Most studies that have explored the value of combination therapy have shown significant improvements over single agents alone, and it may be time to think of combination therapy as first-line therapy. Initially, the inhaled combination of ipratroprium and albuterol proved effective in the management of COPD.26 More recently, the combination of tiotropium once daily and formoterol twice daily was better than either agent alone. In that study,62 the administration of once-daily tiotropium and once-daily formoterol was very effective, suggesting that once-daily dosing of combinations may offer a viable option to the more complex twice-daily therapy. In another trial,22 the combination of theophylline and salmeterol was significantly more effective than either agent alone in lung function and health status. The TORCH study48 showed the benefits of the salmeterol/fluticasone combination on survival, FEV1, exacerbation rate, and quality of life compared with placebo and either of the single components, confirming earlier studies,76–78 evaluating the combination of β-agonists and corticosteroids. A recent trial79 comprising > 400 patients with symptomatic COPD compared the effectiveness of therapy using tiotropium in all patients combined with placebo in group 1, with salmeterol in group 2, and with the combination of salmeterol and fluticasone in the third group. Although the primary outcome, the exacerbation rate, was similar among the groups, the number of hospitalizations, health-related quality of life, and lung function was significantly better in the group receiving tiotropium plus salmeterol and fluticasone compared with tiotropium plus placebo and tiotropium plus salmeterol. Based on these results, it is reasonable to propose the approach shown in Figure 2
. Once symptoms become persistent, therapy should begin with a long-acting antimuscarinic agent such as tiotropium or LABAs twice daily. Once a patient reaches an FEV1 < 60% of predicted, and continues to be symptomatic, the evidence from the TORCH trial supports the addition of the combination of ICS and LABAs. Continuation of tiotropium is reasonable, given its effectiveness and safety record. I believe that all of the trials support the concept that intense and aggressive therapy does modify the course of the disease, including rate of decline of FEV1, as was shown in the TORCH study.,48 The results of the 4-year Understanding Potential Long Term Impacts on Function With Tiotropium trial,62 in which trough FEV1 is the primary outcome, should help clarify the disease-modification effect of the currently available medications.