Mono- and Combination Therapy of Long-Acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD

ABSTRACT

Beta-2 adrenergic agonists are sympathomimetic agents that stimulate bronchodilation by activation of adenyl cyclase to produce cyclic 3′5′ adenosine monophosphate (AMP). Short-acting β-agonists (SABAs) have a 3- to 6-hour duration of action, and the duration of action of long-acting β-agonists (LABAs) exceeds 12 hours. Because of their rapid onset of action, SABAs are effective for rescue from symptoms of chronic obstructive pulmonary disease (COPD). LABAs—salmeterol and formoterol—have been shown to significantly improve lung function, health status, and symptom reduction, compared with ipratropium. Despite safety concerns over the use of LABAs as monotherapy in asthma the use of these medications in COPD has generally been described as safe. Novel bronchodilators for COPD in late-stage development include the β-agonists indacterol and carmoterol.

Parasympathetic activity in the large and medium-size airways is mediated through the muscarinic receptors and results in airway smooth-muscle contraction, mucus secretion, and possibly increased ciliary activity. Although short-acting ipratropium has been used as monotherapy or in combination with albuterol the use of long-acting antimuscarinics is superior in improving health outcomes. The use of tiotropium results in improved health status, dyspnea, and exercise capacity, and reduced hyperinflation and COPD exacerbation rate in patients with moderate to severe COPD. Analysis of prospective clinical trial data shows a mortality reduction in subjects treated with tiotropium, despite retrospective review of insurance claims that show an enhanced mortality.

Theophylline is a nonselective phosphodiesterase inhibitor that acts as both a weak bronchodilator and a respiratory stimulant. Novel approaches include using the inhalation route to reduce side effects and combination with inhaled corticosteroids (ICS). However, because of its potential adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite optimal bronchodilator therapy.

Current guidelines highlight that for COPD patients uncontrolled by bronchodilator monotherapy, combination therapy is recommended. These include LABA/ICS and LAMA/LABA combinations. Bronchodilators and their combination with ICS are central to the management of COPD. The choice of agents is based primarily on disease stage, individual response, cost, side effect profile, and availability.

KEYWORDS

COPD - bronchodilator - inhaled corticosteroid - combination therapy - disease modification end points - FEV₁ decline

REFERENCES

• 1 Celli B R, MacNee W. ATS/ERS Task Force . Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.  Eur Respir J. 2004;  23 932-946
• 2 Global Strategy for the Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from http://www.goldcopd.org
• 3 Wilt T J, Niewoehner D, MacDonald R, Kane R L. Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline.  Ann Intern Med. 2007;  147 639-653
• 4 Cazzola M, Matera M G. Novel long-acting bronchodilators for COPD and asthma.  Br J Pharmacol. 2008;  155 291-299
• 5 Cazzola M, Matera M G, Lötvall J. Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease.  Expert Opin Investig Drugs. 2005;  14 775-783
• 6 Donohue J F, Ohar J A. Bronchodilator therapy of airway disease. In: Chung KF, Barnes PJ Pharmacology and Therapeutics of Airway Disease. New York, NY; Informa Healthcare USA 2009: 198-225
• 7 Hanania N A, Sharafkhaneh A, Barber R, Dickey B F. Beta-agonist intrinsic efficacy: measurement and clinical significance.  Am J Respir Crit Care Med. 2002;  165 1353-1358
• 8 Lötvall J. Pharmacology of bronchodilators used in the treatment of COPD.  Respir Med. 2000;  94(Suppl E) S6-S10
• 9 Sestini P, Renzoni E, Robinson S, Poole P, Ram F S. Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease.  Cochrane Database Syst Rev. 2002;  (4) CD001495
• 10 Ramirez-Venegas A, Ward J, Lentine T, Mahler D A. Salmeterol reduces dyspnea and improves lung function in patients with COPD.  Chest. 1997;  112 336-340
• 11 Boyd G, Morice A H, Pounsford J C, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD).  Eur Respir J. 1997;  10 815-821
• 12 Cazzola M, Matera M G, Santangelo G, Vinciguerra A, Rossi F, D'Amato G. Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose-response study.  Respir Med. 1995;  89 357-362
• 13 Hanania N A, Kalberg C, Yates J, Emmett A, Horstman D, Knobil K. The bronchodilator response to salmeterol is maintained with regular, long-term use in patients with COPD.  Pulm Pharmacol Ther. 2005;  18 19-22
• 14 Mahler D A, Donohue J F, Barbee R A et al.. Efficacy of salmeterol xinafoate in the treatment of COPD.  Chest. 1999;  115 957-965
• 15 Dahl R, Greefhorst L A, Nowak D Formoterol in Chronic Obstructive Pulmonary Disease I Study Group et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2001;  164 778-784
• 16 Appleton S, Jones T, Poole P et al.. Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease.  Cochrane Database Syst Rev. 2006;  3 CD006101
• 17 Cazzola M, Santus P, Matera M G et al.. A single high dose of formoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD.  Respir Med. 2003;  97 458-462
• 18 Di Marco F, Verga M, Santus P, Morelli N, Cazzola M, Centanni S. Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease: a pilot study.  Respir Med. 2006;  100 1925-1932
• 19 Berger W E, Nadel J A. Efficacy and safety of formoterol for the treatment of chronic obstructive pulmonary disease.  Respir Med. 2008;  102 173-188
• 20 Campbell M, Eliraz A, Johansson G et al.. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease.  Respir Med. 2005;  99 1511-1520
• 21 Richter K, Stenglein S, Mücke M et al.. Onset and duration of action of formoterol and tiotropium in patients with moderate to severe COPD.  Respiration. 2006;  73 414-419
• 22 Sin D D, McAlister F A, Man S F, Anthonisen N R. Contemporary management of chronic obstructive pulmonary disease: scientific review.  JAMA. 2003;  290 2301-2312
• 23 Stockley R A, Chopra N, Rice L. Addition of salmeterol to existing treatment in patients with COPD: a 12 month study.  Thorax. 2006;  61 122-128
• 24 Rodrigo G J, Nannini L J, Rodríguez-Roisin R. Safety of long-acting beta-agonists in stable COPD: a systematic review.  Chest. 2008;  133 1079-1087
• 25 Salpeter S R. Cardiovascular safety of beta(2)-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review.  Drugs Aging. 2004;  21 405-414
• 26 Gupta P, O'Mahony M S. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing.  Drugs Aging. 2008;  25 415-443
• 27 Hanrahan J P, Grogan D R, Baumgartner R A et al.. Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting beta2-agonists arformoterol and salmeterol.  Medicine (Baltimore). 2008;  87 319-328
• 28 Salpeter S R, Buckley N S, Salpeter E E. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD.  J Gen Intern Med. 2006;  21 1011-1019
• 29 Nelson H S, Weiss S T, Bleecker E R, Yancey S W, Dorinsky P M. SMART Study Group . The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.  Chest. 2006;  129 15-26
• 30 Calverley P M, Anderson J A, Celli B TORCH investigators et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.  N Engl J Med. 2007;  356 775-789
• 31 Ferguson G T, Funck-Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD.  Chest. 2003;  123 1817-1824
• 32 Cazzola M, Matera M G, Donner C F. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease.  Drugs. 2005;  65 1595-1610
• 33 Donohue J F, van Noord J A, Bateman E D et al.. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.  Chest. 2002;  122 47-55
• 34 Donohue J F, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD.  Respir Med. 2003;  97 1014-1020
• 35 Costello J. Prospects for improved therapy in chronic obstructive pulmonary disease by the use of levalbuterol.  J Allergy Clin Immunol. 1999;  104(2 Pt 2) S61-S68
• 36 Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma.  Chest. 2003;  123 128-135
• 37 Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol.  Drugs R D. 2004;  5 25-27
• 38 Steinke J W, Baramki D, Borish L. Opposing actions of (R,R)-isomers and (S,S)-isomers of formoterol on T-cell function.  J Allergy Clin Immunol. 2006;  118 963-965
• 39 Donohue J F, Hanania N A, Ciubotaru R L et al.. Comparison of levalbuterol and racemic albuterol in hospitalized patients with acute asthma or COPD: a 2-week, multicenter, randomized, open-label study.  Clin Ther. 2008;  30(Spec No.) 989-1002
• 40 Barnes P J. Treatment with (R)-albuterol has no advantage over racemic albuterol.  Am J Respir Crit Care Med. 2006;  174 969-972 discussion 972-974
• 41 Ameredes B T, Calhoun W J. (R)-albuterol for asthma: pro [a.k.a. (S)-albuterol for asthma: con].  Am J Respir Crit Care Med. 2006;  174 965-969 discussion 972-974
• 42 Baumgartner R A, Hanania N A, Calhoun W J, Sahn S A, Sciarappa K, Hanrahan J P. Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial.  Clin Ther. 2007;  29 261-278
• 43 Johnson M, Rennard S. Alternative mechanisms for long-acting beta(2)-adrenergic agonists in COPD.  Chest. 2001;  120 258-270
• 44 Hanania N A, Moore R H. Anti-inflammatory activities of beta2-agonists.  Curr Drug Targets Inflamm Allergy. 2004;  3 271-277
• 45 Bennett W D, Almond M A, Zeman K L, Johnson J G, Donohue J F. Effect of salmeterol on mucociliary and cough clearance in chronic bronchitis.  Pulm Pharmacol Ther. 2006;  19 96-100
• 46 Donnelly L E, Tudhope S J, Fenwick P S, Barnes P J. Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages.  Eur Respir J. 2009;  , Nov 19. [Epub ahead of print]
• 47 Rennard S, Bantje T, Centanni S et al.. A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.  Respir Med. 2008;  102 1033-1044
• 48 Beier J, Beeh K M, Brookman L, Peachey G, Hmissi A, Pascoe S. Bronchodilator effects of indacaterol and formoterol in patients with COPD.  Pulm Pharmacol Ther. 2009;  22 492-496
• 49 Gross N J, Co E, Skorodin M S. Cholinergic bronchomotor tone in COPD. Estimates of its amount in comparison with that in normal subjects.  Chest. 1989;  96 984-987
• 50 Gross N J, Skorodin M S. Role of the parasympathetic system in airway obstruction due to emphysema.  N Engl J Med. 1984;  311 421-425
• 51 Casarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper M. Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs.  J Pharmacol Exp Ther. 2009;  330 660-668
• 52 O'Connor B J, Towse L J, Barnes P J. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma.  Am J Respir Crit Care Med. 1996;  154(4 Pt 1) 876-880
• 53 O'Donnell D E, Lam M, Webb K A. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1999;  160 542-549
• 54 Ayers M L, Mejia R, Ward J, Lentine T, Mahler D A. Effectiveness of salmeterol versus ipratropium bromide on exertional dyspnoea in COPD.  Eur Respir J. 2001;  17 1132-1137
• 55 Casaburi R, Mahler D A, Jones P W et al.. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.  Eur Respir J. 2002;  19 217-224
• 56 O'Donnell D E, Voduc N, Fitzpatrick M, Webb K A. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease.  Eur Respir J. 2004;  24 86-94
• 57 Anzueto A, Tashkin D, Menjoge S, Kesten S. One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium.  Pulm Pharmacol Ther. 2005;  18 75-81
• 58 Vincken W, van Noord J A, Greefhorst A P Dutch/Belgian Tiotropium Study Group et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium.  Eur Respir J. 2002;  19 209-216
• 59 Gauhar U, Dransfield M, Cooper J A. Sequential comparison of tiotropium to high-dose ipratropium in patients with chronic obstructive pulmonary disease in a practice setting.  Int J Chron Obstruct Pulmon Dis. 2009;  4 391-395
• 60 Niewoehner D E, Rice K, Cote C et al.. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.  Ann Intern Med. 2005;  143 317-326
• 61 Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.  Thorax. 2003;  58 399-404
• 62 Briggs Jr D D, Covelli H, Lapidus R, Bhattycharya S, Kesten S, Cassino C. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD.  Pulm Pharmacol Ther. 2005;  18 397-404
• 63 Barr R G, Bourbeau J, Camargo C A, Ram F S. Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis.  Thorax. 2006;  61 854-862
• 64 Anzueto A, Leimer I, Kesten S. Impact of frequency of COPD exacerbations on pulmonary function, health status and clinical outcomes.  Int J Chron Obstruct Pulmon Dis. 2009;  4 245-251
• 65 Gershon A S, Wang L, To T, Luo J, Upshur R E. Survival with tiotropium compared to long-acting beta-2-agonists in chronic obstructive pulmonary disease.  COPD. 2008;  5 229-234
• 66 Tashkin D P, Celli B, Senn S UPLIFT Study Investigators et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease.  N Engl J Med. 2008;  359 1543-1554
• 67 Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin D P. UPLIFT Study Investigators . Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2009;  180 948-955
• 68 Anzueto A, Miravitlles M. Efficacy of tiotropium in the prevention of exacerbations of COPD.  Ther Adv Respir Dis. 2009;  3 103-111
• 69 Singh S, Loke Y K, Furberg C D. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.  JAMA. 2008;  300 1439-1450
• 70 Salpeter S R. Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events?: a synthesis of the available evidence.  Drugs. 2009;  69 2025-2033
• 71 Hilleman D E, Malesker M A, Morrow L E, Schuller D. A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.  Int J Chron Obstruct Pulmon Dis. 2009;  4 253-263
• 72 Grosso A, Douglas I, Hingorani A D, MacAllister R, Hubbard R, Smeeth L. Inhaled tiotropium bromide and risk of stroke.  Br J Clin Pharmacol. 2009;  68 731-736
• 73 Belmonte K E. Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease.  Proc Am Thorac Soc. 2005;  2 297-304 discussion 311-312
• 74 Profita M, Giorgi R D, Sala A et al.. Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients.  Allergy. 2005;  60 1361-1369
• 75 Chanez P, Burge P S, Dahl R et al.. Aclidinium bromide provides long-acting bronchodilation in patients with COPD.  Pulm Pharmacol Ther. 2010;  23 15-21
• 76 Barnes P J. Theophylline in chronic obstructive pulmonary disease: new horizons.  Proc Am Thorac Soc. 2005;  2 334-339 discussion 340-341
• 77 Barnes P J. Histone deacetylase-2 and airway disease.  Ther Adv Respir Dis. 2009;  3 235-243
• 78 Braganza G, Chaudhuri R, Thomson N C. Treating patients with respiratory disease who smoke.  Ther Adv Respir Dis. 2008;  2 95-107
• 79 Lee T A, Schumock G T, Bartle B, Pickard A S. Mortality risk in patients receiving drug regimens with theophylline for chronic obstructive pulmonary disease.  Pharmacotherapy. 2009;  29 1039-1053
• 80 Shukla D, Chakraborty S, Singh S, Mishra B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease.  Expert Opin Pharmacother. 2009;  10 2343-2356
• 81 Momeni A, Mohammadi M H. Respiratory delivery of theophylline by size-targeted starch microspheres for treatment of asthma.  J Microencapsul. 2009;  26 701-710
• 82 Cazzola M, Gabriella Matera M. The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: a pilot study.  Respir Med. 2007;  101 957-962
• 83 Man G C, Champman K R, Ali S H, Darke A C. Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD.  Chest. 1996;  110 648-653
• 84 Cyr M C, Beauchesne M F, Lemière C, Blais L. Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease.  Br J Clin Pharmacol. 2008;  65 40-50
• 85 ZuWallack R L, Mahler D A, Reilly D et al.. Salmeterol plus theophylline combination therapy in the treatment of COPD.  Chest. 2001;  119 1661-1670
• 86 Barnes P J. Current therapies for asthma: promise and limitations.  Chest. 1997;  111(2, Suppl) 17S-26S
• 87 Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication.  Nephrology (Carlton). 2003;  8 239-242
• 88 Barnes P J. Theophylline for COPD.  Thorax. 2006;  61 742-744
• 89 Hanania N A, Ambrosino N, Calverley P, Cazzola M, Donner C F, Make B. Treatments for COPD.  Respir Med. 2005;  99(Suppl B) S28-S40
• 90 Barnes P J. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment.  Expert Opin Ther Targets. 2005;  9 1111-1121
• 91 Barnes P J. Theophylline: new perspectives for an old drug.  Am J Respir Crit Care Med. 2003;  167(6) 813-818
• 92 Calverley P M, Rabe K F, Goehring U M, Kristiansen S, Fabbri L M, Martinez F J. M2-124 and M2-125 study groups . Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.  Lancet. 2009;  374 685-694
• 93 Barnes N C, Qiu Y S, Pavord I D SCO30005 Study Group et al. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease.  Am J Respir Crit Care Med. 2006;  173 736-743
• 94 Hanania N A, Darken P, Horstman D et al.. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD.  Chest. 2003;  124 834-843
• 95 Mahler D A, Wire P, Horstman D et al.. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2002;  166 1084-1091
• 96 Calverley P, Pauwels R, Vestbo J TRial of Inhaled STeroids ANd long-acting beta2 agonists study group et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.  Lancet. 2003;  361 449-456
• 97 Calverley P M, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.  Eur Respir J. 2003;  22 912-919
• 98 Fabbri L, Pauwels R A, Hurd S S. GOLD Scientific Committee . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary updated 2003.  COPD. 2004;  1 105-141 discussion 103-104
• 99 Minas M, Dimitropoulos K, Pastaka Ch, Papadopoulos D, Markoulis N, Gourgoulianis K I. Global initiative for chronic obstructive lung disease for chronic obstructive pulmonary disease: GOLD opportunity for lung disorders.  Prev Med. 2005;  40 274-277
• 100 Donohue J F. Combination therapy for chronic obstructive pulmonary disease: clinical aspects.  Proc Am Thorac Soc. 2005;  2 272-281 discussion 290-291
• 101 Rodrigo G J, Castro-Rodriguez J A, Plaza V. Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review.  Chest. 2009;  136 1029-1038
• 102 Nannini L J, Cates C J, Lasserson T J, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease.  Cochrane Database Syst Rev. 2007;  (4) CD006829
• 103 Cazzola M, Di Marco F, Santus P et al.. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD.  Pulm Pharmacol Ther. 2004;  17 35-39
• 104 van Noord J A, Aumann J L, Janssens E et al.. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.  Eur Respir J. 2005;  26 214-222
• 105 van Noord J A, Aumann J L, Janssens E et al.. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD.  Chest. 2006;  129 509-517
• 106 Tashkin D P, Littner M, Andrews C P, Tomlinson L, Rinehart M, Denis-Mize K. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial.  Respir Med. 2008;  102 479-487
• 107 Tashkin D P, Pearle J, Iezzoni D, Varghese S T. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD.  COPD. 2009;  6 17-25
• 108 Rabe K F, Timmer W, Sagkriotis A, Viel K. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD.  Chest. 2008;  134 255-262
• 109 COMBIVENT Inhalation Aerosol Study Group . In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial.  Chest. 1994;  105 1411-1419
• 110 D'Urzo A D, De Salvo M C, Ramirez-Rivera A FOR-INT-03 Study Group et al. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium : a 3-week, randomized, double-blind, within-patient, multicenter study.  Chest. 2001;  119 1347-1356
• 111 van Noord J A, de Munck D R, Bantje T A, Hop W C, Akveld M L, Bommer A M. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium.  Eur Respir J. 2000;  15 878-885
• 112 Johnson M. Corticosteroids: potential beta2-agonist and anticholinergic interactions in chronic obstructive pulmonary disease.  Proc Am Thorac Soc. 2005;  2 320-325 discussion 340-341
• 113 Perng D W, Wu C C, Su K C, Lee Y C, Perng R P, Tao C W. Additive benefits of tiotropium in COPD patients treated with long-acting beta agonists and corticosteroids.  Respirology. 2006;  11 598-602
• 114 Singh D, Brooks J, Hagan G, Cahn A, O'Connor B J. Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD.  Thorax. 2008;  63 592-598
• 115 Aaron S D, Vandemheen K L, Fergusson D Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.  Ann Intern Med. 2007;  146 545-555
• 116 Lee T A, Wilke C, Joo M et al.. Outcomes associated with tiotropium use in patients with chronic obstructive pulmonary disease.  Arch Intern Med. 2009;  169 1403-1410
• 117 Tashkin D P, Celli B, Decramer M et al.. Bronchodilator responsiveness in patients with COPD.  Eur Respir J. 2008;  31 742-750
• 118 Calverley P M, Burge P S, Spencer S, Anderson J A, Jones P W. Bronchodilator reversibility testing in chronic obstructive pulmonary disease.  Thorax. 2003;  58 659-664
• 119 Donohue J F. Therapeutic responses in asthma and COPD. Bronchodilators.  Chest. 2004;  126(2, Suppl) 125S-137S discussion 159S-161S