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

Marie-Christyne Cyr; Marie-France Beauchesne; Catherine Lemière; Shawn D Aaron; Lucie Blais


The Annals of Pharmacotherapy. 2010;44(4):613-622. 

In This Article

Abstract and Introduction


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 bronchodilator, 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% CI 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% CI 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.


Chronic obstructive pulmonary disease (COPD) is a chronic respirato ry disorder associated with progressive airflow limitation and intermittent acute respiratory exacerbations.[1,2] Worldwide, COPD is the fourth leading cause of death, representing 5.1% of all deaths in 2004.[3] The prevalence and mortality rates of COPD are expected to increase in the upcoming decades.[4]

The goals of COPD treatment are to minimize symptoms, improve lung function and quality of life, as well as to prevent the progression, exacerbations, and deaths associated with the disease.[1,2] Recent guidelines for the diagnosis, management, and prevention of COPD suggest that inhaled corticosteroids (ICS) should be used only when combined with long-acting β2-agonists (LABAs) and that the ICS/LABA combination is principally indicated for patients with moderate-to-severe COPD who have a history of recurrent exacerbations.[1,5] Randomized clinical trials (RCTs) have shown that ICS monotherapy[6–9] or in combination with an LABA[10–13] can reduce the rate of COPD exacerbations compared to placebo. Moreover, RCTs have reported that an ICS/LABA combination was more effective in reducing COPD exacerbations than was ICS monotherapy[11,13] or LABA monotherapy.[11–14]

The effects of ICS and LABAs on COPD mortality have been of recent interest, but remain controversial. One meta-analysis of 5 RCTs found that ICS monotherapy reduced all-cause mortality in COPD patients by 27% within a 2-year period compared to matching placebo.[15] However, this pooled analysis' weakness is that the assessment of deaths was not performed for patients who prematurely withdrew from the studies. Differential withdrawal rates between the placebo and ICS groups would have led to differential assessment of deaths, potentially producing biased hazard ratios.[16] The TORCH study was the first RCT that assessed whether the ICS/LABA combination provides greater clinical benefit and reduces mortality compared to ICS or LABAs alone. This study assessed mortality in all randomized patients and performed a complete intention-to-treat analysis of mortality over a 3-year period.[17] Its results showed that users of the combination of salmeterol (LABA) and fluticasone (ICS) were 17% less likely to die than were placebo users (HR 0.83; 95% CI 0.68 to 1.002), but this reduction did not reach statistical significance.[17] Moreover, patients using an ICS/LABA combination were found to have significant improvements in survival compared to users of ICS monotherapy (HR 0.77; 95% CI 0.64 to 0.93), but not compared to users of LABA monotherapy.[17] Despite the complete assessment of the mortality outcome in this study, a large percentage of patients stopped their assigned therapy during the study period and a greater proportion of patients randomized to placebo prematurely stopped study medications compared to those actively treated. The contamination of patients in the placebo arm by a treatment with open-label ICS or ICS/LABA combination during the study period may have reduced the potential to show differences between the study groups. A few observational studies have also reported that the use of ICS monotherapy[18–23] or ICS/LABA combination[19,21,24] can reduce mortality compared to no use. However, other observational studies have failed to show such a beneficial effect and it has been suggested that the observed mortality reduction might be due to residual confounding, immortal time bias, and/or selection bias.[25–27]

Currently, no observational studies have assessed the relative effect of ICS/LABA combination to ICS or LABA alone on mortality. Therefore, a nested case-control study with time-dependent exposure to medications was performed to estimate whether ICS monotherapy or in combination with an LABA reduces COPD mortality when compared to LABA monotherapy. A secondary objective was to compare mortality rates between users of the ICS/LABA combination and users of ICS monotherapy.


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