Despite extensive research into this common condition, the optimal cost-effective strategy for the initial primary care management of patients with uninvestigated upper GI symptoms remains uncertain. A Cochrane systematic review (14
) of 25 trials reporting 27 comparisons concluded that a strategy of PPI therapy was significantly more effective than either H2
RAs or antacids; more recently, a step-up approach has been shown to be more cost effective than a step-down approach at six months (38
). A strategy of ‘test and treat’ for H pylori
infection may also be more effective than acid suppression alone (14
), perhaps in part because the knowledge of H pylori
absence may decrease subsequent resource use (39
A recent cluster randomized trial (40
) compared empirical PPI therapy with testing for H pylori
, or a combination of the two. The strategies based on H pylori
testing led to similar symptom resolution, but reduced endoscopic workload and lowered one-year total costs compared with empirical antisecretory therapy. Most recently, a meta-analysis (41
) that included the large Medical Research Council-Carbon-13 Urea Breath Test and Eradication (MRC-CUBE) randomized controlled trial (RCT) (17
) of 699 patients suggested that both test and treat, and empirical PPI use were equally cost effective in patients with dyspepsia in a primary care setting, and that the choice should, thus, be driven by patient and physician preference.
In a meta-analysis by Delaney et al (14
), initial endoscopy was associated with a small reduction in the risk of recurrent dyspeptic symptoms compared with the H pylori
test and treat strategy, but was not cost effective. An individual patient meta-analysis from the same group (15
) suggested that prompt endoscopy conferred a small benefit in terms of the cure of dyspepsia, but cost more than ‘test and treat’, and was not a cost-effective strategy for the initial management of dyspepsia (prompt endoscopy eventually became cost effective only when the WTP per patient symptom-free of dyspepsia reached $180,000). Two recent RCTs (42
) completed in Asia suggested that a test-and-treat approach may be more cost effective than prompt endoscopy but results in less satisfaction (42
), while the test-and-treat approach is as effective but more cost effective than prokinetic administration or prompt endoscopy (43
All of the aforementioned data suffer from heterogeneity in trial designs or patient populations, and do not provide a global comparison across the existing wide variety of treatment options in a comparable setting, let alone one that is most adapted to Canadian practice.
Because no RCT has been large enough to compare all viable initial strategies in patients with uninvestigated upper GI symptoms, investigators have also turned to decision models. However, here too (even though accepting and quantifying uncertainty is an aim of cost-effectiveness analyses), many factors may limit analytical conclusions such as the following: disparate modelling methodologies, variations in study parameters such as study design, strategies (some now outdated), patient populations, base case assumptions, measurements of outcome and time horizons. This is especially true because decision models generally also incorporate data from disparate trials, and are highly influenced by parameters such as endoscopy costs, treatment and physician visits, the prevalence of H pylori
, the specificity of diagnostic tests, as well as the short- and long-term benefits of H pylori
eradication in patients with functional nonulcer dyspepsia (44
The CADET program, comprised of one observational and three randomized trials, was specifically designed to provide a large body of homogeneous data on the prevalence and initial management of uninvestigated upper GI symptoms, and currently exists as the most comprehensive sole data source available in uninvestigated dyspepsia, designed to be linked for an analysis such as the current one. As a result – and most importantly – the trials had comparable study populations, comparable validated symptom and health resource outcome measures, comparable follow-up durations, and were all completed within the same four-year time span. Decision modelling using these data, thus, provides a particularly meaningful, homogeneous health economic analysis from the increased statistical power of the pooled study arms. This enables a global quantification of all six initial management strategies. The probabilities included in the model are all taken directly from CADET studies (22
). The sensitivity analysis performed enabled us to assess wide variations of point estimates of probabilities and costs, including H pylori
prevalence, and the cost of omeprazole (as part of an overall direct cost attributable to each strategy).
The CADET studies used the terminology ‘uninvestigated dyspepsia’ to refer to all patients with uninvestigated upper GI symptoms including both heartburn-predominant and nonheartburn-predominant symptoms, consistent with the CanDys recommendations (18
). Indeed, the CanDys terminology is a broader definition of dyspepsia than perhaps used or accepted in other areas of the world, but it was considered to be more in keeping with the conceptual framework adopted by primary care physicians for patients presenting with uninvestigated upper GI symptoms as discussed elsewhere (18
). Nonetheless, all included CADET study patients did have epigastric pain or discomfort; in contradistinction, those with sole heartburn and/or acid regurgitation were considered to have GERD – not dyspepsia – and were not enrolled in the CADET program.
Point estimates suggested that both the empirical ranitidine strategy and the CanDys ranitidine strategy are dominated (less effective and more costly than CanDys omeprazole). The empirical ranitidine strategy is the least effective and the empirical omeprazole strategy is the least costly. The endoscopy strategies are more effective, but at higher incremental costs. In all cases, the ranitidine alternatives were less effective than their corresponding omeprazole/PPI strategies. The CanDys ranitidine strategy in the current model was based on the CADET-HR study in which almost one-half of the patients were stepped-up to omeprazole. This favoured the ranitidine strategies because the patients who stepped-up to omeprazole were considered to be ranitidine responders in the model (intention-to-treat data analysis), thus, artificially increasing the efficacy of a ranitidine-based first strategy.
Unfortunately, despite the large numbers of patients pooled for the present economic analysis, the variability in costs did not allow us to draw a definite conclusion about the respective cost-effectiveness of each strategy when taking into account the usual 95% CIs of the ICERs. Variability was increased by the higher resource use in the CADET-PE trial, which reflected the observational nature of that study.
The cost-acceptability curves provide a good summary of the main conclusions of the study. No strategy distinguished itself as the overwhelming choice across the full range of WTP values. The most clinically relevant WTP range may be the interval over which CanDys omeprazole was the strategy of choice. Indeed, in an attempt to anchor such considerations, the results by Kleinman et al (45
) are useful and suggest that GERD sufferers were willing to pay up to $182 to obtain complete relief in a short period of time without side effects. In the overall interpretation of the results, one should also consider the feasibility of prompt endoscopy in all patients with uninvestigated dyspepsia in the era of screening colonoscopy, with already limited equipment and human endoscopic resources (46
There are several limitations to the model. Costs and outcomes were modelled over one year; however, dyspepsia is often a recurrent condition, which may last for many years and eventually require endoscopy. Thus, the model may overestimate the benefits of the CanDys omeprazole strategy over those of prompt endoscopy. Because all data were derived from the CADET studies, the results are specifically applicable to the Canadian health care system. Factors in other health care systems that may limit generalizability of the results to other countries would include the following: the greater availability of direct or open-access endoscopy, eliminating the cost of a gastroenterological consultation; variability of endoscopy costs and possible differing proportionality of the cost-structure; and the availability of over-the-counter PPIs, which would eliminate pharmacy dispensing fees. Although the results likely represent class effects, there are no such homogeneous, summary, high-quality data using H2RAs or PPIs other than omeprazole and ranitidine.
We have attempted to better characterize the cost-effectiveness of competing initial strategies in the management of patients with uninvestigated upper GI symptoms in the primary care setting using coherent data drawn from the CADET studies. There are marked overlaps in the CIs of the ICER assessments. Based on the model assumptions, the WTP analysis suggests that no single strategy is most likely to be cost effective over a wide range of WTP thresholds; yet, the CanDys omeprazole approach may be the most likely to be cost effective, assuming clinically relevant WTP estimates in the management of patients with uninvestigated upper GI symptoms over the year following the initial patient-physician encounter. Endoscopic approaches may be marginally more effective, but the increased incremental costs are high.