bs_bs_banner

Editor's Choice

ORIGINAL ARTICLE

Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease TRULS S. INGEBRIGTSEN,1,2,3,4 JACOB L. MAROTT,3 JØRGEN VESTBO,1,2,5 BØRGE G. NORDESTGAARD,3,4,6 JESPER HALLAS7 AND PETER LANGE3,4,8,9 1

Department of Respiratory Medicine, Odense University Hospital, 2Institute of Clinical Research and 7Department of Clinical Pharmacology, University of Southern Denmark, Odense, 3The Copenhagen City Heart Study, Frederiksberg Hospital, 4The Copenhagen General Population Study, 6Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 8Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, 9Department of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark, and 5Respiratory and Allergy Research Group, Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, UK

ABSTRACT Background and objective: We tested the hypothesis that gastro-esophageal reflux disease is a risk factor for exacerbations in individuals with chronic obstructive pulmonary disease (COPD). Methods: Among 9622 participants in the Copenhagen City Heart Study, we identified 1259 individuals with COPD and information on gastro-esophageal reflux disease and the regular use of acid inhibitory treatment. These individuals were followed for 5 years with regard to medically treated COPD exacerbations, which we defined as a short course treatment with oral corticosteroids alone or in combination with antibiotics. We applied a multivariable Cox regression analysis with adjustment for well-established risk factors associated with COPD exacerbations or gastro-esophageal reflux disease, including COPD severity, and symptoms. Results: Individuals with COPD and gastroesophageal reflux disease had more chronic bronchitis (31 vs 21%, P = 0.004), more breathlessness (39 vs 22%, P < 0.001), and more of them had a history of respiratory infections (6.8 vs 1.4%, P < 0.001) than individuals with COPD but without gastro-esophageal reflux disease. Among individuals with COPD and gastroesophageal reflux disease, those who did not use acid Correspondence: Truls S. Ingebrigtsen, Department of Respiratory Medicine, Odense University Hospital, Søndre Boulevard 29, 5000 Odense, Denmark. Email: [email protected] Conflict of interest: J.V. has received honoraria from GlaxoSmithKline, Almirall, AstraZeneca, Boehringer-Ingelheim, Novartis and Takeda for consulting and for presenting at meetings and symposia. P.L. has received honoraria from GlaxoSmithKline and other pharmaceutical companies for consulting, teaching and for presenting at meetings and symposia. J.H. has participated in research projects funded by Novartis, Pfizer, MSD, Nycomed and Alkabello with grants paid to the institution where he was employed, and has received fees for teaching or consulting from Nycomed, Pfizer, Novartis, Astra Zeneca and other pharmaceutical companies. Received 4 April 2014; invited to revise 23 June and 7 August 2014; revised 30 June and 9 August 2014; accepted 17 August 2014 (Associate Editor: Paul Thomas). © 2014 Asian Pacific Society of Respirology

SUMMARY AT A GLANCE We tested the hypothesis that gastro-esophageal reflux disease is associated with COPD exacerbations. Our study supports this hypothesis and provides the first prospective analysis showing that this association applies only among those individuals not using acid inhibitory treatment regularly.

inhibitory treatment regularly had an increased risk of COPD exacerbations during follow-up, hazards ratio (HR): HR = 2.7 (1.3–5.4, P = 0.006). Individuals with gastro-esophageal reflux disease, using acid inhibitory treatment regularly did not have an increased risk of exacerbations, HR = 1.2 (0.6–2.7, P = 0.63). Conclusions: Gastro-esophageal reflux disease was associated with an increased risk of medically treated exacerbations of COPD, but only in those individuals who did not use acid inhibitory treatment regularly. Key words: acid inhibitory treatment, chronic obstructive pulmonary disease, reflux. Abbreviations: CCHS, Copenhagen City Heart Study; COPD, Chronic Obstructive Pulmonary Disease; ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastro-esophageal reflux disease; GOLD, Global Initiative of Obstructive Lung Disease; HR, hazards ratio; NSAID, non-steroidal anti-inflammatory drug.

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is one of the most prevalent global health problems.1,2 COPD is characterized by the presence of airflow limitation, breathlessness, coughing, sputum and exacerbations.3 Exacerbations are frequent in some individuals with COPD4 and constitute key elements in assessment, prognosis and choice of treatment.5–8 Respirology (2015) 20, 101–107 doi: 10.1111/resp.12420

102 During the last decade, several studies have suggested an association between airway pathology and gastro-esophageal reflux disease (GERD),9 and there is a growing body of evidence indicating an increased prevalence of GERD in COPD.10–13 Nevertheless, to our knowledge, only few studies have prospectively investigated the association between GERD in COPD and exacerbations, and few studies have addressed the role of acid inhibitory treatment in this association.4,14,15 We therefore tested the hypothesis that GERD is a risk factor for exacerbations in individuals with COPD.

METHODS Study populations In this study, we had access to data from 9622 participants who had answered a questionnaire and had performed pulmonary function tests as part of the 1991–1994 examination of the Copenhagen City Heart Study (CCHS).16 This study was approved by an institutional review board and the Danish ethics committee (No. KF-100.2039/91) and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all participants including participants’ consent to collect further information on health issues. An additional permission to merge data from the Copenhagen City Heart Study with data on medication use has been given by the Danish Health and Medicines Authority in 2005 (Journal number 5121-59). Among these participants, for this study, we identified a subgroup of 1279 (13.3%) individuals with COPD defined by a forced expiratory volume in 1 s (FEV1) divided by forced vital capacity (FVC), FEV1/FVC < 0.7, age above 40 years, and no self-reported asthma. Among these individuals with COPD, 1259 (98.4%) had answered questions on presence or absence of night-time and daytime GERD. The exact questions used to define these conditions were: ‘Do you experience heartburn during night-time?’ and ‘Do you experience heartburn during daytime?’ Reporting night-time and daytime GERD is likely to represent the same disease, and it has been shown that particularly reporting night-time heartburn in addition to more unspecific clinical symptoms, such as pain or discomfort in the chest, significantly increases the validity of identifying esophageal disease.17 We therefore based our main clinical definition of GERD on reporting coexisting night-time and daytime GERD. Using complete record linkage to the national Danish Registry of Medicinal Products Statistics,18 we identified all prescriptions of oral corticosteroids and antibiotics. Clusters of oral corticosteroids, with or without antibiotics, dispensed less than 4 weeks apart, were used to define medically treated exacerbations of COPD.7,8,19 The national Danish Registry of Medicinal Products Statistics was established in 1995 and the information is thus available from 1 January 1995. Therefore, the first individual examined in the 1991–1994 examination of the CCHS on 10 October 1991 was followed-up for 5 years, starting from 1 January 1995. This time difference of 1179 days Respirology (2015) 20, 101–107

TS Ingebrigtsen et al.

between 10 October 1991 and the index date 1 January 1995 was added to the starting point in time for the follow-up of all individuals. This way, the last individual examined in the CCHS on 29 June 1994 was followed-up from 20 September 1997, until 20 September 2002, thus ensuring that all individuals had an equal follow-up of 5 years and an equal shift in time frame of 1179 days from their examination date.

Statistical analysis Demographics We used the statistical software package R (version 3.0.1) in all analyses.20,21 Characteristics of individuals with COPD reporting coexisting night-time and daytime GERD symptoms, either night-time or daytime GERD but not coexisting, night-time GERD, or daytime GERD at the examination were compared using chi-square tests or ANOVA for categorical or continuous variables as appropriate.22 Gastro-esophageal reflux and medically treated exacerbations Univariable and multivariable Cox regression analyses22 were applied to explore the association of coexisting night-time and daytime GERD at the examination, regular use of acid inhibitory treatment and time to the first medically treated exacerbation of COPD for each individual during the 5-year follow-up. Among the 1259 individuals with data on coexisting night-time and daytime GERD, 148 (11.8%) died before the index date of data access in the national Danish Registry of Medicinal Products Statistics and were excluded from these analyses. During follow-up, among the remaining 1111 individuals, censoring was death (n = 310) or end of follow-up (5 years). As our main analysis, we analyzed GERD defined as reporting coexisting night-time and daytime GERD, with or without a regular use of acid inhibitory treatment. The regular use of acid inhibitory treatment was defined by reporting a daily or almost daily use of acid inhibitory treatment. Furthermore, since we only had pre-bronchodilator values, we did a subgroup analysis, where we included only individuals with Global Initiative of Obstructive Lung Disease3 (GOLD) 2–4 grade airflow limitation. In addition, we did two sensitivity analyses with night-time GERD, or daytime GERD, as independent variables of interest. In multivariable analyses, we included confounders associated with GERD and/or exacerbations of COPD according to previous literature: age, gender, GOLD 1–4 grade, body mass index, smoking, symptoms (breathlessness, chronic bronchitis, wheezing, dysphagia), history of respiratory infections and regular use of respiratory medications.3,23–25 Table S1 in the online supporting information shows a detailed description of all variables. To adjust for confounding by a possible healthy user effect,26 we also adjusted our analysis for regular use of vitamin pills defined by reporting a daily or almost daily use of vitamin pills. Furthermore, because arthritis medication, which include non-steroidal anti-inflammatory drugs (NSAID), is associated with gastro-esophageal reflux and gastric © 2014 Asian Pacific Society of Respirology

103

Gastro-esophageal reflux and COPD Table 1 Coexisting night-time and daytime GERD

Variables Age (mean (SD)) BMI ≥ 25 (% (No.)) GOLD 1 (% (No.)) GOLD 2 (% (No.)) GOLD 3+4 (% (No.)) Men (% (No.)) Chronic bronchitis (% (No.)) Breathlessnessa (% (No.)) History of respiratory infectionsb (% (No.)) Wheezing (% (No.)) Current smoking (% (No.)) Former smoking (% (No.)) Dysphagiac (% (No.)) Regular use of acid inhibitory treatmentd (% (No.)) Regular use of pulmonary medicatione (% (No.)) Regular use of vitamin pillsf (% (No.)) Regular use of arthritis medicationsg (% (No.))

No GERD

Either night-time or daytime GERD, but not coexisting

Coexisting night-time and daytime GERD

n = 1097 (87.1%)

n = 88 (7.0%)

n = 74 (5.9%)

P-value

66.9 (9.7) 42.8 (469) 32.1 (352) 54.0 (592) 13.9 (153) 52.9 (580) 21.2 (231) 22.1 (242) 1.4 (15) 36.8 (403) 69.2 (759) 21.2 (233) 2.3 (25) 3.7 (40) 5.0 (54) 59.3 (644) 6.3 (69)

67.3 (9.5) 46.6 (41) 37.5 (33) 45.5 (40) 17.0 (15) 47.7 (42) 34.1 (30) 33.0 (29) 8.0 (7) 44.8 (39) 68.2 (60) 21.6 (19) 12.5 (11) 20.9 (18) 4.7 (4) 62.1 (54) 11.6 (10)

67.8 (10.5) 52.7 (39) 36.5 (27) 55.4 (41) 8.1 (6) 64.9 (48) 31.1 (23) 39.2 (29) 6.8 (5) 44.6 (33) 55.4 (41) 39.2 (29) 16.2 (12) 56.2 (41) 4.2 (3) 61.1 (44) 13.7 (10)

0.71 0.21 0.33*

0.08 0.004

Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease.

We tested the hypothesis that gastro-esophageal reflux disease is a risk factor for exacerbations in individuals with chronic obstructive pulmonary di...
199KB Sizes 0 Downloads 13 Views