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Naples, Italy
Dr. Cazzola is Consultant of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital, Naples, Italy. Dr. Matera is Researcher, Department of Experimental Medicine, Unit of Pharmacology, Second University, Naples, Italy.
Correspondence to: Mario Cazzola, MD, FCCP, A. Cardarelli Hospital, Department of Respiratory Medicine, Unit of Pneumology and Allergology, Via del Parco Margherita 24, 80121 Naples, Italy; e-mail mcazzola{at}qubisoft.it
A volume of published evidence sustains the role of long-acting ß2-agonists in the treatment of stable COPD.1 2 3 4 5 These agents not only induce prolonged bronchodilation, but also translate this action into other health-outcome measures that relate to quality of life, such as the severity of dyspnea, exercise capacity, and exacerbations.6 Both formoterol and salmeterol are superior to ipratropium.1 3 4
When optimal monotherapy is insufficient, combined treatment with a ß2-agonist and an antimuscarinic agent may be useful.7 Once more, there is evidence that long-acting ß2-agonists may represent the most effective option for combined treatment with ipratropium.8
Because of these findings, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines9 state that long-acting bronchodilators are more convenient than short-acting bronchodilators in symptomatic management of all stages of COPD. It is noteworthy that the GOLD guidelines do not specifically mention long-acting ß2-agonists, but only recommend the use of long-acting bronchodilators. This likely happened because in these last few years there has been a factual interest in developing new antimuscarinic compounds that, contrary to traditional agents, could also be long-acting bronchodilators.10
Tiotropium is a new long-acting antimuscarinic agent indicated for the maintenance treatment of COPD. The prolonged duration of effect is likely due to its very slow dissociation from muscarinic M1 and M3 receptors, demonstrating its kinetic receptor subtype selectivity.11 Unusually for a new product, there is a considerable body of published evidence available on long-term clinical trials and comparisons of this drug against existing therapies.12 13 14 15 16 In studies comparing either ipratropium14 or salmeterol16 to tiotropium, the new therapy has been shown to be superior to either of the existing therapies. However, we do not know how it compares with the antimuscarinic agent oxitropium, which requires fewer daily doses than ipratropium.
Data from 1-year studies have suggested that tiotropium may reduce the rate of decline in FEV1 over time compared with placebo15 or ipratropium.14 This is an interesting finding because no single bronchodilator has been shown to affect lung function decline and the progression of this disabling disease. Nonetheless, recently it has been documented that a regular 1-year treatment with a fixed combination of a long-acting ß2-agonist and an inhaled corticosteroid may reduce the rate of decline over time compared to single compounds alone.17 18 Obviously, the real impact of the influence of these therapies on decline in pulmonary function will be established by longer time trials. All these exciting findings and the possibility of using new interesting therapies are stimulating the scientific community to consider the treatment of COPD with more interest.
In this issue of CHEST (see page 249), Tashkin and Cooper highlight the role of long-acting bronchodilators in the management of stable COPD, and propose a treatment algorithm. We agree that an algorithm, which could support physicians in their therapeutic choice, is needed because the recommendations of GOLD guidelines are too scant. However, we think that the current level of knowledge does not support the proposals of Tashkin and Cooper. In our opinion, this algorithm is premature due the lack of fundamental information.
Using the traditional method of integrating research studies, Tashkin and Cooper provide a narrative discourse on previous findings. This method is the process of synthesizing primary studies and exploring heterogeneity descriptively rather than statistically, and it is rather difficult to really detect intervention effects by this means.19 We know that a formal meta-analysis of the different trials with long-acting bronchodilators is impossible because of substantial differences in sample size, effect size, research design, type of enrolled patients, primary efficacy outcomes (eg, exacerbations and exercise capacity), and durations of therapy across published studies. Nonetheless, Tashkin and Cooper quote an overwhelming number of studies on the topic, with no two studies exactly alike. In such circumstances, it is difficult to determine if the differences between the study outcomes are due to chance, to inadequate study methods, or to systematic differences in the characteristics of the studies.
The study of Donohue and coworkers16 was specifically designed to explore the potential differences between tiotropium and salmeterol. It is the first trial that really indicates a higher efficacy of tiotropium when compared to a long-acting ß2-agonist, although it also shows no significant differences between the bronchodilators in the incidence of exacerbations or use of rescue salbutamol. Recently, Brusasco and coworkers20 undertook a study to record exacerbations and health-resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos. Exacerbations of COPD and health-resource usage were positively affected by daily treatment with tiotropium, whereas, with the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. These studies seem to indicate a greater efficacy of tiotropium than long-acting ß2-agonists. However, peer-reviewed published studies comparing tiotropium and formoterol are still lacking. The different pharmacodynamic profile of formoterol when compared to salmeterol might induce a different type of broncholytic effect, mainly if one considers onset of action or peak bronchodilation. This might not only drive to a different conclusion compared with salmeterol when weighted against tiotropium, but also influence compliance to treatment.21
Moreover, there is no published documentation that an association of tiotropium and a short-acting ß2-agonist used for rescue is more efficacious than salmeterol or formoterol plus an anticholinergic agent or a short-acting ß2-agonist, again used as rescue medication, in patients with stage IIA COPD according to the GOLD stratification of severity.9 In any case, apart from any other consideration, oxitropium is a more suitable short-acting antimuscarinic agent as rescue medication than ipratropium.22 Therefore, an exhaustive international algorithm should also include this drug.
Recently, the European Committee for Proprietary Medicinal Products23 has given a positive opinion for the use of a fixed combination of a long-acting ß2-agonist and an inhaled corticosteroid for stages IIB and III. Nevertheless, Tashkin and Cooper apparently do not consider this opinion important. In fact, they only suggest the use of tiotropium plus salmeterol or formoterol for stage IIB. Unfortunately, there is no evidence that this suggested combination is better than tiotropium. In fact, we are still waiting for published evidence that might prove that the use of the combination of tiotropium and a long-acting ß2-agonist is really more efficacious than single agents alone, although we must stress that this is an expected finding. Moreover, we do not know if the choice of the specific long-acting ß2-agonist to be used is trivial. In effect, the characteristics of formoterol let us hypothesize a faster onset of action of the combination compared to tiotropium alone, whereas the addition of salmeterol might permit the once-daily contemporaneous administration of the two drugs that could simplify the therapy. In any case, there is no documentation that a combination with two long-acting bronchodilators really works better that a combination of a long-acting ß2-agonist and an inhaled corticosteroid or, even, of tiotropium and an inhaled corticosteroid. Deplorably, although tiotropium has entered or is entering the market with a wide and solid documentation of its efficacy in stable COPD, the interesting comparison of tiotropium vs the combination inhaler with a long-acting ß2-agonist and an inhaled corticosteroid has not yet been undertaken.
We are also still waiting to know the real impact, if any, of an early intervention with an inhaled corticosteroid (if necessary, associated with a long-acting ß2-agonist or tiotropium) for patients at stages I and IIA. This is an extremely important question, considering that the Lung Health Study24 has documented that use of ipratropium did not influence the long-term decline of FEV1 even in patients with mild airway obstruction.
Obviously, all these considerations have scientific assumptions, but in these last years economic attention is becoming even more important, at least for many health-care authorities worldwide. In view of the cost of tiotropium, one could argue that a trial of therapy should be reserved for patients who remain symptomatic in spite of optimized treatment with ipratropium or a long-acting ß2-agonist. We do not believe that this can be considered a correct approach because the price of drugs is only a part of the total cost of management of COPD. In effect, the cost of each single hospitalization is higher, and there is documentation that tiotropium reduces the number of admissions to hospital.14 20 This point of view can also be translated to regular use of fixed combinations of a long-acting ß2-agonist and an inhaled corticosteroid in patients with COPD.
In conclusion, it is our opinion that the general understanding of treatment of COPD is still in its infancy and only large, long-term studies that will explore all points awaiting an answer will permit the formulation of a really exhaustive algorithm for the management of stable COPD. At present, the scientific community can only affirm that long-acting bronchodilators are the first-choice option for the treatment of stable COPD. Obviously, the introduction into the market of new efficacious compounds, such as tiotropium, will augment our capacity for treating a disease that has been considered in a nihilist manner for too many years.
Footnotes
Dr. Cazzola has received fees for speaking and consulting and/or financial support for attending meetings from Altana, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GSK, Menarini Farmaceutici, Novartis, and Pfizer. Dr. Matera has received financial support for attending meetings from AstraZeneca, and GSK.
References
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