of very rare outcomes is rarely available. One means of bridging this gap is to use simulation modeling. The basic approach of all models is to use knowledge about disease processes, prevalence, and the effect of treatments to predict outcomes that have not or cannot be measured directly. In the basic sciences, this usually relates to cellular organ systems, but in the health sciences, populations are modeled. In this case, the impact of management strategies on health outcomes (quality-adjusted life years [QALYs]) and

he randomized controlled trial (RCT) design is the gold standard for determining the effectiveness of treatments. RCTs have also been applied to the problems of cost-effectiveness and determining the most effective management strategy where options of testing or empirical treatment are involved. Although RCTs can be used to inform health service

Received 20 November 2006 from the Health Economics Facility (PMB) and Department of Primary Care and General Practice (BCD), University of Birmingham, UK; Department of Gastroenterology, McMaster University, Hamilton, Ontario, Canada (PM); Center for Enteric Neurosciences and Translational Epidemiological Research (CENTER), Mayo Clinic College of Medicine, Rochester, Minnesota, and Department of Medicine, University of Sydney, Sydney, Australia (NJT); and University of Wisconsin Medical School, Milwaukee, Wisconsin (NBV). Revision accepted for publication 27 April 2007. Address correspondence to Brendan Delaney, MD, FRCP, MRCGP, Department of Primary Care and General Practice, Primary Care Clinical Sciences Building, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; e-mail: [email protected]. DOI: 10.1177/0272989X07309644

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SIMULATION MODEL OF DYSPEPSIA MANAGEMENT

health resource utilization (and hence costs) was modeled. Simple decision models consider effects over fixed periods of time, averaging costs and probabilities over a year, for example. More sophisticated models, known as Markov processes, allow for patients to flow between states and are more suitable for modeling chronic conditions over time.2 When faced with many alternatives, the numerous branches and separate states of Markov models become too complex to represent, and ‘‘simulation’’ modeling becomes more computationally efficient.3 Discrete event simulation has been used to overcome some of these difficulties. A log is kept of individuals and events, with the model running through unique series of these sequence logs, generating costs and outcomes. An alternative but related approach, an individual sampling model (ISM), works by generating a sequence of virtual patient histories.3 Uncertain events are determined by the use of a random number generator, generating the first-order uncertainty in the model. Total costs and QALYs are calculated for each patient and summary statistics generated for a simulated population. ISMs allow for events to take place in continuous time and allow for patient attributes such as age and previous disease history to be updated through the model. In addition to simulating individual patients in the cohort to estimate the mean costs and effects, we also need to represent the statistical uncertainty of existing knowledge and carry that through to the model output. Using the technique of probabilistic sensitivity analysis, the inputs to the model are represented not as discrete numbers or ranges but as mathematically defined formulas or ‘‘probability density functions.’’ A random number generator is used to sample from these distributions to simulate a population with the same mean and confidence interval as the input data. The combination of both an individual sampling approach and second-order probabilistic sensitivity analysis is unusual, as no computer software exists to compute both first- and second-order uncertainty in an individual simulation model, and times taken to run the models can be very long. These issues are pertinent to the evaluation of dyspepsia (chronic or recurrent upper gastrointestinal pain or discomfort). To particularize this problem to dyspepsia, the 2005 American Gastroenterological Association medical position statement on the evaluation of dyspepsia4 and its associated technical review5 were based extensively on Cochrane Collaboration meta-analyses of RCTs, particularly clinical trials specifically addressing cost-effectiveness.6

However, as the management of dyspepsia is a very complex problem, involving evaluation of competing strategies for both effectiveness and cost, current knowledge in this area is still too incomplete to allow the construction of a clinical guideline based solely on robust trial evidence. There is a paucity of data on the long-term cost-effectiveness of Helicobacter pylori ‘‘test and treat,’’ especially as dyspepsia is a chronic relapsing and remitting problem5, 6 where the impact on quality of life is difficult to capture at fixed follow-up points. There have been a number of previous models of dyspepsia. All these previous models found that strategies involving initial endoscopy in most or all patients were more costly and no more effective than selective endoscopy.7 10 Seven models have compared H. pylori test and treat with other strategies in 6 studies,11 16 although only Ebell and others12 and Spiegel and others16 considered differences in effectiveness as well as costs. All 6 studies found test and treat to be the most cost-effective strategy. However, all of these models have had substantial limitations. Case mix was often poorly considered; most were limited to effects engendered by H. pylori eradication on recurrent peptic ulcer disease alone. Modeling approaches were usually limited to 1 or 2 strategies with no analysis of different follow-on prescribing choices. Non-US models are potentially misleading because of profound differences in health care costs and management philosophies. There were only 3 time-related models,8,10,16 and only 1 of these was designed for the US health care system.16 This was a well-constructed model but did not address all the uncertainty in the data with simulation techniques. The cost-effectiveness of competing strategies was only assessed over 1 year, and the potential long-term effect of gastric cancer prevention and early detection was not considered. Recent advances in simulation modeling, particularly the use of individual patient, or ‘‘discrete event’’ simulation, allow for the full impact of statistical uncertainty to be expressed in a ‘‘probabilistic’’ sensitivity analysis17 ; no previous model of dyspepsia has used such an approach. The potential for oversimplification and false certainty inherent in previous models may therefore be avoided. The aim of this study was to test the more controversial assumptions in the 2005 American Gastroenterological Association (AGA) medical position statement on the evaluation of dyspepsia4 and its associated technical review5 using the recent Cochrane reviews and other evidence from the

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BARTON, MOAYYEDI, TALLEY, VAKIL, DELANEY

technical review, but extending the evidence using a sophisticated probabilistic simulation model. METHODS Definition of Dyspepsia and Cohort Entering Model The model was designed to reflect the management options available to either primary care physicians or specialists working in a community office setting. We therefore used a definition of dyspepsia appropriate to define a cohort of uninvestigated patients without ‘‘alarm’’ features that are generally considered to be suggestive of malignancy. Although the AGA position statement proposes that reflux disease can be distinguished from dyspepsia and defined separately based on symptoms,18 at the primary care level, there is considerable overlap between these symptom complexes, and the statement recognizes that it has not proved a reliable means of predicting disease.19 In Canada, a recent study reported on 1040 patients presenting with uninvestigated dyspepsia at 1 of 49 Canadian family physician centers, aged 18 years or older and undergoing endoscopy within 10 days of presentation. The findings were stratified according to whether the patients fitted the Rome II criteria (where predominant heartburn is classified as gastroesophageal reflux disease [GERD]) or the Canadian guideline definition that only defines patients as having GERD where the sole symptom is heartburn. Even in patients without dominant heartburn, 37% had esophagitis, and duodenal ulcer was as common in patients with dominant heartburn as epigastric pain.20 The model therefore included both patients with epigastric pain or discomfort and/or heartburn symptoms. Structure of the Model We constructed a simulation model reflecting US costs and assumptions and built using the programming language Borland Delphi (www.borland.com). We chose to program the model directly to incorporate both first- and second-order simulation into the individual sampling model. Some discrete event simulation software may perform probabilistic sensitivity analysis, but we did not wish the model to be tied irretrievably to a specific software package, and programming directly should be seen as the equivalent of running the model in a spreadsheet. The model measured the effectiveness of strategies in terms of the cost per QALY over a 5-year period,

incorporating a full second-order probabilistic analysis. The objective of this model was to determine the effect of follow-on strategies over 5 years and to examine the impact of symptom case mix, H. pylori prevalence, and quality of life (QoL). The model ran a simulated cohort of individual patients through a series of fixed strategies that could be varied and events that occurred with varying probability. At commencement of the model, the characteristics of the patient were chosen at random. Characteristics consisted of an underlying ‘‘cause’’ of dyspepsia (gastric ulcer, duodenal ulcer, nonulcer dyspepsia, GERD) and a ‘‘tendency to reconsult.’’ GERD was divided into nonerosive esophagitis, mild to moderate erosive esophagitis (Los Angeles grades A and B esophagitis), or severe erosive esophagitis (Los Angeles grades C and D esophagitis).21 A proportion of patients with peptic ulcer disease could also have another cause for their dyspepsia (nonerosive reflux disease or nonulcer dyspepsia). The model was designed to run a cohort of patients from a fixed starting age for a fixed period of time (1 or 5 years). Five years was chosen as the maximum reasonable extrapolation from available effect data. Each patient was therefore given the appropriate starting and finishing age, either 30 years or 60 years. We did not include patients with symptoms suggestive of upper gastrointestinal malignancy, as it was assumed that all these patients would receive urgent endoscopy as recommended in current guidelines. For the tendency to reconsult, patients were classified as ‘‘returners’’ or ‘‘nonreturners’’: nonreturners were assumed not to seek further treatment if dyspepsia recurred after successful initial treatment. Once the initial characteristics had been set, patients passed through a series of events (which were assumed to take no time) and activities (during which time was advanced). QALYs were calculated as the time spent in a given health state, determined by the model, multiplied by the utility for that state as measured on a scale of 0 (death) to 1 (perfect health). Costs were obtained by weighting units of resource consumed and logged as patients passed through the model by the unit cost of the resource. When the duration of an activity reached the set finishing age of the patient, the process was stopped, and total costs and QALYs were recorded. Mortality from dyspepsia was assumed to be negligible in the age ranges modeled and was not included. Costs were obtained for the US setting, including estimated indirect costs associated with each element to enable a societal perspective to be taken (see Table 3). Drug costs were obtained from the average



Table 1

Initial Entry Parameters

Parameter

Initial parameters for 30-year-old entry Helicobacter pylori prevalence36 Probability of duodenal ulcer if H. pylori positive37–39 Probability of duodenal ulcer if H. pylori negative37–39 Probability of gastric ulcer if H. pylori positive37–39 Probability of gastric ulcer if H. pylori negative37–39 Other dyspepsia with ulcer40 Nonulcer dyspepsia if other dyspepsia40 Erosive esophagitis41 Severe esophagitis if erosive esophagitis41 Probability of nonreturner42 Consultation rate for established dyspepsia (per year)43 Initial parameters for 60-year-old entry H. pylori prevalence36 Probability of duodenal ulcer if H. pylori positive37–39 Probability of duodenal ulcer if H. pylori negative37–39 Probability of gastric ulcer if H. pylori positive37–39 Probability of gastric ulcer if H. pylori negative37–39 Other dyspepsia with ulcer40 Nonulcer dyspepsia if other dyspepsia40 Erosive esophagitis41 Severe esophagitis if erosive esophagitis41 Probability of nonreturner42 Consultation rate for established dyspepsia (per year)6

retail prices for pharmaceuticals.22 Physician costs, including procedures, were obtained from the American Medical Association Procedural Code Book and the 2005 Medicare Fee Schedule. Utilities for the US population were applied for each specific age.23 The model compared 6 different management strategies, with alternative substrategies, as follows (Figure 1): 1. Baseline: all patients received antacid alone on any consultation with no further interventions. This is not a realistic strategy but was used as a baseline comparison so that information from placebo controlled trials could be used in the model. 2. Treatment with empirical acid suppression (substrategy −H2 receptor antagonist (H2 RA) or proton pump inhibitor [PPI]) for a month. No follow-up appointment was made; if the patient returned, he or she was given further courses of the same antisecretory agent if it had been successful in controlling symptoms. 3. Test for H. pylori and treat positives with eradication therapy: patients were first tested for H. pylori using either serology, the urea breath test (UBT), or stool antigen test, with test performance characteristics being set at ‘‘typical’’ clinical practice levels

Point Estimate

Distribution

95% Confidence Limits

0.15 0.05 0.0025 0.025 0.0025 0.3333 0.5 0.5 0.2 0.34 3

Beta Beta Beta Beta Beta Beta Beta Beta Beta Beta None

0.034 0.0018 0.000022 0.00023 0.000022 0.15 0.22 0.29 0.061 0.16

0.33 0.17 0.010 0.10 0.010 0.55 0.78 0.71 0.40 0.56

0.4 0.2 0.01 0.1 0.01 0.3333 0.5 0.5 0.2 0.25 4

Beta Beta Beta Beta Beta Beta Beta Beta Beta Beta None

0.21 0.11 0.0024 0.038 0.0024 0.15 0.22 0.29 0.061 0.078

0.61 0.31 0.023 0.19 0.023 0.55 0.78 0.71 0.40 0.48

rather than optimal (serology 85% sensitivity and specificity, or UBT/stool antigen test 95% sensitivity and specificity).24;25 All patients testing positive were given eradication therapy, which was assumed to be effective in eradicating H. pylori, as the intention-to-treat relative risk for remaining dyspepsia symptoms was used rather than dividing results into ‘‘cured’’ and ‘‘not cured’’ groups. H. pylori–positive peptic ulcer patients were assumed to heal with eradication therapy. All patients testing negative for H. pylori and infected patients with symptoms despite eradication therapy were managed with PPI therapy as outlined in strategy 2. 4. Initial endoscopy (substrategy: biopsy for ulcers only or all biopsied for H. pylori): management was based on the result of the endoscopy. If a peptic ulcer was found, or if a biopsy was taken for H. pylori and had a positive result, eradication therapy was given; all other patients received a PPI. Patients with severe erosive esophagitis were given double-dose PPI therapy if they remained symptomatic, but this was not offered in the strategies that did not include an endoscopy. 5. Initial treatment with PPI followed by endoscopy if needed (substrategy: with or without biopsy for H. pylori): patients reconsulting after having had a PPI for initial therapy were subsequently endoscoped and managed as in strategy 4.


47


H. pylori test entry

First consultation Posttest consultation Early endoscopy

Eradication effects

Established consult consul Initial effects

Eradication fail consultation Established dyspepsia Wait to relapse

Second appointment

Late endoscopy

Relapse consultation Second effects

Relapse effects

Figure 1 Events and activities in the model.

6. UBT and treat first followed by PPI then endoscopy if needed: patients were initially managed as strategy 2, reconsulters then all received a month’s PPI, and further reconsulters were then managed by endoscopy (strategy 4).

At each consultation, the probability of continuing dyspeptic symptoms was calculated by using the relative risk obtained from Cochrane metaanalyses of RCTs evaluating either H. pylori eradication therapy26 or acid suppression for the relevant underlying disease causing dyspepsia (Table 2).27 All strategies were compared with each other. Conduct of the Second-Order Probabilistic Sensitivity Analysis The results of meta-analyses were used to estimate the statistical uncertainty inherent in the medical literature. For example, the Cochrane review on the effect of H. pylori eradication on nonulcer dyspepsia estimated a risk ratio for remaining symptomatic of

0.91 with a confidence interval of 0.87 to 0.96.28 This was represented in the model as a log-normal distribution with the same mean and standard error. The log-normal distribution is a suitable distribution for the risk ratio as it is the natural distribution of the statistical model employed in meta-analysis. A random number is drawn from the desired distribution. To run this type of model, several thousand ‘‘cohorts’’ of 10,000 individuals each with a unique set of randomly sampled inputs are used to generate a statistical or graphical estimate of the distribution of outcome variables of cost-effectiveness. The analysis is known as a ‘‘second-order’’ analysis as the uncertainty expressed is from the statistical variation in the inputs and not the random path through strategies taken by an individual patient in a cohort (first-order uncertainty).29 The value of this modeling approach is that it allows policy makers or guideline developers to directly reflect uncertainty in evidence in their guideline. A probabilistic sensitivity analysis was therefore performed to estimate the impact of parameter uncertainty on the cost-effectiveness of competing strategies.30



Table 2 Condition

Parameters for Recurrence and Relapse after Initial Treatment Point Estimate

Distribution

Probability that condition remains without medication (or with antacid) 0.6 Beta Ulcer40,44 Nonulcer dyspepsia45 0.78 Beta 0.8 Beta Esophagitis46 Relative risk that condition remains with PPI Ulcer47 0.2 Log-normal Nonulcer dyspepsia27 0.86 Log-normal 0.63 Log-normal Nonerosive esophagitis48 Moderate erosive esophagitis49-52 0.25 Log-normal 0.72 Log-normal Healing severe compared to moderate erosive esophagitis53 Probability that severe or moderate 0.8 Log-normal esophagitis remains with double PPI after failure with single dose54,55 Relative risk that condition remains with eradication therapy compared with antacid 0.2 Log-normal Ulcer47 Nonulcer dyspepsia27 0.91 Log-normal 1 Log-normal Esophagitis56 Success rate for H2RA compared to PPI 0.81 Log-normal Ulcer47 Nonulcer dyspepsia57 0.93 Log-normal 0.81 Log-normal Nonerosive esophagitis48 Moderate or severe esophagitis53 0.57 Log-normal Probability of relapse within 1 year with no medication 0.64 Log-normal Ulcer47 Nonulcer dyspepsia57 0.8 Log-normal 0.8 Log-normal Esophagitis (any)54 Relative risk of relapse Ulcer eradication v. do nothing47 0.2 Log-normal 1.34 Log-normal Ulcer PPI v. eradication47 Nonulcer dyspepsia PPI v. do nothing57 0.25 Log-normal 0 None Nonulcer dyspepsia eradication v. do nothing27 Esophagitis PPI v. do nothing54 0.25 Log-normal Esophagitis eradication v. do nothing56 1 Log-normal

95% Confidence Limits

0.45 0.69 0.72

0.74 0.86 0.87

0.10 0.78 0.52 0.17 0.60

0.40 0.95 0.77 0.37 0.87

0.66

0.97

0.10 0.86 0.96

0.40 0.97 1.04

0.72 0.84 0.55 0.52

0.91 1.03 1.20 0.63

0.62 0.66 0.77

0.67 0.97 0.83

0.18 1.02 0.19

0.22 1.76 0.33

0.20 0.98

0.32 1.02

Note: H2RA, H2 receptor antagonist; PPI, proton pump inhibitor.

Log-normal distributions were fitted to relative risks, and beta distributions were fitted to all other parameters. Beta distributions are bounded between 0 and 1 and are conjugate, meaning a beta combined with a beta remains a beta. This makes them the choice for binomial or probability data. Comparisons of cost-effectiveness between strategies using secondorder probabilistic analysis were made using paired cost-effectiveness acceptability curves (CEACs).31 In Bayesian terms, the choice of preferred option should be according to mean outcomes (not the outcome most likely to be cost-effective). The incremental cost-effectiveness ratio (ICER) between 2 options,

based on mean outcomes, is independent of the choice of other options in the model. It is claimed that the CEAC gives a representation of the total uncertainty surrounding a decision. However, the multilateral CEAC gives a misleading impression of this uncertainty because it fails to distinguish between options that are nearly as good as the ‘‘best’’ option and options that are considerably worse. When several options are compared in the same model, it may be that (at a given threshold) the modeling shows a robust preference for 1 group of options over another, while showing considerable uncertainty within the group of possibly preferred options.


49


Table 3

Costs and Utilities Including Societal Costs

Item

Cost ($)

Clinician visit PPI (1 month single dose) H2RA (1 month) Antacid (1 month) Eradication therapy Serology Urea breath test Endoscopy Biopsy (additional to endoscopy)

170 99.99

188.45 99.99

112.29 8.49 152 100 150 450 100

112.29 8.49 152 100 150 494.20 100

Annual costs of dyspepsia

0

Base Value

Utility of dyspeptic symptoms58

0.9

11 95% Confidence Limits

0.79–0.97

Note: H2RA, H2 receptor antagonist; PPI, proton pump inhibitor.

Only a selection of bilateral CEACs can properly represent this. RESULTS For all patients, strategies involving initial endoscopy were dominated by empirical strategies, with antacid alone being the cheapest and least effective strategy (age 30, 4.2 QALYs over 5 years at a cost of $1976, and at age 60, 4.2 QALYs over 5 years at a cost of $2842). H2RA alone was also dominated at age 60 and gave only marginal additional benefit at age 30 (Tables 4 and 5). For patients consulting at age 30, PPI alone was cost-effective compared to antacid alone, giving an additional 0.14 QALY at an additional $1364 ($9740 per QALY). The test-and-treat strategies were closely bunched with PPI followed by endoscopy at an additional 0.15 QALY and $1605 ($10,800 per QALY). At age 60, PPI alone, test and treat, and PPI then endoscopy were cost-effective compared to antacid alone at less than $8000 per QALY (Table 5). At both the ages of 30 and 60, endoscopy with biopsy for H. pylori and eradication was more effective than endoscopy without biopsy. Also in each case, the strategy of PPI, followed by endoscopy with biopsy, was the most effective but most costly strategy. At age 30, PPI followed by endoscopy led to an additional 0.014 QALYs at an additional cost

of $316 (ICER $23,100 per QALY) compared to PPI alone. At age 60, PPI followed by endoscopy led to an additional 0.007 QALYs at an additional cost of $247 (ICER $37,500 per QALY) compared to test and treat. As far as noninvasive tests for use in test and treat were concerned, there was little difference in cost-effectiveness between serology and UBT or stool antigen. The full base case point estimates of cost-effectiveness are shown in Table 4 and Table 5. The base case analysis gives a spurious picture of certainty, and the results of the probabilistic sensitivity analysis need to be examined to explore the effect of uncertainty in the input data from metaanalyses. This can be best shown by plotting CEAC. The CEAC plots the probability that the preferred strategy is cost-effective against the maximum willingness to pay for a dyspepsia-free month. This is determined by the proportion of a scatterplot of cost-effective simulations beneath a gradient line representing willingness to pay. The more that can be paid, the more likely the strategy is to be costeffective, although uncertainty puts a ceiling on the maximum probability of the strategy being costeffective. Figures 2 through 4 show 3 curves comparing PPI with H2 RA, test and treat with PPI, and endoscopy with PPI in patients consulting at age 30 years. Figure 2 shows a steep gradient rising to certainty that at a willingness to pay of $25,000 per QALY, PPI will be cost-effective compared to H2 RA. In contrast, the other 2 curves show that even at very high willingness-to-pay levels, there is very little certainty that either test and treat or endoscopy (EGD) would be cost-effective compared to PPI alone. In contrast, for 60-year-olds, there is virtual certainty that test and treat will be more cost-effective than PPI alone (Figures 5–7). Endoscopy also performs reasonably well against PPI alone, with an 80% likelihood of being cost-effective at $50,000 per QALY, but test and treat is preferred to endoscopy (shown by the flat, shallow CEAC). A further sensitivity analysis explored the specific effect of varying the prevalence of H. pylori, allowing for the other uncertainties in the model with a series of probabilistic sensitivity analyses in patients at age 60. Figure 8 shows that below a prevalence of H. pylori of 20%, the willingness to pay for a month free of dyspepsia rises sharply above $50,000 per QALY, with wide confidence intervals. DISCUSSION This probabilistic simulation model carried out to examine areas of controversy in the 2005 AGA



Table 4

Cost-Effectiveness of Managing Dyspepsia in 30-Year-Olds Average per Patient

Strategy

Cost/$

QALYs

Antacid H2RA PPI then scope (no biopsy) Scope (no biopsy) PPI UBT-treat-PPI-scope Scope (biopsy all) ELISA and treat UBT and treat PPI then scope (biopsy all) PPI then scope v. PPI

1976 2897 3591 3986 3340 3842 4008 3581 3598 3656

4.2004 4.2203 4.3381 4.3387 4.3404 4.3488 4.3496 4.3497 4.3511 4.3541

Diff Cost

Diff QALY

ICER v. Base

921 1614 2009 1364 1866 2031 1605 1622 1679 316

0.0199 0.1377 0.1383 0.1400 0.1484 0.1492 0.1493 0.1507 0.1537 0.0137

46,300 Dominated Dominated 9740 Dominated Dominated 10,800 10,800 10,900 23,100

Note: H2RA, H2 receptor antagonist; PPI, proton pump inhibitor; ELISA, enzyme-linked immunosorbent assay; UBT, urea breath test; QALY, qualityadjusted life-year; ICER, incremental cost-effectiveness ratio.

Table 5

Cost-Effectiveness of Managing Dyspepsia in 60-Year-Olds Average per Patient

Strategy

Cost/$

QALYs

Antacid H2RA PPI then scope (no biopsy) PPI Scope (no biopsy) ELISA and treat UBT-treat-PPI-scope Scope (biopsy all) UBT and treat PPI then scope (biopsy all) PPI then scope v. UBT and treat

2842 4103 4298 4070 4557 4087 4315 4486 4087 4334

4.2031 4.2281 4.3665 4.3680 4.3712 4.3852 4.3852 4.3860 4.3876 4.3942

Diff Cost

Diff QALY

ICER v. Base

1260 1455 1227 1714 1244 1473 1643 1244 1491 247

0.0251 0.1635 0.1650 0.1682 0.1821 0.1822 0.1830 0.1845 0.1911 0.0066

Dominated Dominated 7440 Dominated 6830 Dominated Dominated 6740 7800 37,500

Note: H2RA, H2 receptor antagonist; PPI, proton pump inhibitor; ELISA, enzyme-linked immunosorbent assay; UBT, urea breath test; QALY, qualityadjusted life-year; ICER, incremental cost-effectiveness ratio.

dyspepsia guideline confirmed that, in a US setting with a low prevalence of H. pylori, empirical acid suppression with a PPI is probably the most costeffective option in younger patients (age 30). In older patients, H. pylori test and treat becomes more cost-effective. Although the model suggested that endoscopy was a cost-effective follow-on strategy in patients with recurrent symptoms, this was associated with both lower certainty and greater costs in the probabilistic analysis. Previous models have also shown that endoscopy-based management is less cost-effective than empirical treatment, but only 1 model has examined this from the US perspective, and that both limited its analysis to a 1-year timeframe and did not examine the effect of uncertainty

in the input variables.24 Moreover, this model suggested that empiric PPI therapy may be dominant, in contrast to our results showing the cost-effectiveness of test and treat and endoscopy in older patients.16 The model reported here more accurately examined the effect of age and H. pylori prevalence on the cost-effectiveness of H. pylori test and treat, as dynamic simulation models allow for individual patients in the model to follow separate paths over time. The effect of a given ‘‘strategy’’ is determined by the net effects on a large cohort of simulated patients, rather than having to structure separate decision tree arms for each sequence of possible events. This is more like reality, and results should be closer to those observed in the health care setting


51


EGD v. PPI P EGD Cost-Effectiveness

P PPI Cost-Effectiveness

PPI v. H2RA 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

50000

100000

150000

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

50000 100000 150000 Willingness to pay ($/QALY)

200000

200000

Willingness to pay ($/QALY)

Figure 2 Cost-effectiveness acceptability curve for PPI versus H2 RA for the management of dyspepsia in 30-year-olds. P, probability; PPI, proton pump inhibitor; H2 RA, histamine 2 receptor antagonist; T&T, test and treat; EGD, endoscopy; QALY, qualityadjusted life-year.

Figure 4 Cost-effectiveness acceptability curve for endoscopy versus PPI alone for the management of dyspepsia in 30-year-olds. P, probability; PPI, proton pump inhibitor; T&T, test and treat; EGD, esophagogastroduodenoscopy or upper endoscopy; QALY, qualityadjusted life-year.

EGD v. PPI P EGD Cost-Effectiveness

P T&T Cost-Effectiveness

Test and Treat v. PPI 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

50000

100000

150000

200000


1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

50000

100000

150000

200000


Figure 3 Cost-effectiveness acceptability curve for test and treat versus PPI alone for the management of dyspepsia in 30-yearolds. P, probability; PPI, proton pump inhibitor; T&T, test and treat; EGD, endoscopy; QALY, quality-adjusted life-year.

Figure 5 Cost-effectiveness acceptability curve for endoscopy versus PPI for the management of dyspepsia in 60-year-olds. P, probability; PPI, proton pump inhibitor; T&T, test and treat; EGD, upper endoscopy; QALY, quality-adjusted life-year.

than less dynamic models and therefore provide a more accurate test of the recommendations made in the AGA policy statement. One test of a model’s accuracy is the extent to which it fits with data from clinical trials of dyspepsia strategies. A Cochrane review found 12 RCTs of the management of dyspepsia.32 The review determined that there was no significant difference in the effectiveness between empirical management with either PPI alone or test and treat and endoscopy-based management.

This review has recently been updated as an individual patient data meta-analysis, incorporating health care cost data from the trials.6 This suggests that although there is a small benefit in favor of endoscopy-based management, this is not sufficient to warrant the additional cost. Three recent studies have also compared eradication therapy with PPI and placebo eradication in H. pylori–positive patients with dyspepsia, showing a significant benefit in favor of eradication,33 35 in line with the findings of this model.



200000

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0


P T&T Cost-Effectiveness

Test and Treat v. PPI

0

50000

100000

150000

200000

180000 160000 97.5% 50% 2.5%

140000 120000 100000 80000 60000 40000


20000

Figure 6 Cost-effectiveness acceptability curve for test and treat versus PPI alone for the management of dyspepsia in 60-yearolds. P, probability; PPI, proton pump inhibitor; T&T, test and treat; EGD, upper endoscopy; QALY, quality-adjusted life-year.

0 0%

10%

20% 30% Prevalence of H. pylori

40%

50%

Figure 8 Point estimate and 95% confidence limits for maximum willingness to pay for a quality-adjusted life-year (QALY) by test and treat rather than empiric proton pump inhibitor (PPI), shown as a sensitivity analysis against the prevalence of Helicobacter pylori in 60-year-olds.

P EGD Cost-Effectiveness

EGD v. T&T 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

50000

100000

150000

200000


Figure 7 Cost-effectiveness acceptability curve for endoscopy versus test and treat for the management of dyspepsia in 60-yearolds. P, probability; T&T, test and treat; EGD, upper endoscopy; QALY, quality-adjusted life-year.

The findings of this detailed probabilistic model, incorporating both recent trial evidence from Cochrane reviews and cost and prevalence data specific to the United States, support the AGA dyspepsia guidelines and suggest that empirical acid suppression is the strategy of choice in young patients, even in areas with low prevalence of infection. In patients older than age 55, early endoscopy is a sensible strategy, although more data on the benefit of this procedure in preventing gastric cancer mortality are needed.

In conclusion, the modeling approach, combining a first-order individual simulation model and a second-order probabilistic sensitivity analysis, allowed both a sophisticated comparison of the consequences over 5 years of a particular management strategy and a realistic estimate of the limits of knowledge on that comparison. This method can be used to model strategies in any chronic condition where multiple clinical strategies exist—for example, prevention of coronary artery disease or the choice of disease-modifying agents in rheumatoid arthritis. One problem is that the models can be computationally intense. This is partly avoided by using a specifically designed programmed model that is economic in its use of computation. However, some more complex models may need parallel or ‘‘grid’’ computing facilities to run in a reasonable timeframe. ACKNOWLEDGMENT Financial support for this study was provided in part by a grant from Novartis to support a meeting of the investigators. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. NJT, NBV, PM, and BCD provided content


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