title: Is combination therapy with inhaled anticholinergics and beta2-adrenoceptor agonists justified for chronic obstructive pulmonary disease?
abstract: Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterised by progressive, irreversible airflow limitation. The economic and social burden of the disease is enormous. The treatment of COPD is guided by the stage of the disease and is aimed primarily at control of symptoms. Bronchodilators are the cornerstone of pharmacological management of COPD. Short-acting bronchodilators (beta(2)-adrenoceptor agonists and anticholinergics) have been available for many years and have been extensively studied as individual agents and in combination. When administered in combination, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. However, the improvement in bronchodilation does not translate into an improvement in quality-of-life (QOL) indices. More recently, long-acting beta(2)-adrenoceptor agonists (LABAs) and anticholinergics have been introduced, and current guidelines recommend regular use of these agents in COPD of Global initiative for chronic Obstructive Lung Disease (GOLD) stage II or more. Combining short-acting anticholinergics with LABAs for daily use has been evaluated, but this combination does not confer any advantage in terms of subjective improvement or prevention of exacerbations. Combining the long-acting anticholinergic tiotropium bromide with formoterol given once or twice daily improves airway obstruction and hyperinflation. However, the effects of combinations of long-acting bronchodilators on patients' symptom scores, QOL and exacerbations remain to be studied. Ultra-LABAs, which are in development, may enable use of a combination of long-acting bronchodilators in a single inhaler for once-daily use, thus simplifying the regimen. This article discusses the results of various clinical trials comparing the efficacy of bronchodilators given alone or in combination to patients with COPD, with emphasis on the effects of these agents on bronchodilation, symptomatic and objective improvements in QOL and prevention of exacerbations.
authors: Department of Medicine, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84132-4701, USA. charkravarthy.reddy@hsc.utah.edu
authors: Chakravarthy B
authors: CB
authors: Reddy
authors: Richard E
authors: RE
authors: Kanner
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011788:Quality of Life
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D003692:Delayed-Action Preparations
references: Eur Respir J. 2005 Aug;26(2):214-22
references: 16055868
references: Am J Med. 1996 Jan 29;100(1A):62S-69
references: 8610720
references: JAMA. 1994 Nov 16;272(19):1497-505
references: 7966841
references: Eur Respir J. 2002 Feb;19(2):209-16
references: 11871363
references: Lancet. 1997 May 24;349(9064):1498-504
references: 9167458
references: Respiration. 1986;50 Suppl 2:144-7
references: 2951793
references: Am J Respir Crit Care Med. 2001 Sep 1;164(5):778-84
references: 11549532
references: J Appl Physiol (1985). 1994 Jul;77(1):397-405
references: 7525529
references: Thorax. 2003 May;58(5):399-404
references: 12728159
references: Science. 1996 Nov 1;274(5288):740-3
references: 8966556
references: Chest. 2000 Feb;117(2 Suppl):5S-9S
references: 10673466
references: Chest. 2001 Jan;119(1):85-92
references: 11157588
references: Chest. 1997 Dec;112(6):1514-21
references: 9404747
references: Eur Respir J. 2001 May;17(5):946-53
references: 11488331
references: Respiration. 1993;60(2):84-8
references: 8341859
references: Am J Respir Crit Care Med. 1995 Sep;152(3):838-60
references: 7663795
references: Postgrad Med J. 1984;60 Suppl 1:24-7
references: 6233547
references: Am J Respir Crit Care Med. 2006 Mar 1;173(5):519-26
references: 16322642
references: Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):822-6
references: 9517597
references: N Engl J Med. 1986 Sep 18;315(12):735-9
references: 2943994
references: Eur Respir J. 2004 Jun;23(6):832-40
references: 15218994
references: Chest. 1995 Feb;107(2):401-5
references: 7842768
references: Chest. 2006 Mar;129(3):509-17
references: 16537846
references: Eur J Respir Dis. 1984 Aug;65(6):441-6
references: 6236095
references: Am J Respir Crit Care Med. 2001 Sep 1;164(5):770-7
references: 11549531
references: Br J Pharmacol. 1994 Feb;111(2):641-7
references: 7911722
references: Proc Am Thorac Soc. 2005;2(4):282-9; discussion 290-1
references: 16267349
references: Am Rev Respir Dis. 1983 Nov;128(5):833-8
references: 6556892
references: Thorax. 2004 Jun;59(6):471-6
references: 15170026
references: Thorax. 1996 Oct;51(10):1051-6
references: 8984693
references: Pulm Pharmacol Ther. 2004;17(1):35-9
references: 14643169
references: Am Rev Respir Dis. 1983 Jun;127(6):758-62
references: 6305241
references: Am J Respir Crit Care Med. 2002 Aug 1;166(3):333-9
references: 12153966
references: Clin Exp Immunol. 1996 Oct;106(1):97-102
references: 8870705
references: Eur Respir J. 2002 Feb;19(2):217-24
references: 11866001
references: Eur Respir J. 2006 Feb;27(2):397-412
references: 16452599
references: Am J Respir Crit Care Med. 2001 Apr;163(5):1087-92
references: 11316640
references: Chest. 2002 May;121(5 Suppl):121S-126S
references: 12010839
references: Eur Respir J. 2002 Nov;20(5):1138-46
references: 12449166
references: Am J Respir Crit Care Med. 1997 Jan;155(1):327-36
references: 9001332
references: Am J Respir Crit Care Med. 2000 Jul;162(1):75-80
references: 10903223
references: Int J Clin Pract. 1999 Apr-May;53(3):185-8
references: 10665129
references: Am Rev Respir Dis. 1987 May;135(5):1069-74
references: 3579005
references: Br J Dis Chest. 1981 Apr;75(2):190-6
references: 7023528
references: Chest. 1999 May;115(5):1338-45
references: 10334150
references: Chest. 2001 May;119(5):1347-56
references: 11348938
references: Am J Respir Crit Care Med. 1997 Apr;155(4):1428-35
references: 9105089
references: Respir Med. 1996 Sep;90(8):497-9
references: 8869445
references: Thorax. 1996 Jan;51(1):48-53
references: 8658369
references: Respir Med. 1999 Dec;93(12):909-11
references: 10653054
references: Biochem Pharmacol. 1995 Jun 16;49(12 ):1809-19
references: 7598743
references: Am J Med. 1996 Jan 29;100(1A):40S-48S
references: 8610716
references: Eur Respir J. 2001 May;17(5):982-94
references: 11488336
references: Chest. 1994 May;105(5):1411-9
references: 8181328
references: Chest. 2002 Jul;122(1):47-55
references: 12114338
references: Thorax. 1999 Dec;54(12):1083-6
references: 10567627
references: Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 2):S28-38
references: 11734464
references: Respiration. 1986;50 Suppl 2:298-301
references: 2951825
references: Chest. 1999 Mar;115(3):635-41
references: 10084468
references: Chest. 1999 Apr;115(4):957-65
references: 10208192
references: Eur Respir J. 2000 May;15(5):878-85
references: 10853852
references: Am J Respir Crit Care Med. 1997 Mar;155(3):852-7
references: 9117016
references: Respiration. 1998;65(5):354-62
references: 9782217
references: Chest. 2002 May;121(5 Suppl):156S-159S
references: 12010845
references: Thorax. 1982 Sep;37(9):667-70
references: 6218647
references: Ann Intern Med. 2006 Jun 20;144(12):904-12
references: 16754916
references: Chest. 1996 Jul;110(1):62-70
references: 8681667
references: N Engl J Med. 1995 Aug 24;333(8):499-506
references: 7623883
references: Arch Intern Med. 1999 Jan 25;159(2):156-60
references: 9927098
references: Respir Med. 2004 Dec;98(12):1214-21
references: 15588043
references: Am J Respir Crit Care Med. 1999 Aug;160(2):542-9
references: 10430726
references: Am J Physiol. 1997 Apr;272(4 Pt 1):L580-7
references: 9142928
references: J Gen Intern Med. 2006 Oct;21(10):1011-9
references: 16970553
references: Eur Respir J. 1998 Jan;11(1):86-90
references: 9543275
references: Thorax. 1997 Dec;52 Suppl 5:S1-28
references: 9474238