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Original Research: COPD |

Relapse in FEV1 Decline After Steroid Withdrawal in COPDLong-term Steroid Withdrawal in COPD FREE TO VIEW

Lisette I. Z. Kunz, MD; Dirkje S. Postma, MD, PhD; Karin Klooster, BSc; Thérese S. Lapperre, MD, PhD; Judith M. Vonk, PhD; Jacob K. Sont, PhD; Huib A. M. Kerstjens, MD, PhD; Jiska B. Snoeck-Stroband, MD, PhD; Pieter S. Hiemstra, PhD; Peter J. Sterk, MD, PhD; the GLUCOLD Study Group
Author and Funding Information

From the Department of Pulmonology (Drs Kunz, Lapperre, and Hiemstra and the GLUCOLD Study Group) and Department of Medical Decision Making (Drs Sont and Snoeck-Stroband), LUMC, Leiden, The Netherlands; Department of Pulmonary Medicine (Drs Postma and Kerstjens and Ms Klooster) and Department of Epidemiology (Dr Vonk), UMCG, University of Groningen, Groningen, The Netherlands; Department of Respiratory and Critical Care Medicine (Dr Lapperre), Singapore General Hospital, Singapore; and Department of Respiratory Medicine (Dr Sterk), Academic Medical Center, Amsterdam, The Netherlands.

CORRESPONDENCE TO: Lisette I. Z. Kunz, MD, Department of Pulmonology, LUMC, Albinusdreef 2, NL2333-ZA Leiden, The Netherlands; e-mail: L.I.Z.Kunz@lumc.nl


Part of this article has been presented in poster form at the American Thoracic Society International Conference, May 16-21 2014, San Diego, CA, and published in abstract form (Kunz LIZ, Lapperre T, Snoeck-Stroband J, et al.; the GLUCOLD study group. American Thoracic Society International Conference Abstract. 2014;271:A6674.

FUNDING/SUPPORT: The study was funded by the Netherlands Organisation for Scientific Research (NWO) [Grant 940-35-033], Lung Foundation Netherlands [Grant 93.96.3], GlaxoSmithKline plc of The Netherlands [Grant SCO107656], UMCG, and LUMC.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):389-396. doi:10.1378/chest.14-3091
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BACKGROUND:  We previously observed that 30 months of inhaled corticosteroid (ICS) treatment can attenuate FEV1 decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1 decline, airway hyperresponsiveness (AHR), and quality of life (QOL) deteriorate after ICS cessation even after prolonged use.

METHODS:  One hundred fourteen patients with moderate to severe COPD finished randomized 6-month or 30-month treatment with fluticasone (500 μg bid), 30-month treatment with fluticasone and salmeterol (500/50 μg bid), or placebo (first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease [GLUCOLD] study [GL1]). The subsequent 5 years, patients were prospectively followed annually, treated by their physician (GLUCOLD follow-up study [GL2]). Postbronchodilator FEV1, AHR, and QOL were initially recorded at baseline, at 30 months (GL1), and annually during GL2. Analysis was performed by linear mixed-effects models.

RESULTS:  Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2-GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, −68 mL/y [−112 to −25], P = .002; 30-month treatment with fluticasone, −73 mL/y [−119 to −26], P = .002), accompanied by deterioration in AHR and QOL.

CONCLUSIONS:  ICS discontinuation after 30 months in COPD can worsen lung function decline, AHR, and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00158847; URL: www.clinicaltrials.gov

Figures in this Article

Patients with stable COPD are currently treated with long-acting bronchodilators and in case of frequent exacerbations with inhaled corticosteroids (ICSs).1 In these patients, ICS use reduces exacerbations, the rate of decline in quality of life (QOL), and the risk of death and hospitalization.2,3 However, the effect of ICSs on lung function decline remains controversial.

Several studies on COPD presented transient improvements in lung function with ICS, whereas others failed to show benefits on FEV1, QOL, and frequency of exacerbations.46 We have previously reported that 30-month treatment with fluticasone and salmeterol (FS30) in 114 well-characterized patients with moderate to severe COPD decreased inflammation, attenuated lung function decline, and improved QOL.7

In contrast, long-term effects after ICS withdrawal on lung function and QOL have been little studied. Recent research indicates that discontinuation after 6 weeks of ICS in patients with severe to very severe COPD leads to a greater decrease in FEV1 without effect on the number of exacerbations during a 1-year follow-up compared with the ICS continuation group.8 Other ICS withdrawal studies found a deterioration in lung function, increased frequency of exacerbations, and a lower QOL during 6-month to 12-month follow-up compared with the non-ICS group.9,10 Thus, there is a clinical need for careful monitoring of disease outcomes after withdrawal of long-term ICS treatment in COPD.11

We hypothesized that lung function decline, airway hyperresponsiveness (AHR), and health-related QOL deteriorate after withdrawal of ICS in patients with COPD who had previously been randomized to 30-month ICS treatment, but had no or reduced ICS treatment during 5 subsequent years of prospective follow-up.

Patients and Design

For the first interventional part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study (GL1) (a double-blind placebo-controlled randomized trial), 114 stable steroid-naive patients with moderate to severe COPD were included.7 Participants were randomized to receive one of the following bid treatments as dry-powder inhaler: 6-month (F6) or 30-month (F30) treatment with fluticasone propionate (500 μg), FS30 (500/50 μg; single Diskus), or 30-month placebo.

During the present observational prospective GLUCOLD follow-up study (GL2), participants visited the outpatient clinic annually for 5 consecutive years. At the start of GL2, the participants’ physicians were recommended to treat the patients according to the guidelines.12 This implies that some patients stopped using ICSs, whereas others intermittently or continuously used ICSs during GL2.

After completion of GL2, the patients’ pharmacies presented an overview of delivered medications during the past 5 years of inhaled/oral steroids and antibiotics. Treatment adherence to the prescribed medication during GL2 was not checked.

Postbronchodilator spirometry and measures of QOL were recorded at baseline and after 30 months (GL1) and subsequently yearly during follow-up (GL2).7 AHR to methacholine (provocative concentration of methacholine that causes a 20% decrease in FEV1 [PC20]) was measured at baseline, after 30 months, and at 2-years and 5-years follow-up. The ethics committees of LUMC and UMCG approved the original and follow-up study (approval numbers P01-122, P211/98, P04-065, MEC98/07/112, and MEC2004/111). All patients provided new written informed consent for GL2.

Outcomes

The primary outcome was the difference in the annual decline in postbronchodilator FEV1 during 5 years of follow-up (GL2) compared with the first 30 months (GL1). Secondary outcomes were differences between GL2 and GL1 in AHR and QOL, measured by the Medical Research Council (MRC) dyspnea score, St. George’s Respiratory Questionnaire (SGRQ),13 and Clinical COPD Questionnaire (CCQ).14

Statistical Analysis

We used only data of adherent patients in GL1 (using ≥ 70% of the prescribed dose).7 Data of participants who did not complete GL2 were also used for analysis and analyzed with SPSS 22.0 software (IBM Corporation). The analysis was stratified for original treatment group and ICS use during GL2. We used linear mixed-effect models with a random intercept for each subject using all FEV1 measurements during the entire study as the outcome variable and an unstructured covariance matrix. To assess the difference in FEV1 decline between GL1 and GL2, we included two time variables in the models: time 1 (time since start of GL1; range, 0-7½ years) and time 2 (time since start of GL2; range, 0-5 years [during GL1 this value is zero]). ICS use during GL2, based on delivered prescriptions by the pharmacies, was divided into the following groups: all (compliant) patients, patients who did not use ICSs, patients who used ICSs 0% to 50% of the time (which included the group that did not use ICSs), and patients who used ICSs 50% to 100% of the time. The daily dose of ICS (μg, in beclomethasone dipropionate equivalents) during 5 years was calculated as the daily sum of the different doses of ICS (μg/d) divided by the total time that ICS were used (days). For selected analyses, we combined the original FS30 and F30 groups to increase power. Given the limited sample size of patients completing the 7½ years of prospective follow-up, possible confounders (smoking, age, sex, and center) were not included in the model. A previous post hoc analysis showed that smoking was unlikely to be a major confounder.7 Baseline patient characteristics and daily dose of ICS dose were analyzed by Kruskal-Wallis tests, analysis of variance, or χ2 tests. Data are presented as change in estimates between GL2 and GL1 with 95% CI, means with SDs or medians with interquartile range. Statistical significance was inferred at P ≤ .05 (two-sided).

At the start of the GLUCOLD study (GL1), 114 patients had been randomized to receive one of the previously mentioned randomized 30-month treatments; 101 participants were adherent during GL1.7 Eighty-six patients completed GL1, 79 started the GLUCOLD follow-up study (GL2), and 58 patients completed GL2 (Fig 1). Patient characteristics at baseline and at start of GL2 (Table 1) were similar among the original treatment groups, except for a significantly higher postbronchodilator FEV1 after 30-month treatment among the FS30 and F30 groups, compared with the F6 and placebo groups.7

Figure Jump LinkFigure 1 –  Study flow diagram. Number of randomly assigned patients who were adherent to the original therapy (used ≥ 70% of prescribed dose during GL1). After 2.5 y, GL2 started. The number of patients who remained in GL2 and those withdrawn are presented. GL1 = first part of the Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease study; GL2 = Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease follow-up study.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics at Baseline of Randomized Therapy (GL1) and at the Start of 5-Year Posttreatment Follow-up (GL2) for the Original GL1 Treatment Groups

Data are given as mean (SD) unless otherwise indicated. PC20 is expressed as mean doubling doses. CCQ = Clinical COPD Questionnaire; F6 = 6-mo treatment with fluticasone (and 24 mo with placebo); F30 = 30-mo treatment with fluticasone; FS30 = 30-mo treatment with fluticasone and salmeterol; GL1 = first part of the Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease study; GL2 = Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease follow-up study; IQR = interquartile range; IVC = inspiratory vital capacity; MRC = Medical Research Council; PC20 = provocative concentration of methacholine that causes a 20% decrease in FEV1; % pred = percent predicted; SGRQ = St. George’s Respiratory Questionnaire.

Most patients (56 of 79) did not use any ICSs, or used ICSs 0% to 50% of the time, during GL2. The mean daily ICS dose during 5 years was 960 μg (SD 496 μg, in beclomethasone dipropionate equivalents, Table 2), which was not significantly different between the original treatment groups.

Table Graphic Jump Location
TABLE 2 ]  Number of Compliant Patients at the Start of GL2 Using ICS and a Daily Dose of ICS During 5 Years in Those Patients Who Used ICS During GL2

The daily dose of ICS (in beclomethasone dipropionate equivalents) during 5 y was calculated by the sum of the different doses of ICS per d (in μg/d), divided by the total time that ICS were used (in d). Doses were based on data provided by the patients’ pharmacies. ICS = inhaled corticosteroids. See Table 1 legend for expansion of other abbreviations.

Lung Function Decline

Annual FEV1 decline was significantly faster during GL2 than GL1 in patients who used ICSs 0% to 50% of the time during GL2 in the original FS30 group (difference in FEV1 decline between GL2 and GL1; 95% CI) (−68 mL/y [−112 to −25 mL/y]; P = .002) and F30 group (−73 mL/y [−119 to −26 mL/y]; P = .002) (Fig 2, Table 3). When analyzing patients who did not use ICSs during GL2, FEV1 decline during GL2 compared with GL1 was even more pronounced (original FS30 group: −106 mL/y [−171 to −41 mL/y]; P = .002; F30 group: −84 mL/y [−149 to −18 mL/y]; P = .01). Patients in the original combined FS30/F30 groups using ICS 50% to 100% of the time during GL2 had a decline in FEV1 of −59 mL/y ([−106 to −11 mL/y]; P = .02) in GL2 compared with GL1.

Figure Jump LinkFigure 2 –  A, B, Mean postbronchodilator FEV1 (L) and 95% CI during GL1 and GL2 over time for all compliant patients (A) and those using inhaled corticosteroids 0% to 50% of the time during GL2 (B) of the four original treatment groups. F6 = 6-mo treatment with fluticasone (and 24 mo with placebo); F30 = 30-mo treatment with fluticasone; FS30 = 30-mo treatment with fluticasone and salmeterol. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Table Graphic Jump Location
TABLE 3 ]  Annual Decline in Postbronchodilator FEV1 (mL/y) During GL2 Compared With GL1

See Table 1 and 2 legends for expansions of abbreviations.

a 

P < .05.

Airway Hyperresponsiveness

Patients of the combined original FS30/F30 groups that did not use ICSs and patients who used ICSs 0% to 50% of time during GL2 showed a deterioration in methacholine PC20 in GL2 compared with GL1 (−1.3 doubling dose/y [−2.0 to −0.5], P = .002; −1.1 doubling dose/y [−1.8 to −0.5], P = .001, respectively) (e-Fig 1, e-Table 1). Patients in the original placebo group who used ICSs 50% to 100% of the time during GL2 had an increase in PC20 in GL2 compared with GL1 (1.5 doubling dose/y [0.06-2.9]; P = .04).

Health-Related Quality of Life

Complete withdrawal of ICSs during GL2 in the original combined FS30/F30 groups was accompanied by worsening of scores as follows: the MRC dyspnea score in GL2 by 0.2 points/y (0.06-0.3 points/y, P = .006), SGRQ total score by 2.5 points/y (0.2-4.7 points/y, P = .03), CCQ total score by 0.1 point/y (0.008-0.2 points/y, P = .03), and CCQ symptom score by 0.2 points/y (0.05-0.3 points/y, P = .008) compared with GL1. Other QOL analyses are presented in e-Appendix 1.

This study shows that discontinuation of ICSs after long-term use in COPD seems to accelerate lung function decline during subsequent follow-up together with deterioration in AHR and health-related QOL. This indicates that the initial benefits of 30-month ICS treatment on COPD progression are confined to active treatment and are not sustained after long-term cessation of ICS.

This is the first observation, to our knowledge, that lung function decline significantly accelerates during 5-year follow-up in patients with moderate to severe COPD who did not use or intermittently continued ICS after 30-month randomized ICS treatment. Our results on FEV1 decline are in-line with those of previous trials.810,15 However, different study designs, follow-up time, disease severities, sample sizes, and definitions of ICS withdrawal make it difficult to compare the annual decline in FEV1 between these studies. Furthermore, QOL measured by MRC dypsnea score, SGRQ, and CCQ deteriorated during long-term follow-up compared with the previous randomized treatment period, although the minimal clinically important difference was not reached.16,17 SGRQ total score gradually declines over time after withdrawal of ICS in patients who previously used long-term ICSs (figure not published), which is similar to the decline in SGRQ found in the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial.15 Our data extend previous observations, showing a deterioration in QOL after discontinuation of ICSs compared with salmeterol or placebo during follow-up in patients with COPD.9,10 Finally, we observed a deterioration in AHR during the 5 years after ICS cessation, which thus far had only been described in patients with asthma and after short-term treatment in COPD.7,18,19 In contrast to asthma, where AHR is mostly related to the degree of inflammation,20 we previously showed that AHR in this group of patients with COPD is associated with both airflow limitation and airway inflammation.7,21 Taken together, the present study provides novel data on relapse of FEV1 decline and AHR after discontinuation of ICS after long-term use in patients with COPD.

The strength of our study is represented by its long-term prospective design with repeated monitoring during 5 years of observational follow-up. In addition, the concordance of the currently observed changes in lung function decline, AHR, and QOL further contribute to the confidence in our data. Nevertheless, this study had some limitations. First, only one-half of the patients randomized at baseline completed the entire 7½ year follow-up, mostly due to the natural course of the disease with associated mortality and comorbidities. This could have led to a loss of statistical power compared with GL1 and a selection bias, even though the number of withdrawn patients during GL2 was similar among the original treatment groups. Second, few patients used ICSs 50% to 100% of the time during GL2 (n = 23). Although only adherent patients during GL1 were used for the follow-up analysis, compliance to inhalation medication was not checked during GL2, thereby reflecting adherence in daily practice.22 Creating small subgroups of patients using steroids during GL2 made it difficult to detect a difference in annual decline of FEV1 in the FS30 group between those who used ICS 0% to 50% and 50% to 100% of the time during GL2. Third, pneumonia and exacerbation rates were not recorded during GL2, though prolonged use of ICSs in COPD may have adverse effects, like the risk of serious pneumonia, especially with high-dose fluticasone.23 However, retrospectively retrieved rates of antibiotics and prednisolone courses were similar between the groups. Among the 26 patients who died during the 7½ year follow-up, only one patient in the original F6 group (not participating in GL2) died of pneumonia, which occurred as a complication of a lung carcinoma (e-Table 2). Furthermore, overall survival was not statistically different between the original treatment groups (e-Fig 2). Hence, our data do not allow conclusions on the incidence of pneumonia or exacerbations during or after ICS usage.

How can we interpret our results? Effects of ICS in COPD are affected by the complexity of this heterogeneous disease, classified by clinical, physiologic, pathologic, and radiologic variables, and vary by host susceptibility and/or cigarette smoking.24,25 Previously, we described that ICS treatment attenuates lung function decline and decreases inflammation in this group of patients with COPD.7 The present study shows a relapse in lung function decline after discontinuation of ICSs. The presently observed rate of decline is higher compared with that in the recent Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management (WISDOM) study.8 Patients with moderate-severe COPD as in our study are representing a pathophysiologically distinct group and are thereby potentially more responsive to ICS.4 The annual rate of decline after ICS discontinuation could, therefore, be larger compared with severe airflow obstruction.9,10,15 This suggests (at least) temporary disease modification of COPD, especially during active and prolonged periods of ICS use. Future analyses should focus on inflammatory outcomes to determine whether our previously observed antiinflammatory effects of ICS in COPD are also ablated.

Our results may have consequences for future treatment of patients with COPD. Although meta-analyses show limited benefits of ICSs in COPD,3 the original GLUCOLD study suggests that maintenance use of ICSs can lead to attenuated lung function decline at least in this subset of patients with COPD.7 Notably, the current long-term follow-up study indicates that such benefits are not maintained after prolonged cessation of treatment. Though these data may suggest that ICS treatment in COPD should not be discontinued, this study was not designed to show evidence of any continued benefits of prolonged ICS therapy.

The present data indicate that ICS discontinuation after 30 months of use, in this group of patients with moderate to severe COPD, deteriorates lung function decline during 5 years of follow-up. This is accompanied by worsening in AHR and a small drop in QOL. These results suggest that, although initial long-term ICS use can have a disease-modifying effect in particular patients with COPD, such benefits disappear when ICSs are discontinued.

Author contributions: L. I. Z. K. takes responsibility for the content of the manuscript, including data and analysis. D. S. P., T. S. L., H. A. M. K., J. B. S.-S., P. S. H., and P. J. S. contributed to the design of the original GLUCOLD study; L. I. Z. K., D. S. P., P. S. H., and P. J. S. contributed to the design of the GLUCOLD follow-up study; L. I. Z. K., K. K., T. S. L., and J. B. S.-S. contributed to the patient visits; L. I. Z. K., J. M. V., and J. K. S. contributed to statistical analysis; and all authors contributed to the draft and critical revision and approval of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Postma received a grant from CHIESI Farmaceutici SpA and was a consultant for AstraZeneca, Boehringer Ingelheim GmbH, Teva Pharmaceutical Industries Ltd, GlaxoSmithKline plc, Takeda Pharmaceutical Company Limited, and CHIESI Farmaceutici SpA. Dr Sont reported a grant from Boehringer Ingelheim GmbH and CHIESI Farmaceutici SpA. Dr Kerstjens received grants from GlaxoSmithKline plc and the Dutch government and was a member of the advisory board of AstraZeneca, Almirall, Novartis AG, CHIESI Farmaceutici SpA, Boehringer Ingelheim GmbH, and Pfizer Inc, and received fees per patients’ study participation from Boehringer Ingelheim GmbH and Pfizer Inc. Dr Hiemstra received grants from Galapagos NV and Boehringer Ingelheim GmbH. Drs Kunz, Lapperre, Vonk, Snoeck-Stroband, and Sterk and Ms Klooster have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Collaborators: The GLUCOLD study group consists of: H. F. Kauffman, MD, PhD; D. de Reus, BSc; H. M. Boezen, PhD; D. F. Jansen, PhD; J. M. Vonk, PhD; M. D. W. Barentsen, BSc; W. Timens, MD, PhD; M. Zeinstra-Smit, MSc; A. J. Luteijn, MD; T. van der Molen, MD, PhD; G. ter Veen, MSc; M. M. E. Gosman, MD, PhD; N. H. T. ten Hacken, MD, PhD; H. A. M. Kerstjens, MD, PhD; M. S. van Maaren, MD; D. S. Postma, MD, PhD; C. A. Veltman, MSc; A. Verbokkem, BSc; I. Verhage, MSc; K. Klooster, BSc; H. A. Thiadens, MD, PhD; J. B. Snoeck-Stroband, MD, PhD; J. K. Sont, PhD; J. Gast-Strookman, BSc; P. S. Hiemstra, PhD; K. Janssen, BSc; K. F. Rabe, MD, PhD; A. van Schadewijk, MSc; J. A. Schrumpf, BSc; J. Smit-Bakker, BSc; J. Stolk, MD, PhD; A. C. J. A. Tire, BSc; H. van der Veen, BSc; M. M. E. Wijffels, MD; L. N. A. Willems, MD, PhD; P. J. Sterk, MD, PhD; T. S. Lapperre, MD, PhD; and T. Mauad, MD, PhD.

Role of sponsors: The funding sources had no role in the design, collection and analysis of the data, in the writing of the manuscript, and in the decision to submit the manuscript for publication.

Other contributions: The authors thank the patients for their cooperation in our study.

Additional information: The e-Appendix, e-Tables, and e-Figures can be found in the Supplemental Materials section of the online article.

AHR

airway hyperresponsiveness

CCQ

Clinical COPD Questionnaire

F6

6-month treatment with fluticasone

F30

30-month treatment with fluticasone

FS30

30-month treatment with fluticasone and salmeterol

GL1

first part of the Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease study

GL2

Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease follow-up study

GLUCOLD

Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease

ICS

inhaled corticosteroid

MRC

Medical Research Council

PC20

provocative concentration of methacholine that causes a 20% decrease in FEV1

QOL

quality of life

SGRQ

St. George’s Respiratory Questionnaire

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Grönke L, Kanniess F, Holz O, Jörres RA, Magnussen H. The relationship between airway hyper-responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease. Clin Exp Allergy. 2002;32(1):57-63. [CrossRef] [PubMed]
 
van den Berge M, Vonk JM, Gosman M, et al. Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD. Eur Respir J. 2012;40(5):1098-1105. [CrossRef] [PubMed]
 
Ingebrigtsen TS, Marott J, Nordestgaard BG, et al. Low use and adherence to maintenance medication in chronic obstructive pulmonary disease in the general population. J Gen Intern Med. 2015;30(1):51-59. [CrossRef] [PubMed]
 
Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. [CrossRef] [PubMed]
 
Wedzicha JA. Oral corticosteroids for exacerbations of chronic obstructive pulmonary disease. Thorax. 2000;55(suppl 1):S23-S27. [CrossRef] [PubMed]
 
Van Overveld FJ, Demkow U, Górecka D, De Backer WA, Zieliński J. Differences in responses upon corticosteroid therapy between smoking and non-smoking patients with COPD. J Physiol Pharmacol. 2006;57(suppl 4):273-282. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Study flow diagram. Number of randomly assigned patients who were adherent to the original therapy (used ≥ 70% of prescribed dose during GL1). After 2.5 y, GL2 started. The number of patients who remained in GL2 and those withdrawn are presented. GL1 = first part of the Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease study; GL2 = Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease follow-up study.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, Mean postbronchodilator FEV1 (L) and 95% CI during GL1 and GL2 over time for all compliant patients (A) and those using inhaled corticosteroids 0% to 50% of the time during GL2 (B) of the four original treatment groups. F6 = 6-mo treatment with fluticasone (and 24 mo with placebo); F30 = 30-mo treatment with fluticasone; FS30 = 30-mo treatment with fluticasone and salmeterol. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics at Baseline of Randomized Therapy (GL1) and at the Start of 5-Year Posttreatment Follow-up (GL2) for the Original GL1 Treatment Groups

Data are given as mean (SD) unless otherwise indicated. PC20 is expressed as mean doubling doses. CCQ = Clinical COPD Questionnaire; F6 = 6-mo treatment with fluticasone (and 24 mo with placebo); F30 = 30-mo treatment with fluticasone; FS30 = 30-mo treatment with fluticasone and salmeterol; GL1 = first part of the Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease study; GL2 = Groningen and Leiden Universities in Corticosteroids in Obstructive Lung Disease follow-up study; IQR = interquartile range; IVC = inspiratory vital capacity; MRC = Medical Research Council; PC20 = provocative concentration of methacholine that causes a 20% decrease in FEV1; % pred = percent predicted; SGRQ = St. George’s Respiratory Questionnaire.

Table Graphic Jump Location
TABLE 2 ]  Number of Compliant Patients at the Start of GL2 Using ICS and a Daily Dose of ICS During 5 Years in Those Patients Who Used ICS During GL2

The daily dose of ICS (in beclomethasone dipropionate equivalents) during 5 y was calculated by the sum of the different doses of ICS per d (in μg/d), divided by the total time that ICS were used (in d). Doses were based on data provided by the patients’ pharmacies. ICS = inhaled corticosteroids. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Annual Decline in Postbronchodilator FEV1 (mL/y) During GL2 Compared With GL1

See Table 1 and 2 legends for expansions of abbreviations.

a 

P < .05.

References

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Grönke L, Kanniess F, Holz O, Jörres RA, Magnussen H. The relationship between airway hyper-responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease. Clin Exp Allergy. 2002;32(1):57-63. [CrossRef] [PubMed]
 
van den Berge M, Vonk JM, Gosman M, et al. Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD. Eur Respir J. 2012;40(5):1098-1105. [CrossRef] [PubMed]
 
Ingebrigtsen TS, Marott J, Nordestgaard BG, et al. Low use and adherence to maintenance medication in chronic obstructive pulmonary disease in the general population. J Gen Intern Med. 2015;30(1):51-59. [CrossRef] [PubMed]
 
Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. [CrossRef] [PubMed]
 
Wedzicha JA. Oral corticosteroids for exacerbations of chronic obstructive pulmonary disease. Thorax. 2000;55(suppl 1):S23-S27. [CrossRef] [PubMed]
 
Van Overveld FJ, Demkow U, Górecka D, De Backer WA, Zieliński J. Differences in responses upon corticosteroid therapy between smoking and non-smoking patients with COPD. J Physiol Pharmacol. 2006;57(suppl 4):273-282. [PubMed]
 
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