Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Return to Current Issue | RSS Options

Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD

Christine de la Loge, MSc1 Béatrice Tugaut, MSc1 Fatoumata Fofana, MSc1 Jérémy Lambert, PhD1 Michael Hennig, PhD2 Uta Tschiesner, MD3 Mitra Vahdati-Bolouri, MRCP, MFPM4 Afisi Segun Ismaila, PhD5 Yogesh Suresh Punekar, PhD6

Author Affiliations

  1. Mapi, Patient-Centered Outcomes, Lyon, France
  2. Biostatistics and Epidemiology, GlaxoSmithKline, Munich, Germany
  3. Former employee of GlaxoSmithKline, Munich, Germany
  4. Research and Development, Global Respiratory Franchise, GlaxoSmithKline, Brentford, United Kingdom
  5. Value Evidence and Outcomes, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina; Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
  6. Value Evidence and Outcomes, GlaxoSmithKline, Brentford, United Kingdom

Address correspondence to:

Yogesh Suresh Punekar, PhD
GlaxoSmithKline
Brentford, TW8 9GS, UK
Email: yogesh.q.punekar@gsk.com
Phone: +44 (0) 208 047 4264

Abstract

Background: This meta-analysis assessed the relationship between change from baseline (CFB) in spirometric measurements (trough forced expiratory volume in 1 second [FEV1] and FEV1 area under the curve [AUC]) and patient-reported outcomes (St. George’s Respiratory Questionnaire total score [SGRQ] CFB, Transition Dyspnea Index [TDI] and exacerbation rates) after 6-12 months’ follow-up, using study treatment-group level data.

Methods: A systematic literature search was performed for randomized controlled trials of ≥24 weeks duration in adults with chronic obstructive pulmonary disease (COPD). Studies reporting ≥1 spirometric measurement and ≥1 patient-reported outcome (PRO) at baseline and at study endpoint were selected. The relationships between PROs and spirometric endpoints were assessed using Pearson correlation coefficient and meta-regression.

Results: Fifty-two studies (62,385 patients) were included. Primary weighted analysis conducted at the last assessment showed a large significant negative correlation (r, −0.68 [95% confidence interval (CI); −0.77, −0.57]) between trough FEV1 and SGRQ. Improvement of 100 mL in trough FEV1 corresponded to a 5.9 point reduction in SGRQ. Similarly, a reduction of 4 points on SGRQ corresponded to 40 mL improvement in trough FEV1 (p<0.001). The weighted correlation coefficients of trough FEV1 with TDI, exacerbation rate (all) and exacerbation rate (moderate/severe) at last assessment point were 0.57, -0.69 and -0.57, respectively (all p<0.05). For the analyses excluding placebo groups, the correlations of FEV1 with SGRQ and TDI were lower but significant.

Conclusions: A strong association exists between changes in spirometric measurements and changes in PROs.

Citation

Citation: de la Loge C, Tugaut B, Fofana F, et al. Relationship between FEV1 and patient-reported outcomes changes: Results of a meta-analysis of randomized trials in stable COPD. Chronic Obstr Pulm Dis. 2016; 3(2): 519-538. doi: http://doi.org/10.15326/jcopdf.3.2.2015.0152

PDF Download

PDF PDF Version (20829)

Running Head: Relationship Between FEV1 and PROs: A Meta-analysis

Funding Support: This study (GK15920) was funded by GlaxoSmithKline

Date of Acceptance: December 9, 2015

Abbreviations: change from baseline, CFB; forced expiratory volume in 1 second, FEV1; area under the curve, AUC; St. George’s Respiratory Questionnaire total score, SGRQ; transition dyspnea index, TDI; chronic obstructive pulmonary disease, COPD; patient-reported outcome, PRO; confidence interval, CI; Global initiative for chronic Obstructive Lung Disease, GOLD; randomized controlled trial, RCT; long-acting muscarinic antagonist, LAMA; long-acting β2-agonist, LABA; minimal clinically important difference, MCID; Cochrane Database of Systematic Review, CDSR; Cochrane Central Register of Controlled Trials, CENTRAL; Database of Abstracts of Reviews of Effects, DARE; EU Clinical Trials Register, EU-CTR; health technology assessment, HTA; National Institute for Health Research-Health Technology Assessment, NIHR-HTA; World Health Organization International Clinical Trials Registry Platform, WHO ICTRP; standard deviation, SD; baseline dyspnea index, BDI; 2 times a day, BID; not applicable, NA; once a day, OD; 4 times a day, QID

Citation: de la Loge C, Tugaut B, Fofana F, et al. Relationship between FEV1 and patient-reported outcomes changes: Results of a meta-analysis of randomized trials in stable COPD. Chronic Obstr Pulm Dis. 2016; 3(2): 519-538. doi: http://doi.org/10.15326/jcopdf.3.2.2015.0152

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease of the respiratory system characterized by chronic airway inflammation. The resulting airflow limitation is not fully reversible. Disease progression is associated with more severe and frequent exacerbations and declining lung function.1 Nevertheless, COPD is frequently under-diagnosed and under-treated.

The global burden of COPD is high and by 2020 will increase to reach a rank of 5 for burden of disease and 3 for cause of death.2 According to Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, assessment of COPD is based on the patient’s level of symptoms, exacerbation history, severity of spirometric abnormality, and identification of comorbidities.2 Although spirometry is now required for a confident diagnosis of COPD, diagnosis and management of the disease should not be purely based on spirometric categorization. Given the evidence that the level of forced expiratory volume in 1 second (FEV 1) poorly represents COPD status, revised GOLD guidelines recommend that both disease impact (symptom burden and activity limitation) and future risk of disease progression, particularly exacerbations, must be considered for adequate management of stable COPD.2

Patient-reported outcomes (PROs) based on symptom severity, activity limitation or health status are highly relevant for assessing disease severity or treatment impact from the perspective of policy makers and payers.3,4 Such outcomes are routinely collected in clinical trials using fully validated and widely accepted PRO instruments such as St. George’s Respiratory Questionnaire (SGRQ) and the Transition Dyspnea Index (TDI). However, there is limited evidence on the relationship between the typical regulatory endpoints such as FEV1 and the PRO endpoints which often creates challenges for policy makers while making reimbursement decisions for specific treatments.

The primary objective of the study was to assess the relationship between changes in spirometric measurements (particularly trough FEV1) and changes in PROs (SGRQ, TDI, and exacerbation rates) after at least 6 months of follow-up, using study treatment group level data. The analysis was repeated using treatment arms with active treatments (excluding placebo groups) and using treatment effect measurements (difference over placebo) for placebo-controlled studies.

Methods

Search Strategy

A systematic literature review was performed using a predefined search strategy to identify randomized controlled trials (RCTs) of 24 weeks’ duration or more in patients with COPD. Independent bibliographic systematic searches were conducted in April 2014 using the following databases (from inception to April 2014): MEDLINE, MEDLINE In‑Process, EMBASE, the Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment websites. Secondary systematic searches in clinical trial registries such as Clinicaltrials.gov (the U.S. National Institutes of Health clinical trial register), World Health Organization International Clinical Trials Registry Platform, International Standard Randomised Controlled Trial Number registry, and the European and Clinical Trials Register, were performed. Experienced researchers developed search strategies specifically tailored for each database. As an example, the search strategy for MEDLINE and MEDLINE In-Process is provided in Appendix 1 of the online supplementary data.

 

Selection Criteria

RCTs of at least 24 weeks’ duration conducted in adults with COPD (per GOLD guidelines) receiving long-acting muscarinic antagonists (LAMAs) and/or long-acting β2-agonists (LABAs) were included. Furthermore, only studies reporting at least 1 spirometric measurement of interest (trough FEV1, time-adjusted FEV1 AUC) and at least one PRO of interest (SGRQ, TDI, and exacerbation rates) at baseline and 6 and/or 12 months were selected. The search was limited to English language.

The search was directed to studies with similar pharmacodynamics properties: studies of monotherapy with LAMAs or LABAs (monotherapy with aclidinium bromide, formoterol, glycopyrronium, indacaterol, salmeterol, tiotropium, umeclidinium, or vilanterol) and/or the fixed-dose or free combination of both (umeclidinium/vilanterol, aclidinium/formoterol, tiotropium/olodaterol, or indacaterol/glycopyrronium). Studies with any of these treatments were included.

Studies were excluded if: (a) data were not available simultaneously for spirometric measurement and PRO endpoints at any time-point of interest; (b) the reported FEV1 was measured postdose; or (c) there was no evidence that FEV1 was measured predose. Furthermore, studies limited to patients with alpha-1 antitrypsin deficiency-related COPD and to non-white populations (e.g., Chinese, Japanese patients) were excluded.

The SGRQ assesses 3 domains (symptoms, activity, and impacts), with a total score ranging between 0 and 100. Higher values of SGRQ are associated with lower health-related quality of life.5,6 TDI characterizes a change in dyspnea from baseline and provides values between −9 and 9.7 Positive values in the TDI score correspond to clinical improvement. A 4-unit change in the total score of the SGRQ,8 a 1-unit change in TDI,9 and a change of 100 mL in FEV110 are considered as minimal clinically important differences (MCIDs) for these instruments. There is no agreed MCID for exacerbation rates although several estimates have been reported in literature.11

Selection Process

The relevance of each identified citation was assessed according to the predefined selection criteria. Selection was performed by 2 researchers (BT and JL) independently along with standardized quality assessments of the selected studies. Any discrepancies between researchers were resolved by consensus. The selected citations were grouped per study, as 1 study could have been published in several sources such as a conference abstract, full-text article, or trial registration.

Data Extraction

Data extraction was performed by 2 researchers (BT and JL) independently. Any discrepancies were discussed and resolved by consensus.

Data were primarily extracted from the text and tables of the source documents. If the data of interest were available solely as figures, these were extracted using DigitizeIt software version 2.0.3 (Digitize It, Braunschweig, Germany, http://digitizeit.de ). For each study, study characteristics, population characteristics, treatment groups, and spirometric and PRO endpoints of interest at selected time points (mean CFB, mean baseline, and mean follow-up values) were extracted. If mean CFB values were unavailable, these were calculated by subtracting the mean value at baseline from the mean value at follow-up.

Statistical Analysis

Study and patient characteristics, as well as outcome results (spirometric measurements and PROs at 6 or 12 months follow-up and last assessment) were summarized across all studies using (1) weights proportional to the sample size of the study treatment group in relation to the total number of patients across all treatment groups (weighted approach), and (2) equal weights for each study treatment group (unweighted approach).

Methods used to assess the relationship between PROs and spirometric endpoints included scatter and bubble plots (1 dot representing a treatment group results for both endpoints considered; the size of the dot being proportional to the sample size of the considered treatment group), linear regressions, and Pearson correlation coefficients with 95% confidence interval (CI). The linear regression equations were used to estimate the mean change in FEV1 corresponding to the established MCID thresholds of the PROs and to estimate the mean change in PROs corresponding to the established MCID threshold of a 100-mL change in FEV1.10 Similarly, the rate and incidence of exacerbations corresponding to a change of 100 mL in FEV1 also were calculated.

Primary analysis involved quantifying the relationship between trough FEV1 CFB and SGRQ CFB at last assessment (i.e., assessment at the 12-month follow-up if available for both considered endpoints, or if not available, at the 6-month follow-up).

Further statistical analyses were conducted to facilitate interpretation of results and explore the data. The regression and correlation analyses were conducted after exclusion of the placebo groups. We also conducted regression and correlation analyses between the active treatment group effect beyond placebo in FEV1 CFB and the effect beyond placebo in the various PROs (analyses conducted using data from placebo-controlled studies only, where the placebo group result is subtracted from each treatment group result).

All these analyses were conducted only when data for at least 15 study treatment groups were available. Such a sample size allows detecting a correlation coefficient of 0.7 with more than 85% power and associated type I error of 0.05.12 Interpretation of the amplitude of the absolute values of correlation coefficients were based on Cohen’s conventions (0.1-0.3, small/weak; 0.3-0.5, medium/moderate; > 0.5, large).12 No statistical correction for multiple tests was performed. All statistical analyses were conducted based on a predefined statistical analysis plan and using SAS software for Windows (Version 9.2, SAS Institute, Inc., Cary, NC, USA).

Results

Literature Search

The systematic bibliographic search identified 3006 abstracts from which a total of 2515 were excluded in the abstract/title screening phase. After full-text screening, a further 261 publications were excluded. The systematic registry search identified 4720 trial registrations from which 4636 were excluded (Figure 1). Three additional recently published references were identified through conference abstract and the registry search. Therefore, 233 full text publications and 84 trial registrations were retained for final study selection.

JCOPDF-2015-0152-Figure1

Overall, 118 studies were identified from the citations extracted based on the systematic literature search. Thirty-nine studies from the registry search did not have any results published or posted on the registry websites at the time of the search. The outcomes of 27 studies were out of scope of present meta-analysis; these studies were also excluded.In total, 52 unique studies13-62 were selected for this meta-analysis and the data for all these studies were extracted from all available sources, including clinical trial registries.

Study Characteristics

A description of key study characteristics is summarized in Table 1. The 52 unique studies included 163 treatment groups and 62,385 patients. The median study duration was 11.7 months. A majority of the studies (80.8%) did not allow background LABA and 57.7% allowed background ICS treatment. A majority of studies considered a lower threshold inclusion criterion of 10 pack years of cigarette smoking (82.7%) but no inclusion criteria regarding the number of exacerbations over the past year (71.2%). The upper thresholds most commonly encountered for the percentage of FEV1 inclusion criterion were 80% (28.8%) and 70% (23.1%).

JCOPDF-2015-0152-Table1a JCOPDF-2015-0152-Table1b JCOPDF-2015-0152-Table1c

 

Population Baseline Characteristics

The patients’ characteristics weighted by the sample size of each group across the 163 treatment groups from the 52 selected studies are summarized in Table 2. The number of patients in each study treatment group varied from 6 to 3006, with a median of 419. The mean (standard deviation [SD]) age was 63.7 (25.0) years. The proportion of men across the treatment groups varied from 43.0% to 100.0% (weighted mean proportion 70.4%). Large variation in baseline characteristics was seen for disease severity with the percentage of patients classified as severe or very severe (GOLD stage III or IV) ranging from 19.7% to 100.0% (median, 53.0%) and mean baseline trough FEV1 ranging from 890 to 1681 mL (median, 1180 mL).

JCOPDF-2015-0152-Table2

Most treatment groups were receiving LABA (25.2%), LAMA (21.5%), placebo (20.9%), or LABA and ICS (19.6%).

Data Availability for the Endpoint Combinations

The online supplementary Table 1 provides treatment group-level data on endpoints of interest for all the included studies. The combinations of endpoints with at least 15 study-treatment groups (N) are described in Table 3. In combination with FEV1, SGRQ was the most reported endpoint (111 treatment groups; 38 studies) followed by TDI (68; 22), all exacerbations (24; 10) and moderate/severe exacerbations (69; 23). FEV1 AUC0-12h and SGRQ data at last assessment were available from 5 studies with 22 treatment arms.

JCOPDF-2015-0152-Table3

The duration between baseline and the last assessment varied across endpoint combinations. The duration was longest for the analysis of the combination of SGRQ with trough FEV1 (median, 11.1 months; 55.9% at 12 months) and shortest for the analysis of FEV1 AUC0-12h with trough FEV1 (median, 6.0 months; 81.8% at 6 months).

Correlation and Regression Analyses Between Spirometric Measurements and PROs

The correlation and regression results of the primary and secondary analyses are shown in Tables 4-6 and Figures 2-4. Table 4 provides weighted and unweighted Pearson correlation coefficients and linear regression results showing values corresponding to known MCIDs for each combination of endpoints at available time points. Figure 2 provides visual representation of the association between these combinations of endpoints at the last assessment using bubble plots.

JCOPDF-2015-0152-Table4

JCOPDF-2015-0152-Table5

JCOPDF-2015-0152-Table6

JCOPDF-2015-0152-Figure2

JCOPDF-2015-0152-Figure3

JCOPDF-2015-0152-Figure4

Primary analysis conducted at the last assessment with weighted means of changes from baseline in trough FEV1 and SGRQ showed a large, significant negative correlation coefficient (r [95% CI], N), corresponding to −0.68 ([−0.77, −0.57], 111) (Table 4). The regression results (weighted) confirmed this highly significant association (p < 0.0001) with an improvement of 100 mL in trough FEV1 corresponding to a reduction of 5.9 in SGRQ total score and a reduction of 4 units on the SGRQ total score, equating to a 40 mL improvement in trough FEV1 (Table 4, Figure 2A). Results of weighted analyses between trough FEV1 and the TDI score at the last assessment showed a large, significant positive correlation, with an improvement of 100 mL in trough FEV1 corresponding to an improvement of 1.9 on the TDI score, while an improvement of 1 point on TDI was equivalent to a 48 mL reduction in trough FEV1 (p < 0.0001) (Table 4, Figure 2B). A large, negative correlation coefficient was obtained using the time-adjusted FEV1 AUC0-12h and SGRQ at the last assessment. Weighted regression results also indicated a highly significant association (p = 0.0031) between FEV1 AUC0-12h and SGRQ at last assessment, with an improvement of 100mL in FEV1 AUC0-12h corresponding to an improvement of -5.75 on SGRQ, while an improvement of 4 units on SGRQ corresponds to a 10 mL reduction in FEV1 AUC0-12h (Table 4, Figure 2C). Statistically significant negative correlations were obtained between trough FEV1 and the annual rate of exacerbations (overall, moderate or severe). Table 4 and Figures 2D and 2E show that improvement in FEV1 leads to reduction in the annual rate of exacerbations. An improvement of 100 mL in trough FEV1 corresponds to an annual rate of exacerbations of 0.5, while no change on FEV1 corresponds to an annual rate of exacerbations of 2.3 (p = 0.0002). An improvement of 100 mL in trough FEV1 corresponds to an annual rate of moderate or severe exacerbations of 0.7, while no change on FEV1 corresponds to an annual rate of moderate or severe exacerbations of 0.9 (p < 0.0001).

Results of the sensitivity analyses conducted at other time points (6 and/or 12 months, subject to availability of data, Table 4) were comparable. Results of the unweighted analyses (Table 4) also were consistent with the results of the weighted analyses.

Further analyses conducted at the last assessment excluding the placebo groups are shown in Table 5. The weighted correlation coefficients at last assessment for the following pairs, trough FEV1 and SGRQ (−0.63), trough FEV1 and TDI (0.31), FEV1 AUC0-12h and SGRQ (−0.49), exacerbation rate (overall) and trough FEV1 (−0.88) and exacerbation rate (moderate/severe) and trough FEV1 (−0.67) were statistically significant (all p < 0.05) (Table 5, Figure 3). Overall, these results limited to active treatment were similar to the main analysis. The correlations of FEV1 with PROs were significant although slightly decreased; correlations with exacerbation rates were significant and slightly increased.

Further analyses conducted at the last assessment with weighted means of difference over placebo in trough FEV1 and in SGRQ showed a medium and statistically significant correlation coefficient −0.35 [(−0.56, −0.08), 53] (Table 6). The weighted regression results indicate a significant association between the change beyond placebo in trough FEV1 and in SGRQ at the last assessment (p < 0.05), with an improvement over placebo of 100 mL in trough FEV1 corresponding to a reduction of 2.9 in SGRQ total score and conversely, a reduction of 4 units on the SGRQ total score, corresponding to a 201 mL improvement in trough FEV1 beyond placebo (Table 6, Figure 4). Analysis of all other combinations of endpoints exploring the association of effects beyond placebo on FEV1 and on PROs, with weighted or unweighted approach (Table 6) lead to non-significant results (p > 0.05).

Discussion

Both objectively measured lung function and subjectively measured PROs are frequently assessed during COPD clinical management. Both of these endpoints remain important to decision makers with regulators preferring to assess benefits of new treatments on lung function and payers on PROs. However, data on the association between spirometric measurements and PROs among patients with COPD are sparse, generally limited to a single study context and with different methodologies and outcomes potentially leading to variable conclusions.63-66 A previous meta-analysis67 evaluated the association between lung function measurements and PROs in bronchodilator trials. This study further explores the relationship between spirometric measurements and PROs and includes current evidence from combination therapies in COPD trials.

Our primary analysis showed a large and highly significant association between SGRQ and trough FEV1. Analyses with other pairings of spirometric measurements and PROs showed correspondingly large correlation coefficients, and a similar trend: A MCID change in FEV1 corresponding to a larger than MCID change in PROs. Such trends, where significant changes in PROs are associated with subclinical changes in objective parameters (such as FEV1), are often encountered in clinical trials. Potential contributing factors to this phenomenon are the Hawthorne effect, wherein the study participants change their behavior because they are observed, or the Pygmalion effect whereby the patients’ desire to meet the expectations of their clinician or the study sponsor tends to exaggerate their symptoms and their impacts at inclusion and minimize these at follow-up,68 leading to optimistic change over time. As these factors are observed in both active and placebo arms, there are no consequences for treatment group comparisons, though the phenomena may result in apparent discrepancies in MCID values and regression estimates for subjective and objective measurements, as observed in the present study. Further, it must be considered that as each MCID has been established independently and using different methods,8-10 it is therefore not surprising to obtain results that do not match. Result of our analyses on combination therapies including newly launched combination bronchodilators, provides a more comprehensive meta-analysis (52 studies; 62,385 patients versus 22 studies; 23,654 patients) compared to the Westwood et al analysis.67 The results of the analysis at 6 and 12 months’ follow-up suggest that the correlation of trough FEV1 with SGRQ and TDI strengthens with time, consistent with the previous study.67 This association decreased slightly after removal of the placebo groups from the analysis and decreased largely when analyzing treatment effects beyond placebo. The association between FEV1 and SGRQ however, remained significant. Overall, the results were consistent with the Westwood et al study suggesting that the association between trough FEV1 and PROs observed in bronchodilator studies remains with combination therapies.

Results of the analysis exploring the association of treatment effects beyond placebo are of particular interest. The correlation between FEV1 and SGRQ at last assessment was significant while all other associations did not reach statistical significance. Corresponding regression results indicated that an improvement of 100 mL over placebo in trough FEV1 corresponds to a reduction of 2.9 in SGRQ total score and conversely, a reduction of 4 units in the SGRQ total score corresponds to a 201 mL improvement in trough FEV1 beyond placebo. These estimates are broadly consistent with the results observed in recent studies of dual bronchodilators17,69 and indicate that after eliminating the placebo effect, a 4 point (MCID) change difference on the SGRQ score represents a much larger change than the 100 mL MCID for FEV1. It must be noted that these analyses beyond placebo effect excluded 17 clinical trials that were not placebo-controlled– generally conducted in patients with more severe disease–which may have led to a selection bias. Limiting the analysis to more severe disease with limited variability is particularly detrimental to regression analyses. Further research is needed to address this conclusively.

Some limitations of our meta-analysis must be acknowledged. Given the unavailability of individual-patient data, the meta-analysis was conducted using study-level data and the precision of the results would have been increased if the individual-patient data were available. Although we conducted an extensive search of the clinical trial registries and websites of the regulatory authorities to minimize publication bias, this meta-analysis is still limited by the availability of data in the public domain. Furthermore, not all endpoints of interest are available for all studies and also, the endpoint definitions may differ between studies especially for variables such as exacerbation rate and severity of exacerbation. However, given the rigorous methodology followed while ascertaining the endpoint definitions for each study, the risk of misclassification should be minimal. As the studies included are clinical trials of bronchodilators, the study populations for these trials do not usually include an exacerbating patient population, which may lead to fewer exacerbations in these trials. Furthermore, exacerbations are included as safety rather than efficacy endpoints. Thus, these trials are not powered to assess differences in exacerbation rates of the study groups, which would affect the corresponding results of our study.

Conclusions

The results of this meta-analysis provide important clinically meaningful insights into the relationship between FEV1, the standard primary endpoint for COPD clinical trials, and PROs, namely SGRQ health status measure, TDI, and annual exacerbation rates. Besides including additional clinical trials published in the past few years, the study provides results on new endpoints such as the relationship between FEV1 and the annual rate of exacerbations. The strength of these associations is largely decreased when results beyond placebo effect are assessed. Overall, the results of our correlation and regression analyses demonstrate a strong association between changes in spirometric measurements and changes in PROs from their baseline values.

Acknowledgments

This study was funded by GlaxoSmithKline. All listed authors met the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors would like to acknowledge Eline Huisman for her technical support in the systematic review and data extraction and Juliette Meunier for her technical support in SAS programming. Medical writing services were provided by Vidula Bhole, MD, MHSc, of Cactus Communications and funded by GlaxoSmithKline.

Declaration of Interest

YSP, MH, M V-B and ASI are employees of GlaxoSmithKline and hold stock in GlaxoSmithKline. UT was an employee of GlaxoSmithKline at the time of this study and held stock in GlaxoSmithKline. BT, FF, and JL are employed by Mapi and were paid consultants to GlaxoSmithKline. CdL works as an independent consultant and was paid by Mapi to participate in this study. All authors contributed to the conception and design of the study. CdL, BT, FF and JL contributed to data acquisition and analysis. All authors contributed to data analysis and interpretation.

Online Supplement

JCOPDF-2015-0152-SupTable1

1. Viegi G, Pistelli F, Sherrill DL, et al. Definition, epidemiology and natural history of COPD. Eur Respir J. 2007; 30(5): 993-1013. doi :http://dx.doi.org/10.1183/09031936.00082507

2. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013; 187(4): 347-365. doi: http://dx.doi.org/10.1164/rccm.201204-0596PP

3. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007; 176(6): 532-555. doi: http://dx.doi.org/10.1164/rccm.200703-456SO

4. IQWiG: Institute for Quality and Efficiency in Health Care [German]. General Methods Version 4.1. IQWiG website. https://www.iqwig.de/download/IQWiG_General_Methods_Version_%204-1.pdf Published November 28, 2013. Accessed February 25, 2016

5. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992; 145(6): 1321-1327. doi: http://dx.doi.org/10.1164/ajrccm/145.6.1321

6. Jones PW, Quirk FH, Baveystock CM. The St. George's Respiratory Questionnaire. Respiratory Med. 1991; 85 (Suppl 2):25-31. doi: http://dx.doi.org/10.1016/S0954-6111(06)80166-6

7. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984; 85(6): 751-758. doi: http://dx.doi.org/10.1378/chest.85.6.751

8. Jones PW. St. George's Respiratory Questionnaire: MCID. COPD. 2005; 2(1): 75-79. doi: http://dx.doi.org/10.1081/COPD-200050513

9. Mahler DA, Witek TJ, Jr. The MCID of the transition dyspnea index is a total score of one unit. COPD. 2005; 2(1): 99-103. doi: http://dx.doi.org/10.1081/COPD-200050666

10. Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005; 2(1): 111-124. doi: http://dx.doi.org/10.1081/COPD-200053377

11. Chapman KR, Bergeron C, Bhutani M, et al. Do we know the minimal clinically important difference (MCID) for COPD exacerbations? COPD. 2013; 10(2): 243-249. doi: http://dx.doi.org/10.3109/15412555.2012.733463

12. Cohen J. Statistical Power Analysis For The Behavioral Sciences. Maywah, New Jersey: Lawrence Erlbaum Associates. 1988.

13. Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. Chest. 2014; 145(5): 981-991. doi: http://dx.doi.org/10.1378/chest.13-1579

14. Abrahams R, Moroni-Zentgraf P, Ramsdell J, et al. Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD. Respir Med. 2013; 107(6): 854-862. doi: http://dx.doi.org/10.1016/j.rmed.2013.02.005

15. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013; 42(6): 1484-1494.doi: http://dx.doi.org/10.1183/09031936.00200212

16. Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013; 1(7): 524-533. doi: http://dx.doi.org/10.1016/S2213-2600(13)70158-9

17. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013; 107(10): 1538-1546. doi: http://dx.doi.org/10.1016/j.rmed.2013.06.001

18. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013; 1(3): 210-223. doi: http://dx.doi.org/10.1016/S2213-2600(13)70040-7

19. D'Urzo A, Kerwin E, Rennard S, et al. One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. COPD. 2013; 10(4): 500-510. doi: http://dx.doi.org/10.3109/15412555.2013.791809

20. Gelb AF, Tashkin DP, Make BJ, et al. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Respir Med. 2013; 107(12): 1957-1965. doi: http://dx.doi.org/10.1016/j.rmed.2013.07.001

21. Kerwin EM, Scott-Wilson C, Sanford L, et al. A randomised trial of fluticasone furoate/vilanterol (50/25 mug; 100/25 mug) on lung function in COPD. Respir Med. 2013; 107(4): 560-569. doi: http://dx.doi.org/10.1016/j.rmed.2012.12.014

22. Martinez FJ, Boscia J, Feldman G, et al. Fluticasone furoate/vilanterol (100/25; 200/25 mug) improves lung function in COPD: a randomised trial. Respir Med. 2013; 107(4): 550-559. doi: http://dx.doi.org/10.1016/j.rmed.2012.12.016

23. Vogelmeier CF, Bateman ED, Pallante J, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med. 2013; 1(1): 51-60. doi: http://dx.doi.org/10.1016/S2213-2600(12)70052-8

24. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013; 1(3): 199-209. doi: http://dx.doi.org/10.1016/S2213-2600(13)70052-3

25. Doherty DE, Tashkin DP, Kerwin E, et al. Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD. Int J Chron Obstruct Pulmon Dis. 2012; 7:57-71. doi: http://dx.doi.org/10.2147/COPD.S27320

26. Hanania NA, Crater GD, Morris AN, et al. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med. 2012; 106(1): 91-101. doi: http://dx.doi.org/10.1016/j.rmed.2011.09.002

27. Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012; 40(4): 830-836. doi: http://dx.doi.org/10.1183/09031936.00225511

28. Kerwin E, Hebert J, Gallagher N, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012; 40(5): 1106-1114. doi: http://dx.doi.org/10.1183/09031936.00040712

29. Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ. Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med. 2012; 106(2): 257-268. doi: http://dx.doi.org/10.1016/j.rmed.2011.07.020

30. Tashkin DP, Doherty DE, Kerwin E, et al. Efficacy and safety of a fixed-dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52-week Phase III trial. Int J Chron Obstruct Pulmon Dis. 2012; 7:43-55. doi: http://dx.doi.org/10.2147/COPD.S27319

31. Chapman KR, Rennard SI, Dogra A, et al. Long-term safety and efficacy of indacaterol, a long-acting beta(2)-agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest. 2011; 140(1): 68-75. doi: http://dx.doi.org/10.1378/chest.10-1830

32. D'Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011; 12:156. doi: http://dx.doi.org/10.1186/1465-9921-12-156

33. Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011; 12:55. doi: http://dx.doi.org/10.1186/1465-9921-12-55

34. Bateman E, Singh D, Smith D, et al. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis. 2010; 5:197-208.

35. Bateman ED, Tashkin D, Siafakas N, et al. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med. 2010; 104(10): 1460-1472. doi: http://dx.doi.org/10.1016/j.rmed.2010.06.004

36. Calverley PM, Kuna P, Monso E, et al. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med. 2010; 104(12): 1858-1868. doi: http://dx.doi.org/10.1016/j.rmed.2010.09.008

37. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010; 65(6): 473-479. doi: http://dx.doi.org/10.1136/thx.2009.125435

38. Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010; 182(2): 155-162. doi: http://dx.doi.org/10.1164/rccm.200910-1500OC

39. Hanania NA, Donohue JF, Nelson H, et al. The safety and efficacy of arformoterol and formoterol in COPD. COPD. 2010; 7(1): 17-31. doi: http://dx.doi.org/10.3109/15412550903499498

40. Anzueto A, Ferguson GT, Feldman G, et al. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009; 6(5): 320-329. doi: http://dx.doi.org/10.1080/15412550903140881

41. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009; 69(5): 549-565. doi: http://dx.doi.org/10.2165/00003495-200969050-00004.

42. Donohue JF, Hanania NA, Sciarappa KA, et al. Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: a one year evaluation of safety and tolerance. Ther Adv Respir Dis. 2008; 2(2): 37-48. doi: http://dx.doi.org/10.1177/1753465808089455.

43. Ferguson GT, Anzueto A, Fei R, et al. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med. 2008; 102(8): 1099-1108. doi: http://dx.doi.org/10.1016/j.rmed.2008.04.019

44. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008; 68(14): 1975-2000. doi: http://dx.doi.org/10.2165/00003495-200868140-00004

45.Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008; 359(15): 1543-1554. doi: http://dx.doi.org/10.1056/NEJMoa0805800

46. Tonnel AB, Perez T, Grosbois JM, et al. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis. 2008; 3(2): 301-310. doi: http://dx.doi.org/10.2147/COPD.S2463

47. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007; 146(8): 545-555. doi: http://dx.doi.org/10.7326/0003-4819-146-8-200704170-00152

48. Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT, on behalf of the SAFE Study Group. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J. 2007; 14(8): 465-472.

49. Stockley RA, Chopra N, Rice L. Addition of salmeterol to existing treatment in patients with COPD: a 12 month study. Thorax. 2006; 61(2): 122-128. doi: http://dx.doi.org/10.1136/thx.2004.033266

50. GlaxoSmithKline. A multicentre, randomised, double-blind, parallel group, 24-week study to compare the effect of the salmeterol/fluticasone propionate combination product 50/250mcg, with salmeterol 50mcg both delivered twice daily via the DISKUS/ACCUHALER inhaler on lung function and dyspnoea in subjects with chronic obstructive pulmonary disease (COPD). GlaxoSmithKline Clinical Trial Register website. http://www.gsk-clinicalstudyregister.com/study/100470#rs2005 Published 2005. Accessed February 25, 2016.

51. GlaxoSmithKline. Multicentre, randomised, parallel group, placebo-controlled, double-blind study, stratified on tobacco status at enrollment, evaluating during 6 months the efficacy of salmeterol powder for inhalation, 50μg two times per day for the reduction of thoracic distension in subjects with chronic obstructive pulmonary disease (COPD). GlaxoSmithKline Clinical Trial Register website. http://www.gsk-clinicalstudyregister.com/study/SLMF4010#rs. Published2005. Accessed February 25, 2016.

52. Wouters EF, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005; 60(6): 480-487. doi: http://dx.doi.org/10.1136/thx.2004.034280

53. Brusasco V, Hodder R, Miravitlles M, et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003; 58(5): 399-404. doi: http://dx.doi.org/10.1136/thx.58.5.399

54. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003; 361(9356): 449-456. doi: http://dx.doi.org/10.1016/S0140-6736(03)12459-12462

55. Dal Negro RW, Pomari C, Tognella S, Micheletto C. Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline. Pulm Pharmacol Ther. 2003; 16(4): 241-246.

56. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003; 124(3): 834-843. doi: http://dx.doi.org/10.1378/chest.124.3.834

57. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002; 19(2): 217-224. doi: http://dx.doi.org/10.1183/09031936.02.00269802

58. Chapman KR, Arvidsson P, Chuchalin AG, et al. The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Can Respir J. 2002; 9(3): 178-185.

59. Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002; 122(1): 47-55. doi: http://dx.doi.org/10.1378/chest.122.1.47

60. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002; 166(8): 1084-1091. doi: http://dx.doi.org/10.1164/rccm.2112055

61. Rossi A, Kristufek P, Levine BE, et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest. 2002; 121(4): 1058-1069. doi: http://dx.doi.org/10.1378/chest.121.4.1058

62. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J. 2002; 19(2): 209-216. doi: http://dx.doi.org/10.1183/09031936.02.00238702

63. Spencer S, Calverley PM, Sherwood Burge P, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001; 163(1): 122-128. doi: http://dx.doi.org/10.1164/ajrccm.163.1.2005009

64. Ferrer M, Alonso J, Prieto L, et al. Validity and reliability of the St George's Respiratory Questionnaire after adaptation to a different language and culture: the Spanish example. Eur Respir J. 1996; 9(6): 1160-1166. doi: http://dx.doi.org/10.1183/09031936.96.09061160

65. Stahl E, Lindberg A, Jansson SA, et al. Health-related quality of life is related to COPD disease severity. Health Qual Life Outcomes. 2005; 3:56. doi: http://dx.doi.org/10.1186/1477-7525-3-56

66. Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996; 154(6): 1726-1734. doi: http://dx.doi.org/10.1164/ajrccm.154.6.8970362

67. Westwood M, Bourbeau J, Jones PW, et al. Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review. Respiratory Res. 2011; 12:40. doi: http://dx.doi.org/10.1186/1465-9921-12-40

68. Berthelot JM, Le Goff B, Maugars Y. The Hawthorne effect: stronger than the placebo effect? Joint Bone Spine. 2011; 78(4): 335-336. doi: http://dx.doi.org/10.1016/j.jbspin.2011.06.001

69. Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med. 2014; 108(12): 1752-1760. doi: http://dx.doi.org/10.1016/j.rmed.2014.10.002

Keywords (Click on any keyword for related articles)

Images

  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD
  • Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD

Share This Article

E-mail this article to a friend   

Copyright 2024 by COPD Foundation Disclaimer| Privacy|

The COPD Foundation is a nonprofit, tax-exempt charitable organization under Section 501(c)(3) of the Internal Revenue Code.