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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)

BMJ 2013; 346 doi: (Published 29 May 2013) Cite this as: BMJ 2013;346:f3306
  1. Christer Janson, professor in respiratory medicine1,
  2. Kjell Larsson, professor in respiratory medicine2,
  3. Karin H Lisspers, general practitioner3,
  4. Björn Ställberg, general practitioner3,
  5. Georgios Stratelis, senior medical advisor4,
  6. Helena Goike, research scientist4,
  7. Leif Jörgensen, research statistician4,
  8. Gunnar Johansson, professor in public health sciences5
  1. 1Department of Medical Sciences, Respiratory Medicine, Uppsala University, Uppsala, Sweden
  2. 2Unit of Lung and Allergy Research, National Institute of Environmental Medicine, Karolinska Institute, Stockholm
  3. 3Department of Public Health and Caring Science, Family Medicine and Clinical Epidemiology, Uppsala University, Uppsala, Sweden
  4. 4AstraZeneca Nordic, Södertälje, Sweden
  5. 5Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
  1. Correspondence to: C Janson christer.janson{at}
  • Accepted 16 May 2013


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 β2 agonist.

Design Observational retrospective pairwise cohort study matched (1:1) for propensity score.

Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.

Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.

Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.

Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).

Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.

Trial registration Clinical NCT01146392.


  • English language editing and assistance with figures was provided by Anna Mett of inScience Communications, Springer Healthcare, and funded by AstraZeneca.

  • Contributors: All authors participated equally in the study conception, design, and statistical analysis planning. LJ was responsible for statistical analyses, CJ for the manuscript draft and finalisation, and GJ for handling of data and the study database. All authors analysed and interpreted the data, revised the manuscript, had access to complete study data, and had authority over manuscript preparation, approval of final version and the decision to submit for publication. KL is guarantor.

  • Funding: This study was funded by AstraZeneca. AstraZeneca was a member of the study steering committee that carried overall responsibility for the study concept and design. Project management was provided by AstraZeneca. Data collection was performed by Pygargus AB, Uppsala, Sweden, and funded by AstraZeneca. The statistical analysis plan was agreed on by the study steering committee, and data analysis was performed by the study database owner in collaboration with AstraZeneca. As member of the study steering committee AstraZeneca took part in the interpretation of the data and the drafting of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: CJ has received honorariums for educational activities from AstraZeneca, GlaxoSmithKline, and Merck Sharp and Dohme. KL has served in an advisory board and/or served as a speaker and/or participated in education arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Meda, MSD, Nycomed, Novartis, and Pfizer. KL has also received unrestricted research grants from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. KHL has received speaking fees from AstraZeneca, Boehringer Ingelheim, and Merck Sharp and Dohme. BS has received honorariums for educational activities from AstraZeneca, GlaxoSmithKline, and Merck Sharp and Dohme. GJ has served on an advisory board arranged by AstraZeneca and Takeda. GS, HG, and LJ are fulltime employees of AstraZeneca Nordic.

  • Ethical approval: The study protocol was reviewed and approved by the regional ethics committee in Uppsala, Sweden (Dnr 2010/040) and registered at (clinical trial identifier NCT01146392).

  • Data sharing: The dataset is still subject to further analyses, but will continue to be held and managed by the Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. Relevant anonymised patient level data are available on reasonable request from the authors.

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