COPD: early diagnosis and treatment to slow disease progression

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1 REVIEW ARTICLE COPD: early diagnosis and treatment to slow disease progression T. Welte, 1 C. Vogelmeier, 2 A. Papi 3 1 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany 2 Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany 3 Research Center on Asthma and COPD, University of Ferrara, Ferrara, Italy Correspondence to: Tobias Welte, Klinik f ur Pneumologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 3659 Hannover, Germany Tel.: Fax: welte.tobias@ mh-hannover.de Disclosures Alberto Papi received research grants, served on scientific advisory boards, and/or gave presentations at sponsored symposia funded by Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Dompe, GlaxoSmithKline, Guidotti, Menarini, MSD, Mundipharma, Novartis, Pfizer, Takeda, TEVA and Zambon. Claus Vogelmeier gave presentations at symposia and/or served on scientific advisory boards sponsored by Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Janssen, Mundipharma, Novartis and Takeda. Tobias Welte is member of the advisory boards of Boehringer Ingelheim, MSD, Novartis and Pfizer. He has received fees for providing lectures from Almirall, Boehringer Ingelheim, GlaxoSmithKline, MSD, Novartis and Pfizer. SUMMARY Aims: Chronic obstructive pulmonary disease (COPD) is usually a progressive condition. Undiagnosed early-stage disease, particularly in symptomatic patients, is likely to become more severe with time. Hence, prevention or reduction in disease progression is highly relevant. We evaluated the published data and discussed the potential impact of early intervention on the course of COPD. Methods: We performed PubMed searches of studies in early or mild COPD, focusing on those relating to lung function decline. Results: Smoking cessation reduced lung function decline at all stages of COPD, and the earlier the intervention, the greater the impact on lung function. Accumulating data from placebo-controlled trials suggested that long-acting bronchodilators can slow the decline in lung function, as well as reduce exacerbation and mortality rates and improve health-related quality of life (HRQoL) in patients with mild-to-moderate COPD. Inhaled corticosteroids (ICS) do not impact lung function in early COPD, and further research is needed on the role of long-acting b 2 -agonist-ics combination therapy in these patients. Conclusions: Initiating treatment early in the course of COPD is likely to slow disease progression and improve HRQoL. Current data support maintenance treatment with a long-acting bronchodilator in this patient group. However, many questions remain unanswered regarding the optimal treatment of mild COPD, and further research is required to develop evidence-based recommendations in this field. Introduction Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised by persistent and progressive airflow limitation. Worldwide, COPD is one of the leading causes of morbidity and mortality (1). Global prevalence rates are variable, most likely because of methodological differences between studies. The prevalence of spirometry-defined COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage 2] in adults was estimated as 1% in the international Burden of Obstructive Lung Diseases (BOLD) survey (2). The Global Burden of Disease Study predicts that COPD will become the third leading cause of death worldwide in 22 (1); an alternative analysis by the World Health Organization predicts this will occur slightly later in 23 (3). In addition, the disease has a significant economic burden, with direct healthcare costs due primarily to exacerbation-related Review criteria We conducted a PubMed search with the following search terms: chronic obstructive pulmonary disease OR COPD AND early, earlier, mild, moderate, Stage, Stage 1, Stage 2 OR Stage I, Stage II AND progression, lung function decline (632 items found). The search was restricted to sources published in English (552 items), and no date limits were applied. The search was last performed on 31 March 214. The titles and abstracts were screened and full texts of relevant articles were obtained. Cited evidence was selected from peer-reviewed journals, with a focus on recent randomised controlled trials of pharmacotherapy. Message for the clinic Even patients with mild chronic obstructive pulmonary disease (COPD) show signs of impaired health-related quality of life and physical activity levels, reduced exercise tolerance and increased healthcare resource utilisation. Early intervention in COPD with smoking cessation and maintenance pharmacological therapy can slow down lung function decline, reduce the risk of exacerbations and improve quality of life. hospitalisations (4), and indirect costs because of loss of productivity (1). Unfortunately, despite the rising prevalence and significant burden of this disease, COPD remains under-diagnosed and undertreated, even though it is now considered to be treatable (1,5). In the majority of patients, COPD is a progressive condition, with deteriorating lung function over time in addition to the natural decline in pulmonary function that occurs with increasing age (6). Undiagnosed earlystage COPD, particularly in symptomatic patients, is therefore likely to progress to more severe stages of the disease, with an increased impact on healthrelated quality of life (HRQoL), healthcare costs (5,7) and greater healthcare resource utilisation (8). However, not all patients progress at the same rate, and it is currently not clear which patient subgroups are best suited for early intervention approaches. In this review, we discuss the burden of disease in patients with mild or early-stage COPD and explore 336. doi: /ijcp.12522

2 COPD: early diagnosis and treatment 337 the evidence for early intervention in this patient group. Methods For this review, we conducted a PubMed search with the following search terms: chronic obstructive pulmonary disease OR COPD AND early, earlier, mild, moderate, Stage, Stage 1, Stage 2 OR Stage I, Stage II AND progression, lung function decline. The search was restricted to sources published in English, and no date limits were applied. We identified the most relevant evidence available from the results to describe the burden of early COPD. To ensure that the current article had the broadest relevance to an international audience, the GOLD strategy was used to describe diagnostic and treatment recommendations. We selected studies on treatment effects based on study design (focus on randomised controlled trials) and date of publication (focus on research published within the past 15 years, to best reflect current clinical practice). Defining early COPD Although a clinical diagnosis of COPD can be considered based on the presence of symptoms and on medical history, spirometry is required to confirm the diagnosis (1), because it is the best established method for identifying the airflow obstruction characteristic of COPD. The spirometric definition of COPD is the presence of a postbronchodilator forced expiratory volume in 1 s (FEV 1 )/forced vital capacity ratio <.7. Until recently, the GOLD strategy classified COPD based on the severity of airflow limitation determined by FEV 1 as Stage 1 (mild; FEV 1 8% predicted), Stage 2 (moderate; FEV 1 5% and < 8% predicted), Stage 3 (severe; FEV 1 3% and < 5% predicted) and Stage 4 (very severe; FEV 1 < 3% or < 5% predicted with chronic respiratory failure) (9). A recent comprehensive revision of the GOLD strategy, first released in 211, recommends a classification based on a combination of symptoms and the risk of exacerbation (the latter based on the degree of airflow limitation or history of exacerbations; Figure 1) (1). Risk GOLD classification of airflow limitation (C) Less symptoms, high risk (A) Less symptoms, low risk (D) More symptoms, high risk (B) More symptoms, low risk 2 or 1 leading to hospital admission 1 (not leading to hospital admission) Exacerbation history Risk CAT < 1 CAT 1 Symptoms mmrc 1 mmrc 2 Breathlessness In patients with FEV 1 /FVC <.7: GOLD 1 GOLD 2 GOLD 3 GOLD 4 Mild airflow limitation (FEV 1 8% predicted) Moderate airflow limitation (5% FEV 1 < 8% predicted) Severe airflow limitation (3% FEV 1 < 5% predicted) Very severe airflow limitation (FEV 1 < 3% predicted) Figure 1 Symptom/risk evaluation of COPD. The highest risk according to exacerbation history ( 1 hospitalisation for COPD exacerbations is high risk) or GOLD Grade is used to assess risk level (1). Adapted from (9), GOLD, all rights reserved. CAT, COPD Assessment Test; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mmrc, modified Medical Research Council score

3 338 COPD: early diagnosis and treatment For this review, mild COPD/mild disease refers to COPD with mild airflow limitation (FEV 1 8% predicted) and moderate COPD/moderate disease refers to COPD with moderate airflow limitation (FEV 1 5% and < 8% predicted). In addition, in one section of this review, we use early disease to refer to patients with mild and moderate airflow limitation, as well as those at initial presentation of symptoms or diagnosis with previously untreated COPD. We are aware that the characterisation of the latter group is rather loose, and we acknowledge the possible heterogeneity of the clinical conditions (in terms of COPD pathophysiology and evolution) included under this latter label. The burden of early COPD In a study that used spirometry to screen current or ex-smokers in a primary care population, who were 4 years of age or older and had no prior history of diagnosis or treatment of airway disease, the prevalence of COPD was 19%, including 57% of subjects with mild disease and 37% with moderate COPD (11). Similarly, a Spanish study that utilised spirometry and questionnaires to screen subjects in the general population aged 4 8 years showed that nearly 95% of patients with undiagnosed COPD had mild or moderate disease (56% and 38%, respectively) (1,12). Patients with symptoms of COPD often do not seek medical help until the symptoms interfere with their daily life (1,13). Since many COPD patients are smokers or ex-smokers, they often accept that their symptoms are caused by smoking, and ignore or dismiss them as self-inflicted or a consequence of smoking, rather than seeking treatment (14). A study in the UK found that only 19% of patients who met the GOLD spirometric criteria for COPD reported having been diagnosed with a respiratory disease of any kind (15). Patients with early COPD are not a homogenous group (16). Symptomatic patients with mild airflow limitation may show signs of impaired HRQoL and physical activity levels, reduced exercise tolerance and increased healthcare resource utilisation compared with asymptomatic patients with mild airflow limitation (12,16 2). Evidence indicates that healthcare utilisation and HRQoL are similar in asymptomatic patients with mild airflow limitation and in those with normal lung function, after adjustment for age, sex, smoking and educational status (17). These asymptomatic patients with COPD are less likely to be identified and to receive treatment. Conversely, other patients have significant symptoms with near-normal lung function early in the course of the disease; this could be attributed to early disproportionate ventilator demands, decreased inspiratory capacity with dynamic hyperinflation and ventilation-perfusion mismatch during exercise (21). Physical inactivity reduces patients day-to-day functional ability, and is the most important factor in determining self-rated general health and HRQoL in patients with COPD (22). Physical activity is also a predictor of mortality and hospitalisation (23 26), and even mild airflow limitation has been associated with increased mortality (2). Some patients tend to reduce their physical activity early in the course of COPD, even before they develop marked breathlessness or activity impairment (18,27). A sedentary lifestyle leads to a downward spiral of symptom-induced inactivity, as the physical deconditioning that follows inactivity makes patients even more breathless on exertion, and they tend to compensate by reducing activity further (28,29). Skeletal muscle dysfunction is a recognised extra-pulmonary complication of COPD (3,31). Diminished quadriceps strength is associated with exercise intolerance, impaired HRQoL, increased use of healthcare resources and increased mortality (3,31). Recent studies have demonstrated upper and lower extremity muscle weakness in patients with mild airflow limitation (3 32), indicating that physical deconditioning is present in early disease. Although COPD exacerbations are usually associated with more severe disease, they can occur in patients with milder COPD (33). In a 1-year prospective study, 7% of patients with mild or moderate COPD (FEV 1 5% predicted) experienced at least one exacerbation (defined as events leading to prescription of antibiotics and/or corticosteroids) (33). In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, Hurst et al. reported an annualised exacerbation rate of.85 per person for patients with moderate COPD (34). The actual incidence of these exacerbations in early COPD may be higher, as exacerbations in patients with mild COPD are more likely to be unreported/underreported than those in patients with more severe disease (33,35). In a study of patients with mild COPD, the incidence of acute respiratory infections was higher (1.8 episodes per year) compared with non-copd controls (1.4 episodes per year) (36). This becomes more relevant in smokers and ex-smokers who present with infections frequently. Since exacerbations substantially impair HRQoL, work productivity and healthcare resource use, the occurrence of undiagnosed events in patients with mild-to-moderate COPD may contribute to an underestimation of the burden of COPD.

4 COPD: early diagnosis and treatment 339 An additional element of the overall burden of COPD is the prevalence of comorbidities that are often seen early in the disease process (37), including diabetes, cardiovascular disease, osteoporosis, gastrooesophageal reflux and depression (38,39). Patients with COPD are at significantly higher risk of developing depression compared with demographically matched healthy individuals, even at the mildest stages of the disease (4). In the ECLIPSE study, comorbidities appeared to be independent of the degree of airflow limitation and occurred with a similar frequency in moderate and severe COPD (16). The exact mechanism of these comorbidities is not fully understood. Further studies are needed to evaluate whether early treatment reduces inactivity and the prevalence/severity of comorbidities. Early COPD and decline in FEV 1 Fletcher and Peto first described the progressive decline in lung function considered a hallmark feature of COPD (Figure 2) (6). In addition to the normal decline in lung function with age, patients with COPD typically experience progressively declining pulmonary function as a part of the disease process. Other studies have confirmed these findings, reporting that the average rate of FEV 1 decline in patients with COPD is approximately double that of subjects without the disease (41 45). The 3-year ECLIPSE study found considerable variability in the rate of lung function decline in COPD and reported that more than one-half of patients with the disease had a yearly rate of FEV 1 decline that was no greater than that previously observed in subjects without lung disease (46). These findings confirm the heterogeneity of the COPD population, and question whether results can be generalised from clinical trials evaluating responses to treatment in such a diverse condition. Although Fletcher and Peto postulated that the rate of decline in FEV 1 increases with increasing COPD severity (6), evidence from more recent studies indicates that the absolute value of FEV 1 decline is greater in patients with moderate disease compared with those with more severe COPD (17,46). Presumably this reflects the fact that there is a higher baseline FEV 1 in the early stages of the disease that enables large losses, whereas later in the progression of COPD, the FEV 1 curve flattens out. Table 1 summarises the mean rate of FEV 1 decline observed in large COPD studies in patients with different degrees of airflow limitation (17,41 43,47 52). Unfortunately, data are limited on COPD progression in patients with mild airflow obstruction. However, in one study specifically evaluating early disease, Bridevaux et al. reported that the annual rate of decline in prebronchodilator FEV 1 was significantly greater in patients with mild COPD than in patients with normal lung function (4 ml/year vs. 35 ml/year; p <.1) (17). A symptom-based evaluation of the same populations showed that the decline in FEV 1 was faster than that in the reference group (asymptomatic patients with normal lung function) only for symptomatic patients with normal lung function (p =.1) and for symptomatic patients with mild COPD (p <.1). Further clinical studies to characterise FEV 1 decline in patients with mild disease are therefore warranted. Studies in patients with mild-to-moderate COPD report higher rates of FEV 1 decline than those seen FEV 1 (% of value at age 25) Disability Death Smoked regularly and susceptible to its effects Never smoked or not susceptible to smoke Stopped at 45 Stopped at Age (years) 75 Figure 2 The Fletcher Peto curve illustrating the effect of continued smoking and smoking cessation on FEV 1. Reproduced from (6) with permission from BMJ Publishing Group Ltd. Death, the underlying cause of which is irreversible chronic obstructive lung disease, whether the immediate cause of death is respiratory failure, pneumonia, cor pulmonale or aggravation of other heart disease by respiratory insufficiency. FEV 1, forced expiratory volume in 1 s

5 34 COPD: early diagnosis and treatment Table 1 Rate of annual decline in FEV 1 in patients with mild-to-very severe COPD randomised in the placebo arm of large interventional studies Reference Severity of airflow obstruction (n) Follow-up period (years) Mean postbronchodilator FEV 1 decline (ml/year) Bridevaux et al. (17) Mild (519) 11 4 CCHS Mild-moderate (145) 3 5 Vestbo et al. (41) EUROSCOP Mild-moderate (643) 3 65 Pauwels et al. (42) UPLIFT Mild-moderate (578) 4 49 Tashkin et al. (47) LHS Mild-moderate (1964) 5 55 Anthonisen et al. (48) TORCH Moderate (535) 3 6 Jenkins et al. (49) UPLIFT Moderate (1355) 4 49 Decramer et al. (5) ISOLDE Moderate-severe (375) 3 59 Burge et al. (43) Lapperre et al. (51) Moderate-severe (29) 3 79 TORCH Severe (775) 3 56 Jenkins et al. (49) UPLIFT Severe (1331) 4 38 Decramer et al. (5,52) TORCH Very severe (214) 3 34 Jenkins et al. (49) UPLIFT Decramer et al. (5,52) Very severe (271) 4 23 CCHS, Copenhagen City Heart Study; COPD, chronic obstructive pulmonary disease; EUROSCOP, European Respiratory Society Study on COPD; FEV 1, forced expiratory volume in 1 s; ISOLDE, Inhaled Steroids in Obstructive Lung Disease in Europe; LHS, Lung Health Study; TORCH, TOwards a Revolution in COPD Health; UPLIFT, Understanding Potential Long-Term Impacts on Function with Tiotropium. Number of patients randomised to the placebo group; prebronchodilator; patients did not receive placebo (no intervention given); unweighted means analysis. exclusively in patients with mild disease, and it is not clear whether this is an actual trend in the data or because of the limited and heterogeneous nature of the information currently available. For example, the European Respiratory Society Study on COPD (the EUROSCOP study) reported a rate of decline in FEV 1 of 65 ml/year in patients with mild-to-moderate COPD on placebo treatment (n = 643) (42), and the placebo group in the Copenhagen City Heart Study (n = 145) had a rate of FEV 1 decline of 5 ml/year in patients with mild-to-moderate COPD (41). Similarly, in patients with moderate COPD, a subgroup analysis of the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study demonstrated a rate of decline of FEV 1 of 49 ml/year in patients receiving placebo (5). Data on lung function decline in patients with very severe airflow limitation are rare, but the rate of FEV 1 decline has been shown to be greater in earlier vs. later stages of the disease (46,49,5,52). The longitudinal ECLIPSE study, undertaken in patients with moderate-to-severe COPD, reported a mean rate of decline in FEV 1 of 35 ml/year in patients with moderate disease compared with 33 ml/year in patients with severe COPD, and 25 ml/year in those with very severe COPD (46). This is in line with a subgroup analysis of the TOwards a Revolution in COPD Health (TORCH) study, where Jenkins et al. reported a higher rate of decline in patients with mild COPD in the placebo group (6 ml/year) compared with patients with severe and very severe COPD in the placebo group (56 and 34 ml/year, respectively; Figure 3) (49). What does the GOLD strategy recommend for early COPD? Key elements of COPD management are the identification and reduction in risk factors, particularly

6 COPD: early diagnosis and treatment 341 Adjusted rate of decline in FEV 1 (ml/year) Placebo Salmeterol Fluticasone propionate Salmeterol/fluticasone propionate % FEV 1 at baseline > 3% 3% to < 5% 5% Baseline FEV 1 (ml) Figure 3 Rate of decline in FEV 1 by baseline postbronchodilator FEV 1 % predicted. 29 Jenkins et al. (49); licensee BioMed Central Ltd. FEV 1, forced expiratory volume in 1 s tobacco smoke exposure, the maintenance of an active lifestyle and influenza/pneumococcal vaccination (1). In COPD, influenza infection can contribute to acute exacerbations and leads to an increased risk of hospitalisation (53,54). Similarly, pneumococcal colonisation, which occurs more frequently in the airways of patients with COPD vs. healthy controls (55), is associated with an increased risk of exacerbations (56). A reduction in the number of hospitalisations, incidence of pneumonia, risk of death and number of acute exacerbations has been reported in studies evaluating the effectiveness of influenza and pneumococcal vaccines (57). Bronchodilators represent the appropriate pharmacological treatment for patients with mild-tomoderate airflow limitation in Groups A and B of the 214 GOLD classification (Figure 1) (1). In patients with FEV 1 5% predicted, < 2 exacerbations per year, no exacerbations leading to hospitalisation and few symptoms (Group A), short-acting b 2 -agonist bronchodilators or short-acting muscarinic antagonist bronchodilators (SAMAs) are recommended as first-choice treatments. Alternative therapies recommended by GOLD include long-acting muscarinic antagonists (LAMAs), long-acting b 2 -agonists (LABAs) or a combination of short-acting bronchodilators. In patients with FEV 1 5% predicted, < 2 exacerbations per year, no exacerbations leading to hospitalisation and more symptoms (Group B), LAMAs or LABAs should be offered as first choice, with a combination of LAMA and LABA recommended as an alternative. The current strategy makes no distinction between mild or moderate airflow limitation, other than assessing the presence of symptoms and exacerbation history, while recommending pharmacological treatment. This reflects a change from previous GOLD recommendations that patients with mild airflow limitation (GOLD 1) should only receive symptomatic treatment with short-acting bronchodilators as pharmacological therapy, and patients with moderate airflow limitation (GOLD 2) should receive treatment with one or more long-acting bronchodilators (9). The 214 GOLD strategy approach to COPD management does not recommend the use of inhaled corticosteroids (ICS) alone in COPD. An ICS/LABA combination is recommended in GOLD Group C and D patients, who have severe or very severe airflow limitation and/or a history of 2 exacerbations per year or 1 exacerbation per year requiring hospitalisation. There is no indication for initial treatment with ICS/LABA in patients with mild-tomoderate airflow limitation and/or < 2 exacerbations per year (with no exacerbations leading to hospitalisation) (1). Evidence supporting treatment in early disease stages Smoking cessation has been shown to reduce the decline in lung function at all stages of COPD (44,48,58,59), and the earlier the cessation the greater the impact on lung function (44). In the Lung Health Study, smoking cessation was reported to halve the rate of decline in FEV 1 in patients with mild-to-moderate COPD, compared with the rate seen in patients who continued to smoke (44). When the effects of smoking cessation plus ipratropium bromide (a SAMA), smoking cessation plus placebo, or usual care were compared in mild-to-moderate COPD, the prevalence of symptoms (cough, phlegm, wheeze and shortness of breath) was found to be significantly lower in both smoking cessation groups

7 342 COPD: early diagnosis and treatment compared with the usual-care group (p <.1) at the 5-year follow-up (6). Early studies investigating the impact of treatment in patients with mild-to-moderate COPD found no significant improvements in the rate of lung function decline with active pharmacological treatments (41,42,61). However, in the last decade, evidence supporting the benefits of pharmacological intervention in early COPD has been slowly accumulating (Tables 2a, b). There are limited data on the effects of pharmacological treatment in mild COPD (FEV 1 8% predicted), or in patients who only experience symptoms during exertion. However, O Donnell et al. demonstrated that the SAMA ipratropium bromide provided moderate improvements compared with placebo in lung function outcomes, such as FEV 1, residual volume and specific airway resistance (p <.5) in mild COPD (68). This suggests that patients with early COPD who experience symptoms only on exertion may benefit from treatment with a short-acting bronchodilator. A number of clinical studies support using longacting bronchodilators in COPD patients with more mild disease, although many of them were not designed specifically to recruit patients with mild or moderate COPD. For example, in an exploratory analysis of pooled 6-month data from three randomised, double-blind pivotal studies including over 4 patients, the LABA indacaterol significantly improved trough FEV 1, dyspnoea and health status [based on the Transitional Dyspnea Index (TDI) and St George s Respiratory Questionnaire (SGRQ), respectively] in patients with predominately moderate disease [n = 2353; this population included a small proportion of patients ( 4%) with mild disease], compared with placebo (p <.5; Table 2a) (63). In this patient subpopulation, the effects of the two indacaterol doses (15 and 3 lg) were not significantly different and were above the minimum clinically important difference for all assessments, except for SGRQ score with the 3 lg dose. In addition, either or both indacaterol doses provided significantly greater improvement in FEV 1 than open-label tiotropium or double-blinded formoterol or salmeterol, and greater improvement in SGRQ score than tiotropium (all p <.5). The authors concluded that indacaterol was the most effective of the four active treatments in patients with moderate disease. Recently, preliminary findings were reported from a second indacaterol sub-analysis showing that in GOLD 211 Groups A and B, indacaterol 15 and 3 lg significantly improved FEV 1, SGRQ and TDI total score, as well as rescue medication use vs. placebo (all p <.1; Table 2a) (64). Similarly, pooled 6-month data for the LAMA glycopyrronium demonstrated significant improvements in FEV 1, TDI and SGRQ compared with placebo in a subgroup analysis of 1169 patients with moderate COPD (Table 2a) (67). In addition, tiotropium delayed time to first exacerbation and reduced healthcare resource utilisation in a 1-year study in 11 patients with COPD (prebronchodilator FEV1 3 65% predicted; Table 2a) (65). Much of the initial evidence supporting the efficacy of long-acting bronchodilators in patients with moderate COPD came from sub-analyses of two large-scale randomised trials, the TORCH trial and the UPLIFT study (49,5). The TORCH study was a randomised, double-blind, placebo-controlled study of the LABA salmeterol, the ICS fluticasone propionate and their combination, in patients with prebronchodilator FEV 1 < 6% predicted (69), while UPLIFT was a randomised, double-blind, placebocontrolled trial of the LAMA tiotropium in patients with postbronchodilator FEV 1 7% predicted (7). Both studies investigated the effects of these treatments on mortality, as either a primary (TORCH) or secondary (UPLIFT) end-point (69,7). A post hoc analysis of the TORCH study in patients with moderate COPD (GOLD 2; FEV 1 5% to < 8%; n = 2156) showed that compared with placebo, salmeterol plus fluticasone propionate (LABA + ICS) treatment was associated with an improvement in FEV 1 of 11 ml and a decrease in the decline of FEV 1 of 16 ml/year (GOLD 2; FEV 1 5% to < 8%) (Table 2b) (49). Patients with GOLD 2 COPD in TORCH showed improvements in SGRQ scores by 2.3 units and a reduction in the annual rate of moderate-to-severe exacerbations by 31% with the combination of LABA + ICS vs. placebo. Similarly, the combination of salmeterol and fluticasone propionate reduced the risk of death by 33% compared with placebo [hazard ratio (HR).67; 95% confidence interval (CI).45.98], in patients with moderate COPD (49). In a prespecified analysis of the UPLIFT study in patients with moderate COPD (GOLD 2; FEV 1 5% to < 8%; n = 2739), tiotropium significantly reduced the rate of decline in FEV 1 vs. placebo (Table 2b; 43 vs. 49 ml/year; p =.24) (5). In addition, tiotropium reduced the number of exacerbations per patient per year (p <.1), increased the median time to first exacerbation (p <.1) and improved SGRQ scores (p.6) (5). More recently, the UPLIFT investigators conducted a post hoc analysis of data in patients with milder disease (postbronchodilator FEV 1 6%; n = 121) to address the lack of evidence in this group (47). Similar to the findings in the GOLD 2 subgroup

8 COPD: early diagnosis and treatment 343 Table 2a Randomised controlled trials of pharmacological treatment in patients with mild-to-moderate COPD. Trials in patients with predominantly mild or moderate COPD Efficacy outcomes at week 26 Study (COPD severity) Treatment n Study duration Trough FEV 1 SGRQ total score TDI total score LABA INHANCE, INVOLVE and INLIGHT-2 pooled post hoc analysis in maintenance-naive patients (moderate/severe), Decramer et al. (62) INHANCE, INVOLVE and INLIGHT-2 pooled post hoc analysis (GOLD Stage II ), Decramer et al. (63) INHANCE, INVOLVE and INLIGHT-2 pooled post hoc analysis (GOLD Groups A and B), Kerstjens et al. (64) Indacaterol 15 lg months to 1 year Active placebo differences in Indacaterol 3 lg 22 all treatments > MCID Tiotropium 156 Placebo 325 Indacaterol 15 lg months to 1 year Active placebo differences in Indacaterol 3 lg 496 all treatments except Tiotropium 236 formoterol > MCID Formoterol 39 Salmeterol 189 Placebo 675 Indacaterol 15 lg NR 6 months to 1 year Significant improvement vs. Indacaterol 3 lg NR placebo for all treatments Tiotropium NR Formoterol NR Salmeterol NR Placebo NR Active placebo differences in indacaterol 15 lg only > MCID Active placebo differences in indacaterol 15 lg and salmeterol only > MCID GOLD A: only indacaterol 15 and 3 lg had significant improvement vs. placebo GOLD B: significant improvement vs. placebo for all treatments LAMA NR NR MISTRAL (moderate/severe ), Dusser et al. (65) Tiotropium 5 1 year Significant improvement vs. Placebo 51 placebo UPLIFT secondary analysis in maintenance-naive patients (moderate-to-very severe), Troosters et al. (66) Pooled GLOW1 and GLOW2 post hoc analysis (moderate disease), D Urzo et al. (67) Tiotropium 43 4 years Significant improvement vs. Active placebo differences > MCID Placebo 47 placebo only after 25.5 months Glycopyrronium months to 1 year Significant improvement vs. Significant improvement vs. placebo Tiotropium 172 placebo for all treatments for all treatments Placebo 338 Active placebo differences in indacaterol 15 and 3 lg only > MCID Active placebo differences in indacaterol 15 and 3 lg only > MCID GOLD A: only indacaterol 15 and 3 lg and tiotropium had significant improvement vs. placebo GOLD B: Significant improvement vs. placebo for all treatments NR Significant improvement vs. placebo for all treatments FEV1, forced expiratory volume in 1 s; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GLOW, GLycopyrronium bromide in COPD airways; INHANCE, INdacaterol to Help Achieve New COPD treatment Excellence; INLIGHT, INdacaterol efficacy evaluation using 15 lg doses with COPD patients; INVOLVE, INdacaterol Value in COPD: Longer term Validation of Efficacy and safety; MCID, minimum clinically important difference; MISTRAL, Mesure de l Influence de Spiriva â sur les Troubles Respiratoires Aigus a Long terme; NR, not reported; SGRQ, St. George s Respiratory Questionnaire; TDI, Transition Dyspnea Index; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium. Postbronchodilator FEV1 < 8% and 3% predicted entry criterion (baseline mean 57 59%); includes 4% of patients with GOLD Stage I disease; total GOLD Group A n = 1134, GOLD Group B n = 18; prebronchodilator FEV1 3 65% predicted entry criterion (baseline mean %); at 1 year; postbronchodilator FEV 1 7% predicted entry criterion (baseline mean 52%); at 1 month and 4 years; at Week 12.

9 344 COPD: early diagnosis and treatment Table 2b Randomised controlled trials of pharmacological treatment in patients with mild-to-moderate COPD. Long-term studies in mild-to-moderate COPD Reference Treatment n Postbronchodilator FEV 1 criterion, % predicted (baseline mean) Study duration Outcomes Mean change in postbronchodilator FEV 1 (ml/year) Exacerbations Respiratory hospitalisations All-cause mortality (%) ICS EUROSCOP, Pauwels et al. (42) Budesonide (76.8) 3 years 57 NR NR 1.3 Placebo (76.9) 69 NR NR 1.6 CCHS, Vestbo et al. (41) Budesonide 145 NR (86.9) 3 years events NR 2.8 Placebo 145 NR (86.2) events NR 3.4 LHS (61) Triamcinolone (67.2) Mean per 1 patient-years,.99 per 1 patient-years 2.7 Placebo (68.5) months per 1 patient-years 2.1 per 1 patient-years 3.4 ICS and/or LABA TORCH post hoc analysis, Jenkins et al. (49) LAMA UPLIFT prespecified sub-analysis, Decramer et al. (5) UPLIFT post hoc analysis, Tashkin et al. (47) Fluticasone propionate + salmeterol (NR) 3 years per year NR 7.8 Fluticasone propionate (NR) per year NR 9.9 Salmeterol (NR) 4.71 per year NR 9.2 Placebo (NR) 6.82 per year NR 11.4 Tiotropium (59) 4 years per patient-year 15% 8.5 Placebo (59) 49.7 per patient-year 19% 9.6 Tiotropium (64) 4 years 41 56%, 13% 7.4 Placebo (64) 49 62% 15% 11.1 CCHS, Copenhagen City Heart Study; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EUROSCOP, European Respiratory Society Study on COPD; FEV1, forced expiratory volume in 1 s; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting b2-agonist; LAMA, long-acting muscarinic antagonist; LHS, Lung Health Study; MISTRAL, mesure de l Influence de Spiriva â sur les Troubles Respiratoires Aigus a Long terme; NR, not reported; TORCH, TOwards a Revolution in COPD Health; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium. Prebronchodilator; between months 9 and 36; rate of any new or worsening breathing problems categorised as moderate or severe; p =.5 vs. placebo; p =.7 vs. placebo; mean baseline FEV1 not reported for individual treatment cohorts within the GOLD 2 subgroup, but overall mean in this subgroup was 58.8% predicted; p =.24 vs. placebo; rate ratio (tiotropium to control),.8 (95% CI.72.88), p <.1; p =.7; HR.83 (95% CI.71.96), p =.11; HR.66 (95% CI.45.96), p =.31.

10 COPD: early diagnosis and treatment 345 (A) 4 Tiotropium Control Improvement SGRQ total score (units) Δ = units 3 (B) Month 48 Probability of first exacerbation (%) (C) Control Tiotropium Hazard ratio,.83 (95% CI.71.96); p = Month Probability of death from any cause (%) Control Tiotropium Hazard ratio,.66 (95% CI.45.96); p = Month Figure 4 Impact of long-term treatment with tiotropium or placebo on (A) health status (SGRQ total score), (B) probability of a first exacerbation and (C) probability of death from any cause, in patients with FEV 1 6% predicted at baseline in the UPLIFT study (47) p <.5 vs. control. Tashkin et al. (47), copyright 212, Informa Healthcare. Adapted with permission of Informa Healthcare. CI, confidence interval; SGRQ, St George s Respiratory Questionnaire. analysis, tiotropium was numerically superior to placebo in slowing the annual rate of decline in FEV 1 (Table 2b; 41 vs. 49 ml/year rate of decline with tiotropium vs. placebo; p =.7). In this subpopulation, tiotropium was also significantly more effective than placebo in preserving HRQoL (treatment difference in SGRQ scores of units; p <.5), preventing exacerbations [HR.83 (95% CI.71.96); p =.11] and reducing mortality [HR.66 (95% CI.45.96); p =.31; Figure 4). In another prespecified analysis of the UPLIFT study, the effect of tiotropium was examined in younger patients ( 5 years) (71). In this subgroup, half of the analysed population had moderate COPD, and the mean duration of COPD was 7.1 years in the tiotropium group and 7.8 years in the placebo group. Tiotropium significantly reduced the rate of decline in postbronchodilator FEV 1 (difference in the decline in postbronchodilator FEV 1 between tiotropium and placebo was 19 ml/year, p =.1), support-

11 346 COPD: early diagnosis and treatment ing the importance of early intervention bronchodilator treatment. These data suggest that early initiation of pharmacological therapy with bronchodilators can provide substantial improvements in variables such as lung function, health status and exacerbation rates. This is even more relevant in a younger population of COPD patients who would likely require treatment for a longer overall duration than those diagnosed at an older age. Further research is needed to assess the benefits of maintenance bronchodilator therapy in patients with mild-to-moderate COPD, particularly in those with mild COPD who are rarely included in clinical studies, and to understand the underlying pathophysiological mechanisms of this type of treatment. An approach of active case finding, for example in older patients with a smoking history and chronic cough, is advocated by several bodies to improve rates of detection of COPD (1,72,73) and may allow more patients to benefit from early intervention. Early COPD and maintenance-na ıve patients In real life, most patients with COPD start treatment with short-acting bronchodilators on an asneeded basis, and there is a paucity of data on the impact of initiating maintenance therapy with longacting agents in patients with COPD who have not previously received maintenance therapy for COPD ( maintenance-na ıve ). A subgroup analysis of the UPLIFT study was conducted in patients who were maintenance-na ıve at baseline, before randomisation to tiotropium or placebo (Table 2a) (66). Compared with the overall UPLIFT population, the maintenance-na ıve subgroup was younger (63 vs. 65 years in the overall population; p <.1), had a shorter duration of COPD (9 vs. 1 years; p <.1) and a more preserved baseline lung function (postbronchodilator FEV 1 52% vs. 47% predicted; p <.1); 6% of the patients in the maintenance-na ıve subgroup were categorised as having moderate COPD compared with 44% in the overall UPLIFT population (p <.1). The outcomes of treatment with tiotropium in the maintenance-na ıve subgroup were similar to those reported in the younger subgroup in UPLIFT: postbronchodilator FEV 1 decline was lower in the tiotropium group compared with placebo (42 and 53 ml/year, respectively; p =.26), and the morning trough FEV 1 was 134 ml higher in the tiotropium group compared with placebo (p =.1). In addition, the decline in health status (measured by SGRQ total score) in the maintenance-na ıve subgroup was slower in those receiving tiotropium compared with placebo (p =.2). A prospective, 26-week study in maintenance-naive COPD patients with moderate airflow limitation showed that tiotropium improved lung function and some patient-reported outcomes compared with placebo (74). Similarly, a pooled post hoc analysis of data from three trials evaluating the LABA indacaterol 15 and 3 lg, open-label tiotropium and placebo included 933 maintenance-na ıve patients, approximately 65% of whom had moderate COPD (Table 2a) (63). Indacaterol 15 and 3 lg provided clinically relevant ( 12 ml) and statistically significant (p <.1) improvements in trough FEV 1 vs. placebo at Week 26. Both doses of indacaterol significantly improved TDI total scores vs. placebo (p <.1), with clinically meaningful differences. Patients receiving either dose of indacaterol were 2.5-fold more likely to achieve a clinically meaningful improvement in TDI score compared with those on placebo. Indacaterol 15 and 3 lg also improved health status, with statistically significant differences in SGRQ total scores vs. placebo ( 6.1 units and 2.5 units, respectively). Results from these analyses, indicating that longacting bronchodilators are beneficial as maintenance therapy, are particularly important given the more rapid decline in lung function in mild COPD and younger patients, compared with that observed in more severe disease and older patients. Future investigations In recent years, there has been increasing interest in the relevance of early intervention in COPD (75). Current data evaluating early treatment have been obtained as subgroup analyses from large studies conducted in a more heterogeneous population. To make a compelling argument for early treatment of COPD, there is a need for more structured trials specifically in patients with early COPD, investigating the effect of pharmacotherapy in patients with mild disease. These studies should take into account not only lung function but also clinical outcomes that are of greater relevance to patients, such as breathlessness and the impact of symptoms on everyday activities. It may also be of interest to explore treatment effects in specific subpopulations, by stratifying patients according to symptom level and/or rate of FEV 1 decline. In addition, to demonstrate treatment benefits in patients with mild COPD, it is important to include a wide array of end-points, in a large number of patients over the long term (to evaluate treatment effects on disease progression). These studies are complex and expensive to conduct. Several years of follow-up are

12 COPD: early diagnosis and treatment 347 required to demonstrate a significant effect of treatment on lung function decline. In addition, patients with COPD at the milder end of the disease severity spectrum are less likely to have exacerbations, so a large number of patients and long period of time would be required to observe an effect on this outcome. Smaller and shorter studies could be considered using biomarkers or imaging to assess disease progression, but such methods are not available to date and have not been validated. In addition, large observational studies or cohort studies in patients with mild COPD could provide information on the effectiveness of early COPD treatment outside of a clinical trial setting. Another unanswered question relates to the choice of maintenance therapy in this population. Which bronchodilator(s) should be recommended in early COPD? Currently, there are limited data to determine whether differences exist in the efficacy of LAMAs or LABAs as maintenance therapy, or in different agents within each class of long-acting bronchodilators in this population. Given that the risk of exacerbation increases with worsening disease severity (1), it is probably reasonable that ICS have a preferential indication in later stages of COPD. Initial studies showed that ICS (fluticasone propionate or budesonide) had no effect on lung function decline in patients with early COPD (42,76). However, the data from TORCH indicated a benefit from the combination of a LABA and ICS that is not simply attributable to the LABA component (49), suggesting that further research is needed into the role of ICS in early disease. It is advisable to weigh the potential benefits of ICS treatment vs. the risk of side effects in individual patients with COPD (77). Conclusion There is good evidence that smoking cessation (at any time) is beneficial for slowing the progression of COPD. There is some evidence that treatment with long-acting bronchodilators in early-stage disease influences the decline in lung function and health status. Further research is needed in this under-studied patient group, to develop more evidence-based recommendations for the management of early disease. Funding and acknowledgements The authors were assisted in the preparation of this manuscript by Dr Melanie Stephens and Shilpa Mudgal (professional medical writers from Circle- Science, part of KnowledgePoint36, an Ashfield Company). Medical writing support was funded by Novartis Pharma AG (Basel, Switzerland). Author contributions All authors contributed to the concept and objectives of the review, and provided guidance on the literature search, presentation and discussion of the findings, as well as critically reviewing the article. In addition, all authors reviewed and approved the final manuscript. References 1 Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, (accessed January 214). 2 Buist AS, Vollmer WM, McBurnie MA. Worldwide burden of COPD in high- and low-income countries. Part I. The burden of obstructive lung disease (BOLD) initiative. Int J Tuberc Lung Dis 28; 12: World Health Statistics whosis/whostat/en_whs8_full.pdf (accessed January 214). 4 Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 21; 19: British Lung Foundation. Invisible lives. Chronic obstructive lung disease (COPD) finding the missing millions, (accessed April 213). 6 Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1: Kohansal R, Martinez-Camblor P, Agustí A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 29; 18: Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 27; 37: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, (accessed April 213). 1 D Urzo A. Optimizing the management of chronic obstructive pulmonary disease: applying the GOLD strategy. Clin Pract 213; 1: Tinkelman DG, Price D, Nordyke RJ, Halbert RJ. COPD screening efforts in primary care: what is the yield? Prim Care Respir J 27; 16: Miravitlles M, Soriano JB, Garcıa-Rıo F et al. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities. Thorax 29; 64: Van den Boom G, Rutten-van M olken MP, Tirimanna PR, van Schayck CP, Folgering H, van Weel C. Association between health-related quality of life and consultation for respiratory symptoms: results from the DIMCA programme. Eur Respir J 1998; 11: Barnett M. Chronic obstructive pulmonary disease: a phenomenological study of patients experiences. J Clin Nurs 25; 14: Shahab L, Jarvis MJ, Britton J, West R. Prevalence, diagnosis and relation to tobacco dependence of chronic obstructive pulmonary disease in a nationally representative population sample. Thorax 26; 61: Agusti A, Calverley PA, Celli B et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 21; 11: Bridevaux PO, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 28; 63: Troosters T, Sciurba F, Battaglia S et al. Physical inactivity in patients with COPD, a controlled multi-center pilot-study. Respir Med 21; 14: Ora J, Laveneziana P, Ofir D, Deesomchok A, Webb KA, O Donnell DE. Combined effects of obesity and chronic obstructive pulmonary disease on dyspnea and exercise tolerance. Am J Respir Crit Care Med 29; 18:

13 348 COPD: early diagnosis and treatment 2 Mannino DM, Doherty DE, Buist AS. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 26; 1: Ofir D, Laveneziana P, Webb KA, Lam YM, O Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease. Am J Resp Crit Care Med 28; 177: Arne M, Lundin F, Boman G, Janson C, Janson S, Emtner M. Factors associated with good self-rated health and quality of life in subjects with selfreported COPD. Int J Chron Obstruct Pulmon Dis 211; 6: ZuWallack RL. Functional status and survival in COPD. Monaldi Arch Chest Dis 23; 59: Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax 26; 61: Garcia-Aymerich J, Serra I, Gomez FP et al. Physical activity and clinical and functional status in COPD. Chest 29; 136: Waschki B, Kirsten A, Holz O, M uller KC, Meyer T, Watz H, Magnussen H. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 211; 14: Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 29; 33: Reardon JZ, Lareau SC, ZuWallack R. Functional status and quality of life in chronic obstructive pulmonary disease. Am J Med 26; 119: S ZuWallack R. How are you doing? What are you doing? Differing perspectives in the assessment of individuals with COPD. COPD 27; 4: Shrikrishna D, Patel M, Tanner R et al. Quadriceps wasting and physical inactivity in patients with COPD. Eur Respir J 212; 4: Eisner MD, Blanc PD, Yelin EH et al. COPD as a systemic disease: impact on physical functional limitations. Am J Med 28; 121: Seymour JM, Spruit MA, Hopkinson NS et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 21; 38: O Reilly JF, Williams AE, Holt K, Rice L. Defining COPD exacerbations: impact on estimation of incidence and burden in primary care. Prim Care Respir J 26; 15: Hurst JR, Vestbo J, Anzueto A et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 21; 363: Langsetmo L, Platt RW, Ernst P, Bourbeau J. Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med 28; 177: Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2; 162: Decramer M, Rennard S, Troosters T et al. COPD as a lung disease with systemic consequences clinical impact, mechanisms, and potential for early intervention. COPD 28; 5: Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 27; 37: Fabbri LM, Luppi F, Beghé B et al. Complex chronic comorbidities of COPD. Eur Respir J 28; 31: Omachi TA, Katz PP, Yelin EH et al. Depression and health-related quality of life in chronic obstructive pulmonary disease. Am J Med 29; 122(778): e Vestbo J, Sørensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353: Pauwels RA, Löfdahl CG, Laitinen LA et al. Longterm treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999; 34: Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2; 32: Scanlon PD, Connett JE, Waller LA et al. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med 2; 161: Bosse R, Sparrow D, Garvey AJ, Costa PT Jr, Weiss ST, Rowe JW. Cigarette smoking, aging, and decline in pulmonary function: A longitudinal study. Arch Environ Health 198; 35: Vestbo J, Edwards LD, Scanlon PD et al. ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 211; 365: Tashkin DP, Celli BR, Decramer M, Lystig T, Liu D, Kesten S. Efficacy of tiotropium in COPD patients with FEV 1 6% participating in the UPLIFT â trial. COPD 212; 9: Anthonisen NR, Connett JE, Kiley JP et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV 1. The Lung Health Study. JAMA 1994; 272: Jenkins CR, Jones PW, Calverley PM et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 29; 1: Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. UPLIFT Investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 29; 374: Lapperre TS, Snoeck-Stroband JB, Gosman MM et al. ; Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 29; 151: Decramer M, Cooper CB. Treatment of COPD: the sooner the better? Thorax 21; 65: Griffin MR, Coffey CS, Neuzil KM, Mitchel EF Jr, Wright PF, Edwards KM. Winter viruses: influenzaand respiratory syncytial virus-related morbidity in chronic lung disease. Arch Intern Med 22; 162: Yap FH, Ho PL, Lam KF, Chan PK, Cheng YH, Peiris JS. Excess hospital admissions for pneumonia, chronic obstructive pulmonary disease, and heart failure during influenza season in Hong Kong. J Med Virol 24; 73: Hass H, Morris JF, Samson S, Kilbourn JP, Kim PJ. Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberoptic, and oropharyngeal sampling methods. Am Rev Respir Dis 1977; 116: Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 22; 347: Pesek R, Lockey R. Vaccination of adults with asthma and COPD. Allergy 211; 66: Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 22; 166: Burchfiel CM, Marcus EB, Curb JD et al. Effects of smoking and smoking cessation on longitudinal decline in pulmonary function. Am J Respir Crit Care Med 1995; 151: Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med 1999; 16: Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2; 343: Decramer M, Rossi A, Lawrence D, McBryan D. Indacaterol therapy in patients not receiving other maintenance treatment. Respir Med 212; 16: Decramer M, Dahl R, Kornmann O, Korn S, Lawrence D, McBryan D. Effects of long-acting bronchodilators in COPD patients according to COPD severity and ICS use. Respir Med 213; 17: Kerstjens H, Kornmann O, Deslee G, Young D, Lawrence D, McBryan D. Once-daily indacaterol 15 µg or 3 µg and other bronchodilators in COPD patients of GOLD 211 groups A and B. Eur Respir J 213; 42(Suppl. 57): 144s. Abstract P Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 26; 27: Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, Decramer M. UPLIFT Investigators. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT â trial. Eur Respir J 21; 36: 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. Curr Med Res Opin 214; 3: O Donnell DE, Laveneziana P, Ora J, Webb KA, Lam YM, Ofir D. Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD. Thorax 29; 64: