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Sleep disturbances associated with gastro-oesophageal reflux disease: Prevalence and impact of treatment in French primary care patients
Digestive and Liver Disease 43 (2011) 784–787
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Sleep disturbances associated with gastro-oesophageal reflux disease: Prevalence and impact of treatment in French primary care patients夽 Guillaume Cadiot a,∗ , Pierre-Henri Delaage b , Caroline Fabry b , Christine Soufflet b , Philippe Barthélemy b a b
Service d’Hépato-Gastro-entérologie, CHU Robert Debré, Rue du Général Koenig, Reims Cedex, France AstraZeneca, Rueil-Malmaison Cedex, France
a r t i c l e
i n f o
Article history: Received 15 July 2010 Accepted 2 June 2011 Available online 12 July 2011 Keywords: Epidemiology Hypnotic drugs Proton pump inhibitors
a b s t r a c t Aim: To evaluate the prevalence of sleep disturbances in French patients with gastro-oesophageal reflux disease and the impact of gastro-oesophageal reflux disease treatment on sleep. Methods: A registry was compiled of all gastro-oesophageal reflux disease patients seen during a 2-week period by 1983 French primary care physicians. Data from the first two patients with nocturnal gastrooesophageal reflux disease symptoms and gastro-oesophageal reflux disease-related sleep disturbances seen by each physician were derived from physician questionnaires and medical records. These patients completed a questionnaire during the initial consultation and after 1-month treatment. Results: A total of 33,391 patients were included in the study: physician questionnaires were available for 3269 patients and patient questionnaires for 2876. Nocturnal gastro-oesophageal reflux disease symptoms were reported by 21,337 patients (63.9%) and regular (at least once weekly) gastro-oesophageal reflux disease-related sleep disturbances by 19,313 (61.7%). Multivariate analysis showed that nocturnal gastro-oesophageal reflux disease symptoms, use of hypnotic drugs, and age over 50 years were significant independent predictors of sleep disturbances. The proportion of patients reporting at least one nocturnal gastro-oesophageal reflux disease symptom during the previous week decreased following treatment, from 98.8% to 39.3% (P < 0.001). Conclusions: Nocturnal gastro-oesophageal reflux disease symptoms are common in the French population and are associated with sleep disturbances. Effective treatment can significantly improve sleep duration and quality. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastro-esophageal reflux disease (GERD) is characterized by symptoms such as heartburn and regurgitation resulting from reflux of acidic gastric contents into the oesophagus. Such reflux episodes can occur both during the day and during the night [1]. Nocturnal episodes are less common than daytime episodes, but are more prolonged due to delayed clearance of acid from the oesophagus [2]. As a result, nocturnal reflux is associated with an increased risk of GERD complications such as oesophageal erosion, ulceration, or respiratory symptoms [2,3]. Nocturnal GERD symptoms are a common finding in clinical practice. In a telephone survey conducted in the USA, the overall prevalence of nocturnal symptoms was 10%, and 74% of participants
夽 Financial support: This study was sponsored by AstraZeneca France. ∗ Corresponding author at: Service d’Hépato-Gastro-entérologie, CHU Robert Debré, Rue du Général Koenig, 51092 Reims Cedex, France.Tel.: +33 3 26 78 84 41; fax: +33 3 26 78 88 36. E-mail address: [email protected] (G. Cadiot).
with frequent (at least once weekly) GERD symptoms reported nocturnal symptoms [4]. Similarly, in a Gallup survey conducted on behalf of the American Gastroenterological Association, 79% of respondents reported experiencing heartburn during the night, and 75% of these reported that these symptoms affected their sleep [5]. Recent studies suggest that effective treatment of GERD symptoms with proton pump inhibitors results in improvements in sleep duration and quality [6,7]. The primary aim of the present study was to obtain data on the prevalence of sleep disturbances associated with GERD in France; data from previous studies cannot be extrapolated directly to the French population because of differences in study populations and documented gender-related and age-related variations in sleeping disturbances in the French population [8]. The study used a cluster sampling technique among primary care physicians with chronological sampling of the first patients presenting with GERD symptoms, in order to achieve a good representation of French GERD patients. Secondary aims included evaluation of the prevalence of nocturnal GERD, the relationship between nocturnal GERD symptoms and sleeping disorders, and the impact of treatment on GERD symptoms and sleeping disturbances.
1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.06.004
G. Cadiot et al. / Digestive and Liver Disease 43 (2011) 784–787
785
2. Methods 1983 GPs
This observational study was approved by the National Commission for Information and Liberties, and the French Conseil National de l’Ordre des Médecins. During September 2006, 11,406 French primary care physicians were contacted by telephone and invited to take part in the study. Physicians were selected from a national database of all practicing primary care physicians (estimated to be 58,048 on 1 January 2005); the sample was selected to ensure a balanced geographical distribution. Physicians who agreed to take part were asked to complete a registry of all consecutive adult (≥18 years) GERD patients seen during a 2-week period. Data from the first two patients on each physician’s registry, who had at least one nocturnal GERD symptom (nocturnal heartburn and/or nocturnal acid regurgitations and/or nocturnal cough) with GERD-related sleep disturbances (at least twice during the previous week) and had not been treated with proton pump inhibitors or H2 -receptor antagonists during the previous 15 days, were derived from a questionnaire completed by the physician during the initial consultation and from medical records. In addition, each of these patients completed a questionnaire during the initial consultation, and again after 1 month of treatment. Data obtained from the initial consultation and medical records encompassed: sociodemographic characteristics and habits (age, gender, weight, height, alcohol and tobacco consumption, professional activity); frequency and intensity of diurnal and nocturnal heartburn and acid reflux, nocturnal cough, and other digestive and non-digestive symptoms; and GERD treatment. The patients’ questionnaire covered: frequency and intensity of diurnal and nocturnal GERD-specific digestive symptoms, nocturnal cough and other digestive and nondigestive symptoms; sleep duration and quality, and correlated GERD symptoms; and compliance with, and overall satisfaction with, treatment. 2.1. Statistical methods Descriptive statistics were derived for demographic and clinical variables. Exploratory analyses were performed by means of t tests, 2 -tests, Kruskal–Wallis tests or Wilcoxon’s tests, as appropriate; MacNemar’s tests and Cochran–Mantel–Haenszel tests were used to evaluate the impact of GERD treatment on nocturnal symptoms and sleep disturbances, and the relationship between GERD symptoms and sleep disturbances. Multivariate analysis was used to identify potential risk factors for GERD-related sleep disturbances. All statistical tests were two-sided, and P values below 0.05 were considered significant. Analyses were performed with SAS® (version 8.2) software (SAS Institute, Cary, NC, USA). It was anticipated that 40% of the included patients would be male, 20% would be aged 60 years or older, and approximately one third would be receiving hypnotic drugs. The smallest subgroup was assumed to be men over 60 years of age receiving hypnotics, who were expected to account for 2.7% of the total population. On this basis, it was calculated that a total of 54,667 observations would be required to identify an event occurring with a frequency of 60% and an ˛ risk of 5% (95% confidence interval [CI] 57.5–62.5%). Taking into account missing or unusable data, it was determined that a total of 60,000 lines of medical records (equivalent to 20 lines per participating physician over a 2-week period) would be required. To address the secondary objectives linked to the questionnaires, a sample size of 6000 patients should permit the assessment of atypical symptoms occurring at a frequency of 5% with an accuracy of 2% (i.e. 95% CIs comprised between 3% and 7%), taking into account the age group and gender. It was estimated that 457 patients would be required in the smallest category in the study (i.e. men aged 60 or older; 8% of the total popu-
Register 33,391 patients analysed
For each GP, the first 2 patients from the register with nocturnal GERD symptoms and sleep disturbance were eligible for extensive questionnaires
3,890 questionnaires filled in by GPs 3,269 questionnaires analysed
3,413 questionnaires (initial AND final) filled in by patients 2,876 questionnaires (initial AND final) analysed
Fig. 1. Patients flow distribution.
lation), corresponding to a required total number of patients of 5713. 3. Results Between September 2006 and March 2007, a total of 1983 (17.4%) physicians agreed to take part in the study, and 33,391 patients with GERD were prospectively included in the register (Fig. 1). The diagnosis of GERD was based by the investigator on specific GERD symptoms (heartburn and/or acid regurgitation) in 98.3% of the patients and on isolated nocturnal cough in only 1.7%. Among these patients, the two first patients of each participating physician with nocturnal GERD symptoms over the past week with no proton pump inhibitors or H2 -receptor antagonist treatment and the physician himself were asked to complete an extensive questionnaire: physician questionnaires were available for 3269 and patient questionnaires for 2876. The mean (±SD) age of patients in the overall study population was 52.3 ± 15.8 years, and 52.1% were male. 23% had not previously consulted a physician because of GERD, whereas 44.0% had a history of GERD symptoms of between 1 and 10 years. More than half (58.4%) of patients had not received proton pump inhibitors or H2 -receptor antagonists within the preceding 15 days, and 25.3% were currently receiving hypnotic drugs. Among the patients for whom physician questionnaire data were available (n = 3269), the mean age was 51.0 ± 13.6 years, and the mean weight was 76.6 ± 13.6 kg. Of this group, 59.5% were male, 42.7% smoked, and 54.8% consumed alcohol; 63.6% had a professional occupation, while 23.8% were retired. 3.1. Nocturnal GERD symptoms and sleep disturbances Nocturnal GERD symptoms were reported by 63.9% of the overall population (n = 33,391). Of these, 43.4% had only one nocturnal symptom, 34.1% had two symptoms, and 22.5% had three symptoms. The most commonly reported nocturnal symptom was heartburn, which was reported by 50.9% of the patients, followed by acid regurgitation (39.5%) and cough (33.8%). Among the overall study population (n = 33,391), frequent (at least once weekly) GERD-related sleep disturbances were reported by 61.7%. The prevalence of sleeping disorders in patient subgroups
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G. Cadiot et al. / Digestive and Liver Disease 43 (2011) 784–787
Table 1 Prevalence of GERD-related sleeping disorders according to age, gender, and use of hypnotics in the overall registry population (n = 33,391). Data are presented as numbers (percentages) of patients. MDa Age (years) <40 40–60 >60 Gender Male Female Hypnotics Yes No a
None
Once per week
More than once per week
Total
459 941 703
3558 (47.9) 5074 (36.9) 3343 (33.0)
1677 (22.6) 3422 (24.9) 2736 (27.0)
2187 (29.5) 5248 (38.2) 4043 (39.9)
7422 (100) 13,744 (100) 10,122 (100)
1028 942
6072 (38.0) 5680 (38.6)
3912 (24.5) 3768 (25.6)
5994 (37.5) 5272 (35.8)
15,978 (100) 14,720 (100)
492 1390
2158 (27.8) 9605 (41.9)
2254 (29.1) 5494 (24.0)
3342 (43.1) 7812 (34.1)
7754 (100) 22,911 (100)
MD: missing data.
Table 2 Prevalence of nocturnal symptoms among patients from the register (n = 33,391). Prevalence (%) Nocturnal heartburn Nocturnal acid regurgitation Nocturnal cough If at least one nocturnal symptom Only one nocturnal symptom Two nocturnal symptoms Three nocturnal symptoms
50.9 39.5 33.8 43.4 34.1 22.5
divided by age, gender, and use of hypnotic drugs is shown in Table 1. Prevalence of nocturnal GERD symptoms is reported in Table 2. Overall, 39% (95% CI 39–40.9%) of patients aged more than 60 years reported experiencing GERD-related sleep disturbances more than once weekly, compared with 29.5% (95% CI 28.4–30.5%) of patients aged less than 40 years (P < 0.001, 2 -test). Similarly, the prevalence of sleeping disturbances occurring more than once weekly was significantly higher in those receiving hypnotics (43.1% vs 34.1%, P < 0.001, 2 -test). There was a significant association between the presence of nocturnal GERD symptoms and sleep disturbances. Overall, 85.8% of patients with at least one nocturnal GERD symptom reported experiencing sleep disturbances, compared with 18.9% of patients without such symptoms (P < 0.001, 2 -test). Similarly, 88.1% of patients experiencing nocturnal heartburn at least once weekly reported sleep disturbances, compared with 36% of those without nocturnal heartburn; the corresponding figures for nocturnal acid reflux were 90% and 43.9%, respectively (both P < 0.001, 2 test). Multivariate analysis showed that nocturnal GERD symptoms, use of hypnotic drugs and age over 50 years were significant independent predictors of sleep disturbances (Table 3). The strongest predictors were nocturnal heartburn and nocturnal cough, which were associated with odds ratios (OR) of 9.0 (95% CI 8.38–9.71) and 7.8 (95% CI 7.15–8.59), respectively. By contrast, patients experiencing their first episode of GERD were significantly less likely to report sleep disturbances than those with a longer history of GERD symptoms (Table 3).
3.2. Impact of GERD treatment on sleep disturbances Of the 3269 patients for whom questionnaire data were available, 99.8% received some form of treatment from their primary care physician. The principal interventions were proton pump inhibitor therapy in 98.6% and lifestyle advice in 39.2%; 23.2% received a prokinetic agent, an alginate or antacid, or an H2 receptor antagonist, alone or in combination with a proton pump inhibitor. The impact of GERD treatment on sleep disturbances was evaluated in 2876 patients who completed questionnaires before and after 1-month treatment. Among these patients, the proportion reporting at least one nocturnal GERD symptom during the previous week decreased following treatment, from 98.8% to 39.3% (P < 0.001, MacNemar’s test). GERD treatment was associated with a significant reduction in the proportion of patients who reported waking during the night because of GERD symptoms, from 89.4% to 18.0% (P < 0.001, MacNemar’s test). Similarly, the mean number of nights with interrupted sleep by week was significantly reduced after GERD treatment, from 3.8 to 1.8 (P < 0.001, Wilcoxon Signed Rank test). Treatment was also associated with significant improvements in the duration and quality of sleep, as rated by the patients (Fig. 2). Overall, 94.7% of the patients declared themselves to be “satisfied” or “fully satisfied” with their treatment. 4. Discussion The aim of this observational study was to investigate the prevalence of sleep disturbances in GERD patients, and the relationship between such disturbances and GERD symptoms, in the general French population. In order to optimize the quality of the data, the physician sample was chosen to be representative of the general
Table 3 Factors associated with GERD-related sleep disturbances (multivariate analysis, n = 33,391). Odds ratio Nocturnal heartburn Nocturnal cough Nocturnal acid regurgitation Use of hypnotics Daytime acid regurgitation Age ≥50 years vs age <50 years First episode of GERD
9.0 7.8 5.3 1.5 1.4 1.1 0.8
95% confidence interval 8.38–9.71 7.15–8.59 4.94–5.80 1.40–1.65 1.26–1.45 1.06–1.22 0.77–0.91
P value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0005 <0.0001
Fig. 2. Effects of GERD treatment on the duration and quality of sleep, rated on a 10-point Graded Visual Scale (n = 2876) from “0” (worse case) to “10” (best case). Figures show mean scores ± confidence interval. All differences were statistically significant (P < 0.001, Wilcoxon’s test).
G. Cadiot et al. / Digestive and Liver Disease 43 (2011) 784–787
population, and a small and consistent cluster size was used (i.e. each physician could include only two patients for questionnaire sampling). Thus, biases resulting from excessive recruitment by a small number of physicians in a particular town or region should have been avoided. The results of this study confirm those of previous studies in the USA [4–9] or in Europe [10], showing that sleep disturbances are widespread among patients with GERD, more than 60% in our study. Indeed, sleep disruption may be one of the most common non-oesophageal manifestations of the condition [5–7,11,12]. This study has highlighted the close relationship between nocturnal GERD symptoms and sleep disruption: such symptoms, particularly heartburn and cough, were found to be strong independent predictors of sleep disturbances in our study. In the most recent case–control study in the US in which 88.9% of patients with GERD experienced nighttime symptoms, sleep difficulties, difficulty in initiating asleep and difficulty in maintaining sleep were observed in 68.3%, 49.1% and 58.3%, respectively [9]. In a recent case–control study in Norway, significant association was observed between severe reflux symptoms and insomnia (OR: 3.2), sleeplessness (OR: 3.3) and problems falling asleep (OR: 3.1) [10]. However, nocturnal GERD and sleep disturbance raises questions about their respective role. Indeed it has been shown that sleep deprivation was hyperalgesic in patients with GERD [13]. The authors suggested a new conceptual model of a “vicious cycle” in which GERD leads to poor quality of sleep that in turn enhances perception of intraoesophageal stimuli that further exacerbates GERD [13]. Hypnotic drug use, which was a significant factor associated with sleep disturbances in our study, as in that of others [14], might also modify GERD. It has been shown that benzodiazepines slow gastric emptying and relax the pressure of the lower oesophageal sphincter [5–16], although it is more likely that it only reflects sleep disturbances. GERD-related nocturnal symptoms and sleep disturbances can severely impair patient’s quality of life. In one study, patients with nocturnal GERD symptoms showed significantly greater impairment of health-related quality of life, measured using the Medical Outcomes Study Short-Form 36 Health Survey, than either healthy volunteers or GERD patients without nocturnal symptoms [4]. Indeed, patients with nocturnal symptoms had significantly more pain than patients with hypertension or diabetes, and similar pain to those with angina or congestive heart failure. Impairment of quality of life has been confirmed by numerous authors [9,17,18]. Furthermore, nocturnal symptoms and sleep disruption can result in decreased work productivity [5,18,19]. In a Gallup survey in the USA, 40% of patients with nocturnal heartburn said that it affected their ability to function on the following day [5]. Although the impact of GERD treatment on nocturnal symptoms and sleep was evaluated in an uncontrolled manner in this study, the findings (Fig. 2) are consistent with those of previous controlled trials [7–20]. Sleep disturbances were resolved following treatment in 60.5% of patients. By comparison, in a double-blind, placebo-controlled trial, treatment with the proton pump inhibitor esomeprazole, 20 or 40 mg/day, resolved sleep disturbances in 73% of patients, compared with 41% of placebo-treated patients, and resulted in significant improvements in sleep quality [7]. The concept of “GERD-related symptoms” relies on patient’s assumption relationship and this is a limitation of our study. But in a population-based study, it was not possible to investigate all patients enrolled in a specialized sleep disorders clinic.
787
In conclusion, this study has shown that nocturnal GERD symptoms are common in the French population, and are associated with marked sleep disturbances. Effective treatment of nocturnal GERD symptoms could improve sleep duration and quality, with important implications for a patient’s quality of life and productivity. Conflict of interest statement Pierre-Henri Delaage, Caroline Fabry, Christine Soufflet and Philippe Barthélemy are employees of AstraZeneca. Guillaume Cadiot has received fees from AstraZeneca. Acknowledgements We thank Ann McIlhinney, Anagram Communications Ltd, for her contribution in the preparation of the manuscript and all primary care physicians who participated in the study. References [1] Johnson LF, DeMeester TR. Twenty-four hour pH monitoring of the distal esophagus. Am J Gastroenterol 1974;62:325–32. [2] De Meester TR, Johnson LF, Guy JJ, et al. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1996;184:459–70. [3] Orr W. Clinical implications of nocturnal gastroesophageal reflux. Pract Gastroenterol 1994;28, 28D–28H. [4] Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001;161:45–52. [5] Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. [6] Chand N, Johnson DA, Tabangin M, et al. Sleep dysfunction in patients with gastro-oesophageal reflux disease: prevalence and response to GERD therapy, a pilot study. Aliment Pharmacol Ther 2004;20:969–74. [7] Johnson DA, Orr WC, Crawley JA, et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebocontrolled trial. Am J Gastroenterol 2005;100:1914–22. [8] Leger D, Guilleminault C, Dreyfus JP, et al. Prevalence of insomnia in a survey of 12778 adults in France. J Sleep Res 2000;9:35–42. [9] Mody R, Bolge SC, Kannan H, et al. Effects of gastroesophageal reflux disease on sleep and outcomes. Clin Gastroenterol Hepatol 2009;7:953–9. [10] Jansson C, Nordenstedt H, Wallander M-A, et al. A population-based study showing an association between gastroesophageal reflux disease and sleep problems. Clin Gastroenterol Hepatol 2009;7:960–5. [11] Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 1991;32:1275–9. [12] Orr WC. Review article: sleep-related gastro-oesophageal reflux as a distinct clinical entity. Aliment Pharmacol Ther 2010;31:47–56. [13] Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787–95. [14] Fass R, Quan S, O’Connor G, et al. Predictors of heartburn during sleep in a large prospective cohort study. Chest 2005;127:1658–66. [15] Lagergren J, Bergstrom R, Adami HO, et al. Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med 2000;133:165–75. [16] Corley DA, Levin TR, Habel LA, et al. Barrett’s esophagus and medications that relax the lower esophageal sphincter. Am J Gastroenterol 2006;101: 937–44. [17] Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity. Aliment Pharmacol Ther 2007;25: 487–500. [18] Dean BB, Aguilar D, Johnson LF, et al. Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: frequency, severity and impact on health-related quality of life. Aliment Pharmacol Ther 2008;27:327–37. [19] Dean BB, Crawley JA, Schmitt CM, et al. The burden of illness of gastrooesophageal reflux disease: impact on work productivity. Aliment Pharmacol Ther 2003;17:1309–17. [20] Orr WC, Harnish MJ. Sleep-related gastro-oesophageal reflux: provocation with a late evening meal and treatment with acid suppression. Aliment Pharmacol Ther 1998;12:1033–8.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Sleep disturbances associated with gastro-oesophageal reflux disease: Prevalence and impact of treatment in French primary care patients夽 Guillaume Cadiot a,∗ , Pierre-Henri Delaage b , Caroline Fabry b , Christine Soufflet b , Philippe Barthélemy b a b
Service d’Hépato-Gastro-entérologie, CHU Robert Debré, Rue du Général Koenig, Reims Cedex, France AstraZeneca, Rueil-Malmaison Cedex, France
a r t i c l e
i n f o
Article history: Received 15 July 2010 Accepted 2 June 2011 Available online 12 July 2011 Keywords: Epidemiology Hypnotic drugs Proton pump inhibitors
a b s t r a c t Aim: To evaluate the prevalence of sleep disturbances in French patients with gastro-oesophageal reflux disease and the impact of gastro-oesophageal reflux disease treatment on sleep. Methods: A registry was compiled of all gastro-oesophageal reflux disease patients seen during a 2-week period by 1983 French primary care physicians. Data from the first two patients with nocturnal gastrooesophageal reflux disease symptoms and gastro-oesophageal reflux disease-related sleep disturbances seen by each physician were derived from physician questionnaires and medical records. These patients completed a questionnaire during the initial consultation and after 1-month treatment. Results: A total of 33,391 patients were included in the study: physician questionnaires were available for 3269 patients and patient questionnaires for 2876. Nocturnal gastro-oesophageal reflux disease symptoms were reported by 21,337 patients (63.9%) and regular (at least once weekly) gastro-oesophageal reflux disease-related sleep disturbances by 19,313 (61.7%). Multivariate analysis showed that nocturnal gastro-oesophageal reflux disease symptoms, use of hypnotic drugs, and age over 50 years were significant independent predictors of sleep disturbances. The proportion of patients reporting at least one nocturnal gastro-oesophageal reflux disease symptom during the previous week decreased following treatment, from 98.8% to 39.3% (P < 0.001). Conclusions: Nocturnal gastro-oesophageal reflux disease symptoms are common in the French population and are associated with sleep disturbances. Effective treatment can significantly improve sleep duration and quality. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastro-esophageal reflux disease (GERD) is characterized by symptoms such as heartburn and regurgitation resulting from reflux of acidic gastric contents into the oesophagus. Such reflux episodes can occur both during the day and during the night [1]. Nocturnal episodes are less common than daytime episodes, but are more prolonged due to delayed clearance of acid from the oesophagus [2]. As a result, nocturnal reflux is associated with an increased risk of GERD complications such as oesophageal erosion, ulceration, or respiratory symptoms [2,3]. Nocturnal GERD symptoms are a common finding in clinical practice. In a telephone survey conducted in the USA, the overall prevalence of nocturnal symptoms was 10%, and 74% of participants
夽 Financial support: This study was sponsored by AstraZeneca France. ∗ Corresponding author at: Service d’Hépato-Gastro-entérologie, CHU Robert Debré, Rue du Général Koenig, 51092 Reims Cedex, France.Tel.: +33 3 26 78 84 41; fax: +33 3 26 78 88 36. E-mail address: [email protected] (G. Cadiot).
with frequent (at least once weekly) GERD symptoms reported nocturnal symptoms [4]. Similarly, in a Gallup survey conducted on behalf of the American Gastroenterological Association, 79% of respondents reported experiencing heartburn during the night, and 75% of these reported that these symptoms affected their sleep [5]. Recent studies suggest that effective treatment of GERD symptoms with proton pump inhibitors results in improvements in sleep duration and quality [6,7]. The primary aim of the present study was to obtain data on the prevalence of sleep disturbances associated with GERD in France; data from previous studies cannot be extrapolated directly to the French population because of differences in study populations and documented gender-related and age-related variations in sleeping disturbances in the French population [8]. The study used a cluster sampling technique among primary care physicians with chronological sampling of the first patients presenting with GERD symptoms, in order to achieve a good representation of French GERD patients. Secondary aims included evaluation of the prevalence of nocturnal GERD, the relationship between nocturnal GERD symptoms and sleeping disorders, and the impact of treatment on GERD symptoms and sleeping disturbances.
1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.06.004
G. Cadiot et al. / Digestive and Liver Disease 43 (2011) 784–787
785
2. Methods 1983 GPs
This observational study was approved by the National Commission for Information and Liberties, and the French Conseil National de l’Ordre des Médecins. During September 2006, 11,406 French primary care physicians were contacted by telephone and invited to take part in the study. Physicians were selected from a national database of all practicing primary care physicians (estimated to be 58,048 on 1 January 2005); the sample was selected to ensure a balanced geographical distribution. Physicians who agreed to take part were asked to complete a registry of all consecutive adult (≥18 years) GERD patients seen during a 2-week period. Data from the first two patients on each physician’s registry, who had at least one nocturnal GERD symptom (nocturnal heartburn and/or nocturnal acid regurgitations and/or nocturnal cough) with GERD-related sleep disturbances (at least twice during the previous week) and had not been treated with proton pump inhibitors or H2 -receptor antagonists during the previous 15 days, were derived from a questionnaire completed by the physician during the initial consultation and from medical records. In addition, each of these patients completed a questionnaire during the initial consultation, and again after 1 month of treatment. Data obtained from the initial consultation and medical records encompassed: sociodemographic characteristics and habits (age, gender, weight, height, alcohol and tobacco consumption, professional activity); frequency and intensity of diurnal and nocturnal heartburn and acid reflux, nocturnal cough, and other digestive and non-digestive symptoms; and GERD treatment. The patients’ questionnaire covered: frequency and intensity of diurnal and nocturnal GERD-specific digestive symptoms, nocturnal cough and other digestive and nondigestive symptoms; sleep duration and quality, and correlated GERD symptoms; and compliance with, and overall satisfaction with, treatment. 2.1. Statistical methods Descriptive statistics were derived for demographic and clinical variables. Exploratory analyses were performed by means of t tests, 2 -tests, Kruskal–Wallis tests or Wilcoxon’s tests, as appropriate; MacNemar’s tests and Cochran–Mantel–Haenszel tests were used to evaluate the impact of GERD treatment on nocturnal symptoms and sleep disturbances, and the relationship between GERD symptoms and sleep disturbances. Multivariate analysis was used to identify potential risk factors for GERD-related sleep disturbances. All statistical tests were two-sided, and P values below 0.05 were considered significant. Analyses were performed with SAS® (version 8.2) software (SAS Institute, Cary, NC, USA). It was anticipated that 40% of the included patients would be male, 20% would be aged 60 years or older, and approximately one third would be receiving hypnotic drugs. The smallest subgroup was assumed to be men over 60 years of age receiving hypnotics, who were expected to account for 2.7% of the total population. On this basis, it was calculated that a total of 54,667 observations would be required to identify an event occurring with a frequency of 60% and an ˛ risk of 5% (95% confidence interval [CI] 57.5–62.5%). Taking into account missing or unusable data, it was determined that a total of 60,000 lines of medical records (equivalent to 20 lines per participating physician over a 2-week period) would be required. To address the secondary objectives linked to the questionnaires, a sample size of 6000 patients should permit the assessment of atypical symptoms occurring at a frequency of 5% with an accuracy of 2% (i.e. 95% CIs comprised between 3% and 7%), taking into account the age group and gender. It was estimated that 457 patients would be required in the smallest category in the study (i.e. men aged 60 or older; 8% of the total popu-
Register 33,391 patients analysed
For each GP, the first 2 patients from the register with nocturnal GERD symptoms and sleep disturbance were eligible for extensive questionnaires
3,890 questionnaires filled in by GPs 3,269 questionnaires analysed
3,413 questionnaires (initial AND final) filled in by patients 2,876 questionnaires (initial AND final) analysed
Fig. 1. Patients flow distribution.
lation), corresponding to a required total number of patients of 5713. 3. Results Between September 2006 and March 2007, a total of 1983 (17.4%) physicians agreed to take part in the study, and 33,391 patients with GERD were prospectively included in the register (Fig. 1). The diagnosis of GERD was based by the investigator on specific GERD symptoms (heartburn and/or acid regurgitation) in 98.3% of the patients and on isolated nocturnal cough in only 1.7%. Among these patients, the two first patients of each participating physician with nocturnal GERD symptoms over the past week with no proton pump inhibitors or H2 -receptor antagonist treatment and the physician himself were asked to complete an extensive questionnaire: physician questionnaires were available for 3269 and patient questionnaires for 2876. The mean (±SD) age of patients in the overall study population was 52.3 ± 15.8 years, and 52.1% were male. 23% had not previously consulted a physician because of GERD, whereas 44.0% had a history of GERD symptoms of between 1 and 10 years. More than half (58.4%) of patients had not received proton pump inhibitors or H2 -receptor antagonists within the preceding 15 days, and 25.3% were currently receiving hypnotic drugs. Among the patients for whom physician questionnaire data were available (n = 3269), the mean age was 51.0 ± 13.6 years, and the mean weight was 76.6 ± 13.6 kg. Of this group, 59.5% were male, 42.7% smoked, and 54.8% consumed alcohol; 63.6% had a professional occupation, while 23.8% were retired. 3.1. Nocturnal GERD symptoms and sleep disturbances Nocturnal GERD symptoms were reported by 63.9% of the overall population (n = 33,391). Of these, 43.4% had only one nocturnal symptom, 34.1% had two symptoms, and 22.5% had three symptoms. The most commonly reported nocturnal symptom was heartburn, which was reported by 50.9% of the patients, followed by acid regurgitation (39.5%) and cough (33.8%). Among the overall study population (n = 33,391), frequent (at least once weekly) GERD-related sleep disturbances were reported by 61.7%. The prevalence of sleeping disorders in patient subgroups
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Table 1 Prevalence of GERD-related sleeping disorders according to age, gender, and use of hypnotics in the overall registry population (n = 33,391). Data are presented as numbers (percentages) of patients. MDa Age (years) <40 40–60 >60 Gender Male Female Hypnotics Yes No a
None
Once per week
More than once per week
Total
459 941 703
3558 (47.9) 5074 (36.9) 3343 (33.0)
1677 (22.6) 3422 (24.9) 2736 (27.0)
2187 (29.5) 5248 (38.2) 4043 (39.9)
7422 (100) 13,744 (100) 10,122 (100)
1028 942
6072 (38.0) 5680 (38.6)
3912 (24.5) 3768 (25.6)
5994 (37.5) 5272 (35.8)
15,978 (100) 14,720 (100)
492 1390
2158 (27.8) 9605 (41.9)
2254 (29.1) 5494 (24.0)
3342 (43.1) 7812 (34.1)
7754 (100) 22,911 (100)
MD: missing data.
Table 2 Prevalence of nocturnal symptoms among patients from the register (n = 33,391). Prevalence (%) Nocturnal heartburn Nocturnal acid regurgitation Nocturnal cough If at least one nocturnal symptom Only one nocturnal symptom Two nocturnal symptoms Three nocturnal symptoms
50.9 39.5 33.8 43.4 34.1 22.5
divided by age, gender, and use of hypnotic drugs is shown in Table 1. Prevalence of nocturnal GERD symptoms is reported in Table 2. Overall, 39% (95% CI 39–40.9%) of patients aged more than 60 years reported experiencing GERD-related sleep disturbances more than once weekly, compared with 29.5% (95% CI 28.4–30.5%) of patients aged less than 40 years (P < 0.001, 2 -test). Similarly, the prevalence of sleeping disturbances occurring more than once weekly was significantly higher in those receiving hypnotics (43.1% vs 34.1%, P < 0.001, 2 -test). There was a significant association between the presence of nocturnal GERD symptoms and sleep disturbances. Overall, 85.8% of patients with at least one nocturnal GERD symptom reported experiencing sleep disturbances, compared with 18.9% of patients without such symptoms (P < 0.001, 2 -test). Similarly, 88.1% of patients experiencing nocturnal heartburn at least once weekly reported sleep disturbances, compared with 36% of those without nocturnal heartburn; the corresponding figures for nocturnal acid reflux were 90% and 43.9%, respectively (both P < 0.001, 2 test). Multivariate analysis showed that nocturnal GERD symptoms, use of hypnotic drugs and age over 50 years were significant independent predictors of sleep disturbances (Table 3). The strongest predictors were nocturnal heartburn and nocturnal cough, which were associated with odds ratios (OR) of 9.0 (95% CI 8.38–9.71) and 7.8 (95% CI 7.15–8.59), respectively. By contrast, patients experiencing their first episode of GERD were significantly less likely to report sleep disturbances than those with a longer history of GERD symptoms (Table 3).
3.2. Impact of GERD treatment on sleep disturbances Of the 3269 patients for whom questionnaire data were available, 99.8% received some form of treatment from their primary care physician. The principal interventions were proton pump inhibitor therapy in 98.6% and lifestyle advice in 39.2%; 23.2% received a prokinetic agent, an alginate or antacid, or an H2 receptor antagonist, alone or in combination with a proton pump inhibitor. The impact of GERD treatment on sleep disturbances was evaluated in 2876 patients who completed questionnaires before and after 1-month treatment. Among these patients, the proportion reporting at least one nocturnal GERD symptom during the previous week decreased following treatment, from 98.8% to 39.3% (P < 0.001, MacNemar’s test). GERD treatment was associated with a significant reduction in the proportion of patients who reported waking during the night because of GERD symptoms, from 89.4% to 18.0% (P < 0.001, MacNemar’s test). Similarly, the mean number of nights with interrupted sleep by week was significantly reduced after GERD treatment, from 3.8 to 1.8 (P < 0.001, Wilcoxon Signed Rank test). Treatment was also associated with significant improvements in the duration and quality of sleep, as rated by the patients (Fig. 2). Overall, 94.7% of the patients declared themselves to be “satisfied” or “fully satisfied” with their treatment. 4. Discussion The aim of this observational study was to investigate the prevalence of sleep disturbances in GERD patients, and the relationship between such disturbances and GERD symptoms, in the general French population. In order to optimize the quality of the data, the physician sample was chosen to be representative of the general
Table 3 Factors associated with GERD-related sleep disturbances (multivariate analysis, n = 33,391). Odds ratio Nocturnal heartburn Nocturnal cough Nocturnal acid regurgitation Use of hypnotics Daytime acid regurgitation Age ≥50 years vs age <50 years First episode of GERD
9.0 7.8 5.3 1.5 1.4 1.1 0.8
95% confidence interval 8.38–9.71 7.15–8.59 4.94–5.80 1.40–1.65 1.26–1.45 1.06–1.22 0.77–0.91
P value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0005 <0.0001
Fig. 2. Effects of GERD treatment on the duration and quality of sleep, rated on a 10-point Graded Visual Scale (n = 2876) from “0” (worse case) to “10” (best case). Figures show mean scores ± confidence interval. All differences were statistically significant (P < 0.001, Wilcoxon’s test).
G. Cadiot et al. / Digestive and Liver Disease 43 (2011) 784–787
population, and a small and consistent cluster size was used (i.e. each physician could include only two patients for questionnaire sampling). Thus, biases resulting from excessive recruitment by a small number of physicians in a particular town or region should have been avoided. The results of this study confirm those of previous studies in the USA [4–9] or in Europe [10], showing that sleep disturbances are widespread among patients with GERD, more than 60% in our study. Indeed, sleep disruption may be one of the most common non-oesophageal manifestations of the condition [5–7,11,12]. This study has highlighted the close relationship between nocturnal GERD symptoms and sleep disruption: such symptoms, particularly heartburn and cough, were found to be strong independent predictors of sleep disturbances in our study. In the most recent case–control study in the US in which 88.9% of patients with GERD experienced nighttime symptoms, sleep difficulties, difficulty in initiating asleep and difficulty in maintaining sleep were observed in 68.3%, 49.1% and 58.3%, respectively [9]. In a recent case–control study in Norway, significant association was observed between severe reflux symptoms and insomnia (OR: 3.2), sleeplessness (OR: 3.3) and problems falling asleep (OR: 3.1) [10]. However, nocturnal GERD and sleep disturbance raises questions about their respective role. Indeed it has been shown that sleep deprivation was hyperalgesic in patients with GERD [13]. The authors suggested a new conceptual model of a “vicious cycle” in which GERD leads to poor quality of sleep that in turn enhances perception of intraoesophageal stimuli that further exacerbates GERD [13]. Hypnotic drug use, which was a significant factor associated with sleep disturbances in our study, as in that of others [14], might also modify GERD. It has been shown that benzodiazepines slow gastric emptying and relax the pressure of the lower oesophageal sphincter [5–16], although it is more likely that it only reflects sleep disturbances. GERD-related nocturnal symptoms and sleep disturbances can severely impair patient’s quality of life. In one study, patients with nocturnal GERD symptoms showed significantly greater impairment of health-related quality of life, measured using the Medical Outcomes Study Short-Form 36 Health Survey, than either healthy volunteers or GERD patients without nocturnal symptoms [4]. Indeed, patients with nocturnal symptoms had significantly more pain than patients with hypertension or diabetes, and similar pain to those with angina or congestive heart failure. Impairment of quality of life has been confirmed by numerous authors [9,17,18]. Furthermore, nocturnal symptoms and sleep disruption can result in decreased work productivity [5,18,19]. In a Gallup survey in the USA, 40% of patients with nocturnal heartburn said that it affected their ability to function on the following day [5]. Although the impact of GERD treatment on nocturnal symptoms and sleep was evaluated in an uncontrolled manner in this study, the findings (Fig. 2) are consistent with those of previous controlled trials [7–20]. Sleep disturbances were resolved following treatment in 60.5% of patients. By comparison, in a double-blind, placebo-controlled trial, treatment with the proton pump inhibitor esomeprazole, 20 or 40 mg/day, resolved sleep disturbances in 73% of patients, compared with 41% of placebo-treated patients, and resulted in significant improvements in sleep quality [7]. The concept of “GERD-related symptoms” relies on patient’s assumption relationship and this is a limitation of our study. But in a population-based study, it was not possible to investigate all patients enrolled in a specialized sleep disorders clinic.
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In conclusion, this study has shown that nocturnal GERD symptoms are common in the French population, and are associated with marked sleep disturbances. Effective treatment of nocturnal GERD symptoms could improve sleep duration and quality, with important implications for a patient’s quality of life and productivity. Conflict of interest statement Pierre-Henri Delaage, Caroline Fabry, Christine Soufflet and Philippe Barthélemy are employees of AstraZeneca. Guillaume Cadiot has received fees from AstraZeneca. Acknowledgements We thank Ann McIlhinney, Anagram Communications Ltd, for her contribution in the preparation of the manuscript and all primary care physicians who participated in the study. References [1] Johnson LF, DeMeester TR. Twenty-four hour pH monitoring of the distal esophagus. Am J Gastroenterol 1974;62:325–32. [2] De Meester TR, Johnson LF, Guy JJ, et al. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1996;184:459–70. [3] Orr W. Clinical implications of nocturnal gastroesophageal reflux. Pract Gastroenterol 1994;28, 28D–28H. [4] Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001;161:45–52. [5] Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. [6] Chand N, Johnson DA, Tabangin M, et al. Sleep dysfunction in patients with gastro-oesophageal reflux disease: prevalence and response to GERD therapy, a pilot study. Aliment Pharmacol Ther 2004;20:969–74. [7] Johnson DA, Orr WC, Crawley JA, et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebocontrolled trial. Am J Gastroenterol 2005;100:1914–22. [8] Leger D, Guilleminault C, Dreyfus JP, et al. Prevalence of insomnia in a survey of 12778 adults in France. J Sleep Res 2000;9:35–42. [9] Mody R, Bolge SC, Kannan H, et al. Effects of gastroesophageal reflux disease on sleep and outcomes. Clin Gastroenterol Hepatol 2009;7:953–9. [10] Jansson C, Nordenstedt H, Wallander M-A, et al. A population-based study showing an association between gastroesophageal reflux disease and sleep problems. Clin Gastroenterol Hepatol 2009;7:960–5. [11] Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 1991;32:1275–9. [12] Orr WC. Review article: sleep-related gastro-oesophageal reflux as a distinct clinical entity. Aliment Pharmacol Ther 2010;31:47–56. [13] Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787–95. [14] Fass R, Quan S, O’Connor G, et al. Predictors of heartburn during sleep in a large prospective cohort study. Chest 2005;127:1658–66. [15] Lagergren J, Bergstrom R, Adami HO, et al. Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med 2000;133:165–75. [16] Corley DA, Levin TR, Habel LA, et al. Barrett’s esophagus and medications that relax the lower esophageal sphincter. Am J Gastroenterol 2006;101: 937–44. [17] Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity. Aliment Pharmacol Ther 2007;25: 487–500. [18] Dean BB, Aguilar D, Johnson LF, et al. Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: frequency, severity and impact on health-related quality of life. Aliment Pharmacol Ther 2008;27:327–37. [19] Dean BB, Crawley JA, Schmitt CM, et al. The burden of illness of gastrooesophageal reflux disease: impact on work productivity. Aliment Pharmacol Ther 2003;17:1309–17. [20] Orr WC, Harnish MJ. Sleep-related gastro-oesophageal reflux: provocation with a late evening meal and treatment with acid suppression. Aliment Pharmacol Ther 1998;12:1033–8.