Long-acting Anticholinergic Use in Chronic Obstructive Pulmonary Disease: Efficacy and Safety

Donald P. Tashkin

Disclosures

Curr Opin Pulm Med. 2010;16(2):97-105. 

In This Article

Abstract and Introduction

Abstract

Purpose of review This article reviews findings from recently published randomized controlled trials and systematic reviews to provide an up-to-date assessment of the efficacy and safety of tiotropium, the only currently available long-acting muscarinic antagonist, when used alone or in conjunction with other respiratory medications in the treatment of chronic obstructive pulmonary disease (COPD).
Recent findings Results of recent clinical trials support findings from earlier trials in patients with moderate to very severe COPD demonstrating significant benefits of tiotropium compared to placebo, including sustained increases in lung function, reductions in exacerbations and risk of exacerbation-related hospitalizations, and improvement in health status. These benefits were particularly noted in the 4-year UPLIFT study that included 5993 COPD patients, including a large percentage with moderate severity. Whereas the cardiovascular safety of tiotropium has been questioned, results of the UPLIFT trial and a recent pooled analysis of data from 30 trials of tiotropium demonstrated that tiotropium is associated with reductions in the risk of all-cause mortality, cardiovascular mortality and cardiovascular events.
Summary Recent findings confirm the benefits of tiotropium in COPD management and provide reassurance regarding its safety. Moreover, the recent UPLIFT trial provides supportive evidence for the efficacy of tiotropium in COPD patients already receiving treatment with long-acting inhaled beta-agonists and inhaled corticosteroids, suggesting advantages of 'triple' therapy in advanced disease. Further, well designed, adequately powered studies should explore the potential advantages and disadvantages of various combinations of currently available long-acting respiratory medications in COPD, particularly in different clinical phenotypes of this heterogeneous disease.

Introduction

Anticholinergic quaternary ammonium bronchodilators, initially introduced as short-acting agents (ipratropium and oxitropium) and more recently as a long-acting compound (tiotropium), have played an important role in the management of chronic obstructive pulmonary disease (COPD) for nearly 25 years. Their effectiveness stems from the fact that vagally mediated bronchoconstriction is the major reversible component of airflow obstruction in patients with COPD. Therefore, drugs that compete for binding to the muscarinic M3 receptor on bronchial smooth muscle cells with the acetylcholine (Ach) that is released from postganglionic vagal efferent nerves juxtaposed to airway smooth muscle in central airways (or from non-neuronal sources in the distal airways) are capable of abrogating bronchomotor tone and thus dilating the airway. This dilation results in a greater improvement in forced expired volume in 1 s (FEV1) in COPD patients with narrowed airways than in healthy individuals with more patent airways because of the exponential inverse relationship between changes in airway caliber and changes in airflow resistance (Poiseuille's law).

The available anticholinergic bronchodilators (ipratropium, oxitropium and tiotropium) bind with similar affinity to M3 receptors, as well as to the other muscarinic receptor subtypes in human airways (M1 and M2). M1 receptors facilitate cholinergic neurotransmission through parasympathetic ganglia, whereas M2 receptors mediate negative feedback inhibition of Ach release from the postganglionic nerve endings. However, quaternary ammonium anticholinergics dissociate far more slowly from M3 than M2 receptors, thus resulting in a net reduction in bronchomotor tone. Moreover, tiotropium dissociates much more slowly from the M3 receptor than does ipratropium (t½ for receptor occupancy 34.7 ± 2.9 vs. 0.26 ± 0.02 h, respectively),[1] thus providing a mechanism for a much more prolonged duration of action of tiotropium, which has been shown to produce sustained bronchodilation for as long as 24 h with once-daily dosing,[2] as opposed to 6–8 h after each dose of ipratropium. Both tiotropium and ipratropium have a positively charged N atom at the quaternary ammonium end of the molecule, resulting in low lipid solubility. The latter property probably accounts for the slow absorption of these compounds across lipid membranes in the tracheobronchial tree and the gastrointestinal tract, thus reducing bioavailability and enhancing their safety.

Tiotropium in a dry powder formulation (delivered in single doses via the Handihaler) was introduced into clinical practice in 2002 in Europe and 2004 in the USA following extensive preclinical and clinical studies. A number of clinical trials published between 2002 and 2006 have documented its efficacy and safety in COPD, as summarized in a systematic review and meta-analysis of nine trials of at least 12 weeks duration including 8002 patients, as reported by Barr et al.[3] in 2006. Previous studies have also demonstrated significant effects of tiotropium in reducing hyperinflation and improving exercise tolerance.[4–6] In addition, an analysis of pooled patient-level adverse event data from 4435 tiotropium-treated and 3384 placebo-treated patients participating in a total of 19 preapproval and postapproval trials sponsored by the manufacturer, published in 2006, supported the safety of tiotropium.[7] The current study reviews and comments on clinical studies published since 2006 that include trials comparing the efficacy and safety of tiotropium with that of both placebo and other respiratory medication, as well as more recent meta-analyses and observational studies bearing on the safety of tiotropium, particularly with regard to fatal and nonfatal cardiovascular events. In addition, recent studies examining the effects of adding a long-acting beta-agonist (LABA) (formoterol or salmeterol) or a LABA/inhaled corticosteroid (ICS) combination to tiotropium will be reviewed. Finally, alternative long-acting muscarinic antagonists (LAMAs) that are under development will be briefly considered, along with a novel, multidose micronebulizer device for delivering tiotropium as a soft mist (Respimat).

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