Given the detrimental impact of COPD exacerbations on the patient, every effort should be made to prevent their occurrence. Previous exacerbation history is a key risk factor for future exacerbations.[1]Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. November 2017 [internet publication]
http://goldcopd.org/gold-reports/
[54]Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-1138.
http://www.nejm.org/doi/full/10.1056/NEJMoa0909883#t=article
http://www.ncbi.nlm.nih.gov/pubmed/20843247?tool=bestpractice.com
People with a high burden of symptoms and history of frequent exacerbations (Global Initiative for Chronic Obstructive Lung Disease [GOLD] group D) are at particular risk of future exacerbations and mortality.[1]Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. November 2017 [internet publication]
http://goldcopd.org/gold-reports/
[78]Chen CZ, Ou CY, Yu CH, et al. Comparison of global initiative for chronic obstructive pulmonary disease 2013 classification and body mass index, airflow obstruction, dyspnea, and exacerbations index in predicting mortality and exacerbations in elderly adults with chronic obstructive pulmonary disease. J Am Geriatr Soc. 2015;63:244-250.
http://www.ncbi.nlm.nih.gov/pubmed/25641518?tool=bestpractice.com
However, multiple factors impact the risk of subsequent exacerbations and relevant factors vary among individual patients. Following COPD exacerbation, every effort should be made to both identify and intervene in potentially modifiable factors to reduce risk of subsequent exacerbation events.
Once the patient has stabilized following treatment for an exacerbation, the patient’s maintenance medications should be reviewed and consideration should be given to adjusting the medications following exacerbations, with the goal of reducing the risk and/or severity of future episodes,[82]Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942.
http://journal.publications.chestnet.org/article.aspx?articleid=1918414
http://www.ncbi.nlm.nih.gov/pubmed/25321320?tool=bestpractice.com
and use of medications according to evidence-based guidelines.[1]Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. November 2017 [internet publication]
http://goldcopd.org/gold-reports/
The use of long-acting beta-2 agonists and long-acting anticholinergic medications has been associated with a decreased frequency of exacerbations.[91]Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163:1087-1092.
http://www.ncbi.nlm.nih.gov/pubmed/11316640?tool=bestpractice.com
[92]Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.
http://www.ncbi.nlm.nih.gov/pubmed/17314337?tool=bestpractice.com
[93]Niewoehner DE, 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.
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[94]Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115:957-965.
http://www.ncbi.nlm.nih.gov/pubmed/10208192?tool=bestpractice.com
[95]Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217-224.
http://erj.ersjournals.com/content/19/2/217.long
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[96]Brusasco V, Hodder R, Miravitlles M, et al. 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.
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http://www.ncbi.nlm.nih.gov/pubmed/12728159?tool=bestpractice.com
[97]Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554.
http://content.nejm.org/cgi/content/full/359/15/1543
http://www.ncbi.nlm.nih.gov/pubmed/18836213?tool=bestpractice.com
[98]Tashkin DP. Preventing and managing exacerbations in COPD--critical appraisal of the role of tiotropium. Int J Chron Obstruct Pulmon Dis. 2010;5:41-53.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846152/?tool=pubmed
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[99]Halpin D, Menjoge S, Viel K. Patient-level pooled analysis of the effect of tiotropium on COPD exacerbations and related hospitalisations. Prim Care Respir J. 2009;18:106-113.
http://www.ncbi.nlm.nih.gov/pubmed/19407916?tool=bestpractice.com
[100]Cooper CB, Anzueto A, Decramer M, et al. Tiotropium reduces risk of exacerbations irrespective of previous use of inhaled anticholinergics in placebo-controlled clinical trials. Int J Chron Obstruct Pulmon Dis. 2011;6:269-275.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152465/
http://www.ncbi.nlm.nih.gov/pubmed/21845038?tool=bestpractice.com
[101]Morice AH, Celli B, Kesten S, et al. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respir Med. 2010;104:1659-1667.
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[102]Van den BA, Gailly J, Neyt M. Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis. BMC Pulm Med. 2010;10:50.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955630/
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[103]Wang J, Nie B, Xiong W, et al. Effect of long-acting beta-agonists on the frequency of COPD exacerbations: a meta-analysis. J Clin Pharm Ther. 2012;37:204-211.
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[104]Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. Resp Care. 2011;56:477-487.
http://rc.rcjournal.com/content/56/4/477.short
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[105]Decramer ML, Hanania NA, Lötvall JO, et al. The safety of long-acting β2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2013;8:53-64.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558319/
http://www.ncbi.nlm.nih.gov/pubmed/23378756?tool=bestpractice.com
[106]Mahler DA, Buhl R, Lawrence D, et al. Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity. Pulm Pharmacol Ther. 2013;26:348-355.
http://www.ncbi.nlm.nih.gov/pubmed/23434446?tool=bestpractice.com
[107]Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;(10):CD010177.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010177.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/24127118?tool=bestpractice.com
The long-acting anticholinergic agent tiotropium bromide may be more effective than the long-acting beta-2-agonist salmeterol in preventing exacerbations,[108]Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-1103.
http://www.ncbi.nlm.nih.gov/pubmed/21428765?tool=bestpractice.com
particularly among people with moderate-severity airflow obstruction.[109]Vogelmeier C, Fabbri LM, Rabe KF, et al. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients. Respir Med. 2013;107:75-83.
http://www.ncbi.nlm.nih.gov/pubmed/23102611?tool=bestpractice.com
The novel Respimat mist delivery system for tiotropium must, however, be used with caution, given that its use has been associated with a higher mortality rate.[110]Beasley R, Singh S, Loke YK, et al. Call for worldwide withdrawal of tiotropium Respimat mist inhaler. BMJ. 2012;345:e7390.
http://www.ncbi.nlm.nih.gov/pubmed/23144209?tool=bestpractice.com
The once-daily long-acting inhaled beta-2 agonist indacaterol is also effective in improving health status and reducing symptoms and exacerbations in COPD.[111]Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010;65:473-479.
http://www.ncbi.nlm.nih.gov/pubmed/20522841?tool=bestpractice.com
[112]Chapman KR, Rennard SI, Dogra A, et al. Long-term safety and efficacy of indacaterol, a long-acting beta2-agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest. 2011;140:68-75.
http://journal.publications.chestnet.org/article.aspx?articleid=1088000
http://www.ncbi.nlm.nih.gov/pubmed/21349928?tool=bestpractice.com
[113]Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182:155-162.
http://ajrccm.atsjournals.org/content/182/2/155.long
http://www.ncbi.nlm.nih.gov/pubmed/20463178?tool=bestpractice.com
Another once-daily beta-2-agonist, olodaterol, has been approved for use in some countries, including the US.[114]van Noord JA, Smeets JJ, Drenth BM, et al. 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011;24:666-672.
http://www.ncbi.nlm.nih.gov/pubmed/21839850?tool=bestpractice.com
Aclidinium bromide, a novel long-acting muscarinic antagonist, is also an effective bronchodilator that improves lung function, reduces symptoms, and reduces severe exacerbations requiring hospitalization.[115]Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011;12:55.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098801/
http://www.ncbi.nlm.nih.gov/pubmed/21518460?tool=bestpractice.com
[116]Frampton JE. Aclidinium: in chronic obstructive pulmonary disease. Drugs. 2012;72:1999-2011.
http://www.ncbi.nlm.nih.gov/pubmed/23046206?tool=bestpractice.com
[117]Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(9):CD010509.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010509.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/25234126?tool=bestpractice.com
Neither class of agent poses substantial increased risk of adverse cardiovascular events.[105]Decramer ML, Hanania NA, Lötvall JO, et al. The safety of long-acting β2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2013;8:53-64.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558319/
http://www.ncbi.nlm.nih.gov/pubmed/23378756?tool=bestpractice.com
Combination dual-class bronchodilator therapy confers greater benefits on lung function than either individual class (long-acting beta-2-agonist or long-acting anticholinergic) alone.[118]Wang J, Jin D, Zuo P, et al. Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology. 2011;16:350-358.
http://www.ncbi.nlm.nih.gov/pubmed/21138499?tool=bestpractice.com
However, it remains unclear whether a combination of dual-class bronchodilator therapy is more effective than long-acting antimuscarinic agents alone for reducing exacerbations.[119]Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1:199-209.
http://www.ncbi.nlm.nih.gov/pubmed/24429126?tool=bestpractice.com
[
]
In people with chronic obstructive pulmonary disease, what are the effects of combining long-acting beta2-agonists and tiotropium compared with either drug alone?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1160/fullShow me the answer Novel combinations of a long-acting beta-2 agonist with a long-acting muscarinic antagonist (i.e., vilanterol/umeclidinium)[120]National Horizon Scanning Centre. Umeclidinium and vilanterol for chronic obstructive pulmonary disease. February 2012. http://www.hsc.nihr.ac.uk (last accessed 28 December 2015).
http://www.hsric.nihr.ac.uk/topics/umeclidinium-and-vilanterol-for-chronic-obstructive-pulmonary-disease/
[121]Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42:1484-1494.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844137/
http://www.ncbi.nlm.nih.gov/pubmed/23722616?tool=bestpractice.com
are currently under investigation, but their efficacy in reducing the frequency and/or severity of exacerbations is as yet unknown.[122]Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107:1538-1546.
http://www.resmedjournal.com/article/S0954-6111%2813%2900213-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/23830094?tool=bestpractice.com
Inhaled corticosteroids have been shown to decrease the frequency of exacerbations and decrease healthcare utilization for respiratory illnesses.[123]Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297-1303.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10807619
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[124]Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343:1902-1909.
http://www.nejm.org/doi/full/10.1056/NEJM200012283432601#t=article
http://www.ncbi.nlm.nih.gov/pubmed/11136260?tool=bestpractice.com
[125]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. 2007;146:545-555.
http://www.annals.org/content/146/8/545.full.pdf
http://www.ncbi.nlm.nih.gov/pubmed/17310045?tool=bestpractice.com
[126]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;113:59-65.
http://www.ncbi.nlm.nih.gov/pubmed/12106623?tool=bestpractice.com
[127]Spencer S, Karner C, Cates CJ, et al. Inhaled corticosteroids versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;(12):CD007033.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007033.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/22161409?tool=bestpractice.com
Inhaled corticosteroids should not be used as monotherapy in COPD; their use should be considered as additional therapy for people with exacerbations not controlled with long-acting bronchodilators alone.[1]Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. November 2017 [internet publication]
http://goldcopd.org/gold-reports/
The combination of inhaled corticosteroids and long-acting beta-2 agonists appears more effective than either agent alone to decrease the frequency of episodes in people with more severe COPD.[92]Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.
http://www.ncbi.nlm.nih.gov/pubmed/17314337?tool=bestpractice.com
[128]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. 2003;21:74-81.
http://www.ncbi.nlm.nih.gov/pubmed/12570112?tool=bestpractice.com
[129]Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912-919.
http://erj.ersjournals.com/cgi/content/full/22/6/912
http://www.ncbi.nlm.nih.gov/pubmed/14680078?tool=bestpractice.com
In patients with moderate to severe COPD, treatment with salmeterol plus fluticasone propionate reduces the rate of exacerbations and slows the progressive worsening of FEV1.[130]Ferguson GT, Anzueto A, Fei R, et al. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med. 2008;102:1099-1108.
http://www.ncbi.nlm.nih.gov/pubmed/18614347?tool=bestpractice.com
[131]Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178:332-338.
http://www.ncbi.nlm.nih.gov/pubmed/18511702?tool=bestpractice.com
[132]Anzueto A, Ferguson GT, Feldman G, et al. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009;6:320-329.
http://www.ncbi.nlm.nih.gov/pubmed/19863361?tool=bestpractice.com
Importantly, withdrawal of the inhaled corticosteroid component of combination therapy led to deterioration in lung function and worsened symptoms among patients who had two or more exacerbations in the previous year.[133]Wouters EF, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005;60:480-487.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1747438/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/15923248?tool=bestpractice.com
A subsequent large parallel group study among patients with severe COPD and history of previous exacerbation showed similar risk of moderate or severe exacerbation among people who withdrew the inhaled corticosteroid from triple combination treatment gradually over a 12-week period, compared with controls who did not; inhaled corticosteroid withdrawal was, however, associated with a greater reduction in trough FEV1 at 18 weeks of follow-up.[134]Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285-1294.
http://www.nejm.org/doi/full/10.1056/NEJMoa1407154#t=article
http://www.ncbi.nlm.nih.gov/pubmed/25196117?tool=bestpractice.com
Also, an increased risk of pneumonia has been reported following long-term use of inhaled corticosteroids and inhaled corticosteroid/beta-2 agonist combination therapy.[92]Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.
http://www.ncbi.nlm.nih.gov/pubmed/17314337?tool=bestpractice.com
[135]Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 May 31;(5):CD007891.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007891.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/23728670?tool=bestpractice.com
[136]Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34:641-647.
http://erj.ersjournals.com/content/34/3/641.long
http://www.ncbi.nlm.nih.gov/pubmed/19443528?tool=bestpractice.com
[137]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. 2010;5:189-195.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921686/
http://www.ncbi.nlm.nih.gov/pubmed/20714372?tool=bestpractice.com
[138]Calverley PM, Stockley RA, Seemungal TA, et al. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139:505-512.
http://journal.publications.chestnet.org/article.aspx?articleid=1087764
http://www.ncbi.nlm.nih.gov/pubmed/20576732?tool=bestpractice.com
[139]Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010115.pub2/abstract
http://www.ncbi.nlm.nih.gov/pubmed/24615270?tool=bestpractice.com
This increased risk of pneumonia is not accompanied by a clear increase in mortality risk.[139]Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010115.pub2/abstract
http://www.ncbi.nlm.nih.gov/pubmed/24615270?tool=bestpractice.com
Currently, there are limited but encouraging data on the concurrent use of inhaled corticosteroids, long-acting beta-2 agonists, and long-acting anticholinergic medications.[97]Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554.
http://content.nejm.org/cgi/content/full/359/15/1543
http://www.ncbi.nlm.nih.gov/pubmed/18836213?tool=bestpractice.com
[125]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. 2007;146:545-555.
http://www.annals.org/content/146/8/545.full.pdf
http://www.ncbi.nlm.nih.gov/pubmed/17310045?tool=bestpractice.com
[140]Tashkin DP, Littner M, Andrews CP, et al. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med. 2008;102:479-487.
http://www.ncbi.nlm.nih.gov/pubmed/18258423?tool=bestpractice.com
[141]Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:1975-2000.
http://www.ncbi.nlm.nih.gov/pubmed/18778120?tool=bestpractice.com
[142]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. 2008;177:19-26.
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[143]Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180:741-750.
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[144]Gaebel K, McIvor RA, Xie F, et al. Triple therapy for the management of COPD: a review. COPD. 2011;8:206-243.
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[145]Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;(9):CD009039.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009039.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/21901729?tool=bestpractice.com
[146]Rojas-Reyes MX, García Morales OM, Dennis RJ, Karner C. Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Jun 6;(6):CD008532.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008532.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/27271056?tool=bestpractice.com
While long-acting beta-2 agonists, anticholinergics, and inhaled corticosteroids are all helpful, the optimal choice of medications to reduce exacerbations while minimizing potential adverse events remains somewhat uncertain,[135]Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 May 31;(5):CD007891.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007891.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/23728670?tool=bestpractice.com
[147]Baker WL, Baker EL, Coleman CI. Pharmacologic treatments for chronic obstructive pulmonary disease: a mixed-treatment comparison meta-analysis. Pharmacotherapy. 2009;29:891-905.
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[148]Rodrigo GJ, Castro-Rodriguez JA, 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.
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and the impact of triple-class therapy as compared with dual-agent combination therapy or anticholinergic therapy alone on long-term outcomes such as mortality or hospitalizations is as yet unclear.[146]Rojas-Reyes MX, García Morales OM, Dennis RJ, Karner C. Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Jun 6;(6):CD008532.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008532.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/27271056?tool=bestpractice.com
[149]Hanania NA, Crater GD, Morris AN, et al. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med. 2012;106:91-101.
http://www.ncbi.nlm.nih.gov/pubmed/22040533?tool=bestpractice.com
Novel combination therapies including fluticasone/vilanterol and indacaterol/glycopyrronium bromide are emerging, and their impact on exacerbations of COPD is currently being studied.
Treatment of patients with intermittent doses of macrolide,[150]Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365: 689-698.
http://www.ncbi.nlm.nih.gov/pubmed/21864166?tool=bestpractice.com
[151]Simoens S, Laekeman G, Decramer M. Preventing COPD exacerbations with macrolides: a review and budget impact analysis. Respir Med. 2013;107:637-648.
http://www.ncbi.nlm.nih.gov/pubmed/23352223?tool=bestpractice.com
the fluoroquinolone moxifloxacin,[152]Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res. 2010;11:10.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834642/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/20109213?tool=bestpractice.com
[153]Miravitlles M, Marín A, Monsó E, et al. Efficacy of moxifloxacin in the treatment of bronchial colonisation in COPD. Eur Respir J. 2009;34:1066-1071.
http://erj.ersjournals.com/content/34/5/1066.long
http://www.ncbi.nlm.nih.gov/pubmed/19386683?tool=bestpractice.com
phosphodiesterase inhibitors[154]Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD:results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest. 2006;129:56-66.
http://www.ncbi.nlm.nih.gov/pubmed/16424413?tool=bestpractice.com
[155]Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366:563-571.
http://www.ncbi.nlm.nih.gov/pubmed/16099292?tool=bestpractice.com
such as roflumilast, or statins[156]Blamoun AI, Batty GN, DeBari VA, et al. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract. 2008;62:1373-1378.
http://www.ncbi.nlm.nih.gov/pubmed/18422598?tool=bestpractice.com
[157]Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res. 2009;10:45.
http://www.ncbi.nlm.nih.gov/pubmed/19493329?tool=bestpractice.com
[158]Janda S, Park K, FitzGerald JM, et al. Statins in COPD: a systematic review. Chest. 2009;136:734-743.
http://www.ncbi.nlm.nih.gov/pubmed/19376844?tool=bestpractice.com
can also decrease the frequency, severity, and/or duration of COPD exacerbations. The short-term use of prophylactic antibiotics can reduce the rate and number of exacerbations of COPD or chronic bronchitis,[159]Lee JS, Park DA, Hong Y, et al. Systematic review and meta-analysis of prophylactic antibiotics in COPD and/or chronic bronchitis. Int J Tuberc Lung Dis. 2013;17:153-162.
http://www.ncbi.nlm.nih.gov/pubmed/23317949?tool=bestpractice.com
and preventative treatment with macrolides can lead to healthcare cost savings.[151]Simoens S, Laekeman G, Decramer M. Preventing COPD exacerbations with macrolides: a review and budget impact analysis. Respir Med. 2013;107:637-648.
http://www.ncbi.nlm.nih.gov/pubmed/23352223?tool=bestpractice.com
Daily azithromycin therapy was most effective in reducing exacerbations requiring both antibiotic and steroid treatment, and risk reduction was greatest among people of older age and milder GOLD grade; notably, no significant reduction of exacerbation risk was found among current smokers.[160]Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226018/
http://www.ncbi.nlm.nih.gov/pubmed/24779680?tool=bestpractice.com
The impact of long-term use of intermittent (e.g., three-times weekly) macrolides or other prophylactic antibiotics on the development of antibiotic-resistant pathogens and related COPD exacerbations is as yet unknown but is of potential concern. Phosphodiesterase-4 (PDE4) inhibitor therapy is commonly associated with gastrointestinal upset, abdominal pain, weight loss, and other side effects; individual patient tolerance of these agents varies. Importantly, existing studies suggest that the PDE4 inhibitor roflumilast reduced exacerbations among patients with severe airflow obstruction with clinical features of chronic bronchitis (including sputum production and cough), but not among those with a predominance of emphysema without chronic bronchitis features.[161]Rennard S, Calverley PM, Goehring PMA, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040135/
http://www.ncbi.nlm.nih.gov/pubmed/21272339?tool=bestpractice.com
[162]Taegtmeyer AB, Leuppi JD, Kullak-Ublick GA. Roflumilast: a phosphodiesterase-4 inhibitor licensed for add-on therapy in severe COPD. Swiss Med Wkly. 2012;142:w13628.
http://www.ncbi.nlm.nih.gov/pubmed/22833385?tool=bestpractice.com
Oral mucolytics such as N-acetylcysteine may offer benefit in exacerbation reduction, particularly among people with moderate to severe COPD and or history of two or more exacerbations in the previous 2 years, but their role remains controversial.[82]Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942.
http://journal.publications.chestnet.org/article.aspx?articleid=1918414
http://www.ncbi.nlm.nih.gov/pubmed/25321320?tool=bestpractice.com
[163]Davies L, Calverley PM. The evidence for the use of oral mucolytic agents in chronic obstructive pulmonary disease (COPD). Br Med Bull. 2010;93:217-227.
http://bmb.oxfordjournals.org/content/93/1/217.long
http://www.ncbi.nlm.nih.gov/pubmed/20031934?tool=bestpractice.com
[164]Poole P, Chong J, Cates CJ. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;(7):CD001287.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001287.pub5/full
http://www.ncbi.nlm.nih.gov/pubmed/26222376?tool=bestpractice.com
Alpha-1-antitrypsin augmentation therapy may reduce the frequency of exacerbations for selected people with documented alpha-1-antitrypsin deficiency as the etiology of their COPD.[165]Kueppers F. The role of augmentation therapy in alpha-1 antitrypsin deficiency. Curr Med Res Opin. 2011;27:579-588.
http://www.ncbi.nlm.nih.gov/pubmed/21226542?tool=bestpractice.com
Beta-blockers are often withheld from patients with COPD due to concerns regarding precipitation of exacerbations and bronchospasm. However, cardiovascular disease is a common comorbidity of COPD, and many patients have cardiovascular indications for beta-blocker therapy. Current data suggest that cardioselective beta-blockers are not only safe and effective in patients with COPD, but may reduce exacerbation risk and mortality.[166]Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;(4):CD003566.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003566.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/16235327?tool=bestpractice.com
[167]Rutten FH, Zuithoff NP, Hak E, et al. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2010;170:880-887.
http://archinte.jamanetwork.com/article.aspx?articleid=415954
http://www.ncbi.nlm.nih.gov/pubmed/20498416?tool=bestpractice.com
Therefore, beta-blockers should not be withheld from patients with COPD who have cardiovascular indications for their use.
Some data suggest that an oral Haemophilus influenzae vaccine may help reduce recurrent exacerbations of chronic bronchitis in selected patients;[168]Foxwell AR, Cripps AW, Dear KB. Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis. Cochrane Database Syst Rev. 2010;(10):CD001958.
http://www.ncbi.nlm.nih.gov/pubmed/20927727?tool=bestpractice.com
however, one Cochrane review analysis demonstrated that oral H influenzae vaccine did not significantly reduce the number or severity of exacerbations.[169]Teo E, Lockhart K, Purchuri SN, et al. Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017 Jun 19;6:CD010010.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010010.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/28626902?tool=bestpractice.com
Oral Haemophilus vaccines are not formally recommended in existing guidelines.[30]Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections - full version. Clini Microbiol Infect. 2011;17(suppl 6):E1-E59.
http://www.sciencedirect.com/science/article/pii/S1198743X1461404X
http://www.ncbi.nlm.nih.gov/pubmed/21951385?tool=bestpractice.com
Prophylactic antibiotics to prevent exacerbations are also not recommended.
Although retrospective studies suggested that statins might decrease the rate and severity of exacerbations, one large prospective randomized controlled trial of simvastatin versus placebo did not show a reduction in exacerbation rates or time to first exacerbation among people with history of COPD exacerbation requiring emergency department visit or hospitalization in the year prior to study enrollment.[170]Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014;370:2201-2210.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375247/
http://www.ncbi.nlm.nih.gov/pubmed/24836125?tool=bestpractice.com