Recent developments in inhaled therapy in stable chronic obstructive p
http://www.100md.com
《英国医生杂志》
1 Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA
Correspondence to: C B Cooper ccooper@mednet.ucla.edu
We reviewed the most recent guidelines from GOLD (August 2004), NICE (February 2004), and ATS/ERS (June 2004), and supplemented these by searching PubMed, using the criteria ("COPD" or "chronic obstructive pulmonary disease") and "bronchodilator" for publications between January 2002 and March 2004. We found 21 recent clinical trials not cited in the GOLD guidelines, which covered combination therapy (inhaled corticosteroid plus 2 agonist), the anticholinergic tiotropium taken once daily, and several meta-analyses of use of inhaled corticosteroid.7-10 w1-w17
Diagnosis and staging
Inhaled therapy, including bronchodilators and steroids, is one of several, often complementary, approaches to COPD treatment, as shown in figure 1. Inhaled bronchodilators comprise anticholinergics, which relax airway smooth muscle by blocking cholinergic tone (the primary reversible component in COPD), and 2 agonists, which are non-specific, functional bronchodilators that work via the sympathetic pathway. Short acting inhaled bronchodilators are the traditional basis of COPD pharmacotherapy. However, newer long acting bronchodilators are more suitable for maintenance treatment because they are more effective and convenient.2
Short acting inhaled bronchodilators
Long acting inhaled bronchodilators include the anticholinergic tiotropium, given once daily, and the 2 agonists salmeterol and formoterol, given twice daily.2 All improve lung function, although they differ in their mechanisms and duration of effect. Compared with salmeterol twice daily, tiotropium once daily provides superior bronchodilation for 24 hours13 14; also, salmeterol may lose efficacy over time.14
Long acting bronchodilators also improve patient centred outcomes such as exercise capacity, dyspnoea, and health related quality of life.13 Both tiotropium and formoterol improve health related quality of life more than ipratropium.13 Tiotropium also reduces the time to first exacerbation compared with placebo (fig 2).7
Fig 2 Kaplan-Meier estimates of the probability of no exacerbations of chronic obstructive pulmonary disease (COPD) in patients receiving tiotropium 18 μg once a day, salmeterol 50 μg twice a day, or placebo for six months7
The reduction of lung hyperinflation with tiotropium is likely to contribute to the improvements in dyspnoea seen in COPD patients.15 Since long acting bronchodilators provide more effective and longer lasting relief of symptoms than short acting bronchodilators they should be used for patients who have persistent symptoms that require frequent use of medication.13
Inhaled corticosteroids
Since anticholinergics and 2 agonists have differing mechanisms of action, combination therapy can provide additive effects, as has been shown for the combination of a short acting anticholinergic with either a short acting or a long acting 2 agonist.21 w18
Maintenance treatment with a combination of anticholinergic and 2 agonist bronchodilators is suitable for patients who have more severe symptoms, especially those with a history of frequent exacerbations.2 The combination of a long acting anticholinergic and a long acting 2 agonist should also provide additive effects,22 although this has been tested only in one small study.23
Recently, five clinical trials have been published on the combination of a long acting 2 agonist with an inhaled corticosteroid in patients with moderate to severe COPD.8 9 10 24 25 Four of these studies found that combination therapy improved lung function compared with either component alone.8 9 10 24-25 The additive effect on FEV1 of the combination over the monoproducts in one of these trials is illustrated in figure 3.24 Additive effects of treatment with an inhaled corticosteroid or long acting anticholinergic and a long acting 2 agonist over those of both monocomponents for other outcomes were less consistent: two studies showed additive effects for improvement in health status8 10 and for reduction in dyspnoea,8 24 and one study each for a decrease in rescue use of a 2 agonist24 and for improvement in exacerbations.10
Fig 3 Mean change in pre-dose (trough) forced expiratory volume in 1 second (FEV1) after administration of placebo, fluticasone 500 μg twice a day, salmeterol 50 μg twice a day, or the combination10
Implementing treatment
Clinical guidelines provide a useful reference for practising clinicians. However, they are often long, not easily approachable, and therefore underused. The sample case summaries presented here and the treatment flow chart in figure 1 provide a basis for the practical implementation of current guidelines and more recent clinical trial evidence.
Additional references w1-w18 are on bmj.com
Contributors: This review is a combined effort on the part of the two authors. CBC wrote the case examples.
Competing interests: CBC has been a consultant and speaker for Biotechnology General Corp, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and VIASYS Healthcare. He is a member of the scientific advisory board of Boehringer Ingelheim/Pfizer for tiotropium related questions. He has also received research grants from Biotechnology General Corp, Boehringer Ingelheim, GlaxoSmithKline, ONO Pharma, and Pfizer. DPT has been a consultant and speaker for AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, and Pfizer, and he has received research grants from Altana, AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, and Pfizer.
References
Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet 2003;362: 847-52.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart Lung and Blood Institute, World Health Organization, 2003. www.goldcopd.com/2004clean.pdf (accessed 19 Jan 2005).
Celli BR, MacNee W, and committee members. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: 932-46.
National Institute for Clinical Excellence. Chronic obstructive pulmonary disease. Thorax 2004;59: 1-232.
O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease, 2003. Can Respir J 2003;10(suppl A): 11A-65A.
Ramsey SD. Suboptimal medical therapy in COPD: exploring the causes and consequences. Chest 2000;117: 33S-7S.
Brusasco V, Hodder R, Miravitlles M, Lee A, Towse LJ, Kesten S. Health outcomes in a 6-month placebo controlled trial of once-daily tiotropium compared with twice-daily salmeterol in patients with COPD. Thorax 2003;58: 399-404.
Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive disease. Eur Respir J 2003;21: 74-81.
Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, 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: 1084-91.
Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361: 449-56.
Rennard SI, Serby CW, Ghafouri M, Johnson PA, Friedman M. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Chest 1996;110: 62-70.
Liesker JJW, Wijkstra PJ, Ten Hacken NHT, Koeter GH, Postma DS, Kerstjens HAM. A systematic review of the effects of bronchodilators on exercise capacity in patients with COPD. Chest 2002;121: 597-608.
Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest 2004;125: 249-59.
Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med 2003;97: 1014-20.
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003;124: 1743-8.
Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165: 1592-6.
Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;2002: 59-65.
Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58: 937-41.
Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 2003;138: 969-73.
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999;159: 941-55.
van Noord JA, de Munck DRAJ, Bantje T, Hop WCJ, Akveld MLM, Bommer AM. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 2000;15: 878-85.
Tennant RC, Erin EM, Barnes PJ, Hansel TT. Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified? Curr Opin Pharmacol 2003;3: 270-6.
Cazzola M, Marco FD, Santus P, Boveri B, Verga M, Matera MG, et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004;17: 35-9.
Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, 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: 834-43.
Calverley PM, 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: 912-9.
((C B Cooper, professor of medicine and ph)
Correspondence to: C B Cooper ccooper@mednet.ucla.edu
We reviewed the most recent guidelines from GOLD (August 2004), NICE (February 2004), and ATS/ERS (June 2004), and supplemented these by searching PubMed, using the criteria ("COPD" or "chronic obstructive pulmonary disease") and "bronchodilator" for publications between January 2002 and March 2004. We found 21 recent clinical trials not cited in the GOLD guidelines, which covered combination therapy (inhaled corticosteroid plus 2 agonist), the anticholinergic tiotropium taken once daily, and several meta-analyses of use of inhaled corticosteroid.7-10 w1-w17
Diagnosis and staging
Inhaled therapy, including bronchodilators and steroids, is one of several, often complementary, approaches to COPD treatment, as shown in figure 1. Inhaled bronchodilators comprise anticholinergics, which relax airway smooth muscle by blocking cholinergic tone (the primary reversible component in COPD), and 2 agonists, which are non-specific, functional bronchodilators that work via the sympathetic pathway. Short acting inhaled bronchodilators are the traditional basis of COPD pharmacotherapy. However, newer long acting bronchodilators are more suitable for maintenance treatment because they are more effective and convenient.2
Short acting inhaled bronchodilators
Long acting inhaled bronchodilators include the anticholinergic tiotropium, given once daily, and the 2 agonists salmeterol and formoterol, given twice daily.2 All improve lung function, although they differ in their mechanisms and duration of effect. Compared with salmeterol twice daily, tiotropium once daily provides superior bronchodilation for 24 hours13 14; also, salmeterol may lose efficacy over time.14
Long acting bronchodilators also improve patient centred outcomes such as exercise capacity, dyspnoea, and health related quality of life.13 Both tiotropium and formoterol improve health related quality of life more than ipratropium.13 Tiotropium also reduces the time to first exacerbation compared with placebo (fig 2).7
Fig 2 Kaplan-Meier estimates of the probability of no exacerbations of chronic obstructive pulmonary disease (COPD) in patients receiving tiotropium 18 μg once a day, salmeterol 50 μg twice a day, or placebo for six months7
The reduction of lung hyperinflation with tiotropium is likely to contribute to the improvements in dyspnoea seen in COPD patients.15 Since long acting bronchodilators provide more effective and longer lasting relief of symptoms than short acting bronchodilators they should be used for patients who have persistent symptoms that require frequent use of medication.13
Inhaled corticosteroids
Since anticholinergics and 2 agonists have differing mechanisms of action, combination therapy can provide additive effects, as has been shown for the combination of a short acting anticholinergic with either a short acting or a long acting 2 agonist.21 w18
Maintenance treatment with a combination of anticholinergic and 2 agonist bronchodilators is suitable for patients who have more severe symptoms, especially those with a history of frequent exacerbations.2 The combination of a long acting anticholinergic and a long acting 2 agonist should also provide additive effects,22 although this has been tested only in one small study.23
Recently, five clinical trials have been published on the combination of a long acting 2 agonist with an inhaled corticosteroid in patients with moderate to severe COPD.8 9 10 24 25 Four of these studies found that combination therapy improved lung function compared with either component alone.8 9 10 24-25 The additive effect on FEV1 of the combination over the monoproducts in one of these trials is illustrated in figure 3.24 Additive effects of treatment with an inhaled corticosteroid or long acting anticholinergic and a long acting 2 agonist over those of both monocomponents for other outcomes were less consistent: two studies showed additive effects for improvement in health status8 10 and for reduction in dyspnoea,8 24 and one study each for a decrease in rescue use of a 2 agonist24 and for improvement in exacerbations.10
Fig 3 Mean change in pre-dose (trough) forced expiratory volume in 1 second (FEV1) after administration of placebo, fluticasone 500 μg twice a day, salmeterol 50 μg twice a day, or the combination10
Implementing treatment
Clinical guidelines provide a useful reference for practising clinicians. However, they are often long, not easily approachable, and therefore underused. The sample case summaries presented here and the treatment flow chart in figure 1 provide a basis for the practical implementation of current guidelines and more recent clinical trial evidence.
Additional references w1-w18 are on bmj.com
Contributors: This review is a combined effort on the part of the two authors. CBC wrote the case examples.
Competing interests: CBC has been a consultant and speaker for Biotechnology General Corp, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and VIASYS Healthcare. He is a member of the scientific advisory board of Boehringer Ingelheim/Pfizer for tiotropium related questions. He has also received research grants from Biotechnology General Corp, Boehringer Ingelheim, GlaxoSmithKline, ONO Pharma, and Pfizer. DPT has been a consultant and speaker for AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, and Pfizer, and he has received research grants from Altana, AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, and Pfizer.
References
Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet 2003;362: 847-52.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart Lung and Blood Institute, World Health Organization, 2003. www.goldcopd.com/2004clean.pdf (accessed 19 Jan 2005).
Celli BR, MacNee W, and committee members. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: 932-46.
National Institute for Clinical Excellence. Chronic obstructive pulmonary disease. Thorax 2004;59: 1-232.
O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease, 2003. Can Respir J 2003;10(suppl A): 11A-65A.
Ramsey SD. Suboptimal medical therapy in COPD: exploring the causes and consequences. Chest 2000;117: 33S-7S.
Brusasco V, Hodder R, Miravitlles M, Lee A, Towse LJ, Kesten S. Health outcomes in a 6-month placebo controlled trial of once-daily tiotropium compared with twice-daily salmeterol in patients with COPD. Thorax 2003;58: 399-404.
Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive disease. Eur Respir J 2003;21: 74-81.
Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, 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: 1084-91.
Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361: 449-56.
Rennard SI, Serby CW, Ghafouri M, Johnson PA, Friedman M. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Chest 1996;110: 62-70.
Liesker JJW, Wijkstra PJ, Ten Hacken NHT, Koeter GH, Postma DS, Kerstjens HAM. A systematic review of the effects of bronchodilators on exercise capacity in patients with COPD. Chest 2002;121: 597-608.
Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest 2004;125: 249-59.
Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med 2003;97: 1014-20.
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003;124: 1743-8.
Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165: 1592-6.
Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;2002: 59-65.
Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58: 937-41.
Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 2003;138: 969-73.
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999;159: 941-55.
van Noord JA, de Munck DRAJ, Bantje T, Hop WCJ, Akveld MLM, Bommer AM. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 2000;15: 878-85.
Tennant RC, Erin EM, Barnes PJ, Hansel TT. Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified? Curr Opin Pharmacol 2003;3: 270-6.
Cazzola M, Marco FD, Santus P, Boveri B, Verga M, Matera MG, et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004;17: 35-9.
Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, 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: 834-43.
Calverley PM, 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: 912-9.
((C B Cooper, professor of medicine and ph)