Combination of Formoterol and Tiotropium in the Treatment of COPD: Effects on Lung Function

Abstract

Bronchodilators are central in symptomatic management of all stages of COPD. For patients whose COPD is not sufficiently controlled by monotherapy, combining an inhaled anticholinergic and a ß₂-agonist is a convenient way of delivering treatment and obtaining better lung function and improved symptoms. Formoterol (β₂-agonist) and tiotropium (anticholinergic) are long-acting bronchodilators with different mechanisms of action. Formoterol has a fast onset and a bronchodilator effect of approximately 12 h, while tiotropium has a 24-h bronchodilator effect and is given once daily. Currently, there is no documentation that tiotropium is superior to formoterol or the contrary, but a combination of tiotropium and formoterol is more effective than single drugs alone in inducing bronchodilation and a bronchodilator-mediated symptom benefit in patients suffering from COPD. Once-daily or twice-daily formoterol, added to tiotropium, are both better than tiotropium alone, but the published evidence suggests twice-daily formoterol is the best add-on option.

Keywords:

• COPD
• Formoterol
• Tiotropium
• Combination therapy

INTRODUCTION

Current treatment for chronic obstructive pulmonary disease (COPD) is aimed at increasing airflow, decreasing respiratory symptoms (particularly dyspnea), decreasing exacerbations, and improving the quality of life. Consequently, it not surprising that both the Global Initiative for Obstructive Lung Disease (GOLD) guidelines, ([1]), and the American Thoracic Society (ATS)/European Respiratory Society (ERS) position paper for the diagnosis and treatment of patients with COPD ([2]) emphasize the role of bronchodilators in symptomatic management of all stages of COPD.

There are two primary pharmacologic classes of inhaled bronchodilators with different mechanisms of action which are used in the treatment of COPD: ß₂-adrenoceptor (ß₂-AR) agonists and quarternary ammonium anticholinergic agents ([3]), which can be either short-acting (e.g., salbutamol, terbutaline, ipratropium or oxitropium) or long-acting (e.g., formoterol, salmeterol, or tiotropium). Both the GOLD Update and the ATS/ERS position paper recommend, for moderate-to-very severe COPD, use of regular treatment with long-acting bronchodilators rather than short acting bronchodilators, with the choice depending on the availability of medication and the patient's response ([1], [2]).

For patients whose COPD is not sufficiently controlled by monotherapy, these guidelines recommend that combining medications of different classes, in particular an inhaled anticholinergic and a ß₂-AR agonist, as a convenient way of delivering treatment and obtaining better lung function and improved symptoms ([1], [2]).

Rationale for combining ß₂-adrenoceptor agonists and anticholinergic agents

Postganglionic, parasympathetic-cholinergic nerves innervate the airways, mainly the larger, cartilaginous central airways, and are primarily responsible for the regulation of bronchomotor tone. Acetylcholine, released from efferent vagal nerve endings, binds to muscarinic receptors on airway smooth muscle (ASM) causing tonic ASM contraction and consequent narrowing of the airway lumen with increases in airway resistance ([4]). Parasympathenically mediated ASM tone is temporally variable accounting for day-to-day and diurnal variability in airway resistance and forced expiratory airflow measures. Mucus secretion from submucosal bronchial mucous glands is also under parasympathetic nervous system control. Conversely, sympathetic nerves may regulate vasomotor tone in tracheobronchial submucosal blood vessels but do not innervate human airway smooth muscle. On the other hand, ß₂-ARs are abundantly expressed on human airway smooth muscle and activation of these receptors by circulating epinephrine or exogenous adrenergic agonists causes its relaxation ([5]).

Bronchodilation may, therefore, be obtained either by stimulating the ß₂-ARs with ß₂-AR agonists or by inhibiting the action of ACh at muscarinic receptors with anticholinergic agents. Anticholinergics are more likely to decrease resistance in central airways that are richly innervated by the parasympathetic nerves. Although the small airways do not appear to be innervated by cholinergic nerves, muscarinic receptors are also expressed in the smooth muscle of these smaller airways and may be activated by acetylcholine released fron non-neuronal sources. However, ß₂-AR agonists appear to have a greater effect on peripheral airway resistance in patients with COPD ([6]). It is reasonable to postulate that attempts to reduce bronchoconstriction through two distinct mechanisms (anticholinergic and sympathomimetic) with a different preferential site of action may maximize bronchodilator response.

Interestingly, the presence of small dense-cored vesicles containing adrenergic nerve varicosities, occasionally in close proximity to morphologically characteristic cholinergic nerve-endings, has been identified in human airways ([7]), suggesting that catecholamines might modulate cholinergic neurotransmission. However, different studies have led to conflicting conclusions. Early studies relying on force measurements alone suggested that stimulation of presynaptic ß₂-ARs on parasympathetic ganglia inhibits cholinergic neurotransmission ([8]), most probably by the release of inhibitory prostaglandins from the airway mucosa ([9]). However, interpretation of these data is seriously hampered by the large postjunctional effects of ß₂-AR agonists. Zhang and colleagues ([10]) were the first to report an excitatory ß₂-AR in airway parasympathetic nerves in the horse, and this excitatory ß₂-AR was subsequently reported in guinea pigs ([11]) and in human airway parasympathetic nerves ([12]). Activation of ß₂-ARs by isoproterenol, by the racemic mixture of specific ß₂-AR agonists such as salbutamol and formoterol or by R-enantiomers of ß₂-agonists can increase ACh release in a concentration-dependent manner ([13]). Consistent with the results of ß₂-AR stimulation ([14]), direct activation of the ß₂-AR-coupled G_s protein by cholera toxin, which increases the activity of adenylyl cyclase, caused an increase in ACh release in epithelium-denuded guinea pig trachealis ([11]). In airway smooth muscle cells, however, stimulation of G_s protein directly opens large Ca^{2 +} -activated potassium (K_Ca) channels ([15]), and this effect has been found to decrease ACh release in guinea pig trachealis ([16]). Recently, Brichetto and colleagues ([17]) have confirmed that ß₂-AR agonists attenuate cholinergic neurotransmission in the isolated bovine trachealis model via a mechanism not involving cAMP but rather K_Ca channels.

Whatever the type of interaction between the two systems may be, combining ß₂-AR agonists and anticholinergic agents is pharmacologically useful for two reasons. First, the addition of a ß₂-AR agonist decreases the release of ACh through the modulation of cholinergic neurotransmission by prejunctional ß₂-ARs and thereby amplifies the bronchial smooth muscle relaxation directly induced by the anticholinergic agent. Secondly, the addition of an anticholinergic agent can reduce the bronchoconstrictor effects of ACh, whose release has been facilitated by the ß₂-AR agonist, and thereby amplify the bronchodilation elicited by the ß₂-AR agonist through the direct stimulation of smooth muscle ß₂-ARs.

Combination therapy with ipratropium and a ß₂-agonist

It has been documented that standard doses of short acting ß₂-agonists do not give optimal results in patients with COPD and that an anticholinergic agent gives additional bronchodilation that is reproducible over a 3-month span ([18]). Although a few early articles question the value of combination therapy with ipratropium bromide and a ß₂-AR agonist ([19], [20]), several large trials suggest that the two drugs, both at relatively low doses delivered by metered-dose inhaler (MDI) ([21]) and at higher doses given by nebulization ([22], [23]), have complementary, or additive, bronchodilator actions without any increase in the incidence of adverse reactions, which makes them an excellent combination for the treatment of COPD. The overall result is lower total treatment costs and improved cost-effectiveness ([24]).

The introduction of long acting ß₂-AR agonist bronchodilators gives physicians additional therapeutic options for COPD. Both salmeterol and formoterol appear to be more effective than short acting ß₂-AR agonists ([25]), and in patients with stable COPD they are more effective than anticholinergic agents ([26], [27]).

Two published studies that had evaluated small cohorts suggested that there is no substantial additive effect when a long-acting ß₂-AR agonist is combined with ipratropium bromide given acutely at the clinically recommended dose (40 μg) in patients with COPD ([28], [29]). However, the dose of ipratropium bromide needed to produce near maximal bronchodilation may be several times higher than the customary dosage ([30]) (in a study carried out to examine the dose-time-response of 20 to 160 μg of ipratropium on separate days in a large number of stable COPD subjects, the plateau was nearly achieved at about 120 μg ([31])). In fact, the results of some studies suggest that higher than normal doses of an anticholinergic drug must be used for further relief of bronchospasm in patients with COPD when a single conventional inhaled dose of formoterol ([32]) or salmeterol ([33]) is given first.

In contrast to the earlier study of Matera et al. ([29]), van Noord and colleagues ([34]) demonstrated that a 12-week treatment with salmeterol 50 μg twice daily plus ipratropium bromide 40 μg four times daily was more effective than salmeterol 50 μg twice daily in improving forced expiratory volume in 1 second (FEV₁) and specific airway conductance. This study was the first to point out that the combination of a long acting ß₂-AR agonist and an anticholinergic agent is useful in the long term therapy of stable COPD.

Subsequently, D'Urzo and colleagues ([35]) demonstrated that the addition of formoterol (12 μg twice daily) to ipratropium bromide (40 μg four times a day) is more effective than the addition of salbutamol (200 μg four times a day) in patients with COPD who required combined bronchodilator therapy. This finding clearly indicates that long-acting ß₂-AR agonists may represent the most effective option for combination therapy with an antimuscarinic agent.

The functional impact of combining formoterol and tiotropium

Clinical studies show that tiotropium administered 18 μg once daily improves lung function over its 24-hour dosing interval, as shown by FEV₁, forced vital capacity (FVC), peak expiratory flow rate (PEFR) and measures of hyperinflation, and provides superior spirometric improvements compared with ipratropium 40 μg four times daily ([36]). Considering this important finding, in an elegant review in which the pharmacological actions of the long-acting ß₂-AR agonists and a long-acting muscarinic antagonist (tiotropium bromide) were summarized, Tennant and colleagues ([37]) emphasized the need for investigating the combination of tiotropium bromide with a long-acting ß₂-AR agonist. Afterwards, Tashkin and Cooper ([38]), using the traditional method of integrating research studies that does not exclude the possibility that differences between the study outcomes are due to chance, inadequate study methods or different patient characteristics of the study samples, emphasized the advantage of tiotropium over long-acting ß₂-agonists and suggested adding salmeterol or formoterol to tiotropium bromide, at least in patients suffering from COPD with more severe symptoms (stage III or IV of the GOLD classification ([1])). However, Cazzola and Matera ([39]) in an accompanying editorial commented that no published study has documented the superiority of tiotropium over formoterol, although two studies, specifically designed to explore the potential differences between tiotropium and salmeterol, appear to indicate a greater efficacy of tiotropium compared to the latter long-acting ß₂-AR agonist ([40], [41]). The different pharmacodynamic profile of formoterol when compared to salmeterol ([25]) might induce a different type of broncholytic effect, particularly with respect to onset of action or peak bronchodilation, possibly leading to different outcomes when comparing formoterol with salmeterol. Moreover, at the time the latter studies were published, it was not known if the combination of a long-acting ß₂-AR agonist and a long-acting antimuscarinic agent provides further advantages in terms of bronchodilation over either drug alone, nor if the choice of the specific long-acting ß₂-agonist might lead to differing results.

Functional effect of combining formoterol and tiotropium

Some studies have tried to provide an answer to these questions (Table 1). A pilot investigational trial ([42]), which enrolled 20 outpatients clinically diagnosed with stable COPD and a mean baseline FEV₁ of 0.87 l (95% confidence interval (CI): 0.70–1.04) and FVC of 1.49 l (95% CI: 1.30–1.69), showed that 12 μg formoterol (Aerolizer® DPI), either alone or in combination with 18 μg tiotropium (Handihaler® DPI), elicited a significantly faster onset of action (the change in FEV₁ 10 min after inhalation of formoterol alone (0.088 l; 95% CI: 0.049–0.127) was greater than that induced by tiotropium alone (0.039 l; 95% CI: 0.006–0.071), but not than that elicited by formoterol + tiotropium (0.085 l; 95% CI: 0.044–0.126)). Moreover, this study also documented a trend for a greater maximum bronchodilation with the combination than with formoterol or tiotropium alone (the mean maximum increases in FEV₁ from the pre-dose value on each of the dosing days were 0.192 l (95% CI: 0.125–0.259) for formoterol, 0.176 l (95% CI: 0.100–0.253) for tiotropium, and 0.210 l (95% CI: 0.158–0.261) for the combination and occurred two hours after formoterol and three hours after inhalation of tiotropium and the combination, but the difference between treatments was not significant (p = 0.475)). At twenty four hours, mean FEV₁ continued to be significantly higher than the pre-dose value following tiotropium (0.084 l; 95% CI: 0.003–0.134; p = 0.003) and formoterol + tiotropium (0.088 l; 95% CI: 0.002–0.173; p = 0.045), but did not achieve significance for formoterol alone (0.058 l; 95% CI: 0.000–0.117; p = 0.051). However, at this time point, the differences between treatments were not significant (p = 0.731). The failure to show a statistically significant difference between treatments in maximum bronchodilation and duration of action was likely due to insufficient statistical power. Moreover, this single-dose study did not take into account the fact that the maximum steady-state pharmacodynamic effect of tiotropium is not achieved until several days of maintenance daily therapy after initial dosing.

Table 1 Functional effect of combining single doses of formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
Cazzola et al., 2004 ([42])	F 12 μg,; T 18 μg; F 12 μg + T 18 μg with washout period between the test days of at least 96 h.	20 stable outpatients. (mean baseline FEV1:34.8% ± 13.2 predicted).	Double-blind, double-dummy, cross-over, randomized trial.	Rate of onset of action; maximum response; time course of bronchodilating effect over 24 h; FEV1 AUC over 12 and 24 h	Significantly faster onset of action and a trend for a greater maximum bronchodilation with F, alone or in combination with T, than with T alone. At 24 h, mean FEV1 significantly higher than pre-dosing value following T and F +T, but differences between treatments not significant. Mean FEV1 AUC0-12 h and FEV1 AUC0-24 h after F + T higher than, but not statistically significantly different from, that of T or F alone.
Brashier et al., 2005 ([43])	T 18 μg; F 12 μg + T 18 μg in a single inhaler.	23 stable patients (mean baseline FEV1: 40.6% ± 14.1 predicted).	Double-blind, cross-over, randomized trial.	Changes in FEV1 and FVC over 24 h.	Better FEV1 and FVC responses with F + T in a single inhaler than T alone over 24 h.
Cazzola et al., 2005 ([44])	T 18 μg q.d., or F 12 μg b.i.d. over a 5-day period for each drug, with a 10-day washout in between. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence.	20 stable outpatients (mean baseline FEV1: 1.13 L (95% CI: 0.96–1.32) for T and 1.13L (95% CI: 0.94–1.33) for F.	Randomized, crossover trial.	Changes in FEV1 and FVC AUC over 6 h.	Significant improvement in pulmonary function adding T or F in patients already under regular treatment with F or T, respectively, with no statistically significant difference between the different sequences.
Di Marco et al., 2006 ([45])	F 12 μg; T 18 μg; F 12 μg + T 18 μg in randomized sequence on days 1, 3 and 5.	21 patients with a mild to moderate AECOPD (mean FEV1: 38 ± 14% predicted).	Double-blind, double-dummy, cross-over, randomized trial.	Changes in FEV1, FVC and IC AUC over 12 and 24 h; time course of bronchodilating effect; maximum response	Mean FEV1, FVC and IC AUC0 - 12 h and AUC0 - 24 h after F + T significantly larger than F and T alone; differences between F and T not statistically significant Significantly faster onset of action, and a greater maximum bronchodilation with F + T, than with T or F alone.

F: formoterol; T: tiotropium; AUC: area under the curve; AECOPD: acute exacerbation of COPD.

The results of this study indicated that formoterol and tiotropium have different profiles (formoterol has a faster onset of action and greater bronchodilating effect with single doses, while tiotropium has a longer duration of action, which allows for once daily administration) that make both agents attractive alternatives in the treatment of stable COPD. Moreover, the two drugs appear complementary: tiotropium ensures prolonged bronchodilation, whereas formoterol adds fast onset and, at least initially, a greater peak effect. However, because tiotropium is required only once daily but the bronchodilator effect of once daily formoterol does not persist for 24 hours (so that the conventional dosing for this agent is twice daily), the challenge is to develop a combined inhaler that can be employed on a once daily basis ([37]).

The fact that in patients with moderate-to-severe COPD, addition of formoterol to tiotropium produces better FEV₁ and FVC responses than tiotropium alone when measured over 24 hrs has been documented also when the two drugs have been administered in a single inhaler (pMDI plus a non-static spacer) ([43]). The mean baseline FEV₁ value in this study population was 40.6 ± 14.1% predicted. Compared to either agent alone, tiotropium plus formoterol produced a significantly better mean difference in area under the curve change from baseline to 24 hrs for both FEV₁ (p = 0.001) and FVC (p = 0.02). Also, the mean difference in trough (24 hr) values from baseline was significantly better with the combination than with tiotropium alone ((FEV₁ −289.6 mL vs 185.7 mL; p = 0.001)(FVC −503.5 mL vs 297 mL; p = 0.007). The combination showed a faster onset of action for FVC, defined as an increase of at least 150 mL from baseline (5.0 min vs 12.1 min; p = 0.02), and tended to show a longer duration of action when compared to tiotropium alone (FEV₁: p = 0.06; FVC: p = 0.05).

A further study explored the bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients ([44]). A randomized, crossover trial with tiotropium 18 μg (Handihaler® DPI) once daily (group A), and formoterol 12 μg (Modulite® HFA-pMDI) twice daily (group B) over a 5-day period for each drug, with a 10-day washout in between, was conducted in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 μg + formoterol 12 μg; group B: formoterol 12 μg + tiotropium 18 μg). FEV₁ and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV₁ and FVC further improved after crossover with both sequences. The mean maximal change in FEV₁ over baseline was 0.226 L (0.154–0.298) after tiotropium + formoterol and 0.228 L (0.165–0.291) after formoterol + tiotropium; the mean maximal change in FEV₁ over the value just prior to inhalation of the second drug was 0.081 L (0.029–0.133) after tiotropium + formoterol and 0.054 L (0.016–0.092) after formoterol+ tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361–0.676) after tiotropium + formoterol and 0.495 L (0.307–0.683) after formoterol + tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048–0.270) after tiotropium +formoterol and 0.175 L (0.083–0.266) after formoterol + tiotropium. The FEV₁ AUCs_{0-360 min} were 62.70 (45.67–79.74) after tiotropium + formoterol and 69.20 (50.84–87.57) after formoterol + tiotropium, the FEV₁ AUCs_{0-180 min} were 24.70 (18.19–31.21) after tiotropium + formoterol and 29.74 (21.02–38.46) after formoterol + tiotropium, whereas the FEV₁ AUCs_{180-360 min} were 15.70 (10.88–20.52) after tiotropium + formoterol and 11.71 (7.21–16.21) after formoterol + tiotropium. Differences between the two treatments were not statistically significant (P > 0.05).

This study indicates that significant improvement in pulmonary function can be achieved by adding tiotropium or formoterol at the recommended dosages in patients already on regular treatment with formoterol or tiotropium, respectively, with no real difference between the two different sequences. In fact, the gain in FEV₁ was similar in the two sequences studied and, although relatively small, the combination is likely useful for subjects suffering from a chronic airway obstruction that is only partially reversible. Therefore, these results suggest that supplementing a second different long-acting bronchodilator to a regularly administered long-acting bronchodilator is clinically beneficial.

The pharmacodynamic effects of 1-day treatment with formoterol, tiotropium and their combination have also been investigated in patients with an acute exacerbation of COPD (AECOPD) ([45]). Twenty-one (19 males, mean age 72 ± 8 years, mean FEV₁ 38 ± 14% of predicted values) patients with mild to moderate AECOPD were enrolled. Patients received formoterol (12 μg b.i.d.) via HFA-pMDI (Modulite®), tiotropium (18 μg once daily) via Handihaler DPI, and their combination, in randomized sequence. Serial measurements of FEV₁, FVC, IC, SpO₂ and HR were performed over 24 h. Formoterol, tiotropium, and their combination significantly improved the area under curves (AUCs) for FEV₁, FVC and IC over 12 and 24 h. The mean FEV₁, FVC and IC AUC_{0 - 12 h} and AUC_{0 - 24 h} after formoterol and tiotropium combination were significantly higher than after formoterol or tiotropium alone, whereas the differences between the two single drugs were not statistically significant. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action, and the combination elicited a greater magnitude and longer duration of bronchodilation than either single drug as measured by both FEV₁ and FVC. After 24 h the bronchodilating effect on FEV₁ of the single drugs alone (tiotropium once daily or formoterol twice daily) disappeared, while it was still evident for the combination.

The results of this study have documented that, although the time course of the effects of the evaluated drugs differs significantly from that in stable COPD, with a shorter duration of bronchodilation for both tiotropium and formoterol, these two long-acting bronchodilators appear also to be complementary during a mild to moderate AECOPD.

Functional effect of regular treatment with formoterol and tiotropium

Although the above-cited results indicate that a combination of tiotropium and formoterol is more effective than single drugs alone in inducing bronchodilation in patients with COPD, the impact of the three treatments was evaluated only after acute or short-term administration. Acute administration is a potential bias because achievement of the FEV₁ steady state with tiotropium requires up to forty eight hours and continued improvements in FVC can be expected over or beyond the first week of therapy ([46]), suggesting that maintenance bronchodilator therapy is required to achieve maximal reduction in hyperinflation.

In a trial ([47]) comparing the lung function response of 66 patients with moderate–to-severe stable COPD to the free combination of 18 μg tiotropium (Handihaler® DPI) plus 12 μg formoterol (Aerolizer® DPI) once daily with 18 μg tiotropium once daily and 12 μg formoterol twice daily (with each treatment administered for a 6-week period), the free combination of once daily tiotropium plus formoterol was found to be superior to either of the single drugs for most of the spirometric endpoints. The mean ± SE baseline FEV₁ at the start of the treatment periods was 1.019 ± 0.03 L. After 6 weeks of treatment with tiotropium once daily, formoterol b.i.d. or tiotropium plus formoterol once daily, the pre-dose values were 1.127 ± 0.01 L, 1.091 ± 0.01 L and 1.134 ± 0.01 L, respectively, and the difference between the combination and formoterol was significant (p < 0.05). Following inhalation of the morning dose of tiotropium or formoterol, the improvements in FEV₁ were comparable between the two bronchodilators until 8 h after dosing. From 8 to 12 h, post-dose tiotropium provided a significantly greater improvement in FEV₁ compared with formoterol in the range of 0.064 L (p < 0.002) to 0.081 L (p = 0.0001). After inhalation of the second (evening) formoterol dose, no significant differences were observed between tiotropium and formoterol during the night-time, except that, at the 24-h measurement (trough value), tiotropium was again superior to formoterol by 0.042 L (p < 0.05). Compared with the individual components, the once-daily tiotropium plus formoterol treatment performed significantly better during the first 12-h period after inhalation of the morning dose. The additional improvement in FEV₁ versus tiotropium alone ranged from from 0.070 L to 0.151 L (p ≤ 0.001), whereas improvements compared with formoterol b.i.d. ranged from 0.110 to 0.164 L (p < 0.0001). During the night-time (12–24 h), the combination regimen provided a significantly greater bronchodilation of 0.053 L (p < 0.01) compared with formoterol 7 h after the evening dose (i.e. 19 h after the morning dose of the combination at 04:00 h), which gradually increased to 0.079 L (p < 0.001) at the end of the 24-h observation period. The significant difference versus tiotropium alone observed during the daytime was sustained until 13 h after the morning dose (0.060 L; p < 0.02). During the night-time, the combination regimen remained numerically superior until the end of the observation period. Use of rescue salbutamol was significantly reduced in patients receiving the combination of tiotropium + formoterol during the daytime (tiotropium plus formoterol 1.81 puffs· day⁻¹, tiotropium 2.41 puffs· day⁻¹, formoterol 2.37 puffs· day⁻¹) (p < 0.05 versus either drug alone), but not the night-time.

The observation that tiotropium was more active than formoterol during the daytime but not during the night-time is consistent with the fact that the activity in the sympathetic system appears to be predominant during the day as reflected by the peak of the urinary catecholamine excretion occurring around noon, whereas the vagal system appears to be predominant during the remainder of the day ([48]). Alternatively, this observation could simply reflect the waning effect of the once daily administration of tiotropium over the latter half of its 24-hour dosing interval. In any case, these results indicate that once daily combination therapy of tiotropium + formoterol is safe and provides significant additive effects in patients with moderate-to-severe COPD. Moreover, they suggest that once daily administration of the two drugs could be a possibility in the treatment of stable COPD. A bronchodilator-mediated symptom benefit of the once daily combination is also reflected in a significant decrease in salbutamol use as rescue therapy.

However, another trial that explored tiotropium (Handihaler® DPI) maintenance therapy and the twenty four hour spirometric benefit of adding once or twice daily formoterol (Aerolizer® DPI) during two-week treatment periods in 91 patients with COPD who completed the study ([49]), demonstrated that add-on therapy of a second formoterol dose significantly (p < 0.05) improved FEV₁ and FVC variables when compared with tiotropium + formoterol once daily, although most of the spirometric add-on benefit was found with the morning formoterol dose. The average FEV₁ AUC_{0 - 24 h} was 0.08 L after tiotropium, 0.16 L after tiotropium + formoterol once daily and 0.20 L after tiotropium + formoterol twice daily (p < 0.01 for all comparisons). Compared with tiotropium alone, add-on formoterol in the morning produced improvement in FEV₁, FVC, and IC, which is an index of hyperinflation, for > 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV₁ for 12 h, but in FVC and IC for only < 12 h. Peak increase in FEV₁ was 0.23 L (22% of baseline) with tiotropium and 0.39 L (37% of baseline) with tiotropium plus formoterol (p < 0.0001). Compared with tiotropium alone, add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime (p < 0.01) and, with add-on formoterol twice daily, also during the nighttime (p < 0.05).

The effectiveness of a treatment with formoterol 12 μg b.i.d. plus tiotropium 18 μg once daily has been confirmed by a 12-week, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in COPD patients aged ≥40 years who were current or ex-smokers ([50]). Formoterol + tiotropium significantly increased the normalized FEV₁ AUC_{0 - 4 h} compared with tiotropium at all time points post-baseline, with mean treatment differences that reached clinical significance (> 100 mL change). Mean treatment differences (95% CI) at weeks 4, 8, and 12, and endpoint were 150 mL (90, 220), 170 mL (100, 230), 180 mL (120, 240), and 170 mL (120, 230), respectively (all p < 0.001). At endpoint, increases from baseline in trough FEV₁ and FVC were significantly greater with formoterol + tiotropium than with tiotropium alone, with mean treatment differences of 80 mL and 160 mL, respectively (both p = 0.004). The increase in FEV₁ 5 minutes post-dose was significantly greater with formoterol + tiotropium than with tiotropium (180 mL vs 40 mL, respectively; p < 0.001). The combination produced a clinically meaningful reduction in total SGRQ score at the end of the 3-month treatment period compared to baseline, but the difference from tiotropium alone was not statistically significant (−4.81 vs. −3.80, respectively). However, the change in symptom scores was significantly more favourable with the combination than tiotropium alone (−8.33 vs. 3.97, respectively; p < 0.05). While the use of rescue medication decreased in both treatment groups, reduction in daytime use was significantly greater with the combination of formoterol and tiotropium than with tiotropium alone averaged over all time points post-baseline (−1.13 vs. −0.59 puffs, respectively; p < 0.04). Both treatments were similarly well tolerated.

A recent study examined the clinical efficacy and safety of 6-month treatment with formoterol (multi-dose DPI), tiotropium (Handihaler® DPI) and the free combination in 847 patients with COPD ([53]). The study was partially blinded (formoterol and placebo). The addition of formoterol to tiotropium treatment conferred small advantages in terms of the early bronchodilator effect, lung function measured at trough (PEF, pre-bronchodilator) or post-bronchodilator (FEV₁), and fewer exacerbations requiring additional treatment, although the latter finding was not statistically significant. The safety profile of the combination was comparable to either single therapy and was even better in terms of fewer reports of COPD as an adverse event than with either single agent. Similar differences between the two treatments with respect to lung function were found irrespective of concomitant inhaled corticosteroid use ([51]) or smoking status ([52]).

It seems that in patients with moderate to severe COPD, combination therapy with tiotropium administered in the morning is the most effective; in patients with prevailing night-symptoms, treatment with tiotropium in the evening reduces symptoms and use of salbutamol as rescue medication and, moreover, shows less variability of FEV₁ during the 24 h ([54]).

Table 2 summarizes the studies reviewed.

Table 2 Functional effect of regular treatment with formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
van Noord et al. 2005 ([47])	T 18 μg OD; F 12 μg BID or F 12 μg + T 18 μg OD for three 6-week periods.	71 patients (mean FEV1: 37.2± 8.6 predicted).	Randomised, double-blind, three-way, crossover trial.	24-h FEV1, and FVC at the end of each treatment; rescue salbutamol.	Significant improvements FEV1 and FVC with T being superior to F during the daytime (0–12 h), but bronchodilator effects with F + T ODsuperior to single-agent therapy during the daytime (0–12 h) and the night-time (12–24 h). Daytime salbutamol use significantly lower during combination therapy.
van Noord et al. 2006 ([49])	2-week treatment periods of T alone; T + F OD or BID following a 2-week pretreatment period with T.	95 patients with stable COPD (mean FEV1: 38 ± 10 predicted).	Randomized, open-label, placebo-controlled, three-way crossover trial.	Changes in FEV1, FVC- and IC AUC over 0–24 h and 12–24 h; rescue salbutamol.	Combination of T OD with F BID the most effective. Compared with T alone, add-on F in the morning produced improvement in FEV1, FVC, and IC for > 12 h. The second add-on dose of F in the evening caused further improvement in FEV1 for 12 h, but in FVC and IC for < 12 h. Compared with T alone, add-on F OD and BID reduced the use of rescue salbutamol during the daytime and with add-on F BID also during the nighttime.
Tashkin et al. (in press) ([50])	F 12 μg BID + T 18 μg OD or T 18 μg OD + P for 12 weeks.	240 patients with stable COPD	Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial.	Normalized FEV1 AUC over 0–4h at the last visit; trough effects on FEV1 and FVC (average of values 10 and 30 minutes predose); onset of effects on FEV1 following the first dose rescue salbutamol.	Significant increase in the normalized FEV1 AUC0 − 4h after F + T compared with T. At endpoint, increases from baseline in trough FEV1 and FVC significantly greater with F + T than with T. The increase in FEV1 5 minutes postdose was significantly greater with F + T than with T. Use of salbutamol decreased in both treatment groups, but reduction in daytime use significantly greater with F + T than with T.
Vogelmeier et al. 2008 ([51])	F10 μg BID via MDDPI; placebo BID via MDDPI; T18 μg OD via the HandiHaler® + F 10 μg BID via MDDPI; T 18 μg OD via the HandiHaler® + placebo BID via MDDPI.	847 patients (mean FEV1 52% predicted)	Multicenter double-blind for treatment with MDDPI, but not for other comparisons (T administered open-label). Randomization not stratified.	FEV1 measured 2 h post-dose after 24 weeks of treatment. FEV1 and FVC at other time points during the study; COPD exacerbations; symptom scores, rescue medication use and PEF; quality of life; 6-minute walking distance.	FEV1 2 h post-dose after 24 weeks: all three treatments superior to placebo, differences in favour of F + T versus F or T. F + T statistically superior to monotherapy for: FEV1 2 h post-dose after 24 weeks vs. F; FEV1 5 min after the first dose and at 12 weeks vs. T; and PEF averaged over the first 6 weeks vs. both. The three active treatments were significantly more effective than placebo for other endpoints.

F: formoterol; T: tiotropium; AUC: area under the curve; MDDPI: multi-dose dry powder inhaler; P: placebo; OD: once daily; BID: bis in die.

Formoterol solution

COPD prevalence steadily increases with age but elderly patients with COPD, even when in a stable clinical condition, may be unable to gain optimum benefit from their hand-held inhaler ([55]). Under real life conditions patients may make many errors with their usual hand-held inhalation device, which may negate the benefits observed in clinical trials ([56]). Although breath-actuated DPIs have alleviated coordination difficulties, they require a high peak inspiratory flow to disaggregate and disperse the drug powder, which elderly COPD patients may be unable to generate ([55]). Of the three types of devices used to deliver bronchodilators - nebulizers, MDIs, and DPIs - nebulizers require no special technique or coordination, since the medication is converted into a fine mist that the patient inhales through a mouthpiece or face-mask while breathing naturally. Therefore, because nebulization is an easy, effective, and reliable method of delivering medication directly into the lungs, many COPD patients request this form of aerosol delivery, particularly as their symptoms worsen. Formoterol fumarate inhalation solution for nebulization (FFIS) has been approved in U.S.A. (Perforomist® inhalation solution, Dey, L.P.) as an alternative for those who prefer or require a nebulized option due to a lack of hand-lung coordination, visual acuity, mental status, or inspiratory flow needed to use an MDI or DPI correctly.

Findings from dose-ranging and pharmacodynamic and pharmacokinetic studies have shown that a 20 μg dose of FFIS was comparable to formoterol delivered by dry powder inhalation (12 μg) and established the dose proportionality and linear kinetics of formoterol delivered by nebulization ([57]). In a randomized, double-blind, double-dummy trial, COPD subjects (n = 351, mean FEV₁ = 44% predicted) received FFIS (20 μg) or formoterol DPI (12 μg), or placebo twice daily for 12 weeks ([58]). At the 12-week endpoint, FFIS significantly increased FEV₁ AUC_{0-12 h} relative to placebo (p < 0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV₁ AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV₁, trough FEV₁, and standardized FVC AUC_{0-12 h} compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, −4.9, p = 0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Interestingly, however, FFIS treatment was associated with statistically significant and clinically meaningful improvements in total SGRQ score and its symptom and impact components compared to placebo, while formoterol DPI improved only symptom scores. This finding suggests a possible quality-of-life advantage of nebulized treatments over hand-held aerolized delivery of the same medication.

The safety profile of FFIS has been evaluated over a twelve-month period in an open-label, active-control study ([59]). After completing a twelve-week double-blind double-dummy period, 569 subjects with COPD entered an open-label extension study and received twice-daily 20 μg FFIS or 12 μg formoterol DPI for 52 weeks. Most of the FFIS-treated subjects (86%) completed at least six months of open-label treatment with over 90% compliance, comparable to the formoterol DPI group (88%). Results of safety monitoring for adverse events, laboratory values, and cardiac changes were similar between treatment groups. Three hundred forty (73%) of FFIS-treated subjects and 83 (78%) of formoterol DPI-treated subjects experienced an adverse event over the course of the study, the majority of which were mild to moderate and considered unrelated to treatment. A COPD exacerbation occurred in 15.8% of FFIS-treated and 17.9% of formoterol DPI-treated subjects. Deaths, serious adverse events, and discontinuations for adverse events occurred in 1.3, 16.2, and 5.4% of the nebulized group versus 1.9, 17.9, and 7.5% of the DPI group, respectively. There were no clinically important changes from baseline in laboratory tests, including serum potassium and glucose, or vital signs and no treatment-related increases in cardiac arrhythmias, heart rate, or QTc prolongation.

Concomitant treatment with nebulized formoterol and tiotropium

To demonstrate that benefits similar to those that can be obtained adding formoterol by DPI or MDI to tiotropium can also be provided by nebulized formoterol, a randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of adding formoterol inhalation solution to tiotropium maintenance treatment in patients with stable COPD ([60]) (Table 3).

Table 3 Concomitant treatment with nebulized formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
Tashkin et al., 2008 ([60])	FFIS 20 μg BID + T OD via the HandiHaler® or nebulized P BID + T OD via the HandiHaler® for 6 weeks	129 patients (mean FEV1 38.4 ± 10.4 predicted)	Randomized, double-blind (only with FFIS and placebo), placebo-controlled, parallel group trial	FEV1 AUC0-3 h; TDI; SGRQ.	Significant improvements in FEV1 AUC0−3, peak FEV1, and trough FVC for FFIS + T vs. T alone maintained throughout the 6 week-treatment. Statistically significant improvements in TDI for FFIS + T vs. T alone. SGRQ not significantly impacted by FFIS + T vs. T alone.

FFIS: formoterol fumarate inhalation solution;T: tiotropium; P: placebo; OD: once daily; BID: bis in die; TDI: transition dyspnea index; SGRQ: St. George's Respiratory Questionnaire.

After a 7–14-day run-in period using tiotropium 18 μg once daily, subjects with moderate to very severe COPD (≥25% to < 65% predicted FEV₁) were randomized to receive 20 μg formoterol inhalation solution twice daily for nebulization plus tiotropium or nebulized placebo twice daily plus tiotropium for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1 (baseline), and Weeks 1, 3 and 6), the automated self-administered version of the baseline dyspnea index (BDI) (day 1) and the transition dyspnea index (TDI) (weeks 1, 3 and 6), and St. George's Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV₁% predicted. At Week 6, FEV₁ AUC₀₋₃ was 1.52 L for formoterol + tiotropium-treated subjects vs. 1.34 L for placebo + tiotropium-treated subjects (p < 0.0001). The mean TDI scores in the formoterol + tiotropium and placebo + tiotropium groups were 2.30 and 0.16, respectively (p = 0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of improvements in symptom score in the formoterol + tiotropium group compared to the placebo + tiotropium group (p = 0.04). Numerically more placebo + tiotropium- than formoterol + tiotropium-treated subjects experienced adverse events (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious adverse events (3.2% vs. 1.5%).

Results of this study demonstrating that concomitant therapy with twice-daily nebulized formoterol and once-daily tiotropium provides statistically significant and clinically relevant improvements in bronchodilation and COPD symptoms over tiotropium alone further support data previously reported indicating the clinical comparability between the nebulized and DPI formulations of formoterol fumarate.

The best strategy for adding formoterol and tiotropium

The current GOLD guidelines ([1]) recommend considering adding a second long-acting inhaled bronchodilator in moderate COPD in order to optimize the symptom benefit for patients and to add an ICS to maintenance bronchodilator therapy for COPD patients at stages III (severe; FEV1 < 50% and ≥30% predicted) and IV (very severe; FEV1 < 30% predicted), who are still having frequent exacerbations. This recommendation is supported by the results of the TORCH study ([61]) indicating additive benefits of the combination of salmeterol and fluticasone over either component alone with respect to bronchodilation, reduction in excacerbations of COPD and improvement in health-related quality of life in patients with an FEV1 < 60% predicted. Subgroup analysis of the TORCH data also supports the benefits of treating symptomatic patients with an FEV₁ between 50% and 60% of predicted with combination long-acting beta-agonist/inhaled corticosteroid therapy ([62]); and, in effect, the recent extension of the salmeterol/fluticasone combination license by European regulators ([63]) supports this concept. In actual practice, inhaled corticosteroids and “fixed combinations” comprising an inhaled corticosteroid and long-acting beta-agonist are frequently prescribed in earlier stages of COPD, although evidence of the benefits of such combination therapy in COPD patients with an FEV1 > 60% of predicted is lacking. Moreover, in a study of 592 patients with moderate COPD (baseline FEV₁, 1.32 ± 0.43 L/min (± SD)), tiotropium (Handihaler® 7 DPI) plus formoterol (Aerolizer® DPI) resulted in superior improvement in lung function over the day compared to salmeterol plus fluticasone (fixed-combination Diskus DPI) ([64]). After 6 weeks, the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone (mean difference in FEV₁ AUC_{0-12 h}, 78 mL (p = 0.0006); mean difference in FVC AUC_{0-12 h}, 173 mL, p < 0.0001). In addition, peak responses were greater with tiotropium plus formoterol than the fixed combination of fluticasone and salmterol (difference in peak FEV₁, 103 mL (p < 0.0001); difference in peak FVC, 214 mL (p < 0.0001), as were FEV₁ and FVC at each individual time point after dosing (p < 0.05). Predose FVC was significantly higher with the bronchodilator combination, while predose FEV₁ and rescue medication use did not differ significantly between groups. These meaningful differences support current treatment recommendations in moderate COPD to combine two bronchodilators of different classes rather than to add an inhaled corticosteroid, if maintenance treatment with a single long-acting bronchodilator does not suffice.

A small study that examined the additive effect of oral theophylline in patients with stable moderate-to severe COPD (FEV₁ predicted, 42%) who received both tiotropium, 18 μg (Handihaler® DPI) od, and formoterol (Modulite® HFA-pMDI), 12 μg bid on a regular basis ([65]) demonstrated that combination therapy with formoterol + tiotropium produced a significant improvement from baseline in mean predose FEV₁ and FVC and significant reductions in dyspnea score as measured by a visual analogue scale and in use of rescue salbutamol. However, the study failed to demonstrate that the addition of theophylline to the combination of formoterol and tiotropium resulted in any significant further improvement in lung function or in dyspnea.

In 2004, Tashkin and Cooper ([38]), using the traditional method of integrating research studies, emphasized the advantage of combining tiotropium with a long-acting ß₂-agonist and suggested adding salmeterol or formoterol to tiotropium bromide, at least in patients suffering from COPD with more severe symptoms (stage III or IV of the GOLD classification ([1])). At that time, no data supported this suggestion. Since then, the published evidence has documented the benefits of using combination therapy with formoterol and tiotropium even in those COPD patients with more severe symptoms, although published studies of combination long-acting inhaled bronchodilator therapy to date are largely confined to relatively short-term trials focusing mainly on bronchodilation and reduction in the need for rescue medication. Longer-term trials are required to evaluate the benefits of combination therapy with two long-acting inhaled bronchodilators on such patient-centered outcomes as health-related quality of life, exacerbations and hospitalizations for COPD. Moreover, guidelines suggest that regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic COPD patients with an FEV₁ < 50% predicted (stages III and IV) and repeated exacerbations (e.g., three in the last 3 yr) ([1]). The latter suggestion is supported by results of the TORCH study ([57]).

The real problem that we have in our approach to the pharmacotherapy of COPD is that we assume that our patients are all representative of the general population of patients with COPD as if COPD is a homogeneous disease. On the contrary, COPD is a heterogeneous disease that is comprised of a number of different phenotypes ([66]). It is likely that further elucidation of these phenotypes will allow us to understand which kinds of patients may benefit most from an inhaled corticosteroid and which, instead, might best be treated with long-acting bronchodilators. In the meantime, considering that, while the severity of COPD has been classified according to FEV₁ but the latter may not correlate well with symptoms, a symptomatic approach to therapy in which physicians individualize treatment using clinical stages ([67]) may be more useful. In such an individualized approach, if monotherapy with a long-acting ß-agonist is insufficient, physicians might try one form of combination therapy (e.g., a long-acting anticholinergic plus a long-acting ß-agonist) and substitute another type of combination therapy (e.g., a long-acting ß-agonist and an inhaled corticosteroid) if the former regimen is not successful or, alternatively, try a combination of all three types of agents (a long-acting anticholinergic, a long-acting ß-agonist and an inhaled corticosteroid) ([68]).

Declaration of interest

Dr. Tashkin has received financial support for grants and fees for speaking and/or consulting from Boehringer/Ingelheim, Pfizer, Dey Laboratories and Schering-Plough. Dr. Cazzola has received fees for speaking and consulting and/or financial support for attending meetings from Abbott, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dey Laboratories, Encysive, GSK, Keryos, Lallemand, Menarini Farmaceutici, Novartis, Nycomed, Pfizer, Sanovel and Valeas.