Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting  2 agonist: observational matched cohort study (PATHOS)

Janson, Christer; Larsson, Kjell; Lisspers, Karin; Ställberg, Björn; Stratelis, Georgios; Goike, Helena; Jørgensen, Leif; Johansson, Gunnar

doi:10.1136/bmj.f3306

Cited by 171 publications

(182 citation statements)

References 36 publications

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“…Also the previously mentioned PATHOS study supported this observation [23]. Compared with budesonide/formoterol combination, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol combination, with a rate ratio 1.73 (CI: 1.57e1.90; P < 0.001) and 1.74 (1.56e1.94; P < 0.001), respectively.…”

Section: Potential Side Effects Of Ics In Copd: the Risk Of Pneumoniasupporting

confidence: 68%

“…The exacerbation rates in the budesonide/formoterol and fluticasone/salmeterol groups were 0.80 and 1.09 per patient-years, respectively (p < 0.0001), and yearly rates for COPD-related hospitalizations were 0.1 and 0.21, respectively (p < 0.0001). All other healthcare outcome were also significantly reduced with budesonide/formoterol vs fluticasone/salmeterol combination [22,23]. Therefore, also this study suggests that long-term with budesonide/ formoterol combination was associated with fewer healthcare utilization-defined exacerbations than fluticasone/salmeterol combination in patients with moderate and severe COPD.…”

Section: Comparative Clinical Efficacy Of Fluticasone/salmeterol and supporting

confidence: 51%

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Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

Latorre

Novelli

Vagaggini

et al. 2015

Pulmonary Pharmacology & Therapeutics

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a b s t r a c tInhaled corticosteroids (ICS) are frequently recommended for the treatment of asthma and COPD, often in combination with long-acting beta2-agonists (LABA), depending on the severity of the disease and/or on the specific phenotype. Several ICS/LABA combinations are currently available that differ in their pharmacokinetic characteristics and dose of both components. Thus, this review assesses differences in the efficacy and the safety profiles of the ICS components in the two more frequently used ICS/LABA combinations (budesonide/formoterol and fluticasone/salmeterol) for the management of COPD.Whereas the basic mechanism of action is similar for all ICS (binding with the intracellular glucocorticoid receptor, which mediates both genomic and non genomic effects), the pharmacokinetic and characteristics of ICS are quite different in terms of receptor affinity, bioavailability, lipophilicity and drug persistence in the airways. Fluticasone persists longer in airway mucus and requires more time to dissolve in the lining fluid and then enter the airway wall, whereas budesonide is cleared more quickly from the airways.Comparative efficacy of the two major ICS/LABA combinations recommended for the treatment of COPD show similar efficacy in terms of reduction of exacerbations, improvement in forced expiratory volume in the first second (FEV1) and quality of life. One retrospective cohort study suggested a greater efficacy for the budesonide/formoterol combination on hospital or emergency department admissions, oral corticosteroid courses, and addition of tiotropium, and an observational real-life study reported a greater reduction of COPD exacerbations with budesonide/formoterol than with fluticasom/salmeterol combination.Among the potential side effects of chronic ICS treatment in patients with COPD, recently the use of fluticasone or fluticasone/salmeterol combination has been associated with a higher prevalence of pneumonia in the major long-term studies. On the other hand, no similar increased risk of pneumonia has been reported in patients with COPD treated with the budesonide/formoterol combination. A recent population-based cohort study from the Quebec database showed that the adjusted odds ratio for having severe pneumonia was higher for fluticasone (2.1) than for budesonide (1.17) or other ICS (1.41). Of the ICS studied, only fluticasone demonstrated a dose-related increase in risk of pneumonia in patients with COPD. This difference between fluticasone and budesonide may be explained by the longer retention of fluticasone in the airways, with potentially greater inhibition of type-1 innate immunity.Therefore, the risk:benefit ratio should be evaluated thoroughly when choosing an ICS/LABA combination for patients with COPD.

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Section: Potential Side Effects Of Ics In Copd: the Risk Of Pneumoniasupporting

confidence: 68%

Section: Comparative Clinical Efficacy Of Fluticasone/salmeterol and supporting

confidence: 51%

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

Latorre

Novelli

Vagaggini

et al. 2015

Pulmonary Pharmacology & Therapeutics

View full text Add to dashboard Cite

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“…Two observational studies also found a lower risk of severe pneumonia with budesonide compared with fluticasone [65,66]. There is the possibility, however, that in both jurisdictions in which these studies were carried out, use of the formoterol/budesonide combination may have been a marker of asthma where ICS are not associated with an excess in pneumonia [67].…”

Section: Safety Of Ics and Laba/ics In Copdmentioning

confidence: 99%

Inhaled corticosteroids in COPD: the clinical evidence

2014

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In this article, we focus on the scientific evidence from randomised trials supporting treatment with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), including treatment with combinations of long-acting β-agonist (LABA) bronchodilators and ICS. Our emphasis is on the methodological strengths and limitations that guide the conclusions that may be drawn.The evidence of benefit of ICS and, therefore, of the LABA/ICS combinations in COPD is limited by major methodological problems. From the data reviewed herein, we conclude that there is no survival benefit independent of the effect of long-acting bronchodilation and no effect on FEV1 decline, and that the possible benefit on reducing severe exacerbations is unclear. Our interpretation of the data is that there are substantial adverse effects from the use of ICS in patients with COPD, most notably severe pneumonia resulting in excess deaths.Currently, the most reliable predictor of response to ICS in COPD is the presence of eosinophilic inflammation in the sputum. There is an urgent need for better markers of benefit and risk that can be tested in randomised trials for use in routine specialist practice. Given the overall safety and effectiveness of long-acting bronchodilators in subjects without an asthma component to their COPD, we believe use of such agents without an associated ICS should be favoured. @ERSpublicationsThe benefits of ICS in COPD are limited. Better tools are needed to identify which patients might benefit.

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“…TORCH was the largest RCT; it included more than 6,000 patients and was the first trial to show significantly increased risk of pneumonia (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.33-2.02) (19). Several other trials demonstrated increased risk of pneumonia among ICS users (3-7, 17, 20, 21) (23)(24)(25). This could be related to the difference between fluticasone and budesonide in potency or clearance rates from airways (26,27).…”

Section: Pneumoniamentioning

confidence: 99%

Incident Pneumonia and Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Double Effect of Inhaled Corticosteroids?

Festić

Scanlon

2015

Am J Respir Crit Care Med

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Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose-effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

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Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting 2 agonist: observational matched cohort study (PATHOS)

Abstract: Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β 2 agonist.

Cited by 171 publications

References 36 publications

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

Inhaled corticosteroids in COPD: the clinical evidence

Incident Pneumonia and Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Double Effect of Inhaled Corticosteroids?

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