Affiliations: Rome, Italy,
Correspondence to: Mario Cazzola, MD, FCCP, Dipartimento di Medicina Interna, Università di Roma ‘Tor Vergata,’ Via Montpellier 1, 00133 Roma, Italy; e-mail: email@example.com
The results of the Toward a Revolution in COPD Health (TORCH) study1raise the fundamental question of when it is appropriate to add an inhaled corticosteroid (ICS) to a long-acting β-agonist (LABA) for treating a patient with COPD. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines2 recommend that an ICS be added to bronchodilator therapy for COPD patients at stages III (severe) and IV (very severe), who are those with an FEV1/FVC ratio < 0.70 and an FEV1 < 50% of predicted still having exacerbations. However, the results of the TORCH study,1 indicate the potential to also treat all symptomatic patients who present FEV1 between 50% and 60% of predicted; and, in effect, the recent extension of the salmeterol/fluticasone combination (SFC) license by European regulators,3 supports this notion.
In the present issue of CHEST (see page 255), Rabe et al4 document that the combination of once-daily tiotropium plus twice-daily formoterol is superior to SFC twice daily in daytime lung function outcomes over 6 weeks in patients at GOLD stages II and III, which is moderate-to-severe COPD, and is characterized by worsening airflow limitation (FEV1/FVC < 0.70; FEV1 > 30 to ≤ 80% of predicted).,2 Differences seem to support current treatment recommendations in moderate COPD to combine two bronchodilators of different classes rather than to add an ICS if maintenance treatment with a single long-acting bronchodilator does not suffice.2 This is an important message and, consequently, it must be examined critically.
The study by Rabe et al4presents two important biases, lasting only 6 weeks and being focused exclusively on respiratory function. Considering the rate of disease progression and the frequency of exacerbations, it is now recognized that pharmacologic trials in stable COPD should be ≥ 6 months in order to examine potential outcomes or support claims of treatment response.5Moreover, the inability of ICSs to modify FEV1 is well known.6
Nonetheless, unquestionably this study provides intriguing information but cannot lead to firm conclusions, which require a specifically designed and appropriately powered trial. Therefore, we still question whether it is appropriate to treat patients with moderate COPD by only using long-acting bronchodilators or adding an ICS.
Some studies7–10 have compared tiotropium and SFC in patients with COPD. The conclusions of these studies are ambiguous.
In the study by Bateman et al7 6 weeks of treatment with tiotropium resulted in similar bronchodilation compared with SFC, despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline.
Singh and colleagues8 documented that triple therapy with SFC and tiotropium for 14 days improved specific airway conductance to a significantly greater degree compared to treatment with SFC alone or tiotropium alone in moderate-to-severe COPD. Pulmonary function measurements of FEV1 confirmed the superiority of triple therapy both before and after dose on day 14. There was also evidence that triple therapy caused a greater reduction in hyperinflation on day 14 compared to treatment with SFC or tiotropium alone. The superiority of triple therapy translated into clinically important benefits in terms of symptoms scores and rescue medication use, particularly compared to tiotropium used alone.
In the Optimal Therapy of Chronic Obstructive Pulmonary Disease To Prevent Exacerbations and Improve Quality of Life (OPTIMAL) study,9 the proportion of participants with moderate or severe COPD who had an exacerbation did not differ among those receiving monotherapy with tiotropium (62.8%), those receiving combination tiotropium plus salmeterol (64.8%), or those receiving all three therapies (60.0%). Mean exacerbations per patient-year were 1.61 in the tiotropium group, 1.75 in the tiotropium and salmeterol group, and 1.37 in the tiotropium and SFC group. It must be highlighted that many patients went off monotherapy and onto open-label SFC. This crossover may have diluted differences between randomized groups. However, the third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Moreover, 47% of patients in the tiotropium-plus-placebo group discontinued study medications compared with 43% in the tiotropium-plus-salmeterol group and 26% in the tiotropium-plus-SFC group (p < 0.001), although tiotropium added to salmeterol or SFC did not improve dyspnea vs tiotropium monotherapy.
Hodder and colleagues,10 who retrospectively analyzed the relative efficacy of tiotropium and salmeterol as a function of the concomitant use of ICS in patients with moderately advanced COPD using the pooled results of two 6-month studies of tiotropium 18 μg qd compared with salmeterol 50 μg bid, confirmed that tiotropium and salmeterol are effective bronchodilators. However, dyspnea, health status, and frequency of exacerbations were superior with tiotropium compared to salmeterol, regardless of concomitant ICS use. While the direct effect of ICS on COPD outcomes was not studied in this post hoc analysis, concurrent use of ICS neither augmented nor impeded the relative efficacy of the two bronchodilators tested.
All together, these results do not allow defining a therapeutic choice better than another. In particular, the OPTIMAL trial,9 which is certainly the most important study because of the number of patients enrolled and its length, does not allow a subdivision of the enrolled patients in moderate and severe COPD, and this is a real bias that limits our possibility of assessing the real value of the use of an ICS in moderate COPD, although it must be admitted that addition of SFC to therapy with tiotropium improved lung function, quality of life, and hospitalization rates, whereas the benefits of adding salmeterol to tiotropium were less clear. This is an intriguing finding, but we still do not understand whether the improvements in lung function caused by combining SFC and tiotropium are linked to the effect of the combination of two long-acting bronchodilators11or due to a synergistic interaction between the ICS and the long-acting bronchodilators, with the resulting synergetic effect being greater than the sum of responses achieved from each drug alone.12
The real problem that we have when we prescribe a treatment for a patient with COPD is that we tend to treat that patient as a subject of a general population with always the same characteristics since we consider COPD as a homogeneous disease. On the contrary, COPD is a heterogeneous disease that has characteristics that occur with different phenotypes.13It is likely that definition of these phenotypes will allow us to understand which kind of patients can benefit from an ICS and which, instead, should only be treated with long-acting bronchodilators. In the meantime, considering that, historically, the severity of COPD has been classified according to FEV1, which may not correlate directly with symptoms and, consequently, a symptomatic approach to therapy using clinical stages may be more useful,14 physicians should individualize treatment and try an additional type of drug if the patient symptomatically needs for something else to be tried, and yet stop the additional drug if it does not seem to help. In any case, the results from the study of Rabe et al4 will aid planning of larger studies that may be powered to assess the comparative efficacy of tiotropium plus an LABA and an LABA plus an ICS not only on spirometric end points but also on patient-reported outcomes.
Dr. Cazzola is Associate Professor, Unit of Respiratory Medicine, Department of Internal Medicine, University of Rome ‘Tor Vergata,’ Rome, Italy. Dr. Matera is Aggregate Professor, Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Dr. Cazzola has received fees for speaking and consulting and/or financial support for attending meetings from Abbott, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dey, Encysive, GSK, Menarini Farmaceutici, Novartis, Nycomed, Pfizer, and Sanovel. Dr. Matera has received fees for consulting and/or financial support for attending meetings from AstraZeneca, Boehringer Ingelheim, Encysive, GSK, Novartis, and Pfizer.
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