Long-acting β2-agonist (LABA) and corticosteroid combination inhalers are now very widely used as a twice-daily therapy for asthma and chronic obstructive pulmonary disease (COPD) patients. The once-daily, long-acting muscarinic antagonist (LAMA) tiotropium bromide is also very effective for COPD, so this has prompted the idea that a triple inhaler containing a LABA, LAMA and a steroid would be a convenient treatment for COPD. Furthermore, tiotropium has also recently been found to be useful in patients with severe asthma, suggesting that a triple combination inhaler may also be useful in asthmatic patients. Indeed the first triple inhaler containing formoterol, tiotropium and ciclesonide (Triohale, Cipla) has already been marketed in India. The advantages and disadvantages of such a triple inhaler need to be discussed.
Current inhaled therapy in COPD
There is considerable evidence that combination inhalers containing a LABA and a steroid (salmeterol/fluticasone propionate [FP], formoterol/budesonide, formoterol/beclomethasone dipropionate) are beneficial in the long-term management of COPD patients, with reduced exacerbations compared with inhaled corticosteroid, although there is no evidence that disease progression or mortality are significantly reduced Citation[1–4]. The value of inhaled corticosteroids in COPD is uncertain, apart from in those patients who have concomitant asthma (‘overlap syndrome’). There is no evidence that even high doses of inhaled corticosteroids suppress inflammation in COPD and they provide is no clear benefit on disease progression or mortality Citation[5,6]. Even the reduction in severe exacerbations with inhaled corticosteroids has been questioned as an artefact of trial design Citation[7,8]. Nevertheless, inhaled corticosteroids are now recommended in patients with an forced expiratory volume 1 s (FEV1) <50% predicted normal and who have two or more exacerbations a year and this is often conveniently given with a LABA as a combination inhaler Citation[9]. This would apply to less than 10% of COPD patients, yet high-dose combination inhalers are used in over 70% of all patients diagnosed with COPD, suggesting that inhaled corticosteroids are widely overused in this disease. There is some concern about the overuse of inhaled corticosteroids in COPD patients as there is a risk of systemic side effects, such as diabetes, fractures, cataracts and an increased incidence of pneumonia Citation[10–12].
The once-daily LAMA tiotropium bromide is now widely used in the therapy of COPD patients and provides a sustained improvement in symptoms, improved health status, reduced exacerbations and reduced mortality Citation[13]. There is also evidence that it may reduce disease progression in moderate COPD (GOLD stage 2) Citation[14]. There is little difference in efficacy or safety between LABA/steroid combination inhalers and tiotropium in COPD, particularly in reducing exacerbations Citation[15,16]. The beneficial effects of tiotropium are seen when added to existing treatments, including LABA and inhaled corticosteroids Citation[13]. This suggests that a triple inhaler containing LABA, LAMA and steroid might be useful.
What is the evidence for triple combination in COPD?
In a small short-term crossover study of over 2 weeks in patients with severe COPD, combined treatment with tiotropium, salmeterol/FP had a greater effect on FEV1 and inspiratory capacity than tiotropium or salmeterol/FP alone Citation[17]. Although there were also improvements in dyspnoea scores and use of rescue medication with the three drugs, it is difficult to know if these findings are clinically relevant with such short-term treatment periods. In a pilot parallel-group study of 90 patients with severe COPD, the combination of tiotropium and salmeterol/FP gave a similar improvement in FEV1 and symptoms when compared to tiotropium and salmeterol/FP alone, providing no evidence for any additional benefit Citation[18]. Owing to the short duration of this study exacerbations could not be assessed. In a multicenter trial of 449 patients with moderate-to-severe COPD the addition of tiotropium to salmeterol/FP improved lung function and symptoms compared with either therapy alone, but did not significantly further reduce exacerbations, which was the primary end point of the study Citation[19]. However, the study was likely underpowered to detect such a difference. Taking all the studies together, adding tiotropium to LABA/steroid combination inhalers provides some improvement in lung function and quality of life, but the benefit is rather small and has uncertain clinical relevance Citation[20].
Indacaterol, a once-daily LABA is now marketed in some countries and several other once-daily LABAs (sometimes called ultra-LABAs) are also in clinical development, including vilanterol and olodaterol Citation[21]. Once-daily indacaterol is more effective than twice-daily salmeterol or formoterol in COPD patients in improving lung function and reducing symptoms Citation[22,23] and appears to be as effective as tiotropium Citation[24]. The bronchodilator effect of indacaterol is maintained over 1 year of treatment and the drug is well tolerated Citation[25].
There is an additive effect between LABA and LAMA in COPD patients, so that twice-daily formoterol or salmeterol plus tiotropium produce greater bronchodilatation and a greater reduction in symptoms than either drug alone Citation[26–28]. This is seen most impressively with indacaterol and the once-daily inhaled LAMA glycopyrronium bromide. When the maximally effective dose of indacaterol is given, adding glycopyrronium in the form of the combination inhaler (QVA149 [Novartis]) further increases bronchodilatation, achieving a mean increase in FEV1 of approximately 300 ml. This suggests that LABA–LAMA combination inhalers will be the most effective bronchodilators available for COPD patients. Several other once-daily LABA–LAMA combination inhalers are now in development in addition to QVA149, including olodaterol/tiotropium (Boehringer Ingelheim) and vilanterol/GSK573719 Citation[21]. A twice daily combination of formoterol and aclidinium (Almirall) is also in clinical development Citation[29]. Once-daily LABA/steroid combination inhalers, including vilanterol/fluticasone furoate (Relovair™) and indacaterol/mometasone are now in clinical development, so that once-daily triple combinations with once-daily LAMAs are now possible.
It is clear that LABA–LAMA combination inhalers are the most effective bronchodilator therapy for COPD patients. The important question is whether addition of a corticosteroid to the inhaler will provide additional clinical value. This can only be answered by clinical trials, but based on LABA/steroid combination inhalers it is unlikely to be a major additional clinical benefit for most patients. However, COPD patients with concomitant asthma and possibly patients with frequent exacerbations may benefit from a triple inhaler.
Triple combination inhaler for asthma
Long-acting muscarinic antagonist–corticosteroid combination inhalers are very effective in control of asthma and preventing exacerbations and have been shown to be more effective than the same or higher doses of the inhaled corticosteroid – apart from in patients with mild disease and in children Citation[30,31]. Formoterol combination inhalers may also be used as a reliever instead of a short-acting β2-agonist and this provides even further benefit in adults and children, especially in preventing severe exacerbations Citation[32]. Although tiotropium has been used off-label as an add-on bronchodilator in patients with severe asthma for some time, this has recently been supported by controlled clinical trials. Patients who have COPD and concomitant asthma benefit from the addition of tiotropium and in a study of over 400 such patients the majority were taking a LABA as well as inhaled corticosteroid Citation[33]. In 138 patients with severe asthma addition of tiotropium to inhaled corticosteroids and LABA gave a significant bronchodilator response (>15% increase in FEV1) in approximately 30% of patients Citation[34]. The tiotropium responders were more likely to have the Arg16Gly polymorphism of the β2-adrenoceptor, which has previously been associated with a better response to ipratropium bromide compared with salbutamol as rescue therapy Citation[35]. In a recent study of over 200 poorly controlled asthmatic patients, addition of tiotropium to inhaled corticosteroids was as effective as adding salmeterol and more effective than doubling the dose of inhaled corticosteroids Citation[36]. Several other studies are now underway looking at the benefit of adding tiotropium to LABA/steroid combination inhalers in patients with severe asthma, but this does suggest that a triple combination might be useful in some patients with severe asthma.
Advantages & disadvantages
The obvious potential advantage of a triple inhaler in COPD and asthma is convenience for the patient as this reduces the need for using separate inhalers that are often of a differing type and therefore need to be used differently Citation[37]. In a primary care setting a triple inhaler may reduce the need to discriminate between COPD and severe asthma and indeed may be an appropriate treatment for patients who have concomitant asthma and COPD.
However, there are several disadvantages. There may be formulation and stability problems when drugs are mixed within the same device and these may not be predictable. This has recently been found with fluticasone furoate and vilanterol, so that the drugs have to be separated in a dual chamber device. Furthermore, the drugs in a combination inhaler probably need to remain associated on inhalation so that they are delivered to the same regions of the lung. This may require more precise engineering of inhaled particles Citation[38]. Triple inhalers are likely to be more expensive than dual combination inhalers. There may also be regulatory problems as it may be necessary to demonstrate the clinical superiority of the triple combination compared with separate inhalers and dual combinations. This is likely to involve large studies as several treatment arms will be required to address these issues and the added value of triple drug versus dual drug combinations may be difficult to demonstrate. Another disadvantage is loss of flexibility in dosing as a fixed dose of all three drugs will be used. While doses of the LABA and LAMA components may not change, the requirement for inhaled corticosteroid may differ according to disease severity, particularly for patients with asthma. This may necessitate the use of an additional corticosteroid inhaler, which would negate the value of the triple inhaler. Perhaps the greatest disadvantage is the fact that many patients with COPD and asthma do not require all three drugs, as indicated above. While most patients with COPD will benefit from a LABA/LAMA combination and most patients from asthma from a LABA/steroid combination, the triple inhaler will only be useful in the minority of patients with COPD and asthma who would benefit from all three drugs.
Alternative triple inhalers
Dual-acting drugs that have LAMA and LABA activities joined by a linker muscarinic antagonist-β-agonist (MABA) have now been developed by several companies Citation[39]. The first MABA GSK961081 is already in clinical development. The problem with these dual-acting molecules is likely to be a lack of flexibility, as may prove difficult in optimizing both components to get the most effective ratio of pharmacological activities. However, inhaled MABAs combined with a corticosteroid would provide an effective triple inhaler and this might overcome some of the physicochemical and regulatory issues with the mixing of three different drugs in the same device. There is marked corticosteroid resistance in COPD and severe asthma, so there is a search for alternative anti-inflammatory treatments. Broad spectrum anti-inflammatory therapies in development for COPD and severe asthma include phosphodiesterase-4, p38 MAPK and JAK inhibitors Citation[40], but side effects after oral administration are dose-limiting. This has prompted a search for inhaled formulations of these drug classes and if effective, these might be combined with a LABA and LAMA.
Future prospects
The first triple inhaler is already on the market, but the development of once-daily LABA, LAMA and corticosteroids means that several triple combinations inhalers are now feasible. While this might have the attraction of simplicity and convenience, there are likely to be technical and regulatory problems in developing triple inhalers and it is likely that only a minority of patients with COPD and asthma will benefit from these devices. Perhaps the case for triple inhalers will be more persuasive when more effective inhaled anti-inflammatory treatments for COPD and severe asthma are developed.
Financial & competing interests disclosure
Peter Barnes has served on Scientific Advisory Boards for AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Nycomed, Pfizer, Teva and UCB, and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Daiichi-Sankyo, GlaxoSmithKline, Mistubishi-Tanabe, Novartis and Pfizer. He is also a cofounder of RespiVert (now part of Johnson & Johnson), which has discovered novel inhaled anti-inflammatory treatments for asthma and COPD. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Nannini L, Cates C, Lasserson T et al. Combined corticosteroid and long-acting β-agonist in one inhaler versus long-acting β-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev.4, CD006829 (2007).
- Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med.356, 775–789 (2007).
- Szafranski W, Cukier A, Ramirez A et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur. Respir. J.21, 74–81 (2003).
- Calverley PM, Kuna P, Monso E et al. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir. Med.104, 1858–1868 (2010).
- Yang IA, Fong KM, Sim EH et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst. Rev.2, CD002991 (2007).
- Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respiration80, 89–95 (2010).
- Suissa S, Ernst P, Vandemheen KL et al. Methodological issues in therapeutic trials of COPD. Eur. Respir. J.31, 927–933 (2008).
- Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur. Respir. J.34, 13–16 (2009).
- Rabe KF, Hurd S, Anzueto A et al. Global strategy for the diagnosis, management, and prevention of COPD – 2006 Update. Am. J. Respir. Crit. Care Med.176, 532–555 (2007).
- Drummond MB, Dasenbrook EC, Pitz MW et al. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA300, 2407–2416 (2008).
- Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am. J. Med.123, 1001–1006 (2010).
- Singh S, Loke YK. An overview of the benefits and drawbacks of inhaled corticosteroids in chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis.5, 189–195 (2010).
- Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med.359, 1543–1554 (2008).
- Decramer M, Celli B, Kesten S et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet374, 1171–1178 (2009).
- Wedzicha JA, Calverley PM, Seemungal TA et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am. J. Respir. Crit. Care Med.177, 19–26 (2008).
- Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting β2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev.3, CD007891 (2010).
- Singh D, Brooks J, Hagan G et al. Superiority of ‘triple’ therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax63, 592–598 (2008).
- Cazzola M, Ando F, Santus P et al. A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD. Pulm. Pharmacol. Ther.20, 556–561 (2007).
- Aaron SD, Vandemheen KL, Fergusson D et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann. Intern. Med.146, 545–555 (2007).
- Karner C, Cates CJ. Combination inhaled steroid and long-acting β(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev.3, CD008532 (2011).
- Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur. Respir. J.34, 757–769 (2009).
- Korn S, Kerwin E, Atis S et al. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study. Respir. Med.105(5), 719–726 (2011).
- Barnes PJ, Pocock SJ, Magnussen H et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm. Pharmacol. Ther.23, 165–171 (2010).
- Vogelmeier C, Ramos-Barbon D, Jack D et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir. Res.11, 135 (2010).
- Chapman KR, Rennard SI, Dogra A et al. Long-term Safety and Efficacy of Indacaterol, a Novel Long-acting {β}2-Agonist, in Subjects with COPD: a Randomized, Placebo-controlled Study. Chest DOI: 10.1378/chest.10-1830 (2011) (Epub ahead of print).
- van Noord JA, Aumann JL, Janssens E et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest129, 509–517 (2006).
- van Noord JA, Aumann JL, Janssens E et al. Combining tiotropium and salmeterol in COPD: effects on airflow obstruction and symptoms. Respir. Med.104, 995–1004 (2010).
- Tashkin DP, Pearle J, Iezzoni D et al. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD6, 17–25 (2009).
- Cazzola M. Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD. Curr. Opin. Investig. Drugs10, 482–490 (2009).
- Gibson PG, Powell H, Ducharme FM. Differential effects of maintenance long-acting β-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J. Allergy Clin. Immunol.119, 344–350 (2007).
- Ducharme FM, Ni CM, Greenstone I et al. Addition of long-acting β2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst. Rev.5, CD005535 (2010).
- Edwards SJ, von Maltzahn R, Naya IP et al. Budesonide/formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials. Int. J. Clin. Pract.64, 619–627 (2010).
- Magnussen H, Bugnas B, van Noord J et al. Improvements with tiotropium in COPD patients with concomitant asthma. Respir. Med.102, 50–56 (2008).
- Park HW, Yang MS, Park CS et al. Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response. Allergy64, 778–783 (2009).
- Israel E, Chinchilli VM, Ford JG et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet364, 1505–1512 (2004).
- Peters SP, Kunselman SJ, Icitovic N et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N. Engl. J. Med.363, 1715–1726 (2010).
- Lavorini F, Magnan A, Christophe DJ et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir. Med.102, 593–604 (2007).
- Pitchayajittipong C, Shur J, Price R. Engineering of crystalline combination inhalation particles of a long-acting β2-agonist and a corticosteroid. Pharm. Res.26, 2657–2666 (2009).
- Ray NC, Alcaraz L. Muscarinic antagonist-β-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review. Expert Opin. Ther. Pat.19, 1–12 (2009).
- Barnes PJ. Emerging pharmacotherapies for COPD. Chest134, 1278–1286 (2008).