Article date: October 2007
Long-acting beta2 agonists (salmeterol or formoterol) and combination products that contain salmeterol with fluticasone (Seretide Accuhaler) or formoterol with budesonide (Symbicort Turbohaler) are indicated for the management of chronic obstructive pulmonary disease (COPD). Although inhaled corticosteroids are not indicated for monotherapy in COPD, treatment guidelines (including those issued by the Global initiative on Obstructive Lung Disease, GOLD)1recommend that inhaled steroids may be added to ongoing bronchodilator therapy in COPD management.
The TORCH study
TOwards a Revolution in COPD Health (TORCH)2 compared Seretide Accuhaler (50 µg salmeterol/500 µg fluticasone twice a day), 50 µg salmeterol twice a day, and 500 µg fluticasone twice a day with placebo over a 3-year period. The primary endpoint was all-cause mortality within 3 years. The absolute risk for all-cause mortality was reduced by 2·6% for Seretide compared with placebo, and was increased by 0·8% for fluticasone compared with placebo (both nonsignificant).
The table summarises the absolute and relative risks of pneumonia for groups in the TORCH study:
|Placebo (n=1544)||Salmeterol (n=1542)||Fluticasone (n=1552)||Seretide (n=1546)|
|Number of events||139 (9%)||162 (11%)||224 (14%)||248 (16%)|
|Events per 1000 treatment-years||51·9||51·5||84·4||87·6|
|Probability of event by 3 years* (95% CI)||12·3% (10·4–14·3)||13·3% (11·4–15·2)||18·3% (16·1–20·4)||19·6% (17·4–21·9)|
|Active treatment vs placebo|
|Hazard ratio (95% CI)||1·09 (0·87–1·37)||1·53† (1·24–1·89)||1·64† (1·33–2·02)|
|Seretide vs components|
|Hazard ratio (95%CI)||1·51† (1·24–1·84)||1·07 (0·89–1·28)|
Note: Log-Rank test stratified by smoking status. *Kaplan-Meier estimate. †p<0·001
In TORCH, older patients, patients with a lower body mass index (ie, <25 kg/m2), and patients with very severe disease (FEV1<30% predicted) were at highest risk of pneumonia, irrespective of treatment.
A recent case-control study3 of 175 906 elderly patients with COPD suggested that current use of inhaled corticosteroids was associated with a significant increase of 70% in the frequency of hospitalisation for pneumonia compared with non-use in the last year. For patients with pneumonia who died within 30 days of hospitalisation, current use of inhaled corticosteroids significantly increased the frequency by 53%. The risks of hospitalisations for pneumonia and for subsequent death within 30 days were dose-dependent.
Advice for healthcare professionals:
- Physicians should remain vigilant for the development of pneumonia and other infections of the lower respiratory tract (ie, bronchitis) in patients with COPD who are treated with inhaled drugs that contain steroids because the clinical features of such infections and exacerbations frequently overlap
- Any patient with severe COPD who has had pneumonia during treatment with inhaled drugs that contain steroids should have their treatment reconsidered
Article citation: Drug Safety Update October 2007; Vol 1, Issue 3: 5.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2006. ↩
Calverley PM, et al. N Engl J Med 2007; 356: 775–89 ↩
Ernst P, et al. Am J Respir Crit Care Med 2007; 176: 162–66 ↩