Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β₂ agonist: observational matched cohort study (PATHOS)

I have read with great interest the article by Janson et al (1). The authors reported an increase in pneumonia rate and in the risk of mortality related to pneumonia in COPD patients treated with fluticasone/salmeterol compared with budesonide/formoterol. However, all-cause mortality did not differ between the two treatments.

A previous paper derived from the PATHOS study showed fewer COPD exacerbations (including those that required hospitalization) with budesonide/formoterol (2). Given the fact that COPD exacerbations increase the risk of death, independently of baseline severity of the disease (3), it would be expected an increase in mortality in the fluticasone/salmeterol cohort. In an electronic letter to the editor regarding this question, the authors report that all cause mortality was indeed slightly higher in the fluticasone/salmeterol group, although the difference did not reach statistical significance (4). This could be the result of a low statistical power of the study to detect this difference or the consequence of a relative increase in the risk of death from non-respiratory causes in the budesonide/formoterol group that could equilibrate mortality rates up to a point.

I have noted that the percentage of females in the study population (53%) was unusually high for a COPD cohort. A population-based study on the prevalence of COPD carried out in Sweden showed a 40.7% proportion of females among COPD patients (5). This raises the possibility that some of the study subjects were actually asthmatic patients misdiagnosed as COPD. An analysis of the baseline characteristics of the unmatched populations in the PATHOS study show a different profile in the patients treated with budesonide/formoterol and with fluticasone/salmeterol. Previous diagnosis of asthma was more frequent in the fluticasone/salmeterol group (1) and the percentage of smokers was higher in the budesonide/formoterol cohort (2).

Although the authors made every possible effort to match both populations by means of a propensity score matching that included the diagnosis of comorbidities and the use of cardiovascular prescriptions, and although the smoking status was similar in the matched populations, I wonder if it might still be possible that more asthmatics, wrongly diagnosed as COPD, were included in the fluticasone/salmeterol group. If this was the case, it could justify an inequality in cardiovascular deaths between both groups , as cardiovascular diseases seem to be more strongly associated with COPD than with asthma (6).

Another possibility might be an intra-class difference with regard to the effects of both medications in non-respiratory deaths. Previous observational studies suggested that inhaled corticosteroids use might be associated with a reduction in cardiovascular death, although this effect has not been confirmed in randomized controlled trials (7). It would be most interesting if the authors could report if there were significant differences between the budesonide/formoterol and the fluticasone/salmeterol matched cohorts with regard to mortality by cause, with a special emphasis on cardiovascular death.

1-Janson C, Larsson K, Lisspers KH et al. Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroids and long acting ϐ2 agonist: observational matched cohort study (PATHOS). BMJ 2013;346:f3306.

2-Larsson K, Janson C, Lisspers K, et al. Combination of budesonide/formoterol more effective than fluticasone/salmeterol in preventing exacerbations in chronic obstructive pulmonary disease: the PATHOS study. J Intern Med 2013;273:584-94.

3- Soler-Cataluña JJ, Martínez-García MA, Sánchez L, Perpiñá M, Román P. Severe exacerbations and BODE index: two independent risk factors for death in male COPD patients. Respir Med 2009;103.692-9.

4- http://www.bmj.com/content/346/bmj.f3306/rr/664179

5- Danielsson P, Ólafsdóttir IS, Benediktsdóttir B, Gíslason T, Janson C. The prevalence of chronic obstructive pulmonary disease in Uppsala, Sweden – the Burden of Obstructive Lung Disease (BOLD) study: cross-sectional population-based study. Clin Respir J 2012;6:120-7.

6- Cazzola M, Calzetta L, Bettoncelli G, et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respir Med 2012;106:249-56.

7- Loke YK, Kwok CS, Singh S. Risk of myocardial infarction and cardiovascular death associated with inhaled corticosteroids in COPD. Eur Respir J 2010;35:1003-21.