Withdrawal of inhaled corticosteroids in COPD: A meta-analysis

https://doi.org/10.1016/j.pupt.2017.06.002Get rights and content

Abstract

Background

Conflicting findings exist on the benefit of withdrawal of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD). We performed a quantitative synthesis in order to assess real impact of ICS discontinuation in COPD patients.

Methods

We carried out a meta-analysis via random-effects model on the available clinical evidence to evaluate the effect of ICS discontinuation in COPD. Randomized clinical trials and observational real-life studies investigating the effects of ICS withdrawal on the risk of COPD exacerbation, lung function (forced expiratory volume in 1 s [FEV1]) and quality of life (St. George's Respiratory Questionnaire [SGRQ]) were identified by searching from published studies and repository databases.

Results

ICS withdrawal did not significantly (P > 0.05) increase the overall rate of COPD exacerbation, although a clinically important increased risk of severe exacerbation was detected (Relative Risk >1.2). ICS withdrawal significantly (P < 0.001) impaired both lung function (−30 ml FEV1) and quality of life (+1.24 SGRQ units), although in a non-clinically important manner. The time to the first exacerbation was significantly (P < 0.05) shorter in the patients who discontinued ICS.

Conclusions

The discrepancy between statistical analysis and clinical interpretation of this meta-analytic evaluation demonstrates the strong clinical need in understanding what is the real impact of ICS withdrawal in COPD. ICS discontinuation is a complex procedure that requires a well planned and tailored strategy. Further well designed studies on withdrawal of ICS should be performed by clustering COPD patients with regard to the phenotype characteristics, rate of exacerbations/year, decline of lung function, and quality of life.

Introduction

The impact of inhaled corticosteroid (ICS) discontinuation in chronic obstructive pulmonary disease (COPD) has been investigated in several randomized clinical trials (RCTs) and real life studies since 2001. Nevertheless, to date conflicting findings and opinions remain on the real benefit of withdrawal of ICS. In fact, while several RCTs reported that COPD patients may be at increased risk of exacerbation, deterioration of quality of life and lung function after ICS discontinuation [1], [2], [3], [4], the data from two real life studies indicated that withdrawal of ICS can be safe and with no increased risk of exacerbations [5], [6]. Conversely, the results of a large RCT indicated that the risk exacerbations was similar among COPD patients who discontinued ICS and those who continued glucocorticoid therapy [7], whereas an observational prospective study concluded that ICS discontinuation can worsen lung function decline, airway hyperresponsiveness and quality of life [8]. Reassurance in ICS withdrawal was further provided by another RCT that enrolled low exacerbation risk patients [9].

ICS are widely prescribed across all the levels of COPD severity and exacerbation risk, with a rate of over-prescription that is two fold higher than that expected by following guidelines or recommendations such as the Global Initiative for Chronic Obstructive Lung Diseases (GOLD), although since 2007 it was suggested to limit the use of ICS in patients with reduced lung function and/or high exacerbation rate [10]. Nevertheless, the last version of the GOLD recommendation (2017) has highlighted that the studies on withdrawal of ICS produced equivocal results, and suggested that differences among the studies may be related with differences in methodology [11].

In this confusing scenario, we have carried out a quantitative synthesis via meta-analysis of the currently available data in order to provide consistent and homogeneous findings that may help to better clarify the real impact of ICS discontinuation in COPD patients, especially with regards to the risk of exacerbation, lung function and quality of life.

Section snippets

Materials and methods

Detailed meta-analytic methods are reported in the online Supplemental Materials.

Studies characteristics

Results obtained from 6066 COPD patients were selected from 10 published studies Table 1 [1], [2], [3], [4], [5], [6], [7], [8], [9], [22]. Table 2 shows the definition of exacerbation as reported by analyzed. Further results are reported in the online Supplemental Materials.

Primary endpoints

Overall, the withdrawal of ICS did not significantly (P > 0.05) affect the risk of COPD exacerbations. However, the subset analysis including only RTCs shown that, although in a non-significant manner (P > 0.05), there was

Discussion

The results of this meta-analysis demonstrates that ICS withdrawal did not significantly increase neither the overall risk of COPD exacerbation, nor the risk of moderate-to-severe exacerbations, although the time to the first exacerbation was significantly shorter in patients who discontinued ICS compared to those who continued the treatment. However, a signal of higher risk of experiencing at least one exacerbation was detected in patients enrolled in RCTs who discontinued ICS. Furthermore,

Conclusions

Although the current large body of evidence available from both RTCs and real life studies, even a large and rigorous meta-analysis did not allow to bridge the scientific gap concerning the discontinuation of ICS in COPD. This study highlights the strong clinical need of well designed studies aimed to investigate the impact of ICS withdrawal by clustering CODP patients with regard to at least the phenotype characteristics (i.e. frequent exacerbator, emphysema-hyperinflation and COPD with an

Question

Does withdrawal of ICS impair the risk of exacerbation, lung function and quality of life of COPD patients?

Findings

ICS withdrawal did not significantly increase the overall rate of COPD exacerbation, although a clinically important increased risk of severe exacerbation was detected. ICS withdrawal significantly impaired both lung function and quality of life, although in a non-clinically important manner.

Meaning

High-quality evidences concerning the impact of ICS withdrawal in COPD.

Guarantor

LC and PR have the responsibility for the content of the manuscript, including the data and analysis.

Author contributions

LC and PR contributed to study conception and design; contributed to acquisition, analysis, and interpretation of data; drafted the submitted article and revised it critically for important intellectual content and provided final approval of the version to be published.

MGM and MCa contributed to study design; contributed to interpretation of data; drafted the submitted article and revised it

Sources

This study was supported by institutional funds (University of Rome “Tor Vergata”, Rome, Italy).

Sponsor

Not applicable.

Role of sponsor/funder

No sponsor/funder had a role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

References (38)

  • J. Vestbo et al.

    Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial

    Lancet

    (2017 May 13)
  • A.B. Choudhury et al.

    Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial

    Respir. Res.

    (2007)
  • A. O'Brien et al.

    Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction

    Am. J. Respir. Crit. Care Med.

    (2001)
  • P. van der Valk et al.

    Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study

    Am. J. Respir. Crit. Care Med.

    (2002)
  • E.F. Wouters 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)
  • A. Rossi et al.

    Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO)

    Respir. Res.

    (2014)
  • C. Vogelmeier et al.

    “real-life” inhaled corticosteroid withdrawal in COPD: a subgroup analysis of DaCCOrD

    Int. J. Chron. Obstruct Pulmon Dis.

    (2017)
  • H. Magnussen et al.

    Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    N. Engl. J. Med.

    (2014)
  • A. Rossi et al.

    INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD

    Eur. Respir. J.

    (2014)
  • Cited by (48)

    • Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

      2021, Life Sciences
      Citation Excerpt :

      Similarly, the SUNSET trial identified that as ICS was tapered off, it led to a heightened risk of exacerbations among patients with an eosinophil count of ≥300 cells/mL [174]. However, several studies including the Clinical Practice Research Datalink (CPRD) reported that ICS withdrawal among COPD patient did not affect the exacerbation risk of moderate-to-severe severity significantly [172,175–177]. The difference in findings might be due to the use of different patient groups where the WISDOM trial had made use of patients with COPD of high severity, a past medical history of exacerbations and prior treatment with ICS before the trial, the SUNSET trial studied COPD patients treated with ICS regimens long-term and did not have persistent exacerbations whereas other studies such as CPRD utilized a patient population not at high exacerbation risk where the usage of bronchodilators and ICS are lesser than clinical trials [172–174].

    • Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis

      2019, Pulmonary Pharmacology and Therapeutics
      Citation Excerpt :

      The follow-up duration could not be consistent across the RCTs included in this meta-analysis. Therefore, dichotomous have been normalized as a function of person-time (namely person-half year) [18]. This method, supported by the Cochrane Collaboration and successfully used in recent meta-analyses [14,19–21] involves the conversion of the measures into a common metric (events per person-time) prior to meta-analyze the data, leading to improved estimates of effect, precision, and clinical interpretability of results [19,20].

    View all citing articles on Scopus
    View full text