© 2007 American Thoracic Society doi: 10.1164/rccm.200611-1595ED
Inhaled Corticosteroids for Chronic Obstructive Pulmonary DiseaseA Status ReportVeterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota Inhaled corticosteroids (ICS) came into common use for chronic obstructive pulmonary disease (COPD) long before there was firm evidence that they provided meaningful clinical benefits. It was originally thought that long-term administration of ICS might alter the natural history of COPD due to their potent antiinflammatory properties. Multiple trials examined whether high doses of ICS might slow the accelerated age-related losses in lung function that typify this disease. ICS demonstrated no statistically significant effect on lung function decline in any single trial, although meta-analyses do not exclude a small effect (1, 2). As secondary endpoints, numerous randomized trials of ICS for COPD collected information about clinical outcomes using standardized questionnaires. Compared with placebo, the use of ICS was associated with consistent improvements in symptoms and disease-specific health status. However, the average magnitude of these effects was small and uniformly fell short of what are judged to be clinically meaningful changes (3–5). Due to variations in individual responses, it is likely that a small proportion of ICS-treated patients do achieve clinically significant improvements in symptoms and health status compared with placebo. The authors of one meta-analysis of randomized trials concluded that ICS reduce COPD exacerbation rates substantially in symptomatic individuals with severe to very severe airflow obstruction (6). However, these conclusions were challenged on methodologic grounds (7). An updated systematic review concluded that ICS cause a small but statistically significant reduction in exacerbations (8). In addition, a pooled retrospective analysis of seven large ICS trials demonstrated reduced mortality. The absolute benefit was calculated to be small (0.53 per 100 patient-years) and limited to individuals with FEV1 of less than 60% of predicted (9). Preliminary results from TORCH (TOwards a Revolution in COPD Health), the only trial specifically designed to assess the role of inhaled therapies on mortality, demonstrated that fluticasone monotherapy did not reduce all-cause mortality compared with placebo (10).
Inhaled long-acting In this issue of the Journal (pp. 144–149), Kardos and associates address the clinically important question of additive inhalational therapy (12). These investigators compared the combination of fluticasone and salmeterol with salmeterol alone as maintenance therapy in patients with severe COPD (% predicted < 50%) who were also exacerbation prone (2 or more moderate to severe exacerbations in the year prior to enrollment). The trial was sizable (994 randomized patients), and the follow-up extended for 44 weeks. The primary outcome was the frequency of moderate to severe exacerbations, which were defined as typical symptom complexes of worsening respiratory status coupled with prescriptions for at least one of several systemic medications. Compared with salmeterol alone, patients who received salmeterol plus fluticasone experienced fewer exacerbations (annualized rate of 0.92 vs. 1.40, p < 0.001), a decrease that can be viewed as significant in both statistical and clinical terms. Among secondary outcomes, combination therapy was superior to salmeterol monotherapy as assessed by the St. George's Respiratory Questionnaire (SGRQ). Consistent with prior trials, the magnitude of the added improvement with fluticasone was small (mean change of –2.2 units) so that only about one in nine patients achieved the 4-unit improvement deemed clinically noticeable. Available results from the TORCH study appear to be concordant with those from Kardos and colleagues' trial in showing that combined therapy with salmeterol and fluticasone is modestly superior to monotherapy with either one alone for reducing exacerbations and improving SGRQ scores (10). In addition, combination therapy, compared with placebo, was associated with an approximately 1% annual reduction in all-cause mortality, a finding of borderline statistical significance. As in all previous large ICS trials, Kardos and associates administered relatively high doses of drug (fluticasone, 500 µg twice daily). High-dose ICS cause localized adverse effects in the upper airway and on the skin but only infrequently do these complications cause discontinuation of therapy. Of greater concern is the systemic absorption of small amounts of ICS and the potential for long-term sequelae, particularly involving the bones and eyes. The largely elderly population of patients with COPD may be at greater risk and, as discussed in a recent review, the extent of the relationship between long-term ICS and bone and eye complications has yet to be fully clarified (13). Kardos and associates identify an additional safety concern with ICS not mentioned in previous publications. Based on adverse event reporting, 23 cases of pneumonia occurred in the combined-treatment group compared with only 7 in the salmeterol arm. This difference is statistically significant (p < 0.01) and represents an excess pneumonia rate of about 3 per 100 patient-years in patients given fluticasone. Similar results were obtained in patients who received fluticasone in TORCH (10). In light of the known immunosuppressive properties of corticosteroids, an excess pneumonia rate from high local concentrations of ICS is not particularly surprising.
In summary, treatment benefits from ICS in patients with COPD are primarily related to reducing exacerbations among patients who are exacerbation prone and who have severe to very severe disease (FEV1 < FOOTNOTES Conflict of Interest Statement: D.E.N. received fees from Boehringer Ingelheim ($31,709 in 2004, $46,447 in 2005, $32,500 in 2006), Pfizer ($21,500 in 2004, $25,500 in 2005, $15,000 in 2006), Adams Respiratory Therapeutics ($4,200 in 2004, $6,771 in 2005), AstraZeneca ($5,500 in 2004, $3,000 in 2005), Schering Plough ($2,500 in 2006), and Sanofi Aventis ($3,000 in 2006) for lectures, consultancies, or serving on advisory boards; he also received grants from Boehringer Ingelheim ($3,100,000 in 2006) and GlaxoSmithKline ($62,000 in 2005) to perform clinical studies. T.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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-agonists (LABAs), such as salmeterol and formoterol, and the long-acting inhaled anticholinergic tiotropium also prevent exacerbations (
50%). Only a small minority of patients with COPD treated with ICS will achieve a clinically noticeable improvement in health status. Small incremental benefits are apparent when ICS are combined with an LABA. Therefore, decisions to initiate ICS with an LABA should focus on severely symptomatic and exacerbation-prone patients and balance the recently demonstrated benefits against increased drug costs and adverse effects.