Adverse events among COPD patients treated with long-acting anticholinergics and β2-agonists in an outpatient respiratory clinic

  • Claudie Rodrigue
    Affiliations
    Faculty of Pharmacy, Université de Montréal, Montreal, H3C 3J7, Canada
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  • Marie-France Beauchesne
    Affiliations
    Faculty of Pharmacy, Université de Montréal, Montreal, H3C 3J7, Canada

    Pharmacy Department, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, J1H 5N4, Canada

    Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, J1H 5N4, Canada

    Faculty of Medicine, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada
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  • François Savaria
    Affiliations
    Faculty of Pharmacy, Université de Montréal, Montreal, H3C 3J7, Canada
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  • Amélie Forget
    Affiliations
    Faculty of Pharmacy, Université de Montréal, Montreal, H3C 3J7, Canada
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  • Catherine Lemière
    Affiliations
    Faculty of Medicine, Université de Montréal, Montreal, H3C 3J7, Canada

    Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, H4J 1C5, Canada
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  • Pierre Larivée
    Affiliations
    Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, J1H 5N4, Canada

    Faculty of Medicine, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada
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  • Lucie Blais
    Correspondence
    Corresponding author. Université de Montréal, Faculté de Pharmacie, C.P. 6128, Succursale Centre-ville, Montréal, Québec, H3C 3J7, Canada.
    Affiliations
    Faculty of Pharmacy, Université de Montréal, Montreal, H3C 3J7, Canada

    Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, H4J 1C5, Canada
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  • for theRESP Investigators
    Author Footnotes
    1 RESP Investigators in alphabetical order: Simon Bacon, Marie-France Beauchesne, Lucie Blais, Kim Lavoie, Catherine Lemiere, Gregory Moullec, Veronique Pepin, Adriana Spahija.
  • Author Footnotes
    1 RESP Investigators in alphabetical order: Simon Bacon, Marie-France Beauchesne, Lucie Blais, Kim Lavoie, Catherine Lemiere, Gregory Moullec, Veronique Pepin, Adriana Spahija.
Open ArchivePublished:February 17, 2016DOI:https://doi.org/10.1016/j.rmed.2016.02.002

      Highlights

      • About 80% of patients treated with long-acting bronchodilators reported at least one adverse event (AE) in the last week.
      • Overall, dry mouth and throat were the most reported AEs in the last week.
      • Urinary retention in the last month was reported in patients treated with long-acting bronchodilators.
      • Patients reported to have AEs that prevented them from completing a daily activity.

      Abstract

      Background

      Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in Canada. Most patients with COPD receive long-term treatment with long-acting anticholinergics (LAAC) and/or long-acting β2-agonists (LABA). Adverse events (AEs) are also likely during long-term treatment with these medications.

      Objective

      To evaluate the prevalence of AEs in COPD patients on LAAC and LABA in a real-world setting.

      Methods

      We conducted a cross-sectional study of patients enrolled in the Registre de Données en Santé Pulmonaire (RESP) database, which records information on Canadian patients with asthma or COPD. COPD Patients completed a questionnaire about AEs that may be associated with LAAC and/or LABA. The prevalence of AEs and the corresponding 95% CI were calculated for three groups of patients (LAAC + LABA, LAAC alone, and LABA alone).

      Results

      Most patients with COPD (n = 154) were current or ex-smokers. Over 50% of patients were overweight or obese, and had an annual family income of less or equal to $42,000. Dry mouth (55.2%, 40%, and 43.5%) and dry throat (33.6%, 26.7%, and 34.8%) occurred most of the time or always in the LAAC + LABA, LAAC, and LABA groups, respectively. Headache was reported by 17.4% of patients in the LABA group, but less than 11.2% in the other groups.

      Conclusion

      AEs reported in this study deserve clinical attention because they may negatively affect quality of life and treatment adherence of COPD patients.

      Keywords

      Abbreviations:

      AE (Adverse event), BMI (Body mass index), COPD (Chronic obstructive pulmonary disease), FEV1 (Forced expiratory volume in 1 s), FVC (Forced vital capacity), GOLD (Global Initiative for Chronic Obstructive Lung Disease guidelines), ICS (Inhaled corticosteroid), LABA (Long-acting β2-agonist), LAAC (Long-acting anticholinergic), MRC (Medical Research Council), RESP (Registre de Données en Santé Respiratoire)

      1. Introduction

      Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by persistent and progressive airways obstruction associated with an inflammatory response [
      • Decramer M.
      • Agusti A.G.
      • Bourbeau J.
      Global Strategy for the Diagnosis, Management, and Prevention of COPD.
      ]. It is the third leading cause of death worldwide [
      • O'Toole R.F.
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      ] and the fourth in Canada [
      • Criner G.J.
      • Bourbeau J.
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      • Goodridge D.
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      • Balter M.S.
      • Bhutani M.
      • Camp P.G.
      • et al.
      Prevention of acute exacerbations of COPD: American college of chest physicians and Canadian thoracic society guideline.
      ]. Smoking is the most important risk factor for COPD, being present in 80%–90% of cases, but other risk factors include occupational exposure to dust and chemicals, together with indoor and outdoor pollution [
      • Decramer M.
      • Agusti A.G.
      • Bourbeau J.
      Global Strategy for the Diagnosis, Management, and Prevention of COPD.
      ]. According to the Global Initiative for Chronic Obstructive Lung Disease guidelines (GOLD), COPD patients can be classified in four different categories (A, B, C and D) based on the extent of airflow limitation, symptoms (according to the COPD assessment test or modified Medical Research Council [MRC] dyspnea scale) and the number of acute exacerbations of COPD per year [
      • Decramer M.
      • Agusti A.G.
      • Bourbeau J.
      Global Strategy for the Diagnosis, Management, and Prevention of COPD.
      ]. Patients in categories A and B have a low risk of acute exacerbations and less (category A) or more symptoms (category B). Patients in categories C and D have a high risk of exacerbation with less (category C) or more symptoms (category D). The recommended first choices in pharmacologic therapy for stable COPD according to each category are as follows: short-acting bronchodilators are recommended for patients in category A. By contrast, long-acting bronchodilators, either long-acting anticholinergics (LAAC) or long-acting β2-agonists (LABA), are recommended for patients in category B. For patients in category C, the treatments recommended are a fixed combination of an inhaled corticosteroid (ICS) with a LABA, or LAAC in monotherapy. For patients in category D, a fixed combination of an ICS and a LABA associated with a LAAC or a LAAC in monotherapy is recommended [
      • O'Donnell D.E.
      • Hernandez P.
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      • Gervais A.
      • Lacasse Y.
      • et al.
      Canadian thoracic society recommendations for management of chronic obstructive pulmonary disease – 2008 update – highlights for primary care.
      ]. The main objectives of pharmacologic treatments are to relieve the symptoms of COPD and prevent exacerbations.
      Drugs are often associated with adverse events (AEs) that can affect the patient's quality of life. Several randomized controlled trials have investigated the safety of LAAC and LABA in COPD patients. Some of the most common AEs in patients treated with a LAAC included dry mouth (1%–16%) [
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      • Tabberer M.
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      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • D'Urzo A.
      • Kerwin E.
      • Overend T.
      • D'Andrea P.
      • Chen H.
      • Goyal P.
      Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies.
      ,
      • Almirall
      Aclidinium bromide inhalation powder.
      ,
      • Ingelheim B.
      Capsules de tiotropium pour inhalation orale.
      ,
      • Novartis
      Glycopyrronium inhalation powder hard capsules.
      ] and urinary retention (1%–3%) [
      • Ingelheim B.
      Capsules de tiotropium pour inhalation orale.
      ,
      • Novartis
      Glycopyrronium inhalation powder hard capsules.
      ]. Some common AEs in patients treated with a LABA included palpitations (1%–10%) [
      • GlaxoSmithKline
      Xinafoate de salmétérol et propionate de fluticasone en poudre sèche pour inhalation. Xinafoate de salmétérol et propionate de fluticasone en aérosol pour inhalation.
      ,
      • AstraZeneca
      Budésonide/fumarate de formotérol dihydraté.
      ], muscle cramps (0.1%–8%) [
      • GlaxoSmithKline
      Xinafoate de salmétérol et propionate de fluticasone en poudre sèche pour inhalation. Xinafoate de salmétérol et propionate de fluticasone en aérosol pour inhalation.
      ,
      • AstraZeneca
      Formoterol fumarate dihydrate.
      ], and tremors (1%–4%) [
      • GlaxoSmithKline
      Xinafoate de salmétérol et propionate de fluticasone en poudre sèche pour inhalation. Xinafoate de salmétérol et propionate de fluticasone en aérosol pour inhalation.
      ,
      • AstraZeneca
      Budésonide/fumarate de formotérol dihydraté.
      ,
      • AstraZeneca
      Formoterol fumarate dihydrate.
      ,
      • Donohue J.F.
      • Hanania N.A.
      • Sciarappa K.A.
      • Goodwin E.
      • Grogan D.R.
      • Baumgartner R.A.
      • Hanrahan J.P.
      Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: a one year evaluation of safety and tolerance.
      ]. In patients treated with a combination of LAAC and a LABA, headache (1%–9%) [
      • Vogelmeier C.F.
      • Bateman E.D.
      • Pallante J.
      • Alagappan V.K.
      • D'Andrea P.
      • Chen H.
      • Banerji D.
      Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
      ,
      • Dahl R.
      • Chapman K.R.
      • Rudolf M.
      • Mehta R.
      • Kho P.
      • Alagappan V.K.
      • Chen H.
      • Banerji D.
      Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study.
      ,
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • D'Andrea P.
      • Arrasate C.
      • Chen H.
      • Banerji D.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ,
      • Buhl R.
      • Gessner C.
      • Schuermann W.
      • Foerster K.
      • Sieder C.
      • Hiltl S.
      • Korn S.
      Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study.
      ,
      • GlaxoSmithKline
      Umeclidinium (sous forme de bromure) et vinlantérol (sous forme de trifénatate) en poudre sèche pour inhalation par voie orale.
      ,
      • Novartis
      Indacaterol (as maleate)/glycopyrronium (as bromide) inhalation powder hard capsules.
      ], urinary tract infection (1%–1.9%) [
      • Dahl R.
      • Chapman K.R.
      • Rudolf M.
      • Mehta R.
      • Kho P.
      • Alagappan V.K.
      • Chen H.
      • Banerji D.
      Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study.
      ,
      • GlaxoSmithKline
      Umeclidinium (sous forme de bromure) et vinlantérol (sous forme de trifénatate) en poudre sèche pour inhalation par voie orale.
      ,
      • Novartis
      Indacaterol (as maleate)/glycopyrronium (as bromide) inhalation powder hard capsules.
      ], and constipation (1% of patients) were reported [
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • D'Andrea P.
      • Arrasate C.
      • Chen H.
      • Banerji D.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ,
      • GlaxoSmithKline
      Umeclidinium (sous forme de bromure) et vinlantérol (sous forme de trifénatate) en poudre sèche pour inhalation par voie orale.
      ]. Because randomized controlled trials have strict inclusion and exclusion criteria, the characteristics of COPD patients enrolled in these studies may differ in terms of comorbidity and age, for example, compared with patients who are prescribed these drugs in actual clinical practice [
      • Eisenberg Y.
      • Mohiuddin H.
      • Cherukupally K.
      • Zaidi H.
      • Kukreja S.
      • Barengolts E.
      Similarities and differences between patients included and excluded from a randomized clinical trial of vitamin d supplementation for improving glucose tolerance in prediabetes: interpreting broader applicability.
      ,
      • Murthy V.H.
      • Krumholz H.M.
      • Gross C.P.
      Participation in cancer clinical trials: race-, sex-, and age-based disparities.
      ].
      To date, however, very few studies have investigated the AEs associated with long-acting bronchodilators in a real world setting. A retrospective cohort study reported a higher risk of pneumonia in users of ICS compared to other maintenance therapies for COPD (OR = 1.73 95% CI: 1.57–1.90, p < 0.001) but did not investigate the incidence of more common adverse events [
      • Janson C.
      • Larsson K.
      • Lisspers K.H.
      • Stallberg B.
      • Stratelis G.
      • Goike H.
      • Jorgensen L.
      • Johansson G.
      Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting beta2 agonist: observational matched cohort study (PATHOS).
      ]. One cohort study investigated the frequency of AEs in asthma and COPD patients who were treated with the LABA salmeterol, and reported tremor to be the most common AE [
      • Mann R.D.
      • Kubota K.
      • Pearce G.
      • Wilton L.
      Salmeterol: a study by prescription-event monitoring in a UK cohort of 15,407 patients.
      ]. Meanwhile, one open-label, 6-month, prospective, uncontrolled study investigated the frequency of AEs in COPD patients treated with the LAAC tiotropium and reported dry mouth to be the most common AE [
      • Flezar M.
      • Jahnz-Rozyk K.
      • Enache G.
      • Martynenko T.
      • Kristufek P.
      • Skrinjaric-Cincar S.
      • Kadlecova P.
      • Martinovic G.
      SOSPES: SPIRIVA(R) observational study measuring SGRQ score in routine medical practice in Central and Eastern Europe.
      ]. However, no real-life study has evaluated the frequency of AEs among patients treated with a LAAC in combination with a LABA. Therefore, we conducted a cross-sectional study to evaluate the frequency of common AEs in COPD patients who use these drugs in a real-world clinical setting.

      2. Material and methods

      2.1 Study design

      We performed a cross-sectional study of patients who were selected from the Registre de Données en Santé Pulmonaire (RESP), a multicenter prospective database that records sociodemographic and clinical data of adults with asthma or COPD. Recruitment began in 2010 and is ongoing in two centres in Quebec: Hôpital du Sacré-Coeur de Montréal and the Centre Hospitalier Universitaire de Sherbrooke. Patients registered in the RESP database have a diagnosis of asthma or/and COPD confirmed by a pulmonologist and agreed to be contacted by mail or telephone for research projects. Patients invited to participate in this study were eligible if they were recorded in RESP, and if they were treated with a LAAC and/or a LABA when they answered the questionnaire. Patients were excluded if they were not able to speak and read French, if they were unable to answer the questionnaire or if we were unable to contact them. Fig. 1 shows the reasons for exclusion.
      Figure thumbnail gr1
      Fig. 1Patient selection. COPD, chronic obstructive pulmonary disease; RESP, Registre de Données en Santé Pulmonaire; LAAC, long-acting anticholinergics; LABA, long-acting β2-agonists.
      An invitation letter, a written consent form, a questionnaire related to AEs, and a pre-paid return envelope were posted to selected patients. The patients were contacted by telephone within 2 weeks after being sent the invitation in order to provide further explanations regarding the study. Patients who agreed to be interviewed by telephone were given the choice to answer the questionnaire during the informative telephone call or to make an appointment to answer the questionnaire by telephone at another time. Patients who accepted to participate in the study were asked to return the signed consent form. Patients were called again if the consent form was not received within 2 weeks. If the signed consent form was not received within 1 month after the first telephone call, the patient was excluded and any data collected during the telephone call were destroyed.

      2.2 Questionnaire development

      A literature review was performed to identify the AEs reported by patients in clinical trials of LAACs and LABAs; product monographs were also reviewed. The selected adverse effects were those that occur most often and those that are more specific to LAAC and LABA. The questionnaire was reviewed by a pharmacist and was pre-tested by five COPD patients being treated in the outpatient pulmonology clinics at the Hôpital du Sacré-Coeur de Montréal. Three of these patients were registered in the RESP database. Patients were asked to report any unclear questions and how the questions could be improved to increase their understanding. Based on the patients' comments, the questionnaire was modified to improve its clarity and comprehension.

      2.3 Data collection

      The research assistant telephoned the eligible patients in order to complete the questionnaire on AEs during the call. Some patients preferred to complete the questionnaire by themselves and return it by mail. Patients were interviewed on their current use of long-acting bronchodilators to update the information on respiratory medications registered at the time of inscription in the RESP database. They were asked if there had been any changes to their long-acting bronchodilator treatment in the preceding 6 months, including the time and reason for the change. Patients were questioned about AEs, more specifically tremors, nervousness, muscular cramps, palpitations, constipation, headaches, unpleasant sensation in the mouth, dry mouth, dry throat, urinary retention, blurred vision, urinary infections, and respiratory tract infections. They were asked about the presence of these AE in the week, month and 6 months preceding the interview, while being treated with a LAAC and/or a LABA. Sociodemographic data (age, residence, smoking status, body mass index [BMI], and annual family income) and clinical data in the year before inscription in RESP database (participation in a rehabilitation program) and at the inscription in RESP database (oxygen supplementation, mobility assistance, mMRC dyspnea scale, forced expiratory volume in 1 s [FEV1], FEV1/forced vital capacity [FVC], comorbidities and co-medication) were retrieved from the RESP database. Smoking status was categorized as current smoker, ex-smoker, and non-smoker. BMI was categorized as underweight (≤18.5 kg/m2), normal weight (>18.5 to ≤25 kg/m2), overweight (>25 to ≤30 kg/m2), and obese (>30 kg/m2). Annual family income was categorized as ≤$26,000, $26,001 to $42,000, $42,001 to $62,000 and >$62,000.

      2.4 Outcomes

      The use of LAAC more than once per day among patients who had a prescription of LAAC once daily was estimated with the information on patient's respiratory medication. Patients were asked to evaluate the occurrence of AEs on an ordinal scale (never/rarely/sometimes/most of the time/always), or as a dichotomous variable for urinary and respiratory tract infections (i.e. yes/no). Patients were asked about the presence of tremors, nervousness, muscular cramps, palpitations, constipation, headache, unpleasant sensation in the mouth, dry mouth, and dry throat in the week before the telephone interview. Urinary retention and blurred vision were assessed for up to 1 month before the interview, while urinary and respiratory tract infections were assessed for up to 6 months before the interview. If the patient did not remember whether a specific AE occurred, we considered that this AE had not occurred. Patients were also asked whether or not the AE prevented them from completing a daily activity and if it led to a change in the treatment regimen.

      2.5 Statistical analysis

      Descriptive statistics (mean and standard deviation for continuous variables and proportions for categorical variables) were calculated. Statistical tests (t tests for continuous variables and χ2 test for categorical variables) were performed to compare the characteristics of participating and non-participating patients. P-values of <0.05 were considered statistically significant. The participating patients were classified into three groups according to their use of long-acting bronchodilators at the time of completing the questionnaire: LAAC and LABA (LAAC + LABA group), LAAC only (LAAC group) and LABA only (LABA group). Descriptive statistics were also used to describe the characteristics of patients in each group. The proportion and 95% confidence interval (CI) of patients who reported that they experienced each AE most of the time or always in the relevant time period (i.e., prior week, prior month or prior 6 months) was determined for each group separately. The proportion of patients who reported at least one AE (from tremors, nervousness, muscular cramps, palpitations, constipation, headache, unpleasant sensation in the mouth, dry mouth, or dry throat) in the prior week, and the proportion of patients who reported at least one AE (tremors, nervousness, muscular cramps, palpitations, constipation, headache, unpleasant sensation in the mouth, dry mouth, dry throat, urinary retention, blurred vision, urinary tract infection, or respiratory tract infection) in the prior month were estimated. The proportion and 95% CI of patients who reported at least one AE that prevented them from completing a daily activity or whose therapeutic regimen was changed because of an AE in the last 6 months, was calculated in each group. The proportion of patients using their LAAC more than once per day among those prescribed LAAC once daily was estimated. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC).

      3. Ethics approval

      This study was approved by the Ethics Committees of the Hôpital du Sacré-Coeur de Montréal and the Centre Hospitalier Universitaire de Sherbrooke.

      4. Results

      4.1 Patient characteristics

      As shown in Fig. 1, 359 patients registered in the RESP database agreed to be contacted for future research projects, 242 satisfied the eligibility criteria for the present study, and 154 participated in the study. The characteristics of the participants and non-participants were similar (Table 1). The mean age of participants was 69.5 years and 19.5% were current smokers. Most of the participants did not require oxygen supplementation (84.4%) or mobility assistance (76.0%). The MRC dyspnea scale ranged from 3 to 5 in 59.0% of participants.
      Table 1Characteristics of the participating and non-participating patients at their recruitment in RESP database.
      Participants n = 154Non-participants n = 88P value
      Age (years)69.5 ± 8.570.8 ± 9.40.26
      Male gender66 (42.9)43 (48.9)0.37
      Urban residence139 (90.3)84 (95.5)0.15
      Smoking status0.51
       Current smoker30 (19.5)18 (20.5)
       Ex-smoker116 (75.3)61 (69.3)
       Non-smoker7 (4.6)8 (9.1)
       Missing1 (0.7)1 (1.1)
      Body mass index (kg/m2)0.91
       Underweight10 (6.5)4 (4.6)
       Normal45 (29.2)29 (33.0)
       Overweight51 (33.1)29 (33.0)
       Obesity45 (29.2)24 (27.3)
       Missing3 (2.0)2 (2.3)
      Annual family income ($)0.21
       ≤26,00045 (29.2)29 (33.0)
       26,001 to 42,00040 (26.0)17 (19.3)
       42,001 to 62,00022 (14.3)16 (18.2)
       >62,00022 (14.3)6 (6.8)
       Missing25 (16.2)20 (22.7)
      Oxygen supplementation0.12
       Yes24 (15.6)6 (6.8)
       No127 (82.5)79 (89.8)
       Missing3 (2.0)3 (3.4)
      Mobility assistance0.62
       None117 (76.0)62 (70.5)
       Cane/walker25 (16.2)19 (21.6)
       Wheel chair9 (5.8)4 (4.6)
       Missing3 (2.0)3 (3.4)
      MRC dyspnea scale0.15
       1. I only get breathless with strenuous exercise15 (9.7)13 (14.8)
       2. I get short of breath when hurrying on the level or walking up a slight hill45 (29.2)18 (20.5)
       3. I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level29 (18.8)11 (12.5)
       4. I stop for breath after walking about 100 m or after a few minutes on the level23 (14.9)21 (23.9)
       5. I am too breathless to leave the house or I am breathless when dressing or undressing39 (25.3)21 (23.9)
      Missing3 (2.0)4 (4.6)
      Values are presented as the mean ± standard deviation or n (%).
      MRC: Medical Research Council.
      Table 2 presents the characteristics of the participating patients according to their use of inhaled long-acting bronchodilators. Most of the patients in each groups were current or ex-smokers. More than 50% of patients were overweight or obese, and had an annual family income of ≤$42,000. Patients in the LAAC + LABA group appeared to have more severe COPD because a larger proportion of them required oxygen supplementation and used an ICS (mostly as an ICS + LABA combination) and because they had a higher level of dyspnea, lower FEV1, and lower FEV1/FVC ratio than patients in the LAAC or LABA groups.
      Table 2Characteristics of patients treated with long-acting bronchodilators.
      LAAC + LABA n = 116LAAC n = 15LABA n = 23
      Age, years at their recruitment in RESP69.0 ± 8.569.1 ± 9.472.2 ± 7.6
      Male gender49 (42.2)7 (46.7)10 (43.5)
      Urban residence at their recruitment in RESP105 (90.5)13 (86.7)21 (91.3)
      Smoking status at their recruitment in RESP
       Current smoker23 (19.8)3 (20.0)4 (17.4)
       Ex-smoker88 (75.9)10 (66.7)18 (78.3)
       Non-smoker5 (4.3)2 (13.3)0
       Missing data001 (4.4)
      Body mass index at their recruitment in RESP
       Underweight7 (6.0)1 (6.7)2 (8.7)
       Normal38 (32.8)1 (6.7)6 (26.1)
       Overweight36 (31.0)10 (66.7)5 (21.7)
       Obesity33 (28.5)3 (20.0)9 (39.1)
       Missing2 (1.7)01 (4.4)
      Annual family income, Canadian dollar ($) at their recruitment in RESP
       ≤26,00034 (29.3)7 (46.7)4 (17.4)
       26,001 to 42,00027 (23.3)5 (33.3)8 (34.8)
       42,001 to 62,00019 (16.4)1 (6.7)2 (8.7)
       >62,00019 (16.4)1 (6.7)2 (8.7)
       Missing17 (14.7)1 (6.7)7 (30.4)
      Participated in a respiratory rehabilitation program in the year before recruitment in RESP24 (20.7)4 (26.7)8 (34.8)
      Oxygen supplementation at their recruitment in RESP
       Yes22 (19.0)02 (8.7)
       No92 (79.3)15 (100.0)20 (87.0)
       Missing2 (1.7)01 (4.4)
      Mobility assistance at their recruitment in RESP
       None89 (76.7)13 (86.7)15 (65.2)
       Cane/walker18 (15.5)2 (13.3)5 (21.7)
       Wheel chair7 (6.0)02 (8.7)
       Missing data2 (1.7)01 (4.4)
      MRC dyspnea scale at their recruitment in RESP
       1. I only get breathless with strenuous exercise10 (8.6)2 (13.3)3 (13.0)
       2. I get short of breath when hurrying on the level or walking up a slight hill.31 (26.7)8 (53.3)6 (26.1)
       3. I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level.21 (18.1)2 (13.3)6 (26.1)
       4. I stop for breath after walking about 100 m or after a few minutes on the level.17 (14.7)2 (13.3)4 (17.4)
       5. I am too breathless to leave the house or I am breathless when dressing or undressing.35 (30.2)1 (6.7)3 (13.0)
       Missing2 (1.7)01 (4.4)
      FEV1, % of predicted pre-bronchodilator therapy in the year before recruitment in RESP
       Evaluable n (%)79 (68.10)8 (53.3)16 (69.6)
       Mean ± SD49.1 ± 14.568.3 ± 13.361.7 ± 34.0
       >80%2 (1.7)2 (13.3)4 (17.4)
       >50% to ≤80%33 (28.5)5 (33.3)4 (17.4)
       >30% to ≤50%37 (31.9)1 (6.7)6 (26.1)
       ≤30%7 (6.0)02 (8.7)
       Missing37 (31.9)7 (46.7)7 (30.4)
      FEV1/FVC in the year before recruitment in RESP
       Evaluable n (%)82 (70.7)8 (53.3)15 (65.2)
       Mean ± SD53.1 ± 12.164.5 ± 8.153.7 ± 13.3
       ≤70%74 (63.8)5 (33.3)14 (60.9)
       >70%8 (6.9)3 (20.0)1 (4.4)
       Missing34 (29.3)7 (46.7)8 (34.8)
      Treatment regiments at the moment of the questionnaire
       LABA12 (10.3)NA7 (30.4)
      Salmeterol2 (1.7)NA4 (17.4)
      Formoterol9 (7.8)NA2 (8.7)
      Indacaterol1 (0.9)NA1 (4.4)
       LAAC114 (98.3)15 (100.0)NA
      Tiotropium (Handihaler/Respimat)
      Only two patients of the LAAC + LABA group were treated with Tiotropium Respimat.
      104 (89.7)13 (86.7)NA
      Glycopyrronium4 (3.5)2 (13.3)NA
      Aclidinium bromide6 (5.2)0NA
       LAAC/LABA3 (2.6)NANA
      Umeclidinium/vilanterol1 (0.9)NANA
      Glycopyrronium/indacaterol2 (1.7)NANA
       Any ICS
      Patients can be prescribed more than one ICS.
      107 (92.2)1 (6.7)20 (87.0)
       ICS/LABA103 (88.8)NA17 (73.9)
      Fluticasone/salmeterol (metered-dose inhaler/Diskus)67 (57.8)NA8 (34.8)
      Budesonide/formoterol35 (30.2)NA8 (34.8)
      Mometasone/formoterol1 (0.9)NA0
      Fluticasone/vilanterol0NA1 (4.4)
       ICS12 (10.3)1 (6.7)4 (17.4)
      Budesonide1 (0.9)1 (6.7)1 (4.4)
      Fluticasone6 (5.2)01 (4.4)
      Ciclesonide5 (4.3)02 (8.7)
       Other respiratory medications
      Includes phosphodiesterase-4 inhibitors, leukotriene receptor antagonists, oral corticosteroids, short-acting β2-agonists, and short-acting anticholinergics.
      69 (59.5)7 (46.7)9 (39.1)
      Patients using their LAAC more than once per day among those prescribed LAAC once daily, n (%) at the moment of the questionnaire3 (2.6)0NA
      Comorbidities
       Diseases of the respiratory system other than COPD
      Included asthma, respiratory insufficiency, sleep apnea, pulmonary hypertension and perennial rhinitis.
      86 (74.1)8 (53.3)17 (73.9)
       Endocrine, nutritional and metabolic disease80 (69.0)11 (73.3)13 (56.5)
       Diseases of the circulatory system73 (62.9)9 (60.0)16 (69.6)
       Diseases of the musculoskeletal system and connective Tissue53 (45.7)5 (33.3)10 (43.5)
       Respiratory infectious diseases51 (44.0)2 (13.3)10 (43.5)
       Mental and behavioral disorders47 (40.5)4 (26.7)10 (43.5)
       Neoplasms35 (30.2)6 (40.0)8 (34.8)
       Diseases of the digestive system34 (29.3)1 (6.7)14 (60.9)
       Diseases of the genitourinary system25 (21.6)2 (13.3)1 (4.4)
       Diseases of the skin and subcutaneous tissue4 (3.5)02 (8.7)
       Diseases of the central nervous system9 (7.8)04 (17.4)
       Other comorbidities
      Includes anemia (n = 6), iron deficiency anemia (n = 6), cataract (n = 2), macular degeneration (n = 1), alcoholism (n = 7), fibrosis (n = 1), glaucoma (n = 2), ear infection (n = 1), deafness (n = 1), positional vertigo (n = 1), vocal cord polyps (n = 3), and blood diseases else than anemia (n = 15).
      39 (33.6)2 (13.3)8 (34.8)
      Oral anticholinergics used to treat diseases other than COPD8 (6.9)06 (26.1)
      Values are presented as the mean ± standard deviation or n (%).
      LAAC, long-acting anticholinergic; LABA, long-acting β2-agonist; SD, standard deviation; ICS, inhaled corticosteroid.
      a Only two patients of the LAAC + LABA group were treated with Tiotropium Respimat.
      b Patients can be prescribed more than one ICS.
      c Includes phosphodiesterase-4 inhibitors, leukotriene receptor antagonists, oral corticosteroids, short-acting β2-agonists, and short-acting anticholinergics.
      d Included asthma, respiratory insufficiency, sleep apnea, pulmonary hypertension and perennial rhinitis.
      e Includes anemia (n = 6), iron deficiency anemia (n = 6), cataract (n = 2), macular degeneration (n = 1), alcoholism (n = 7), fibrosis (n = 1), glaucoma (n = 2), ear infection (n = 1), deafness (n = 1), positional vertigo (n = 1), vocal cord polyps (n = 3), and blood diseases else than anemia (n = 15).

      4.2 AEs

      As seen in Table 3, the most frequent AEs that were reported most of the time or always in the week before the interview for LAAC + LABA users were dry mouth (55.2%), dry throat (33.6%) and unpleasant sensation in the mouth (29.3%). In the LAAC group, the most reported AEs in the preceding week were dry mouth (40.0%), dry throat (26.7%), unpleasant sensation in the mouth (26.7%), muscle cramps (13.3%), and constipation (13.3%). In the LABA group, dry mouth (43.5%), dry throat (34.8%) and constipation (21.7%) were the most reported AEs occurring in the week before the interview. At least 80% of patients in each group reported that they had experienced an AE in the last week.
      Table 3Frequencies of adverse events.
      LAAC, long-acting anticholinergic; LABA, long-acting β2-agonist; AE, adverse event.
      LAAC + LABA n = 116LAAC n = 15LABA n = 23
      Percent (95% confidence interval)
      Unless otherwise specified.
      AEs in the last week
       Tremors11.2 (9.2–13.2)017.4 (11.8–22.9)
       Nervousness17.2 (14.9–19.6)6.7 (2.1–11.3)17.4 (11.8–22.9)
       Palpitations10.3 (8.4–12.3)08.7 (4.6–12.8)
       Muscle cramps26.7 (23.9–29.5)13.3 (7.0–19.6)17.4 (11.8–22.9)
       Headache11.2 (9.2–13.2)017.4 (11.8–22.9)
       Constipation16.4 (14.0–18.7)13.3 (7.0–19.6)21.7 (15.7–27.8)
       Unpleasant sensation in the mouth29.3 (26.4–32.2)26.7 (18.5–34.9)17.4 (11.8–22.9)
       Dry mouth55.2 (52.0–58.3)40.0 (30.9–49.1)43.5 (36.2–50.7)
       Dry throat33.6 (30.6–36.6)26.7 (18.5–34.9)34.8 (27.8–41.7)
       ≥ 1 adverse events in the last week94.8 (93.4–96.2)80.0 (72.6–87.4)87.0 (82.0–91.9)
      Adverse events in the last month
       Urinary retention6.9 (5.3–8.5)13.3 (7.0–19.6)8.7 (4.6–12.8)
       Blurred vision7.8 (6.1–9.4)026.1 (19.7–32.5)
       ≥1 adverse events in the last month97.4 (96.4–98.4)80.0 (72.6–87.4)87.0 (82.0–91.9)
      Urinary and respiratory tract infections in the last 6 months
       ≥ 1 urinary tract infections in the last 6 months, n (%)8 (6.9)01 (4.4)
       Mean number of urinary tract infections per patient1.63 (1.33–1.92)01.0
       ≥ 1 respiratory tract infections in the last 6 months, n (%)62 (53.5)7 (46.7)12 (52.2)
       Mean number of respiratory tract infections per patient1.73 (1.59–1.86)1.14 (1.04–1.25)1.18 (1.10–1.27)
       Mean duration of respiratory tract infections per patient (days)14.1 (13.0–15.1)16.5 (15.3–17.7)26.7 (21.1–32.3)
      Patients with a change in therapy in the last 6 months, n (%)18 (15.5)4 (26.7)3 (13.0)
      Patients with a change in medication because of an AE in the last 6 months38.9 (30.7–47.0)25.0 (5.9–44.1)0
      Patients with at least one AE, which prevented them from completing a daily activity11.2 (9.2–13.2)08.7 (4.5–12.8)
      a LAAC, long-acting anticholinergic; LABA, long-acting β2-agonist; AE, adverse event.
      b Unless otherwise specified.
      In the month preceding the interview, urinary retention and blurred vision were reported respectively by 6.9% and 7.8% of patients in the LAAC + LABA group. Those two same AEs were reported by 8.7% and 26.1% of patients in the LABA group, respectively. In the LAAC group, urinary retention was reported by 13.3% of the patients (none reported blurred vision). In the last 6 months, 8 patients (6.9%) in the LAAC + LABA group experienced a urinary tract infection, with a mean of 1.63 infections per patient. In the LAAC + LABA group, 62 patients (53.5%) reported a respiratory tract infection in the last six months, with a mean of 1.73 infections per patient. Similar proportions (46.7% and 52.2%) of patients reported a respiratory tract infection in the LAAC and LABA groups, respectively.

      4.3 Changes in respiratory medications

      Overall, 25 of 154 patients reported a change in the molecule used for the treatment of their COPD over the last 6 months. These changes were reported by 18 patients in the LAAC + LABA group, 4 patients in the LAAC group and 3 patients in the LABA group. AEs were reported to be the cause of these changes in 7/18 patients in the LAAC + LABA group and in 1/4 patients in the LAAC group. Those changes were associated with only two changes in treatment class in the LAAC + LABA group in the last 6 months. All other changes of treatment were between molecules of the same class. In the LABA group, changes reported by patients were not caused by AEs. AEs that caused change of treatment included dry mouth, urinary retention, tremors, constipation, respiratory tract infections in the LAAC + LABA group, and dry mouth in the LAAC group. Four patients in the LAAC + LABA group reported that their AEs improved after the change in medication.

      4.4 Influence of AEs on daily activities

      As shown in Table 1, 11.2% of patients in the LAAC + LABA group reported to have at least one AE that prevented them from completing a daily activity. The most frequent AEs reported by patients to prevent them from completing a daily activity were palpitations, respiratory tract infection and an unpleasant sensation in the mouth (30.8%) and headache, constipation, dry throat and blurred vision (23.1%). In the LABA group, 8.7% of patients reported to have at least one AEs that prevented them from completing a daily activity while none of the patients in the LAAC group has reported this event. The AE reported to mostly influence daily activities in patients on LABA was dry mouth (1/2 patients).

      4.5 Use of medications

      Among patients who were prescribed a LAAC once daily, the LAAC was used more than once per day by 3/116 (2.6%) patients in the LAAC + LABA group, and by none of the patients in the LAAC group.

      5. Discussion

      The prevalence of AEs reported by patients in this study was much higher than what was reported in prior randomized clinical trials. However, our results were not adjusted for the use of co-medications and comorbidities. Furthermore, we did not formally included a control group. Therefore, some AEs observed might not be attributable to inhaled long-acting bronchodilators. In the LAAC + LABA group, headache, constipation and urinary tract infection were reported more frequently compared to previous clinical trials where the incidences varied between 1% and 9% [
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      ]. It is, however, important keep in mind that the prevalence of AEs in the LABA and the LAAC groups were determined in only 23 and 15 patients, respectively. Differences between our results and those from prior clinical trials might be explained by the small number of patients in those groups, by differences in the patient characteristics, and by different methods used to collect data on AEs. Patients in our study were older than those in earlier clinical trials, with a mean age ranging from 69 to 72 years in the three groups, compared with a range of 63–68 years in prior LAAC and LABA trials. Moreover, the patients included in our study are likely to be more susceptible to AEs owing to their general health, because no exclusion criteria based on comorbidities were applied to reflect real clinical practice. By contrast, in clinical trials, patients are likely to be excluded if they have clinically significant comorbidities such as unstable cardiovascular disease [
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      ]. About 60%–70% of patients in our study had comorbidities affecting the circulatory system, as documented in their medical records, compared to 20%–68% of patients in clinical trials of inhaled long-acting bronchodilators. Moreover, ICS use was higher in our study for patients in the LAAC + LABA and LABA groups compared with patients in prior clinical trials [
      • Dahl R.
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      ]. This can be explained by the high percentage of patients treated with an ICS/LABA combination who were included in the study. The low percentage (6.7%) of ICS use in the LAAC group can be explained by the small sample size. Another difference between our study and clinical trials is the method used to assess AEs. In our study, patients were directly questioned about specific adverse events, whereas in clinical trials, AEs were most likely collected via open-ended questionnaire on any AE. In fact, when asked about the presence of a specific AE (e.g. dry mouth), patients are possibly more likely to report its presence.
      We found only two observational studies that estimated the prevalence of common AEs in patients treated with long-acting bronchodilators. One cohort study investigated the prevalence of AEs in patients with asthma or COPD treated with the LABA salmeterol. Although the authors did not report the prevalence of AEs, the rate ratios were 2.6, 7.3, 4.5, and 1.6 for headache, tremors, palpitations and respiratory tract infections, respectively, comparing the rate of AEs per 1000 patients within 1 month after starting a LABA to the rate of AEs occurring at 2–6 months. They reported that AEs with a rate ratio of more than 3 were probably related to the administered drug [
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      ]. Meanwhile, one open-label, prospective, uncontrolled, single-group surveillance study evaluated the prevalence of AEs associated with tiotropium as a third study endpoint. In that study, the prevalence of all AEs was 3.8%. They also categorized AEs as (a) respiratory, thoracic and mediastinal disorders, (b) gastrointestinal disorders, and (c) nervous system disorders for which the prevalence were 1.7%, 1.15%, and 0.54%, respectively [
      • Flezar M.
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      SOSPES: SPIRIVA(R) observational study measuring SGRQ score in routine medical practice in Central and Eastern Europe.
      ]. Although the methods used to assess AEs in these two studies were not specifically reported, it seems that the AEs were reported by the patients during each visit.
      The results of our study should be interpreted while considering the following limitations. Lack of precision in the estimation of the AE proportions due to the small number of patients in the LAAC only and LABA only groups. The questionnaire used in this study was pre-tested for clarity and ease of comprehension, but was not formally validated against other questionnaires. The results may have been affected by recall bias because some questions asked about AEs occurring up to 6 months ago. Recent changes in respiratory medications could have influenced the results, but only a few patients had changes in the 3 months before the interview and only one involved a changed from one class to another (i.e. LABA to an LAAC + LABA), so the impact on our results are probably minimal. Patients who experienced more serious AEs might be more likely to report them, leading to an underestimation of less serious AEs. Another limitation of the study is that the comorbidities were collected from the patients' medical records, which may be incomplete. In addition, we are unable to claim with certainty that the AEs were caused by the long-acting inhaled bronchodilators because there was no formal control group. Accordingly, some of the AEs could be related to other factors, including co-administered medications, reduced renal function, and comorbidities. Moreover, the AEs were assessed according to the classes of respiratory drugs but the impact of the device (inhaler vs metered-dose inhaler) was not evaluated. Several strengths of this study warrant mention, including the enrollment of patients whose diagnosis of COPD was confirmed by a pulmonologist, the evaluation of AEs in a real-life setting without excluding patients based on age and comorbidities, and a participation rate of 63.6%. To the best of our knowledge, this study was one of the first to evaluate the incidence of common AEs in a real-life setting of COPD patients using inhaled long-acting bronchodilators.
      Finally, our results clearly demonstrate that COPD patients experience AEs on a daily basis. Whether or not they are related to their respiratory drugs, these AEs can significantly influence COPD management in daily practice.

      6. Conclusion

      In conclusion, this study showed that in every day clinical practice, AEs are frequent in COPD patients treated with inhaled long-acting bronchodilators. Improving understanding of the tolerability profile of LAACs/LABAs in COPD may help clinical management due to AEs affecting quality of life and treatment adherence. Clinicians should consider carefully monitoring the presence of common AEs associated with long-acting bronchodilators, by asking specific questions to the patients. If necessary, they may consider using alternative treatments in patients with AEs. Further studies should evaluate patients' and physician's perception on the burden of common AEs, what leads patients to communicate their concerns, and how AEs influence selection of COPD treatments.

      Funding

      This study was funded by 1) AstraZeneca . This article was reviewed by AstraZeneca but the authors retained full editorial control over the content of the manuscript. RESP is funded by the 2)  Réseau québécois de recherche sur les médicaments (RQRM) / 3)  Fonds de recherche santé Québec (FRQ-S) , the 4) Canadian Institutes for Health Research (CIHR) , the 5) Fondation de l'Hôpital du Sacré-Coeur de Montréal , 6) Merck Frosst Canada Inc , and 7)  Novartis Canada Ltd . Study sponsors had no role in the design of the database and data collection.

      Authors contribution

      Contributors: LB, CR and MFB designed the study and wrote the manuscript. LB and MFB acquired the funding. LB, CR, MFB, AF and FS contributed to data analyses. CR, MFB, AF, FS, PL, CL and LB interpreted the data, revised the manuscript, had access to complete study data, and had authority over manuscript preparation as well as approval of the final version and the decision to submit for publication.

      Disclosure of interest

      CR received a scholarship from the Fonds de recherche du Québec en santé (FRQ-S). LB received funding from AstraZeneca, GlaxoSmithKline, and Novartis for research projects on asthma and COPD. MFB received funding from AstraZeneca, Boehringer Ingelheim and Novartis for research projects and CE programs on asthma and COPD. LB and MFB co-chair the AstraZeneca pharmaceutical Chair in Respiratory Health. PL is an occasional speaker (CME) for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck and Novartis. AF and FS has no conflict of interest. CL is part of the Clinical assembly on asthma of the Canadian Thoracic Society. She have received grant money from AllerGen NCE and the Institut de recherche en santé et sécurité au travail Robert Sauvé in the last 3 years. She has participated to industry-funded research projects with several pharmaceutical companies: AstraZeneca, GlaxoSmithKline, Cephalon, Janssen, Sanofi and Novartis. De Lemiere have received money from Aerocrine Inc for an investigator initiated project. She has also participated to advisory committees for several pharmaceutical companies: AstraZeneca, Merck, GlaxoSmithKline, in the last 3 years.

      Acknowledgments

      We thank Jocelyne L'Archevêque for retrieving data from the patients' medical records. We also thank Julia Sokunthea Yourk and Thalie Labonté for entering data into the RESP database.

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