SUMMARY

INTRODUCTION

Gastroesophageal reflux disease (GERD) symptoms and sequelae cause considerable morbidity and contribute to substantial medication use and costs worldwide [1,2]. In the United States (US) alone, overall spending on all GI diseases is estimated to be $142 billion (in 2009 US dollars) per year in direct and indirect costs [3]. GERD accounts for approximately $15–20 billion of these direct and indirect costs [4]. A study in 1997 found that total unadjusted medical costs of GERD in a US health maintenance organization population (1550 people with GERD) were $2089 higher than for controls; this corresponded to around $471 in attributable costs [5]. Factors contributing to GERD-related costs include direct costs (e.g., medication use, diagnostic testing, physician visits, and hospitalizations) and indirect costs (e.g., decreased quality of life, work absenteeism, and loss of productivity). It has been estimated that prescribed medications for GERD, primarily proton pump inhibitors (PPIs), account for over 50% of prescriptions for all digestive diseases, resulting in around $10 billion in annual direct health care costs [1,4]. In 2010, one PPI (esomeprazole) accounted for the most retail dollars (>$5.2 billion) out of all branded drugs sold in the US [6].

In light of the enormous healthcare burden attributed to GERD, numerous studies have evaluated cost, healthcare utilization, and cost effectiveness of differing management strategies. As economic evaluations are often used as the basis for practice guidelines and resource allocation, it is critical that reporting of data is appropriately scrutinized. The growing field of comparative effectiveness research also often uses cost considerations to determine thresholds of effectiveness. Recently, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) developed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) to guide quality reporting in economic evaluations [7].

Our first objective was to systematically evaluate the existing literature to identify economic evaluations of GERD medical management strategies and assess the scientific quality of these reports using the CHEERS guidelines. Our second objective was to summarize the economic outcomes of the included studies.

METHODS

We identified economic evaluations and cost studies of GERD medical management strategies by searching PUBMED and the National Health Service (NHS) economic evaluation database via the Cochrane library. Searching was restricted to articles in English language journals from July 2003 to July 2013. The search strings for both databases were as follows:

RESULTS

The initial literature search identified 219 and 52 articles from PubMed and the Cochrane/NHS economic evaluation database, respectively (Figure 1). After exclusion criteria were applied and the results were combined, the abstracts and manuscripts (if necessary) of 58 articles were reviewed for initial inclusion in the final review. Of these, 35 (60%) were excluded as they reported cost identification outcomes without linking cost to effectiveness. An additional six articles were subsequently excluded as they did not involve any comparisons of the medical management of GERD (n=4) or focused only on screening for Barrett’s esophagus (n=2). One additional article was obtained via expert opinion that was not identified with the literature search [8]. Thus, eighteen articles were included in the final analysis [8–25] (Figure 1); their general characteristics are shown in Table 1.

The quality of the eighteen articles, as assessed by the CHEERs guidelines is shown in Table 2. Of the 24 items, 11 articles (61%) met all criteria for economic evaluation reporting [8–15,18,19,21]. Only one did not explicitly identify the study as an economic evaluation in the title [16]. The majority of missing items were specific methods including mention of discount rates (n=4) [16,23–25] and study parameters (n=2) [16,25]. Three articles did not disclose funding sources [22–24] and four did not disclose conflicts of interest [17,20,22,23]. Of these, two included neither disclosure of funding nor conflicts of interest [22,23].

Of the eighteen included articles (Table 3), three used a decision analysis [18,22,24] nine used Markov modeling [9,10,12–14,17,20,21,23] and five our reported cost outcomes related to randomized trials [8,11,15,16,19]. Only one used a retrospective cohort design in assessing the incremental annualized healthcare costs of compliant and non-compliant PPI users [25]. Fifteen articles (78%) included comparisons of different PPI strategies (n=7, [16–21,23]) or PPI therapy with surgery (n=8, [8–15,24]). Four articles compared PPI therapy with endoscopic-based management (either as a diagnostic or therapeutic strategy) [9,16,17,22]. Of the twelve papers that used decision analysis or Markov models [9,10,12–14,17,18,20–24], nine were performed from a non-US societal or public health system perspective [9,12–14,17,20,21,23,24]. The majority of articles (n=15) used a public healthcare system perspective (e.g. UK NHS, US Medicare) [9–17,19–23,26]. One study used an employer cost perspective [18], one used a societal perspective [24], and one used a third party payer perspective [25]. More articles reported cost outcomes in US dollars (n=7) than other individual currencies (Table 1). The time horizons used in the decision and Markov models were highly variable ranging from five months [23] to a lifetime [8,13,14].

The economic outcomes for specific articles are summarized in Table 3; most studies reported outcomes as incremental cost effectiveness ratios (ICERs).

DISCUSSION

In this systematic review of economic evaluations of GERD medical management over the past decade, we identified eighteen articles meeting strict inclusion criteria for analysis. PPI therapy was preferred (i.e., both more effective and less costly) as empiric therapy for patients with reflux symptoms, except in patient populations with high H. pylori prevalence, and this is reflected by clinical practice and guideline recommendations [28]. Although surgery is initially costly, many patients have good symptom control over time and thus surgery can be cost saving and cost-effective compared to medical therapy over time periods ranging from 3 years [15] to a lifetime [8]. Endoscopic anti-reflux procedures do not appear cost-effective compared to medical therapy based on available data from studies that examined what are now largely obsolete procedures. Should more innovative endoscopic GERD management strategies be introduced and adopted, more economic research will be needed to evaluate their relative cost-effectiveness.

As healthcare accounts for growing budgetary commitments worldwide, there has been an increased emphasis on evaluating therapies in terms of cost and quality. In turn, the research surrounding disease states often includes cost as a secondary outcome. Reporting of cost, however, is overly simplistic and does not necessarily imply value. Most of the articles that we initially identified were not included as they were simply cost-identification studies, and did not relate cost to actual benefit or effectiveness of therapy. Cost identification articles can be useful, as they may be used to design future economic evaluations. However, it is an important distinction that is often overlooked when reporting cost data and can lead to inappropriate conclusions about the relationship of cost to actual effectiveness of therapy.

In light of the increased emphasis on cost, it is critical that research reporting cost outcomes is evaluated rigorously. Recently, the ISPOR taskforce provided guidance for evaluating quality of economic evaluations with release of the CHEERs checklist. Overall, around 60% of the included articles met all CHEERs criteria. Those not meeting all of the CHEERs criteria mainly omitted method descriptions or disclosures of funding. As many cost studies involve sophisticated modeling techniques based on probability estimates and possible funding from pharmaceutical companies or device manufacturers, disclosure of funding sources is critical to ensure that readers can reliably assess any potential for bias. Investigators embarking on future research with cost outcomes should use the CHEERs checklist to guide study design and reporting of results. In turn, the criteria may help editors and reviewers ensure consistent reporting and identification of bias in economic evaluation research.

Numerous medications can be taken for reflux symptoms including antacids, H₂RAs and PPIs. Economic evaluations comparing medical therapies found that PPI use is more effective than treatment with an H₂RA and less costly due to lower rates of symptom and esophagitis recurrence [20,23]. As there is very little evidence that any one PPI is superior in terms of efficacy, use of the cheapest PPI available dominated specific PPI therapeutic regimens [21]. The most recent Technical Review on GERD from the American Gastroenterological Association reflected the superiority of PPI therapy over H₂RAs [29] but did not specifically recommend one particular PPI formulation over others. A recent US population study using the National Ambulatory Medical Care Survey (NAMCS) found that both branded (esomeprazole) and generic (omeprazole) PPIs had significant increase in use from 2002–2009 [30]. There is very little evidence that more expensive PPIs offer additional major benefits over less costly PPIs for most GERD patients, especially for initial therapy. Therefore, practitioners in countries or settings without fixed formularies should be encouraged to use the least costly PPI formulation.

Numerous studies included in this review compared medical and surgical therapy for GERD. Laparoscopic surgery was found to meet cost-effectiveness thresholds, especially if time horizons were between 3 and 10 years [8,12–15], although was one study showed PPIs to dominate surgery (less costly and more effective) within 10 years [10]. This difference is probably due to the quality of life estimates (utilities) [27] that were essentially the same for both surgical and medical therapy based on two older studies [27,31]. The most recent study with impressive long term patient follow up (5 years) found that more patients randomized to early LNF (vs. medical therapy) had less frequent heartburn and regurgitation at 3 and 5 years follow up [8]. In addition, quality of life scores were greater in surgery patients at 5 years follow up [8]. Laparoscopic techniques to prevent acid reflux have very good long term outcomes in select patients [8,32,33] and non-laparoscopic anti-reflux surgery was the primary therapy for many patients with GERD prior to the introduction of PPIs [32]. However, surgery rates for GERD have declined over time. In 2005, there were 15,737 Nissen fundoplication procedures performed in the United States [34]. Although this is still one of the most common anti-reflux procedures, its use had declined by 27% from the late 1990s [34]. Patient and physician preferences have probably played a role in this trend towards less invasive (and mostly effective) medical treatment. However, the cost-effectiveness of surgery should not be underestimated, especially in patients with a definite diagnosis of GERD that is truly refractory to optimized medical treatment, perhaps because of volume reflux. Based on this review, there is little economic evidence that endoscopic anti-reflux procedures or performing endoscopy prior to PPI therapy are cost-effective strategies. Further research is also needed to determine if other emerging technologies for GERD, such as a magnetic device for lower esophageal sphincter augmentation [35], will be cost-effective, assuming safety and efficacy are demonstrated before widespread clinical adoption.

Limitations of this review include the inability to pool data due to the different time horizons and comparisons made in individual studies. Thus, it is difficult to obtain pooled estimates of cost-effectiveness based on published data. Economic modeling is based on assumptions and probability estimates that usually require sensitivity analyses to test model integrity. The articles included in this review did report robust sensitivity analyses. However, limitations of economic evaluations include inability to account for treatment effects in different patient phenotypes. For instance, the definition for efficacy used in the clinical trials and modeling may vary considerably in studies of GERD (e.g., global symptom scores [19], disease specific patient reported outcomes [8], health related quality of life [10], and symptom free days [21]). GERD is also a diagnosis that is sometimes given to patients as an explanation for a variety of upper gastrointestinal symptoms that, consequently, display a highly variable response to medical therapy. The models employed in the included literature assumed PPI prescribing is systematic and that patient compliance is substantial. In fact, in clinical practice, PPI prescriptions and subsequent PPI utilization have been found to be highly variable across settings [36–40]. The actual realized economic outcomes reported, especially regarding PPI therapy, are probably less than optimal in clinical practice.

In summary, this is the first systematic review of economic evaluations of GERD medical management. Any future evaluations should adhere to standard reporting measures so that readers can assess and compare quality of cost estimates and outcomes. Future economic evaluations of GERD medical management should also attempt to account for, and compare, different patient phenotypes and the large heterogeneity of treatment effects seen with anti-reflux therapy. In clinical practice, the primary focus should be on optimal care coordination of patients with reflux symptoms via cost-effective management strategies that are aligned with patient preferences [41].

Acknowledgments

Abbreviations

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References