Abstract
Introduction
Chronic obstructive pulmonary disease (COPD) is a progressive disease with symptoms that can have a major impact on patients’ physical health. The aim of this study was to evaluate quality of life (QoL), symptom severity and dyspnoea in COPD patients treated with aclidinium up to 24 weeks.
Methods
In this prospective non-interventional multicentre study (198 centres in Sweden, Denmark, and Norway), COPD patients (age ≥40 years) who started treatment with aclidinium (initial therapy, change of treatment, or add-on therapy) could be included. Health-related QoL was obtained by COPD assessment test (CAT). Symptoms were evaluated on a 6-point Likert scale. The modified Medical Research Council (mMRC) Dyspnoea Scale was used as a simple grading system to assess the level of dyspnoea/shortness of breath from0 to 4. Patients on treatment with aclidinium who completed baseline and at least one follow-up visit (week 12 or 24) were included in the study population.
Results
Overall, 1,093 patients were enrolled (mean 69 years, 54% females), one-third had ≥1 exacerbation the year prior to baseline. At enrolment, 48% were LAMA naïve. Mean (standard deviation, SD) CAT score decreased from 16.9 (7.7) at baseline to 14.3 (7.3) at week 24 (p<0.01) with a decrease in all individual CAT items (p<0.05). Mean difference in morning and night-time symptoms from baseline to week 24 was −0.60 (SD 2.51) and −0.44 (SD 2.48), respectively (both p<0.001). Mean (SD) mMRC Dyspnoea Scale changed from 1.6 (1.0) at baseline to 1.5 (1.0) at week 24 (p<0.001).
Conclusion
In this observational study of a Nordic real-life COPD population, treatment with aclidinium was associated with a clinically important improvement in QoL and morning and night-time symptoms, most pronounced in the LAMA naïve group. However, there is still room for improvement in the management of symptomatic COPD patients.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide (Citation1). As the condition progresses, the burden and severity of symptoms increase, leading to physical health limitations and reduced independence in activities of daily living. Current treatment strategies aim to improve symptom control and to reduce the risk of future exacerbations (Citation1). It is recognized that the quality of an effective COPD management should be assessed by parameters such as forced expiratory volume in 1 sec (FEV1), and patient-related outcomes such as daily activities, burden of symptoms and health-related quality of life (QoL). The patient-reported questionnaire, COPD assessment test (CAT) (Citation2), has been included in the current COPD treatment guidelines in addition to the disease classification by spirometry (Citation1).
COPD symptoms such as dyspnoea are generally worse in the morning than during the rest of the day, affecting morning routine activities and basic self-care tasks (Citation3). Patients with COPD also commonly experience night-time symptoms that have an impact on their ability to get up in the morning (Citation4). Also, it has been shown that morning symptoms may affect patients’ ability to perform daily life activities throughout the day (Citation5).
Pharmacotherapy for COPD relies primarily on inhaled medications. In a retrospective real-life study of COPD patients in Sweden, it was shown that the introduction of a long-acting inhaled anticholinergic agent (LAMA) and fixed inhaled corticosteroids (ICS)/long-acting β2 agonist (LABA) combinations in COPD treatment coincides with a decreased number of COPD exacerbations over a 10-year period (Citation6). For symptomatic patients with low risk of exacerbations, guidelines recommend LAMA or LABA as first-line maintenance treatment (Citation1). In addition to current available LAMAs, aclidinium in the Genuair inhaler is a new LAMA and the only LAMA that is administered twice daily. In clinical studies, it has demonstrated an effective bronchodilation, not only during the day but also at night, resulting in a significant improvement of symptoms and QoL (Citation7–Citation9).
There are limited data available about the effect of aclidinium in a real-life COPD population. The aim of this study was to evaluate QoL, symptom severity (including morning and night-time symptoms), and dyspnoea in COPD patients treated with aclidinium for up to 24 weeks.
Materials and methods
Study design and data source
This was a prospective non-interventional multicentre study conducted at 198 primary care and specialist outpatient centres in Sweden, Denmark, and Norway. At baseline (visit 1), sociodemographic data (sex, age, height, and weight) and medical data (smoking status, exacerbations, spirometry including reversibility test, co-morbidities, and concomitant medication) were collected. Data were registered in an electronic data capture system and stored in a secure database managed by the Department of Applied Mathematics and Computer Science, Technical University of Denmark (DTU, Copenhagen, Denmark). Patients were asked to complete a health-related QoL questionnaire at baseline and at the 12 (visit 2) and 24 weeks (visit 3) follow-up visits.
The study was approved by the regional ethics committee in Lund, Sweden (ref. no. 2013/499), the regional committees for medical and health research ethics in Oslo, Norway (ref. no. REK sør-øst 2013/1261), and permission to compile data was granted by Danish data protection agency in Copenhagen, Denmark (ref. no. 2013-41-2236). All patients gave written informed consent to the documentation and processing of their data.
Study population and treatment
Male and female patients (age ≥40 years) with COPD, who started treatment with aclidinium administered according to specifications in the summary of product characteristics (322 µg aclidinium twice daily), either as initial therapy, change of treatment or as add-on therapy could be included in the study. The decision to initiate aclidinium treatment had to be made prior to the decision to include the patient into the study. The COPD diagnosis was established according to clinical practice and a spirometry, not older than 3 months at inclusion. Patients with pulmonary disease other than COPD, acute COPD exacerbation within 1 month prior to inclusion, and women who were pregnant or breast-feeding were not eligible for inclusion. The patient enrolment was conducted from November 2013 to December 2014.
Measurements and outcomes
Assessments
Health-related QoL was obtained from self-administered patient questionnaires by using the Swedish, Danish, and Norwegian versions of the CAT (Citation2, Citation10). The CAT comprises eight items each with a scoring range of 0–5. The CAT total score is derived as the sum of responses given in the eight items with a range of 0–40. A minimum clinically important improvement in CAT has been identified to be −2.0 (Citation11).
COPD symptoms were assessed from patient questionnaires according to five indicators: coughing during morning, coughing during night-time, breathlessness during morning, breathlessness during night-time, and quality of sleep. The severity of these symptoms was evaluated on a 6-point Likert scales rated from 0=‘no symptoms’ to 5=‘very severe symptoms’ and from 0=‘very bad sleep’ to 5=‘very good sleep’ (Citation12) .
The modified Medical Research Council (mMRC) Dyspnoea Scale was used as a simple grading system to assess the level of dyspnoea/shortness of breath in five categories from 0 to 4 (Citation1).
At each study visit, patients reported the presence of any adverse events between visits. If judged causal to aclidinium by the investigator, the event was reported as an adverse drug reaction (ADR).
Other measurements
Classification of patients according to GOLD A–D criteria was based on the GOLD spirometry classifications of the severity of airflow limitation, exacerbation history in the past year, and the patient's symptoms, using CAT (Citation1).
Smoking status was defined as current smoker, ex-smoker, or never smoker.
The BMI was defined as the body weight in kilograms divided by the square of height in meters.
BMI categories: underweight ≤18.5; normal weight=18.5–24.9; overweight=25–29.9; obesity=BMI of 30 or greater.
Lung function was defined as the percentage of FEV1 predicted value and should be no older than 3 months prior to visit 1.
Co-morbidity was defined according to the following selected chronic diseases: current treatment of depression, diabetes, heart failure, ischemic heart disease, hypertension, osteoporosis, gastro-oesophageal reflux, and disease of the musculoskeletal system (or other diseases inhibiting walking).
Concomitant medications to be taken together with aclidinium were categorized as follows: short-acting β2-agonist (SABA), LABA, ICS, oral corticosteroids (OCS), phosphodiesterase (PDE) 4 inhibitor, fixed ICS/LABA combination, fixed SABA/short-acting muscarinic antagonist (SAMA), other concomitant medication, or no concomitant medication.
A combined variable regarding prior medication was constructed based on information about treatment with LAMA prior to inclusion (yes/no) and concomitant maintenance medication to be taken together with aclidinium (LABA, ICS, PDE4, and/or fixed ICS/LABA combination). The patients were categorized into the following four subgroups: LAMA naïve without other maintenance therapies, LAMA naïve with other maintenance therapies, LAMA non-naïve without other maintenance therapies, and LAMA non-naïve with other maintenance therapies. Maintenance treatment included ICS, LABA, and LAMA.
Patient-reported satisfaction with the inhaler and handling of the Genuair device was collected.
Statistical analysis
The study population was defined as all patients who completed the baseline visit and at least one follow-up visit (week 12 or 24) and continued on treatment with aclidinium during the defined study period. Continuous and nominal variables were described using standard statistical measures, that is, number of observations, mean, and standard deviation. All categorical variables were summarized with absolute and relative frequencies.
Baseline characteristics were compared over the four prior medication groups using one-way ANOVA tests for continuous variables and chi-squared test for categorical variables (and in cases where the expected numbers were below five, Fisher's exact test). The paired t-test was used to compare the total CAT score and symptoms from baseline to week 12 or baseline to week 24 to take into account that the same group of patients were followed through the three visits. Similarly, for categorical variables McNemar's chi-squared test was used to compare baseline to week 12 or 24.
An ANCOVA model was fitted to estimate the expected changes in total CAT score for the four prior medication groups from baseline to week 12 or 24 while taking baseline CAT score into account. Finally, a multivariate logistic regression model was used to estimate the odds of reaching a clinically important difference of at least two units on total CAT score from baseline to week 12. This model included the covariates: baseline CAT score, age, sex, current smoker (yes/no), BMI group (underweight, normal, overweight/obese), FEV1 ≥50% of the predicted value (yes/no), heart failure or ischemic disease (yes/no), and prior medication.
Results
Patient flow
A total of 1,093 patients were enrolled across the 198 study sites in Sweden, Denmark, and Norway. Follow-up visits were completed for 78% (n=857) of the enrolled patients at week 12 and 69% (n=753) at week 24 (). Overall, 80% (n=874) completed the baseline visit and at least one follow-up visit, and thus comprised the study population.
Fig. 1 Patient flowchart.
Baseline characteristics
Mean age was 69 years and 54% were females (). The majority had a history of smoking (96% current or ex-smokers) and more than half of the patients (56%) were overweight or obese. Baseline lung function measured within 3 months prior to study enrolment showed a mean FEV1 percentage of predicted normal of 55%. One-third of the patients had experienced one or more exacerbations during the year prior to baseline. The majority of the patients were classified as either GOLD B (42%) or GOLD D (42%). The leading co-morbidity was hypertension (37%) followed by ischemic disease (12%) and diabetes mellitus (11%) (). No differences were seen regarding baseline patient characteristics between the patients included in the study population and the patients who were lost to follow-up (results not shown).
Table 1 Demographic and clinical characteristics at baseline visit among participants who completed baseline and at least one follow-up visit (study population and subgroups based on prior medication)
During enrolment, 52% (n=457) of the patients were switched from another LAMA medication and 48% (n=417) were new initiated to aclidinium. The proportion of patients in each of the four subgroups based on prior medication was 20% LAMA naïve with maintenance, 28% LAMA naïve without maintenance, 39% LAMA non-naïve with maintenance, and 13% LAMA non-naïve without maintenance (). Compared to participants without maintenance medication, those on maintenance medication had a lower FEV1 in % of predicted value and more of them belonged to GOLD D group (). Two-thirds of the patients used aclidinium as add-on therapy; the most frequent maintenance medication was fixed ICS/LABA combinations (32%), followed by LABA (10%). In addition, 27% of the patients used SABA.
Health-related QoL (CAT)
The mean (SD) CAT total score changed significantly from 16.9 (7.7) at baseline to 14.6 (7.3) points at week 12, and to 14.3 (7.3) at week 24 (p<0.01 for both). shows the changes in the total score and in the individual CAT item scores. All individual CAT item scores decreased significantly from baseline (p<0.05; ) with the largest mean improvement in the item ‘breathless when walking up a hill or one flight of stairs’.
Fig. 2 Change in individual CAT item scores and total CAT score from baseline to week 12 (light grey bars) and from baseline to week 24 (dark grey bars). Sample size: N=774 (week 12) and N = 679 (week 24). ‡p<0.01 for baseline versus follow-up (weeks 12 and 24); †p<0.05 for baseline versus follow-up (weeks 12 and 24).
A clinically relevant improvement in the total CAT score (minimal clinically important difference by at least two points) was observed in 55% for the patients with complete CAT data available. The estimated improvement in total CAT score was highest in the LAMA naïve patients without maintenance treatment; while controlling for baseline CAT score, the mean change at week 12 was −3.5 (95% confidence interval [CI] −4.2 to −2.9) and at week 24 −3.8 (95% CI −4.6 to −3.1) (). Looking at the pairwise comparisons between the four groups at week 12, the improvement in the LAMA naïve without maintenance treatment was significantly higher than in the two LAMA non-naïve groups (with maintenance p<0.01, without maintenance p=0.04 [data not shown]).
Table 2 Estimated change in CAT total score from baseline to week 12 and from baseline to week 24 adjusting for baseline CAT score with test for effect of prior medication
Predictors of improvement in CAT total score
The results from the multivariate logistic regression () shows that prior medication was the strongest predictor of reaching a clinically relevant improvement of at least two units on the total CAT score from baseline to week 12 (p<0.01). Compared to the LAMA non-naïve with maintenance, the LAMA naïve groups have significantly higher odds of improving when adjusting for baseline CAT score, sex, age, smoking status, BMI group, FEV1, and cardio vascular disease (odds ratio [OR] 1.9 (95% CI 1.3–2.9) for naïve with maintenance and OR 1.8 [95% CI 1.3–2.7] without maintenance). Also, higher baseline CAT score and FEV1>50% of predicted value were significant predictors of clinically relevant improvement in CAT.
Table 3 Predictors of improvement in CAT total score (at least two points) from baseline to week 12 (multivariate logistic regression)
Severity of morning and night-time symptoms
The proportion of patients with no morning symptoms changed from 35% at baseline to 45% at week 12, and to 42% at week 24 (). Moderate-to-very severe morning symptoms were reported by 40% of the patients at baseline and by 31% after 24 weeks of follow-up (). The proportion of patients with no night-time symptoms was 48% at baseline, 57% at week 12, and 54% at week 24 (). Moderate-to-very severe night-time symptoms were observed for 31% of the patients at baseline and for 23% after 24-week follow-up ().
Fig. 3 Prevalence of morning and night-time COPD symptoms (any) at baseline, week 12, and week 24.
There was a statistically significant improvement in morning and night-time symptoms (any symptom, cough, breathlessness, or/and sleep quality) (p<0.001; ). The largest improvement was found for ‘morning symptoms (any)’: week 12: mean difference of −0.68 (SD 2.34) and week 24 mean difference of −0.60 (SD 2.51). Further, a statistically significant improvement in all subgroups except LAMA non-naïve patients without maintenance was observed for morning and night-time symptoms ().
Fig. 4 Change in severity of morning and night-time symptoms (any symptom, cough, breathlessness, sleep quality) from baseline to week 12 (light grey bars) and from baseline to week 24 (dark grey bars). Sample size: N=797. ‡p<0.001 for baseline versus follow-up (weeks 12 and 24).
Table 4 Subgroup analysis of change in morning symptoms, night-time symptoms, and mMRC Dyspnoea Scale from baseline versus week 12 and baseline versus week 24 according to prior medication
Breathlessness (the mMRC Dyspnoea Scale)
The mean (SD) mMRC Dyspnoea Scale changed significantly (p<0.001) from 1.6 (1.0) at baseline to 1.5 (1.0) at weeks 12 and 24 (). The proportion of patients with an mMRC grade ≥2 changed from 52% at baseline to 45% at week 12 and 42% at week 24 ().
Table 5 Proportion of patients (%) at each mMRC dyspnoea grade from 0 to 4 at baseline (N=797), week 12 (N=774), and week 24 (N=679)
Adverse drug reactions
During this 6-month study, 46 patients (4%) reported in total 102 ADRs, whereof 29 were reported as serious adverse events. Overall, 33 patients discontinued study drug due to ADR. The most commonly reported ADR was dysphonia (0.9%), unpleasant product taste (0.7%), headache (0.7%), dyspnoea (0.5%), and nausea (0.5%). All other ADRs reported had an incidence of <0.5%. One serious adverse event was fatal (cardiac arrest), however, without reported drug causality.
Patient handling and satisfaction of the Genuair device
Overall, 95% of the patients found the Genuair device easy or very easy to use and 68% of the patients were satisfied or very satisfied with the device.
Discussion
In this real-life COPD population recruited from general practice and outpatient specialist care, including both LAMA-naïve patients and LAMA switchers, both with and without concurrent COPD maintenance medications, treatment with aclidinium during 24 weeks was associated with a significant improvement in both QoL and in early morning and night-time COPD symptoms. The most pronounced improvement was observed after 12 weeks, whereas the difference between weeks 12 and 24 was smaller. This indicates an effect within 12 weeks, with the greatest improvement seen in the LAMA-naïve patients. However, approximately one out of four patients still experienced moderate-to-very severe morning and night-time symptoms at follow-up, indicating suboptimal symptom control.
Overall, the addition of a LAMA to ICS and/or LABA treatment was associated with a beneficial effect, but the most important predictor of improvement in CAT score was being LAMA naïve.
The beneficial effect of adding a LAMA to ICS/LABA treatment has previously been reported in randomized clinical trials (Citation13, Citation14). In the present study, almost half of the patients were LAMA naïve at baseline, fewer than in previous studies (Citation8, Citation15). In the recently published Austrian real-life study with a similar design (n=795, 12-week follow-up, mean age 64 years, 44% female), three out of four patients were LAMA naïve at baseline (Citation16). The improvements in CAT, mMRC Dyspnoea Scale, and symptoms observed in that study were greater than what was seen in the present study, which may be explained by the slightly younger study population and the fact that the majority of the patients in that study were LAMA naïve.
The literature suggests that COPD symptoms are worst during morning, with four out of five COPD patients experiencing shortness of breath in the morning (Citation17). Night-time symptoms are also prevalent and have been associated with worsening of COPD severity (Citation18), risk of future exacerbations (Citation19), poor QoL (Citation20, Citation21), increased anxiety and depression (Citation22), and mortality (Citation23, Citation24). Furthermore, it has been shown that patients commonly take their medication too late in the morning to have an effect on morning symptoms (Citation17). The LAMAs available for the treatment of COPD have a once-daily regimen, except for aclidinium which is administered twice daily. Patient preference regarding dosing regimens varies, as shown in a recent study on asthma and COPD patients where only half of the patients actually preferred the once-daily regimen (Citation25). In addition, significant improvements in night-time symptom severity were shown for aclidinium but not for tiotropium compared to placebo (Citation8). Also, a mean FEV1 below baseline was reported for tiotropium during a prolonged period of the night compared to aclidinium (Citation8). For the LAMA-naïve patients in the present study, a positive effect on health status would likely be observed by adding any LAMA. For patients switched from another LAMA to aclidinium, the positive effect on symptoms may be explained by the twice daily dosing of aclidinium, potentially increased by a placebo effect due to study participation.
The main limitation of the present study is the observational design with the absence of a control group. The association found may have been affected by other factors impacting patient-reported outcomes, such as participation in a study. No information regarding the reason for the patients’ visit to the physician during which aclidinium was initiated was collected (scheduled follow-up visit or a visit due to disease deterioration) and patient adherence to treatment was not monitored. Furthermore, two-thirds of the patients used aclidinium as add-on therapy and it cannot be ignored that the use of concomitant maintenance medications for COPD may have influenced the results. Bias due to the unknown disease severity of the patients lost to follow-up cannot be excluded; however, a comparison of patient characteristics between the study population and the lost to follow-up population showed similar groups at baseline. Approximately, 5% of the recruited patients were excluded from the study before the week 24 visit due to lack of medication effect, and as these patients are not included in the study population, our results are slightly skewed towards favouring the effect of aclidinium.
However, as most pivotal pharmacological trials exclude patients suffering from significant co-morbidities, the real-life character of the present study expands currently available knowledge, which is derived almost exclusively from controlled randomized trials, performed in highly selected patients by narrow inclusion criteria, resulting in low external validity.
The safety data obtained in this study are consistent with the safety and tolerability data reported in other studies (Citation7, Citation8) (Citation16).
Conclusion
In this observational study of a Nordic real-life COPD population recruited from general practice and outpatient specialist care, we found that that treatment with aclidinium was associated with a significant and clinically important improvement in QoL and in morning and night-time symptoms after 12 weeks, primarily in LAMA-naïve patients but also in non-naïve patients. However, as a proportion of patients still experienced moderate-to-very severe morning and night-time symptoms at study end, there is still room for improvement in the everyday management of symptomatic patients with COPD.
Conflict of interest and funding
Peter Lange has received teaching and consulting fees from AstraZeneca, Almirall, Oehringer Ingelheim, Novartis, Norpharma, Takeda, Glaxo Smith Kline, Pfizer and TEVA. Bo-Anders Paradis have received consulting fees from Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Medtronic, MSD, Mundipharma, Novartis, Novo Nordisk, Sandoz, Sanofi (Aventis) and Takeda. Gunilla Telg and Helene Nordahl Christensen are both fulltime employees of AstraZeneca. Leif Bjermer, Nina Skavlan Godtfredsen, Sjur Humerfelt, Dan Curiac, Beata Olejnicka, Magnus Alexander Bitch, Elisabeth Wreford Andersen has no conflicts of interest in relation to this publication. This study was supported by AstraZeneca.
Acknowledgements
The authors thank the physicians and nurses from all centres who participated in this study.
References
- Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of COPD. 2014. Available from: www.goldcopd.org [cited 26 January 2016].
- Jones PW, Harding G, Berry P, Wiklund I, Chen W-H, Kline Leidy N. Development and first validation of the COPD assessment test. Eur Respir J. 2009; 34: 648–54.
- Kessler R, Partridge MR, Miravitlles M, Cazzola M, Vogelmeier C, Leynaud D, etal. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J. 2011; 37: 264–72. doi: http://dx.doi.org/10.1183/09031936.00051110 [PubMed Abstract].
- Price D, Small M, Milligan G, Higgins V, Gil EG, Estruch J. Impact of night-time symptoms in COPD: a real-world study in five European countries. Int J Chron Obstruct Pulmon Dis. 2013; 8: 595–603. doi: http://dx.doi.org/10.2147/COPD.S48570 [PubMed Abstract] [PubMed CentralFull Text].
- O'Hagan P, Chavannes NH. The impact of morning symptoms on daily activities in chronic obstructive pulmonary disease. Curr Med Res Opin. 2014; 30: 301–14. doi: http://dx.doi.org/10.1185/03007995.2013.857648 [PubMed Abstract].
- Stallberg B, Janson C, Johansson G, Larsson K, Stratelis G, Telg G, etal. Management, morbidity and mortality of COPD during an 11-year period: an observational retrospective epidemiological register study in Sweden (PATHOS). Prim Care Respir J. 2014; 23: 38–45.
- Kerwin EM, D'Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF. Efficacy and safety of a 12-week treatment with twice-daily aclidinium in COPD patients (ACCORD COPD I). COPD. 2012; 9: 90e101. doi: http://dx.doi.org/10.3109/15412555.2012.661492.
- Beier J, Kirsten AM, Mróz R, Segarra R, Chuecos F, Caracta C, etal. Efficacy and safety of aclidinium compared with placebo and tiotropium in patients with moderate-to severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled phase IIIb study. COPD. 2013; 10: 511–22. doi: http://dx.doi.org/10.3109/15412555.2013.814626 [PubMed Abstract] [PubMed CentralFull Text].
- Fuhr R, Magnussen H, Sarem K, Llovera AR, Kirsten AM, Falqués M, etal. Efficacy of aclidinium 400 mg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012; 141: 745–52. doi: http://dx.doi.org/10.1378/chest.11-0406 [PubMed Abstract].
- Jones PW, Tabberer M, Chen W. Creating scenarios of the impact of COPD and their relationship to COPD assessment test (CAT™) scores. BMC Pulm Med. 2011; 11: 42.
- Kon SSC, Canavan JL, Jones SE, Nolan CM, Clark AL, Dickson MJ, etal. Minimum clinically important difference for the COPD assessment test: a prospective analysis. Lancet Respir Med. 2014; 2: 195–203.
- Likert R. A technique for the measurement of attitudes. Arch Psychol. 1932; 140: 1–55.
- Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, etal. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009; 180: 741–50. doi: http://dx.doi.org/10.1164/rccm.200904-0492OC on August 13, 2009 [PubMed Abstract].
- Lee SD, Xie CM, Yunus F, Itoh Y, Ling X, Yu WC, etal. Efficacy and tolerability of budesonide/formoterol added to tiotropium compared with tiotropium alone in patients with severe or very severe COPD: a randomized, multicentre study in East Asia. Respirology. 2015; 21: 119–27. doi: http://dx.doi.org/10.1111/resp.12646 [PubMed Abstract].
- Gelb AF, Tashkin DP, Make BJ, Zhong X, Garcia Gil E, Caracta C, etal. Long-term safety and efficacy of twice-daily aclidinium in patients with COPD. Respir Med. 2013; 107: 1957–65. doi: http://dx.doi.org/10.1016/j.rmed.2013.07.001 [PubMed Abstract].
- Marth K, Schuller E, Pohl W. Improvements in patient-reported outcomes: a prospective, non-interventional study with aclidinium for treatment of COPD. Respir Med. 2015; 109: 616–24.
- Partridge MR, Karlsson N, Small IR. Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin. 2009; 25: 2043–8.
- Roche N, Small M, Broomfield S, Higgins V, Pollard R. Real world COPD: association of morning symptoms with clinical and patient reported outcomes. COPD. 2013; 10: 679e86. doi: http://dx.doi.org/10.3109/15412555.2013.844784.
- Lange P, Marott JL, Vestbo J, Nordestgaard BG. Prevalence of night-time dyspnoea in COPD and its implications for prognosis. Eur Respir J. 2014; 43: 1590–8.
- Cai Q, Sullivan SD, Stephenson JJ, Tan H, Kavati A, Mocarski M, etal. Health-related quality of life and work productivity of employed COPD patients with nighttime and early morning symptoms. Am J Respir Crit Care Med. 2013; 187: A2939.
- Stephenson JJ, Cai Q, Mocarski M, Tan H, Doshi JA, Sullivan SD. Impact and factors associated with nighttime and early morning symptoms among patients with chronic obstructive pulmonary disease. Int J Chorn Obstruct Pulmon Dis. 2015; 10: 577–86.
- Miravitlles M, Worth H, Soler Cataluña JJ, Price D, De Benedetto F, Roche N, etal. Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study. Respir Res. 2014; 15: 122.
- Omachi TA, Blanc PD, Claman DM, Chen H, Yelin EH, Julian L, etal. Disturbed sleep among COPD patients is longitudinally associated with mortality and adverse COPD outcomes. Sleep Med. 2012; 13: 476e83. doi: http://dx.doi.org/10.1016/j.sleep.2011.12.007.
- Agusti A, Hedner J, Marin JM, Barbe F, Cazzola M, Rennard S. Night-time symptoms: a forgotten dimension of COPD. Eur Respir Rev. 2011; 20: 183–94. doi: http://dx.doi.org/10.1183/09059180.00004311 [PubMed Abstract].
- Price D, Lee AJ, Sims EJ, Kemp L, Hillyer EV, Chisholm A, etal. Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study. Prim Care Respir J. 2013; 22: 161–8.