Salmeterol plus fluticasone fails to reduce mortality in patients with COPD

In a randomized double-blind, parallel- group trial, salmeterol plus fluticasone failed to reduce all-cause death in patients with moderate, severe, or very severe chronic obstructive pulmonary disease (COPD) compared with each of the agents alone or placebo. The results of the Towards a Revolution in COPD Health (TORCH) trial were published in the New England Journal of Medicine (NEJM).

Key Points

In a randomized double-blind, parallel- group trial, salmeterol plus fluticasone failed to reduce all-cause death in patients with moderate, severe, or very severe chronic obstructive pulmonary disease (COPD) compared with each of the agents alone or placebo.

The results of the Towards a Revolution in COPD Health (TORCH) trial were published in the New England Journal of Medicine (NEJM).

The study included 6,112 current or former smokers from 42 countries. All patients were aged 40 to 80 years and had moderate, severe, or very severe COPD (ratio of prebronchodilator forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≤0.70 and FEV1<60% of the predicted value). Patients were randomized to receive salmeterol 50 mcg plus fluticasone 500 mcg (n=1,533) twice daily, salmeterol 50 mcg alone twice daily (n=1,521), fluticasone 500 mcg alone twice daily (n=1,534), or placebo (n=1,524). The primary end point was the time to death from any cause during the 3 years of study follow-up. Secondary end points included the frequency of COPD exacerbations, changes in health status as determined by the St. George's Respiratory Questionnaire and spirometry, and the occurrence of adverse drug events.

In an accompanying editorial, Dr Klaus F. Rabe, a member of the Global Initiative for Obstructive Lung Disease (GOLD) and chair of the group's science committee, commented, "This finding confirms the position of combination therapy in current guidelines for the treatment of patients with COPD that recommend its use for those with severe COPD with frequent exacerbations but not for patients with milder disease or without frequent exacerbations."

Although therapy with salmeterol plus fluticasone did not demonstrate a reduction in mortality, the combination did demonstrate a reduction in the rate of COPD exacerbations from 1.13 to 0.85 annually (number needed to treat=4 patients to prevent 1 exacerbation in 1 year) and an improvement in patient health status; the combination also slowed the decline of scores on pulmonary function tests compared with placebo (P<.001 for all).

Fluticasone was associated with an increased risk of developing pneumonia when taken alone (18.3% probability) and in combination with salmeterol (19.6% probability) compared with placebo (12.3% probability) and salmeterol alone (13.3% probability).

Given the increased risk of pneumonia, Dr Rabe stated that there is an urgent need for further investigation into this combination therapy.

The National Heart Blood and Lung Institute (NHBLI) estimates that there may be as many as 16 million people in the United States diagnosed with COPD. It is the fourth-leading cause of death in the United States and is estimated to result in nearly three-quarters of a million hospitalizations annually. The total estimated cost of COPD in 2002 was $32.1 billion, including $18 billion in direct treatment costs and an additional $14.1 billion in lost productivity.

SOURCES

Calverley PMA, Anderson JA, Celli B, et al; for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–789.

Rabe KF. Treating COPD-The TORCH trial, P values, and the dodo. N Engl J Med. 2007;356:851–854.

Global initiative for chronic obstructive lung disease. Executive summary: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Available at: http:// http://www.goldcopd.org/guidelineitem.asp?l1=2&l2=1&intid=996. Accessed March 22, 2007.