Review
The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD

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Abstract

Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled β2-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting β2-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD.

Introduction

Bronchodilators are the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and are recommended by current national and international guidelines as first-line therapy in symptomatic patients and those who demonstrate airflow limitation [1], [2], [3]. Bronchodilators are given on as-needed basis or on a regular basis to prevent or reduce symptoms. The principal bronchodilator treatments are β2-agonists, muscarinic antagonists and methylxanthines [1]. Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are generally preferred and are more convenient for maintenance treatment of COPD [4], [5].

For patients whose symptoms are not sufficiently controlled by maintenance monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist and β2-agonist, seems a convenient way of delivering treatment and obtaining better results [1], [2], [3]. This includes better lung function and improved symptoms. Specifically, as airflow obstruction becomes more severe, both a long-acting muscarinic antagonist (LAMA) plus a long-acting β2-agonist [LABA] have been advocated [6], although data supporting this therapeutic approach are limited to date.

Here we review the evidence supporting LABA/LAMA combinations for the management of COPD, including the scientific rationale for combining β2-agonists and muscarinic antagonists and clinical evidence from trials combining these agents.

Section snippets

Complementary routes leading to bronchodilation

The airways are innervated by postganglionic, parasympathetic-cholinergic nerves. These nerves release the neurotransmitter acetylcholine (ACh) which regulates muscle tone, bronchoconstriction of small bronchi and bronchioles and airway resistance in larger, cartilaginous airways. Three subtypes of muscarinic receptors are expressed in the human lung (M1, M2 and M3) [7] and are activated at the level of the target cells, such as bronchial smooth muscle and goblet cells [8]. Bronchoconstriction

Combination therapy with short-acting bronchodilators

The observation that standard doses of short-acting β2-agonists (SABAs) did not give optimal improvements in lung function in patients with COPD led to the practice of adding a short-acting muscarinic antagonist (SAMA). This combination provides additional bronchodilation over monotherapy, which is reproducible over a 3-month period [39]. Early studies questioned the value of combination therapy with ipratropium bromide and salbutamol [40], [41]; however, several large trials found that

Current guidelines and the future of LABA/LAMA combinations in COPD

The clinical evidence reviewed suggests there are benefits in combining LABAs and the LAMA tiotropium, and evidence to date from longer-term studies indicate that there is no increase in side effects when these combinations are used. The current GOLD guidelines [1] recommend consideration of a second bronchodilator in moderate COPD in order to optimize the symptom benefit for patients. The addition of an ICS to bronchodilator therapy should be reserved for COPD patients at stages III (severe)

Conclusion

The LABA/LAMA combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators results in significantly greater improvements in lung function and other outcomes compared with individual drugs used alone, and that these combinations are well tolerated in patients with moderate to severe COPD.

Several outstanding research questions remain. From a pharmacological perspective, we need to understand why

Conflicts of interest

M. Cazzola has received financial support for research and attending meetings and fees for speaking and consulting from Abbott, Almirall, Altana (Nycomed), AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dey, Eli Lilly, Gentili, GSK, Meda, Menarini Farmaceutici, Novartis, Pfizer, Sanovel, Sanofi-Aventis, Sigma-Tau and Valeas.

M. Molimard has received financial support for attending meetings and fees for speaking and consulting from GSK, Novartis and Sanofi-Aventis.

Acknowledgements

The authors were assisted in the preparation of the manuscript by Mary Sayers (ACUMED). Writing support was funded by Novartis Pharma AG.

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