Effects of Inhaled Corticosteroids in Monotherapy or Combined with Long-Acting β2-Agonists on Mortality among Patients with Chronic Obstructive Pulmonary Disease

Abstract

Spanish

French

Background

The benefits of inhaled corticosteroids (ICS) in reducing the mortality related to chronic obstructive pulmonary disease (COPD) are controversial.

Objective

To estimate whether ICS in monotherapy or in combination with long-acting β₂-agonists (LABA) reduces the mortality rate among COPD patients compared to those treated with LABA monotherapy.

Methods

Using data from the Canadian province of Quebec's health administrative databases, a nested case-control study was conducted. A cohort of COPD patients aged 50 years and over between 1996 and 2000 was initially formed. Patients were included if they filled at least 6 prescriptions of an inhaled branchodilator, received at least 1 medical service for COPD, and did not receive any diagnosis of asthma over a 12-month period. For each case of death identified in the cohort, up to 37 controls were time matched. For cases and controls, the exposure to ICS and LABA was assessed within the 3 months prior to the date of death for cases and date of selection for controls. Adjusted mortality rate ratios were estimated by conditional logistic regression comparing patients using ICS monotherapy or ICS/LABA combination therapy with patients using LABA monotherapy.

Results

This study included 5996 cases of death and 54,750 controls. The mortality rates were found to be lower among users of ICS monotherapy than users of LABA monotherapy (OR 0.69; 95% CI 0.53 to 0.88) and lower among users of an ICS/LABA combination than users of LABA monotherapy (OR 0.73; 95% Cl 0.56 to 0.96). No significant differences were observed between users of ICS/LABA combination therapy and users of ICS monotherapy (OR 1.07; 95% Cl 0.93 to 1.23).

Conclusions

ICS were found to be associated with a reduction in mortality rate when compared to LABA among patients with COPD, However, the ICS/LABA combination therapy did not provide any additional benefit on mortality when compared to ICS monotherapy.

Keywords

administrative database chronic obstructive pulmonary disease inhated corticosteroids mortality

Get full access to this article

View all access options for this article.

References

O'Donnell

D.E.

, Aaron

, Bourbeau

Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease–2007 update.

Can Respir J 2007; 14(suppl B): 5B–32B.

Pauwels

R.A.

, Buist

A.S.

, Calverley

P.M.

, Jenkins

C.R.

, Hurd

S.S.

. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163: 1256–76.

World Health Organisation 2008. The Global Burden of Disease 2004 Update. World Health Organisation, 2008: 1–160. http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf (accessed 2009 Nov 19).

The Center for Chronic Disease Prevention and Control, Health Canada, Canadian Institute for Health Information.

Editorial Board Respiratory Disease In Canada. Ottawa: Health Canada, 2003.

Lenfant

, Khaltaev

Global initiative for chronic obstructive lung disease: global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (update 2005). 2005: 72. www.goldcopd.com/Guidelineitem.asp?11=2&12=1&intId=1620 (accessed 2009 Nov 19)

Lung Health Study Research Group.

Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.

N Engl J Med 2000; 343: 1902–9.

Burge

P.S.

, Calverley

P.M.

, Jones

P.W.

, Spencer

, Anderson

J.A.

, Maslen

T.K.

. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320: 1297–303.

Paggiaro

P.L.

, Dahle

, Bakran

, Frith

, Hollingworth

, Efthimiou

Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group.

Lancet 1998; 351: 773–80.

Pauwels

R.A.

, Lofdahl

C.G.

, Laitinen

L.A.

Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.

N Engl J Med 1999; 340: 1948–53.

10.

Calverley

, Pauwels

, Vestbo

Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.

Lancet 2003; 361: 449–56.

11.

Celli

, Calverley

, Anderson

, Ferguson

, Jenkins

, Jones

The TORCH (TOwards aRevolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves health status, reduces exacerbations and improves lung function over three years (abstract).

Eur Respir J 2006; 28: 34.

12.

Szafranski

, Cukier

, Ramirez

Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.

Eur Respir J 2003; 21: 74–81.

13.

Calverley

P.M.

, Boonsawat

, Cseke

, Zhong

, Peterson

, Olsson

Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.

Eur Respir J 2003; 22: 912–9.

14.

Kardos

, Wencker

, Glaab

, Vogelmeier

Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2007; 175: 144–9.

15.

Sin

D.D.

, Wu

, Anderson

J.A.

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

Thorax 2005; 60: 992–7.

16.

Ernst

, Suissa

Inhaled corticosteroids and mortality in COPD.

Thorax 2006; 61: 735.

17.

Calverley

P.M.

, Anderson

J.A.

, Celli

Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.

N Engl J Med 2007; 356: 775–89.

18.

Macie

, Wooldrage

, Manfreda

, Anthonisen

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

Chest 2006; 130: 640–6.

19.

Gudmundsson

, Gislason

, Lindberg

Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity.

Respir Res 2006; 7: 109.

20.

Kiri

V.A.

, Pride

N.B.

, Soriano

L.B.

, Vestbo

Inhaled corticosteroids in chronic obstructive pulmonary disease–results from two observational designs free of immortal time bias.

Am J Respir Crit Care Med 2005; 172: 460–4.

21.

Mapel

D.W.

, Hurley

J.S.

, Roblin

Survival of COPD patients using inhaled corticosteroids and long-acting beta agonists.

Respir Med 2006; 100: 595–609.

22.

Soriano

J.B.

, Kiri

V.A.

, Pride

N.B.

, Vestbo

Inhaled corticosteroids with/without long-acting beta-agonists reduce the risk of rehospitalization and death in COPD patients.

Am J Respir Med 2003; 2: 67–74.

23.

Sin

D.D.

, Tu

J.V.

. Inhaled corticosteroids and the risk of mortality and read-mission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 580–4.

24.

Soriano

J.B.

, Vestbo

, Pride

N.B.

, Kiri

, Maden

, Maier

W.C.

. Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J 2002; 20: 819–25.

25.

Fan

V.S.

, Bryson

C.L.

, Curtis

J.R.

Inhaled corticosteroids in chronic obstructive pulmonary disease and risk of death and hospitalization: time-dependent analysis.

Am J Respir Crit Care Med 2003; 168: 1488–94.

26.

Suissa

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.

27.

Suissa

Inhaled steroids and mortality in COPD: bias from unaccounted immortal time.

Eur Respir J 2004; 23: 391–5.

28.

Régie de l'assurance maladie du Québec. Statistiques annuelles. Québec: Régie de l'assurance maladie du Québec, Health Ministry, Government of Québec, 1999.

29.

Tamblyn

, Lavoie

, Petrella

, Monette

The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec.

J Clin Epidemiol 1995; 48: 999–1009.

30.

Pilote

, Lavoie

, Ho

, Eisenberg

M.J.

. Changes in the treatment and’ outcomes of acute myocardial infarction in Quebec, 1988-1995. CMAJ 2000; 163: 31–6.

31.

Martel

M.J.

, Rey

, Beauchesne

M.F.

Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension: nested case-control study.

BMJ 2005; 330: 230.

32.

McKnight

, Scott

, Menzies

, Bourbeau

, Blais

, Lemiere

A cohort study showed that health insurance databases were accurate to distinguish chronic obstructive pulmonary disease from asthma and classify disease severity.

J Clin Epidemiol 2005; 58: 206–8.

33.

Etminan

Pharmacoepidemiology II: the nested case-control study—a novel approach in pharmacoepidemiologic research.

Pharmacotherapy 2004; 24: 1105–9.

34.

Lubin

J.H.

, Gail

M.H.

. Biased selection of controls for case-control analyses of cohort studies. Biometrics 1984; 40: 63–75.

35.

Von Korff

, Wagner

E.H.

, Saunders

A chronic disease score from automated pharmacy data.

J Clin Epidemiol 1992; 45: 197–203.

36.

Bice

T.W.

, Boxerman

S.B.

. A quantitative measure of continuity of care. Med Care 1977; 15: 347–9.

37.

Suissa

Immortal time bias in observational studies of drug effects.

Pharmacoepidemiol Drug Saf 2007; 16: 241–9.

38.

Rothman

K.J.

, Greenland

Modern epidemiology. 2nd ed. Philadelphia: Lippincott-Raven, 1998.

39.

Niewoehner

D.E.

. TORCH and UPLIFT: what has been learned from the COPD “mega-trials”? COPD 2009; 6: 1–3.

40.

Sin

D.D.

, McAlister

F.A.

, Man

S.F.

, Anthonisen

N.R.

. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003; 290: 2301–12.