In gastro-oesophageal reflux disease (GERD), heartburn responds well to acid suppression, but regurgitation is a common cause of incomplete treatment response.
In gastro-oesophageal reflux disease (GERD), heartburn responds well to acid suppression, but regurgitation is a common cause of incomplete treatment response.
To assess the prevalence and burden of persistent, frequent regurgitation in primary care patients with GERD treated with acid suppression.
We analysed observational data from 134 sites across six European countries in patients diagnosed with GERD. Within 3 months of the index visit, symptoms were assessed using the Reflux Disease Questionnaire, and their impact on sleep and work productivity with the Quality of Life in Reflux and Dyspepsia questionnaire and the Work Productivity and Activity Impairment Questionnaire, respectively. Patients provided information on concomitant over-the-counter (OTC) GERD medication use.
Persistent, frequent (3–7 days/week) regurgitation was reported by 13.2% (153/1156) of GERD patients with no heartburn on acid suppression; the prevalence was very similar for patients with up to 2 days/week of ongoing mild heartburn. Among patients without heartburn, sleep disturbance of any type was reported by 50.7–60.1% with persistent, frequent regurgitation, compared with 38.1–51.1% and 14.4–19.2% of those with less frequent or no regurgitation respectively. Persistent, frequent regurgitation was associated with increased use of OTC medication and more hours of work missed, whether mild, infrequent heartburn was present or not.
Frequent regurgitation, which persisted in 12–13% of patients with no or infrequent, mild heartburn on acid suppression, negatively affected sleep and work productivity, and increased use of OTC medication. Persistent, frequent regurgitation is problematic for primary care patients with GERD.
Most patients with gastro-oesophageal reflux disease (GERD) respond well to acid suppression therapy, although the evaluation of symptom response has largely focused on heartburn. Recent analyses of clinical trial data suggest, however, that regurgitation is less responsive to acid suppression than heartburn, and may be a common cause of incomplete treatment response.[2, 3] Furthermore, there is a lack of data describing the impact of regurgitation on patient health-related quality of life (HRQOL). We used observational data collected in the European multicentre Retrospective ANalysis of GERD (RANGE) study on the management of GERD in primary care practice to: (i) quantify the proportion of patients with GERD receiving acid suppression therapy who have persistent, frequent regurgitation despite absent or ongoing infrequent, mild heartburn; and (ii) assess the HRQOL burden of persistent, frequent regurgitation in these patients.
RANGE was an observational study conducted at 134 primary care sites in Germany, Greece, Norway, Spain, Sweden and the UK (AstraZeneca study code: D9612LOO114). Patients with GERD were identified over a 4-month period and enrolled if they consulted their physician about one or more of the following GERD-related factors: troublesome heartburn and/or regurgitation, a GERD diagnosis (heartburn and/or regurgitation, reflux oesophagitis and/or pathological lower oesophageal acid exposure), GERD complications (e.g. stricture or Barrett's metaplasia) or for obtaining a prescription for acid suppression medicine (i.e. a proton pump inhibitor [PPI] or histamine-2 receptor antagonist) and/or antacid for GERD. As this was a primary care study, it is likely that most patients would have had a symptom-defined GERD diagnosis. All patients received acid suppression treatment (76% PPIs) and/or antacids. In most patients (from 40% in Greece to approaching 80% in Sweden), there was no change in treatment from the index visit to the study follow-up visit. The study protocol was approved by the local ethics committees and was conducted in accordance with good clinical practice, with all participating patients having provided written informed consent.
In this observational, cross-sectional study, participants reported their symptoms, complications, treatments and health care utilisation within 3 months of the index visit. Three patient-reported outcome instruments were used to assess symptoms and their impact during the previous 7 days. The Reflux Disease Questionnaire quantified heartburn (‘a burning feeling behind the breastbone’) and regurgitation (‘acid taste in the mouth’ and/or ‘unpleasant movement of material upwards from the stomach’).[6, 7] Secondly, patients completed five questions on sleep disturbance from the Quality of Life in Reflux and Dyspepsia questionnaire. Individuals reported the frequency (on a 1–7 point graded Likert scale ranging from ‘all of the time’ to ‘none of the time’) with which they experienced difficulty getting a good night's sleep, felt ‘tired or worn out’ because of lack of sleep, were woken up at night and were prevented from falling asleep again, or had trouble getting to sleep, owing to their symptoms. Finally, patients completed the Work Productivity and Activity Impairment Questionnaire for individuals with GERD,[9, 10] and also provided information on concomitant over-the-counter (OTC) GERD medication use. Validated local language versions of these PRO instruments were used in the study. Translation of the original English version of the questionnaires involved two independent translations, along with a third independent translation to consolidate a final version. Following this, an independent back-translation into English was made, which was compared with the original English version to ensure content validity. Persistent, frequent regurgitation was defined as occurring on 3–7 of the previous 7 days of treatment.
The study was cross-sectional and descriptive and therefore no formal statistical testing was performed. Hence, only descriptive statistics are presented. Categorical data are reported as frequencies and proportions; continuous data are reported as means and standard deviations. Where considered relevant, 95% confidence intervals (CIs) have been provided.
Of 2052 evaluable patients with GERD, 1156 (56.3%) had no heartburn (Group R), 1446 (70.5%) had, at most, 1 day/week of mild heartburn (Group 1 day) and 1602 (78.1%) had, at most, 2 days/week of mild heartburn (Group 2 day) following acid suppression therapy. Demographic data for Group R are shown in Table 1; the demographic data were very similar for individuals in Groups 1 day and 2 day (data not shown).
|Age (years), mean (s.d.)||59.2 (15.5)||51.6 (14.1)||59.1 (15.0)||61.4 (16.0)||58.6 (15.0)||58.9 (16.3)||58.1 (15.5)|
|Weight (kg), mean (s.d.)||79.8 (15.9)||77.4 (14.7)||79.3 (16.9)||72.6 (13.1)||80.0 (14.0)||76.5 (17.7)||77.8 (15.5)|
|Height (cm), mean (s.d.)||169.5 (9.3)||168.9 (9.5)||171.0 (9.1)||161.7 (9.3)||170.7 (8.8)||167.3 (9.5)||168.4 (9.8)|
|Gender (male), n (%)||88 (42.9)||102 (48.8)||116 (46.0)||85 (41.9)||82 (42.1)||42 (46.7)||515 (44.6)|
|Smoker (current/past), n (%)||73 (36.0)||101 (47.9)||128 (50.8)||74 (36.5)||102 (52.3)||53 (52.3)||531 (46)|
|Alcohol use, n (%)||119 (59.8)||64 (30.5)||172 (68.3)||52 (25.6)||140 (71.8)||69 (76.7)||616 (53.6)|
Overall, among patients who had no heartburn on therapy, most were either employed (487/1155 [42.2%]) or retired (453/1155 [39.2%]) and most patients were educated to either primary or secondary school level (867/1099 [78.9%]). The most common reasons given for the index visit were either the recurrence of symptoms after a remission period or routine follow-up despite the absence of symptoms (360/1142 [31.5%] and (362/1142 [31.7%] respectively).
Persistent, frequent (3–7 days/week) regurgitation (‘acid taste’ and/or ‘unpleasant movement’) was reported by 153/1156 (13.2%, 95% CI: 11.3–15.3%) of Group R, 176/1446 (12.2%, 95% CI: 10.5–14.0%) of Group 1 day, and 213/1602 (13.3%, 95% CI: 11.7–15.1%) of Group 2 day (Figure 1). Moderate/severe ‘acid taste’ was reported by 148/1156 (12.8%) and moderate/severe ‘unpleasant movement’ by 137/1156 (11.9%) of Group R. Corresponding values for Group 1 day were 170/1446 (11.8%) and 164/1446 (11.3%), respectively. For those in Group 2 day, these were 202/1602 (12.6%) and 191/1602 (11.9%), respectively (Figure 2).
In patients with no heartburn at the follow-up visit (Group R), sleep disturbance of any type was reported by 50.7% (95% CI: 42.2–59.2%) to 60.1% (95% CI: 51.6–68.2%) of patients with persistent, frequent regurgitation compared with 38.1% (95% CI: 31.8–44.7%) to 51.1% (95% CI: 44.4–57.7%) of patients with less frequent regurgitation and 14.4% (95% CI: 11.9–17.3%) to 19.2% (95% CI: 16.3–22.4%) of those with no regurgitation (Figure 3). The prevalence data for sleep disturbance were similar for Group 1 day with persistent, frequent regurgitation (53.1–61.3%) and for Group 2 day (56.2–64.2%). Similar prevalence data were observed for patients with infrequent mild heartburn and less frequent or no regurgitation compared to those with no heartburn. Thus, higher frequencies of regurgitation were associated with an increased negative impact on sleep, irrespective of whether the patients had absent or infrequent, mild heartburn.
Concomitant OTC medication for reflux symptoms was used by 65/153 (42.5%, 95% CI: 34.5–50.7%) of Group R with persistent, frequent regurgitation compared with 144/751 (19.2%, 95% CI: 16.4–22.2%) of patients with no regurgitation. The corresponding OTC medication use by Groups 1 day and 2 day with frequent regurgitation were similar at 78/176 (44.3%) and 94/213 (44.1%), respectively. Similar levels of OTC medication use were observed for patients with infrequent mild heartburn and less frequent or no regurgitation, as for those with no heartburn. The mean reported number of hours/week of work missed owing to reflux symptoms in Group R and in Group 2 day both increased as the frequency of regurgitation increased (Figure 4). The same association between the frequency of regurgitation and work hours missed was seen for patients in Group 1 day (data not shown).
The major findings of this large, European, multicentre, observational study were that frequent regurgitation (3–7 days in the previous week of treatment) was reported by 12–13% of patients with GERD receiving acid suppression therapy, with or without mild, infrequent heartburn. More than half of these patients with ongoing frequent regurgitation had sleep disturbances. Nearly half used additional OTC medications for their reflux symptoms. These two markers of the impact of GERD were less prevalent among patients without ongoing frequent regurgitation. In addition, patients with GERD who had ongoing frequent regurgitation despite treatment missed more hours from work than those with no regurgitation or heartburn. Impaired work productivity owing to GERD symptoms represents a financial burden to employers. It is likely that problems sleeping will affect work productivity. For example, shorter sleep times have been shown to be associated with a greater impairment of the ability to work.
The negative impact on daily life of ongoing frequent regurgitation indicates that it is clinically relevant and problematic for patients with GERD in primary care. The prevalence and impact of problematic regurgitation was similar whether patients did not have heartburn (Group R) or, at most, had 1 or 2 days/week of mild heartburn (Groups 1 day and 2 day). This is consistent with findings from other clinical trials: a recent systematic review found only a modest therapeutic gain for PPI treatment over placebo or comparator agents for the relief of regurgitation, which was considerably less than that for heartburn. The conclusion was that regurgitation is an important factor to consider when determining incomplete response to PPI treatment in GERD. Furthermore, the prevalence of problematic regurgitation suggests that a proportion of patients with GERD in primary care is not being sufficiently well managed with currently available treatments. Data suggest that patients with no heartburn but persistent regurgitation should be distinguished from those with unresolved heartburn despite therapy because they may benefit from alternative treatment beyond acid suppression, such as transient lower oesophageal sphincter relaxation inhibitors or fundoplication. There are several possible explanations as to why a proportion of patients with GERD have persistent, troublesome regurgitation despite acid suppressive treatment, including weakly acidic/alkaline reflux, increased reflux volume or visceral hypersensitivity.
The Montreal consensus definition of GERD is ‘reflux of stomach contents causing troublesome symptoms and/or complications’. Symptoms become troublesome when they adversely affect a patient's well-being. In population-based studies, mild heartburn occurring on 2 or more days/week or moderate/severe symptoms occurring at least once a week are often considered troublesome by patients. In clinical practice, however, the precise cut-off at which heartburn (or any other symptom) becomes troublesome can be determined only by the individual patient. In this study, persistent, frequent regurgitation is clearly shown to adversely affect measures of HRQOL, such as the quality of sleep and the ability to work. This suggests that persistent, frequent regurgitation occurring on at least 3 days/week, even without concomitant heartburn, is troublesome for patients in primary care.
In conclusion, the observational and descriptive data presented here provide an important insight at the primary care level into the impact on HRQOL of persistent, frequent regurgitation (irrespective of whether patients had no heartburn or ongoing infrequent, mild heartburn) with acid suppression in patients with GERD. Patients with ongoing frequent regurgitation are currently being managed suboptimally in primary care and there is a medical need for alternative treatment approaches beyond acid suppression in these patients.
Guarantor of the article: Peter J Kahrilas.
Author contributions: Peter J Kahrilas took a lead in determining the study concept and design, analysing and interpreting the data, and drafting and critically reviewing the manuscript for important clinical and intellectual content. Colin W. Howden, Hans Denison and Javier P. Gisbert had major roles in determining the study concept and design, analysing and interpreting the data, and drafting and critically reviewing the manuscript for important clinical and intellectual content. Börje Wernersson had a role in determining the study concept and design, analysing and interpreting the data, and drafting and critically reviewing the manuscript. Javier Nuevo had a role in data acquisition, performed the statistical analysis and critically reviewed the manuscript drafts.
All authors approved the final version of the article, including the authorship list.
Declaration of personal interests: Peter Kahrilas has acted as a consultant for AstraZeneca, EndoGastric Solutions, Ironwood and Torax. Colin Howden has acted as a consultant for Boehringer Ingelheim, Novartis Consumer Health, Novartis Oncology, Otsuka, Takeda, Perrigo and XenoPort, and as a speaker for Novartis, Otsuka, Ironwood, Forest Laboratories, Takeda and GlaxoSmithKline. Börje Wernersson and Hans Denison are employees of AstraZeneca R&D, Mölndal, Sweden. Javier Nuevo is an employee of the Medical Evidence Centre, Global Medical Affairs, AstraZeneca, Madrid, Spain. Javier Gisbert has served as a speaker, a consultant and an advisory member for, and has received research funding from, Almirall, Janssen-Cilag, Nycomed and AstraZeneca.
Declaration of funding interests: This study was supported by AstraZeneca R&D, Mölndal, Sweden. Writing support was provided by Dr Nesta Hughes of Oxford PharmaGenesis Ltd, UK, and funded by AstraZeneca R&D, Mölndal, Sweden.