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Inhaled corticosteroids and pneumonia mortality in COPD patients

Samy Suissa
European Respiratory Journal 2019 54: 1901276; DOI: 10.1183/13993003.01276-2019
Samy Suissa
Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and the Depts of Epidemiology and Biostatistics and of Medicine, McGill University, Montreal, QC, Canada
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  • For correspondence: samy.suissa@mcgill.ca
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Abstract

The “paradoxical” effect of inhaled corticosteroids increasing pneumonia incidence in COPD but reducing post-pneumonia and all-cause mortality is no paradox but due to selection and immortal time biases in the observational studies of mortality http://bit.ly/2Yd3hDh

From the authors:

I thank P. Almagro and co-workers for their letter, which provides updated data regarding the association between inhaled corticosteroids (ICS) and pneumonia mortality in chronic obstructive pulmonary disease (COPD). It confirms the shortage of, and need for, rigorous studies on this question. My article, on the other hand, was focusing on a methodological, causal inference explanation for the paradoxical phenomenon of observational studies reporting that ICS use increases the incidence of pneumonia in contrast with other observational studies reporting that ICS use prior to a pneumonia event decreases mortality [1].

Nevertheless, their conclusion that in using ICS in COPD “clinicians must balance the pneumonia risk with the reduction in both severe exacerbations and the mortality” is not founded on the evidence available to date. This conclusion implies that while ICS increase the risk of pneumonia, they are also effective at reducing the incidence of both severe exacerbations and mortality. The latter is not supported by the totality of evidence. Indeed, a network meta-analysis of 99 randomised controlled trials shows that ICS do not reduce the incidence of severe exacerbations in COPD, on the contrary they appear to increase it, when compared with mono or dual bronchodilators [2]. This meta-analysis also corroborates the increased risk of pneumonia with ICS [2]. With respect to mortality, only observational studies reported a reduction in all-cause death with ICS [3, 4]. However, these studies were shown to be seriously affected by immortal time bias, which tends to exaggerate a drug's beneficial effect [5, 6]. Observational studies that were designed to avoid this bias showed no reduction in mortality [7]. To date, no randomised trial has shown that ICS are associated with a reduction in mortality [2, 8].

Therefore, the evidence-based balance that clinicians should be concerned with when prescribing ICS versus long-acting bronchodilators in patients with COPD is between the risk of pneumonia and perhaps a reduction of mild and moderate exacerbations, but certainly not the severe ones or mortality, as suggested by P. Almagro and co-workers.

The more recent observational studies conducted in real-world clinical practice settings suggest that ICS may be effective at reducing moderate exacerbations only in the subset of patients with significant eosinophilia or frequent exacerbators [9, 10]. Consequently, with the established risk of pneumonia with ICS, this therapy should only be used sparingly in the subset of COPD patients for whom the benefit may outweigh the risk, such as patients with asthma, frequent exacerbators and those with significant eosinophilia [11, 12]. More research is needed to better identify such markers for a more accurate precision medicine approach to the treatment of COPD patients [13].

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Footnotes

  • Conflict of interest: S. Suissa reports personal fees for board membership from Novartis and Boehringer Ingelheim, grants from Boehringer Ingelheim/Pfizer, personal fees for lectures from AstraZeneca, outside the submitted work.

  • Received June 26, 2019.
  • Accepted June 27, 2019.
  • Copyright ©ERS 2019
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References

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    1. Suissa S
    . Inhaled corticosteroids preventing pneumonia mortality: paradox or selection bias? Eur Respir J 2019; 53: 1802112.
    OpenUrlAbstract/FREE Full Text
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    1. Oba Y,
    2. Keeney E,
    3. Ghatehorde N, et al.
    Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis. Cochrane Database Syst Rev 2018; 12: CD012620.
    OpenUrl
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    1. Sin DD,
    2. Tu JV
    . Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 580–584.
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    1. Soriano JB,
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    3. Pride NB, et al.
    Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J 2002; 20: 819–825.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Suissa S
    . Effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immortal time bias in observational studies. Am J Respir Crit Care Med 2003; 168: 49–53.
    OpenUrlCrossRefPubMedWeb of Science
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    1. Suissa S
    . Inhaled steroids and mortality in COPD: bias from unaccounted immortal time. Eur Respir J 2004; 23: 391–395.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Suissa S,
    2. Ernst P
    . Observational studies of inhaled corticosteroid effectiveness in COPD: lessons learned. Chest 2018; 154: 257–265.
    OpenUrl
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    1. Ernst P,
    2. Saad N,
    3. Suissa S
    . Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J 2015; 45: 525–537.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Suissa S,
    2. Dell'Aniello S,
    3. Ernst P
    . Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study. Lancet Respir Med 2018; 6: 855–862.
    OpenUrl
  10. ↵
    1. Suissa S,
    2. Dell'Aniello S,
    3. Ernst P
    . Comparative effectiveness and safety of LABA-LAMA vs LABA-ICS treatment of COPD in real-world clinical practice. Chest 2019; 155: 1158–1165.
    OpenUrl
  11. ↵
    1. Suissa S,
    2. Ariel A
    . Triple therapy in COPD: only for the right patient. Eur Respir J 2019; 53: 1900394.
    OpenUrlAbstract/FREE Full Text
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    1. Suissa S,
    2. Ernst P
    . Precision medicine urgency: the case of inhaled corticosteroids in COPD. Chest 2017; 152: 227–231.
    OpenUrl
  13. ↵
    1. Suissa S,
    2. Ariel A
    . Triple therapy trials in COPD: a precision medicine opportunity. Eur Respir J 2018; 52: 1801848.
    OpenUrlAbstract/FREE Full Text
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Inhaled corticosteroids and pneumonia mortality in COPD patients
Samy Suissa
European Respiratory Journal Sep 2019, 54 (3) 1901276; DOI: 10.1183/13993003.01276-2019

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Inhaled corticosteroids and pneumonia mortality in COPD patients
Samy Suissa
European Respiratory Journal Sep 2019, 54 (3) 1901276; DOI: 10.1183/13993003.01276-2019
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