Digestive and Liver Disease
Volume 39, Issue 11 , Pages 993-1000, November 2007

The lessons learned from randomized clinical trials of GERD

  • F. Pace

      Affiliations

    • Department and Chair of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy
    • Corresponding Author InformationCorresponding author at: Department and Chair of Gastroenterology, “L. Sacco” University Hospital, Milan, Via G. B. Grassi, 74, 20157 Milan, Italy. Fax: +39 02 39042337.
    • ,
  • A. Sonnenberg

      Affiliations

    • Portland VA Medical Center and Oregon Health & Science University, Portland, OR, USA
    • ,
  • G. Bianchi Porro

      Affiliations

    • Department and Chair of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy

Received 17 July 2007; accepted 19 September 2007. published online 17 October 2007.

Article Outline

Abstract 

Despite the huge number of randomized controlled clinical trials published on gastro-oesophageal reflux disease, the translation of the information gathered into clinical practice is rather limited.

The aim of this article is to summarize the results of pivotal randomized controlled clinical trials and review articles on reflux disease and evaluate to what extent their results can be applied to current clinical practice.

We reviewed the most relevant randomized controlled clinical trials and reviews since the publication of the first randomized controlled clinical trial on reflux oesophagitis (1978) to date.

Six areas were explored, namely: (1) diagnostic “entry” criteria, (2) efficacy parameters, (3) duration of therapy, (4) degree of antisecretory effect, (5) placebo effect, (6) follow-up data.

Gastro-oesophageal reflux disease is now the most frequent upper GI disorder treated by gastroenterologists in Europe and North America. There is still a dearth of information regarding the natural history of the disease. The types of information generated through randomized controlled clinical trials have had only limited applicability to routine clinical practice. In the future, large cooperative databases accumulating the clinical histories of a great variety of gastro-oesophageal reflux disease patients may help to provide us with the much needed insights into the natural history of this common disorder.

Keywords: GERD, NERD, Placebo, PPI, RCT, Reflux oesophagitis

 

Gastro-oesophageal reflux disease (GERD) is a common clinical problem in most countries, including Asia where it used to be rare until 20 years ago. Despite the significant disease burden for the individual patient, as well as society as a whole, our knowledge about the natural history of GERD is still limited. The reasons for this have been explored extensively elsewhere [1] and can be summarized as follows:

(1)The nosology of the disease has greatly changed over time. Until 15 years ago, GERD was essentially synonymous with erosive oesophagitis (EE) and its complications, such as stricture or Barrett's oesophagus. The appreciation that non-erosive reflux disease (NERD) comprises more than 60% of all GERD cases occurred only recently.

(2)The knowledge about the clinical outcomes of GERD is based mainly on randomized controlled clinical trials (RCTs) of patients with “pure” erosive oesophagitis. As a consequence, we lack information about the presentation of the disease among large populations of GERD patients with comorbidities or atypical manifestations and among non-consulters, because these patients were generally excluded from RCTs. For similar reasons, we erroneously considered NERD less severe in comparison with erosive oesophagitis, both from the perspective of symptomatic burden and response to therapy.

(3)In the 1970s when our current concepts of the disease began to evolve, GERD was considered a smaller side-branch in the larger tree of the so-called “acid-related diseases”, which included mainly peptic ulcer disease (PUD). PUD was much more prevalent than GERD in the past and, therefore, the primary focus of most RCTs involving antisecretory agents. The situation has now changed completely, and following the discovery of Helicobacter pylori, the epidemiological importance of PUD has progressively declined, whereas the relevance of GERD has steadily increased. Nevertheless, we still prescribe to GERD patients maintenance doses of antisecretory agents that are halved in comparison with doses for treatment of acute flare-ups. This regimen was originally developed for treatment of PUD and subsequently adopted for treatment of GERD before any supportive evidence in its favour became available.

The aim of this article is to summarize the results of pivotal RCTs and review articles on reflux disease and evaluate to what extent their results can be applied to current clinical practice. We would like to separately assess the following issues: (1) diagnostic “entry” criteria, (2) efficacy parameters, (3) duration of therapy, (4) degree of antisecretory effect, (5) placebo effect, (6) follow-up data.

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1. Diagnostic criteria 

At the beginning of the era of RCTs in GERD, case populations were comprised almost exclusively of patients with typical GERD symptoms and erosive or ulcerative oesophagitis. Initially, the equation GERD=oesophagitis was the paradigm underlying all GERD treatment. Subsequently, it was shown that patients with typical symptoms but without endoscopic oesophagitis (so called NERD) represent the majority of GERD cases (>60%) seen in clinical practice [2]. Accordingly, many trials nowadays include patients with NERD or typical symptoms who remain endoscopically uninvestigated. Less frequently, clinical studies also include GERD patients with atypical manifestations, such as chronic cough, nonallergic asthma, posterior laryngitis, who may or may not have been subjected to physiologic tests of gastro-oesophageal reflux. Such tests include pH-metry or impedance measurement to document abnormal oesophageal exposure to acidic or nonacidic gastric contents, respectively. However, none of these test parameters have been validated and reproduced reliably outside single clinical centres.

In patients with NERD or without diagnostic endoscopy, the “entry” criteria relied on symptoms assessed by a visual analogue scale (VAS) or a questionnaire. Many kinds of questionnaires have been proposed, and a recent literature review identified 20 different scales to assess symptoms of GERD. Twelve scales were specific for GERD and eight for GERD and/or other benign gastrointestinal diseases [3]. None of these tools has met the criteria of being internationally validated, reliable and highly responsive and, therefore, acceptable as a primary outcome measure for clinical trials [3]. In conclusions, it seems that we have adequate diagnostic descriptors only for a minority of patients (i.e., those with typical symptoms and endoscopic oesophagitis), but lack hard descriptors for the remainder of the GERD population.

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2. Efficacy parameters 

In the initial trials of GERD, healing of acute endoscopic damage was only one of several outcome parameters considered. As a matter of fact, in the first two trials [4], [5] comparing cimetidine with placebo, six different efficacy parameters were utilized: decrease in the severity and frequency of symptoms, reduction of oesophageal mucosa sensitivity to acid (Bernstein test), decrease of antacid intake, effect on oesophageal histology, effect on the basal lower oesophageal sphincter pressure and changes in endoscopic appearance. Subsequently, the first trial comparing ranitidine with placebo [6] reduced outcome assessment to three variables (symptoms, endoscopy and histology), and the first trial comparing omeprazole versus ranitidine [7] further reduced the number to only two variables: symptoms and endoscopy. This is the present state in the field of RCTs of reflux oesophagitis, although the new concept of “complete remission” may compress outcome measurement even further by integrating endoscopy findings and symptom change into one single parameter [8].

As far as the group of patients with NERD is concerned, again, multiple parameters of efficacy have been used. In a recent review, Zacny et al. [9] reported that the most frequently used outcome measures in NERD studies [10], [11], [12] included the proportion of patients willing to continue, the need to use study drugs for consecutive periods, and the intake of rescue antacids. Relapse of heartburn as outcome measure has a high face validity, especially, if both its frequency and severity are assessed [9]. For the parameter “willingness to continue”, it is less clear whether patients are truly satisfied with on-demand therapy or just want to remain in a study. Patients may be satisfied with on-demand therapy even though they are still required to take medication daily or almost daily for prolonged periods. The number of days that medications are used and the frequency of need for rescue antacids are other clinically important outcome measures. Additional options for outcome measurement include severity of individual symptoms, especially heartburn and acid regurgitation, and the number of symptom free days. There are some data in the literature, which suggest that health-related quality of life (HRQoL) diminishes, if patients complain of mild heartburn more than twice per week or moderate heartburn at least once per week [13]. The current state of affairs in NERD may become changed again by the new concept of “sustained symptom relief” [14] and by the discovery that most NERD patients without macroscopic lesions can harbour microscopic changes of their oesophageal mucosa. Intercellular space dilation occurs frequently among patients with reflux disease in whom endoscopy shows otherwise no mucosal breaks [2].

The situation is even more complicated in the case of atypical GERD manifestations. For example, the recent Cochrane collaborative review of GERD treatment in asthmatic patients [15] considered the following health outcomes for the assessment of therapy: admission/readmission rate, emergency room visits, unscheduled doctor visits, forced expiratory volume and other pulmonary function tests, use of ‘rescue’ (or reliever) medications, nocturnal symptoms, symptoms score, airway hyperresponsiveness and treatment preference.

In conclusion, in spite of the seeming usefulness of outcome measurement in the individual GERD trial, the situation becomes rather confusing when one tries to apply such outcome parameters to routine clinical practice. Paraphrasing an old article, we still do not clearly know when a GERD patient is really healed [16].

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3. Duration of therapy 

Of all issues in the present review, this is the easiest to address. Acute therapy to achieve healing of erosive oesophagitis usually lasted 4–8 weeks in most studies of antisecretory agents [17]. Because GERD is a chronic disease with frequent symptomatic relapses in both NERD and EE after discontinuing acute treatment [18], maintenance treatment is needed in the majority of patients. The optimum length of maintenance therapy to assure a low frequency of recurrences after its discontinuation has not been yet identified. Most maintenance studies involved only a relatively short period of drug administration, ranging between 24 and 52 weeks [19]. Few studies explored longer time periods. One noteworthy example was the study by Caos et al., investigating a 5-year period of continuous rabeprazole therapy of 10 or 20mg daily versus placebo [20]. A second 7-year study by Lundell compared continuous omeprazole therapy (adjusting its dose between 20 and 60mg daily) with antireflux surgery [21]. The underlying pathophysiological abnormalities responsible for the occurrence of gastro-oesophageal reflux do not improve under pharmacological treatment [22]. Therefore, any GERD treatment will need to be continued for a prolonged period of time, possibly even for life. During such prolonged time periods, it may seem advisable to try out various strategies to reduce the dose of drugs, such as step-down or on-demand treatment. Even the most recently updated guidelines do not specify any length of maintenance therapy [23].

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4. Degree of antisecretory effect 

Acid suppression is the mainstay of treatment in both the acute and long-term treatment of the disease. The Cochrane systematic review [17] identified 18 trials involving 2134 patients that compared H2 receptor antagonists (H2RA) with placebo. H2RA were effective in the treatment of oesophagitis compared with placebo. The relative risk of oesophagitis persisting after H2RA was RR=0.72, 95% CI 0.65–0.79 (Fig. 1) with a number needed to treat (NNT) of 5 (95% CI 3–22). There were five trials that compared proton pump inhibitors (PPI) with placebo in 635 patients. PPI were more effective than placebo in the treatment of oesophagitis (0.23, 0.01–0.50; Fig. 2) with an NNT of 2.0 (1.4–2.5). The review also identified 26 trials involving 4064 patients that compared PPI with H2RA. PPI therapy was better than H2RA therapy in the treatment of oesophagitis at 4–8 weeks (0.47, 0.41–0.53; Fig. 3) with an NNT of 3.0 (2.8–3.6). Within the class of PPI agents, a further meta-analysis was performed on 10 studies (n=15,316) [24]. At 8 weeks, there was a 5% increase (RR=1.05, 1.02–1.08) in the probability of healing EE with esomeprazole, yielding an absolute risk reduction of 4% and NNT of 25. The calculated NNTs by Los Angeles grade of EE (grades A–D) were 50, 33, 14 and 8, respectively (Fig. 4). Lastly, esomeprazole conferred an 8% increase (RR=1.08, 1.05–1.11) in the probability of GERD symptom relief at 4 weeks. In comparison with other PPI esomeprazole conferred a statistically significant improvement, yet clinically only modest overall benefit in 8-week healing and symptom relief in all-comers with EE. The clinical benefit of esomeprazole appears negligible in less severe erosive disease but might be important in more severe disease [24]. The recent Cochrane review [19] identified 10 eligible randomized trials involving 1583 patients with oesophagitis that compared the efficacy of PPI with H2RA therapy over 24–52 weeks. The overall relapse of erosive oesophagitis was 22% in the PPI group compared with 58% in the H2RA group with an NNT of 2.5 (2.0–3.4). Similar results were achieved with symptom relapse as endpoint rather than oesophagitis recurrence. This review also identified six trials that compared half-dose PPI with H2RA treatment in 1156 patients. Overall, 40% of the PPI group had a relapse of erosive oesophagitis after 24–52 weeks compared with 66% of the H2RA group (NNT 3.3, 2.5–5.0). Low-dose PPI therapy is, therefore, better than H2RA therapy, but not as effective as a standard dose of PPI. All these trials dealt with patients with erosive oesophagitis. By contradistinction, there are insufficient long-term data on PPI therapy in endoscopy-negative reflux disease or atypical GERD manifestations. Acid inhibition and its effect on the healing of oesophagitis are intimately related to the influences of time and the severity of oesophagitis. To achieve healing of mucosal lesions, severe grades of erosive oesophagitis often require more potent inhibition of acid secretion over longer time periods than mild grades of erosive oesophagitis [25].

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5. Placebo effect 

As a consequence of our limited knowledge about the natural history of GERD, we cannot predict what patients with NERD will resolve their symptoms spontaneously and what patients with EE will spontaneously heal their oesophagitis. Several years ago, we tried to approximate the spontaneous healing of oesophagitis in a meta-analysis of the placebo healing rates in a variety of studies testing the efficacy of H2-RA, PPI and other drugs [26]. We examined 33 studies and eventually included 22 in the analysis. Cimetidine was used in eight studies, ranitidine in six, cisapride and sucralfate each in two, metoclopramide, nizatidine, pirenzepine and omeprazole each in one study. The pooled median healing fraction was 46% with the various active drugs and 24% with placebo after 4–8 weeks of therapy. The pooled difference in healing was 22% in favour of the active drugs (Fig. 5) with an odds ratio of 2.57 (95% CI=1.0–3.0). The amount of healing achieved with active medication did not correlate with the amount of healing under placebo. We estimated, therefore, that less than a quarter of oesophagitis patients may heal spontaneously within 4–8 weeks. No similar meta-analysis has been done regarding maintenance therapy or other GERD subgroups besides erosive oesophagitis. However, a recent meta-analysis of the efficacy of PPI in NERD [27] found that the therapeutic gain over placebo for complete heartburn resolution at 4 weeks was 26%, with PPI healing of 36.7% and placebo healing of 9.5%. Thus, less then 1 out of 10 placebo-treated NERD patients can be expected to experience a spontaneous relief of heartburn within 4 weeks.

  • View full-size image.
  • Fig. 5. 

    Meta-analysis of complete symptoms disappearance after 4–6 weeks of active drugs vs. placebo therapy in reflux oesophagitis RCTs. Pooled rate difference is 0.20 in favour of active drugs (from ref. [26], with permission).

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6. Follow-up data and outcome research 

The Veterans Administration Cooperative Study [28] and the study by the Nordic GORD Group (21) represent two notable exceptions of recent studies, which compared the long-term outcomes of medical with surgical therapy in patients with erosive oesophagitis. Recently we have reviewed the state of art concerning outcome research in gastro-oesophageal reflux disease [29]. Outcomes research is a rapidly evolving field that incorporates epidemiology, health services research, health economics, medical decision analysis and psychometrics [30]. It is devoted to the measurement of effectiveness and other complementary outcome measures of health care, such as quality of life, patient satisfaction and quality of health delivery. Outcomes research can be defined as the discipline that describes, interprets and predicts the impact of medical and non-medical interventions on final endpoints (from survival to satisfaction with care) that matter to decision makers (from patients to society at large) [31]. The emphasis on outcomes research has grown over time, the reasons for this trend being manifold [32]. They include (a) the need for cost containment in health care, (b) the implementation of “managed care” in the United States, which generated tight competition between health maintenance organizations and (c) the recognition of major geographical differences within individual countries in the use of identical medical procedures. Measuring the impact of GERD treatment on heartburn and other reflux symptoms is pivotal to understanding the effectiveness of treatment. However, symptoms alone do not fully capture the impact of therapy on patient functioning and well-being. Since GERD is primarily a symptom-based diagnosis, patient-reported outcomes (PRO) such as symptom and HRQoL measures are important in assessing the effects of treatment [33]. The main distinction between these two PROs relates to the fact that the former assesses the frequency and severity of relevant GERD symptoms but does not evaluate the impact of such symptoms on everyday life, functioning and patient well-being. HRQoL instruments, on the other hand, reflect patients’ self-perception of their physical, psychological and social well-being. The inclusion of both scales in RCTs provides a better and more comprehensive evaluation of treatment success. A review of the effects of pharmacological intervention of GERD on HRQoL measures [34] concluded that GERD significantly decreases HRQoL and that antisecretory therapy significantly improves HRQoL. Reflux disease has a substantial adverse impact on HRQoL, irrespective of whether oesophagitis is present or not. This impact is comparable to other chronic conditions, such as asthma and congestive heart failure. Even mild and moderate symptoms of gastro-oesophageal reflux diminish HRQoL, resulting in costly consequences for work- and non-work-related productivity. The disease burden can be minimized by therapies that provide effective symptom relief. There is good evidence that among the available therapies for reflux disease, PPI resolve symptoms to a greater extent than histamine-2 receptor antagonists or prokinetics, and this in turn improves HRQoL [35]. This effect of PPI therapy occurs regardless of whether oesophagitis is present or not.

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7. Conclusions 

Until now the era of RCTs in the area of GERD has lasted for a relatively short period of only 30 years, during which we have witnessed a marked increase in the prevalence of the disease [36], [37]. GERD is now the most frequent upper GI disorder treated by gastroenterologists in Europe and North America. There is still a dearth of information regarding the natural history of the disease. The types of information generated through RCTs have had only limited applicability to routine clinical practice. In the future, large cooperative databases accumulating the clinical histories of a great variety of GERD patients may help to provide us with the much-needed insights into the natural history of this common disorder.

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Practice points 


•Adequate diagnostic descriptors exist only for a minority of GERD patients (i.e., those with typical symptoms and endoscopic oesophagitis).

•Contrary to the RCT setting, outcome measurement is a seldom-used routine clinical practice.

•The long-term treatment strategy of GERD patients is not well defined even in most updated guidelines.

•It is conceivable that different GERD syndromes (e.g., with or without endoscopic damage, or with or without extra-oesophageal manifestations) may require different degrees of gastric acid inhibition.

•The placebo effect in inducing acute symptomatic relief or mucosal healing can be estimated to range between 10% and 25%, respectively.

•Patient-reported outcome (PRO) instruments are becoming increasingly important tools in clinical trials and possibly in routine practice.

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Research agenda 


•We need more studies addressing the natural history of GERD patients.

•Clinical trials design must take into account the heterogeneity of GERD patients.

•Large clinical database may reveal to be as useful as RCT in gathering useful clinical information on natural history/outcome of GERD patients.

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Conflict of interest statement 

None declared.

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PII: S1590-8658(07)00543-9

doi:10.1016/j.dld.2007.09.008

Digestive and Liver Disease
Volume 39, Issue 11 , Pages 993-1000, November 2007

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