Treatment of Stable Chronic Obstructive Pulmonary Disease: the GOLD Guidelines

HOBART LEE; JEFFREY KIM; KARINE TAGMAZYAN

HOBART LEE, MD, JEFFREY KIM, MD, AND KARINE TAGMAZYAN, MD

A more recent article on COPD is available.

Am Fam Physician. 2013;88(10):655-663

Related editorial: Choosing the Right Inhaled Medication Device for COPD

Author disclosure: No relevant financial affiliations.

Chronic obstructive pulmonary disease (COPD) is a common problem in primary care. COPD is diagnosed with spirometry only in clinically stable patients with a postbronchodilator forced expiratory volume in one second/forced vital capacity ratio of less than 0.70. All patients with COPD who smoke should be counseled about smoking cessation. Influenza and pneumococcal vaccinations are recommended for all patients with COPD. The Global Initiative for Chronic Obstructive Lung Disease assigns patients with COPD into four groups based on the degree of airflow restriction, symptom score, and number of exacerbations in one year. Pulmonary rehabilitation is recommended for patients in groups B, C, and D. Those in group A should receive a short-acting anticholinergic or short-acting beta₂ agonist for mild intermittent symptoms. For patients in group B, long-acting anticholinergics or long-acting beta₂ agonists should be added. Patients in group C or D are at high risk of exacerbations and should receive a long-acting anticholinergic or a combination of an inhaled corticosteroid and a long-acting beta₂ agonist. For patients whose symptoms are not controlled with one of these regimens, triple therapy with an inhaled corticosteroid, long-acting beta₂ agonist, and anticholinergic should be considered. Prophylactic antibiotics and oral corticosteroids are not recommended for prevention of COPD exacerbations. Continuous oxygen therapy improves mortality rates in patients with severe hypoxemia and COPD. Lung volume reduction surgery can improve survival rates in patients with severe, upper lobe–predominant COPD with heterogeneous emphysema distribution.

Chronic obstructive pulmonary disease (COPD) is a common problem in primary care. The estimated prevalence is 6.3% (15 million persons) in the United States,¹ with more than 126,000 deaths each year.² COPD treatments aim to improve quality of life and control symptoms while reducing exacerbation risk, which can lead to increased morbidity and mortality.

This article summarizes expert consensus guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for nonpharmacologic and pharmacologic interventions for patients with stable COPD.³ The GOLD guidelines are widely used in the management of COPD. (Disclosure: the GOLD program is funded by pharmaceutical companies that make medications for COPD, and the board of directors, committee members, and reviewers have ties to the pharmaceutical industry. See http://www.goldcopd.org/disclosure-statements.html.)

Clinical recommendation	Evidence rating	References
Suspected COPD should be confirmed by spirometry in stable patients with a postbronchodilator forced expiratory volume in one second/forced vital capacity ratio of less than 0.70.	C	³
Smoking cessation is recommended for all patients with COPD who smoke.	C	¹⁴, ¹⁵
Patients in GOLD group A should be treated with a short-acting anticholinergic or short-acting beta₂ agonist on an as-needed basis.	A	^19–21
Patients in GOLD group B should be treated with a long-acting anticholinergic or long-acting beta₂ agonist.	A	^22–29
Patients in GOLD group C or D should be treated with a long-acting anticholinergic or a combination of an inhaled corticosteroid and long-acting beta₂ agonist.	B	³, ²⁴, ²⁸, ³⁴, ³⁷, ³⁸
Long-term oxygen therapy improves mortality rates in patients with severe hypoxemia and COPD.	A	⁴², ⁴³

Although some of the GOLD recommendations are derived from outcome-oriented evidence, the guidelines have not been shown to provide better clinical outcomes than other guidelines on COPD management, such as those from the National Institute for Health and Care Excellence⁴ or the joint guidelines from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society.⁵ A comparison of treatment guidelines is shown in Table 1.^3–5 The joint guideline from the American College of Physicians uses the forced expiratory volume in one second (FEV₁) to guide treatment decisions, whereas the National Institute for Health and Care Excellence guideline focuses on symptoms of breathlessness and exacerbations. The GOLD guideline combines the subjective and objective components of COPD to classify severity and guide treatment recommendations.

Diagnosis

A diagnosis of COPD should be considered in patients with progressive dyspnea, chronic cough, or increased sputum production with risk factors (e.g., smoking). COPD can be diagnosed with spirometry only in stable patients (i.e., those not experiencing an acute exacerbation of symptoms) with a postbronchodilator FEV₁/forced vital capacity ratio of less than 0.70.³ The diagnosis of COPD and interpretation of spirometry results have been reviewed previously.^6,7

Assessment

GOLD classifies persons with COPD into four groups based on the severity of disease, as assessed by the following criteria: the degree of airflow restriction, a patient symptom score, and the number of exacerbations in one year (Figure 1).⁸ This grading system uses objective spirometry data and subjective symptoms because the degree of airflow restriction does not always correlate well with symptoms.⁹ The degree of airflow restriction is graded as mild, moderate, severe, or very severe (Table 2).⁸ Persons with mild or moderate airflow restriction are assigned to group A or B, whereas those with severe or very severe airflow restriction are assigned to group C or D.

COPD symptoms are assessed subjectively using one of two validated patient symptom questionnaires.¹⁰ Because FEV₁ does not necessarily correlate with patient symptoms, and because improvement of a patient's health status and reduction in symptoms are the goals of treatment, the inclusion of symptom questionnaires allows for the diagnostic assessment to match treatment goals, similar to the guidelines from the National Institute for Health and Care Excellence.³ GOLD recommends the use of the COPD Assessment Test (CAT) or the modified Medical Research Council Dyspnea Scale (mMRC, Table 3).¹¹ The CAT is available at http://www.catestonline.org/ (eFigure A), and the CAT and the mMRC are available in the smartphone app COPD Pocket Consultant Guide (http://bit.ly/1aTrkIs). Patients with a CAT score less than 10 or an mMRC score of 0 or 1 are assigned to group A or C. Those with a CAT score of 10 or more or an mMRC score of 2 or more are assigned to group B or D.

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Score	Description of breathlessness
0	I get breathless only with strenuous exercise.
1	I get short of breath when hurrying on level ground or walking up a slight hill.
2	On level ground, I walk slower than other people my age because of breathlessness, or I have to stop for breath when walking at my own pace.
3	I stop for breath after walking about 100 yards or after a few minutes on level ground.
4	I am too breathless to leave the house, or I am breathless when dressing.

The third component used to determine the GOLD group is the number of COPD exacerbations in one year. GOLD defines an exacerbation as an acute event characterized by worsening of respiratory symptoms beyond normal day-to-day variations that leads to a change in medication.³ Exacerbations are associated with higher mortality.^12,13 Patients with no or one exacerbation per year are assigned to group A or B, and those with two or more are assigned to group C or D. If there is a discrepancy when all three components are considered, the patient should be assigned to the higher-risk group.

Patients with COPD should be reassessed every two to three months. Symptom questionnaires (e.g., CAT, mMRC), smoking cessation (if applicable), and exacerbation history should be reviewed. Repeat spirometry is recommended on a yearly basis.³

Treatment

COPD treatment is guided by the patient group assignment. As disease severity increases, long-acting inhalers and combination therapies are added to provide additional symptom control and reduce the risk of exacerbations.

SMOKING CESSATION

Patients who smoke should be assisted with smoking cessation through counseling and effective medications.^14,15 The American Academy of Family Physicians' Ask and Act Tobacco Cessation Program provides online resources for physicians and patients (http://bit.ly/1fV71eZ).

IMMUNIZATIONS

Influenza vaccination reduces COPD exacerbations and is recommended yearly.¹⁶ The Centers for Disease Control and Prevention recommends pneumococcal vaccination for all adults 19 years and older who have chronic lung disease, including COPD. However, a meta-analysis of seven studies did not show a decrease in pneumonia rates, hospital admissions, or emergency department visits in patients with COPD who received the pneumococcal vaccine.¹⁷

PULMONARY REHABILITATION

Pulmonary rehabilitation has been shown to improve exercise tolerance, reduce dyspnea, and improve health-related quality of life in patients similar to those in GOLD groups B through D.¹⁸

INHALED MEDICATIONS

For patients in group A, a short-acting anticholinergic (e.g., ipratropium [Atrovent HFA]) or short-acting beta₂ agonist (e.g., albuterol, levalbuterol [Xopenex HFA], pirbuterol [Maxair Autohaler]) is recommended on an as-needed basis for mild intermittent symptoms. A meta-analysis of 13 studies found that short-acting beta₂ agonists improved lung function, dyspnea, and fatigue, and decreased breathlessness compared with placebo.¹⁹ A 2006 Cochrane review that included 3,912 patients showed a small benefit in quality of life and lung function in those receiving ipratropium compared with albuterol.²⁰ Combination therapy with scheduled albuterol and ipratropium has been shown to increase FEV₁ but does not affect patient symptom scores.²¹ It is not known if as-needed dosing is more or less effective than scheduled administration.

For patients in group B, long-acting inhaled medications should be used. Options include long-acting anticholinergics (e.g., tiotropium [Spiriva], aclidinium [Tudorza Pressair]) or long-acting beta₂ agonists (e.g., arformoterol [Brovana], formoterol [Foradil], indacaterol [Arcapta], salmeterol [Serevent Diskus]). Tiotropium has been shown to improve quality-of-life scores, with a number needed to treat of 14 to prevent one exacerbation and 30 to prevent one hospitalization over one year.²² If tiotropium is prescribed, patients should be switched from ipratropium or ipratropium/albuterol (Combivent) to albuterol alone as short-acting rescue medication.

Long-acting beta₂ agonists reduce exacerbation risk and improve FEV₁ and daily symptom scores.²³ A randomized, double-blind trial of 6,112 patients with moderate to severe COPD showed that salmeterol improved FEV₁ and decreased exacerbation risk, but did not reduce mortality.²⁴ Indacaterol is a once-daily long-acting beta₂ agonist that improves FEV₁ and reduces rescue use of albuterol.²⁵ In patients with comorbid asthma or an unclear diagnosis, monotherapy with a long-acting beta₂ agonist is contraindicated because it may increase cardiovascular mortality.²⁶

Tiotropium reduces exacerbations and COPD-related hospitalizations compared with long-acting beta₂ agonists, but does not affect mortality.²⁷ For patients whose symptoms are not controlled with tiotropium or a long-acting beta₂ agonist alone, a combination of tiotropium and a long-acting beta₂ agonist is recommended based on short-term outcomes of improved symptom scores and higher FEV_1.^28,29

A 2008 meta-analysis found an association between the use of inhaled anticholinergics (ipratropium and tiotropium) and cardiovascular mortality in patients with COPD.³⁰ However, a subsequent randomized, double-blind trial with 5,993 patients demonstrated decreased cardiovascular and overall mortality with tiotropium after four years of follow-up.³¹ A large cohort study of U.S. veterans showed an increased risk of cardiovascular events with the use of ipratropium in the previous six months.³² Given this association, ipratropium should be avoided in patients with cardiovascular disease.

Patients in GOLD groups C and D should be prescribed a long-acting anticholinergic or a combination of an inhaled corticosteroid and long-acting beta₂ agonist.³ Compared with tiotropium alone, fluticasone/salmeterol (Advair) improved daily symptom scores and decreased mortality (number needed to treat = 40), but increased the incidence of pneumonia (number needed to harm = 25) and did not change the rate of exacerbations.³³ Patients with poorly controlled symptoms should start triple therapy with an inhaled corticosteroid, long-acting anticholinergic, and long-acting beta₂ agonist. The data for triple therapy are inconsistent, with studies showing improvement in lung function and symptom scores but conflicting results regarding reduction in exacerbation rates compared with tiotropium alone.^28,34 A summary of initial treatment options and common medications is presented in Table 4⁸ andTable 5,³⁵ and patient instructions for inhaler use are reviewed in eFigure B.

Patient group*	First choice	Second choice	Alternatives
A	Short-acting anticholinergic as needed (e.g., ipratropium [Atrovent HFA]) or Short-acting beta₂ agonist (e.g., albuterol) as needed	Long-acting anticholinergic (e.g., tiotropium [Spiriva]) or Long-acting beta₂ agonist (e.g., salmeterol [Serevent Diskus]) or Short-acting beta₂ agonist and short-acting anticholinergic	Theophylline
B	Long-acting anticholinergic or Long-acting beta₂ agonist	Long-acting anticholinergic and long-acting beta₂ agonist	Short-acting anticholinergic as needed and/or short-acting beta₂ agonist as needed Theophylline
C	Inhaled corticosteroid(e.g., fluticasone [Flovent]) and long-acting beta₂ agonist or Long-acting anticholinergic	Long-acting anticholinergic and long-acting beta₂ agonist	Phosphodiesterase-4 inhibitor (e.g., roflumilast [Daliresp]) Short-acting anticholinergic as needed agonist as and/or short-acting beta₂ needed Theophylline
D	Inhaled corticosteroid and long-acting beta₂ agonist or Long-acting anticholinergic	Inhaled corticosteroid and long-acting anticholinergic or Inhaled corticosteroid and long-acting beta₂ agonist and long-acting anticholinergic or Inhaled corticosteroid and long-acting beta₂ agonist and phosphodiesterase-4 inhibitor or Long-acting anticholinergic and long-acting beta₂ agonist or Long-acting anticholinergic and phosphodiesterase-4 inhibitor	Short-acting anticholinergic as needed and/or short-acting beta₂ agonist as needed Theophylline

Medication	Dosage	Cost*	Potential adverse effects
Short-acting anticholinergic
Ipratropium (Atrovent HFA)	Two puffs every six hours as needed	$236 per inhaler	Anaphylaxis, angioedema, bronchospasm (paradoxical), glaucoma (narrow-angle), hypersensitivity reaction, laryngospasm
Short-acting beta₂ agonists
Albuterol	Two puffs every four to six hours as needed	$33 per inhaler (generic)	Angina, angioedema, arrhythmias, bronchospasm (paradoxical), hypertension, hypokalemia, QT-interval prolongation, seizures
Levalbuterol (Xopenex HFA)	Two puffs every four to six hours as needed	$55 per inhaler	Anaphylaxis, arrhythmias, bronchospasm (paradoxical), hypersensitivity reaction, hypertension, hypokalemia, metabolic acidosis, paresthesia, syncope
Pirbuterol (Maxair Autohaler)	One or two puffs every four to six hours as needed	$450 per inhaler	Arrhythmias, bronchospasm (paradoxical), hypersensitivity reaction, hypertension, hypokalemia, seizures
Long-acting anticholinergics
Aclidinium (Tudorza Pressair)	One dose twice per day	$237 for 60 doses	Atrioventricular block, bronchospasm (paradoxical), cardiopulmonary arrest, heart failure, hypersensitivity reaction
Tiotropium (Spiriva)	One dose per day	$282 for 30 doses	Angioedema, bronchospasm (paradoxical), glaucoma, hypersensitivity reaction
Long-acting beta₂agonists
Arformoterol (Brovana)	15 mcg twice per day (nebulizer only)	$249 for 30 vials (15 mcg per vial)	Arrhythmias, bronchospasm (paradoxical), hypersensitivity reaction, hypokalemia, lung cancer
Formoterol (Foradil)	One dose every 12 hours	$200 for 60 doses	Anaphylaxis, arrhythmias, asthma exacerbation, atrial fibrillation, bronchospasm (paradoxical), hypertension, hypokalemia, metabolic acidosis
Indacaterol (Arcapta)	One capsule per day	$187 for 30 capsules	Arrhythmias, bronchospasm (paradoxical), hypersensitivity reaction, hypokalemia, seizure disorder
Salmeterol (Serevent Diskus)	One puff every 12 hours	$205 per inhaler	Anaphylaxis, angioedema, arrhythmias, bronchospasm (paradoxical), fever, glaucoma, hypersensitivity reaction, hypertension, hypokalemia, paresthesia, pelvic inflammatory disease, vasculitis
Inhaled corticosteroids
Beclomethasone (Qvar, 40 to 80 mcg per puff)	40 to 320 mcg twice per day	$176 per inhaler	Anaphylaxis, angioedema, bronchospasm, hypersensitivity reaction, glaucoma, suicidal ideation
Budesonide (Pulmicort, 90 to 180 mcg per puff)	180 to 360 mcg twice per day	$120 to $135 per inhaler, depending on dosage	Adrenal insufficiency, angioedema, benign intracranial hypertension, bronchospasm, glaucoma, hypersensitivity reaction, hypertension, hypokalemia, leukocytosis
Ciclesonide (Alvesco, 80 to 160 mcg per puff)	80 to 160 mcg twice per day	$188 per inhaler	Angioedema, bronchospasm (paradoxical), elevated liver enzymes, increased intraocular pressure
Fluticasone (Flovent HFA, 44 to 220 mcg per puff; Flovent Diskus, 100 to 250 mcg per puff)	44 to 500 mcg twice per day	$130 to $275 per inhaler, depending on dosage and delivery system		Anaphylaxis, angioedema, asthma exacerbation, bronchospasm (paradoxical), Churg-Strauss syndrome, fever, hypersensitivity reaction, muscle injury, vasculitis, wheezing
Mometasone (Asmanex, 220 mcg per puff)	One or two puffs per day	$181 per inhaler		Anaphylaxis, angioedema, bronchospasm, fever, hypersensitivity reaction, increased intraocular pressure, wheezing
Combination medications
Budesonide/formoterol (Symbicort)	Two puffs twice per day	$222 to $253, depending on dosage		Anaphylaxis, angioedema, arrhythmias, bronchospasm, glaucoma, hypersensitivity reaction, hypertension, hypokalemia, hypotension, increased intraocular pressure, tachycardia
Fluticasone/salmeterol (Advair)	One puff twice per day (Diskus); two puffs twice per day (HFA)	$235 to $380 per inhaler, depending on dosage and delivery system		Anaphylaxis, angioedema, arrhythmias, asthma exacerbation, bronchospasm, hypertension, hypokalemia, myocardial ischemia, stridor, tachycardia, wheezing
Ipratropium/albuterol (Combivent Respimat)	One or two puffs every six hours as needed	$280 per inhaler		Anaphylaxis, angioedema, arrhythmias, exacerbation of chronic obstructive pulmonary disease, glaucoma, hypersensitivity reaction, hypertension, hypokalemia, increased intraocular pressure, metabolic acidosis, myocardial ischemia, tachycardia
Mometasone/formoterol (Dulera)	Two puffs twice per day	$241 per inhaler		Adrenal suppression, angioedema, arrhythmias, asthma exacerbation, bronchospasm, glaucoma, hypersensitivity reaction, hypokalemia, seizures, vasculitis
Other
Roflumilast (Daliresp)	500 mcg per day	$215 for 30 500-mcg tablets		Arrhythmias, elevated liver enzymes, hypersensitivity reaction, lung cancer, paresthesia, prostate cancer, renal failure, suicidal ideation
Theophylline (extended-release)	300 mg per day initially, then titrate by serum levels	$10 (generic) for 30 300-mg tablets		Arrhythmias, hyperthyroidism, intractable vomiting, peptic ulcer disease, seizures, status epilepticus

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

ORAL MEDICATIONS

Theophylline can be added or used as an alternative in patients whose symptoms are not controlled with triple therapy or who cannot afford inhaler therapy. Theophylline requires drug level monitoring and improves lung function parameters, but has uncertain effects on symptoms and exacerbations.³⁶

Roflumilast (Daliresp), an oral phosphodiesterase-4 inhibitor approved for use in patients with COPD and chronic bronchitis symptoms, can also be added to long-acting bronchodilators in patients in group C or D. Studies have demonstrated improvement in FEV₁ but inconsistent results regarding reduction of exacerbation rates.^37,38

Prophylactic antibiotic therapy is not recommended to prevent COPD exacerbations. Although erythromycin and azithromycin (Zithromax) have shown a reduced risk of exacerbations,^39,40 there are insufficient data about the effects on macrolide resistance and long-term adverse effects to recommend their use.

Oral corticosteroids do not improve quality of life or reduce exacerbation rates, and are not recommended for patients with stable COPD.⁴¹

OXYGEN

Long-term oxygen therapy is recommended for patients with COPD and severe hypoxemia (oxygen saturation less than 88% or partial arterial oxygen pressure less than 55 mg Hg). Supplemental oxygen improves endurance and exercise capacity in patients with moderate to severe COPD.⁴² A multicenter randomized trial with 203 patients who had hypoxemia and COPD demonstrated that continuous oxygen therapy had benefits on survival rates compared with nocturnal oxygen therapy.⁴³ The goal oxygen saturation should be approximately 90% to avoid respiratory acidosis.⁴⁴

SURGERY

Lung volume reduction surgery improves five-year survival rates in patients with severe COPD and heterogeneous distribution of emphysema with upper lobe predominance.⁴⁵ Conversely, patients with severe COPD and FEV₁ less than 20%, homogenous emphysema, or low carbon monoxide diffusion capacity have increased 30-day mortality after lung volume reduction surgery.⁴⁶

Lung transplantation may improve quality of life and functional capacity in selected patients with severe COPD. Criteria for referral include a score greater than 5 on the BODE (body mass index, obstruction, dyspnea, exercise) Index³ (Table 6⁴⁷ ).

Component	Points
Component	0	1	2	3
Body mass index (kg per m²)	> 21	≤ 21	—	—
Obstruction: percentage of predicted FEV₁	≥ 65	50 to 64	36 to 49	≤ 35
Dyspnea: mMRC score (Table 3)	0 or 1	2	3	4
Exercise: distance walked in six minutes (meters)	≥ 350	250 to 349	150 to 249	≤ 149

Data Sources: A PubMed search was completed in Clinical Queries using the key terms COPD treatment and COPD therapy. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were EBSCO Host Academic Search Premier, DynaMed, Essential Evidence Plus, and UpToDate. Search Date: October 2012.

Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(46):938-943.

Centers for Disease Control and Prevention. Deaths from chronic obstructive pulmonary disease—United States, 2000–2005. MMWR Morb Mortal Wkly Rep. 2008;57(45):1229-1232.

Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2011. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed September 16, 2013.

Gruffydd-Jones K, Loveridge C. The 2010 NICE COPD guidelines: how do they compare with the GOLD guidelines?. Prim Care Respir J. 2011;20(2):199-204.

Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-191.

Stephens MB, Yew KS. Diagnosis of chronic obstructive pulmonary disease. Am Fam Physician. 2008;78(1):87-92.

Barreiro TJ, Perillo I. An approach to interpreting spirometry. Am Fam Physician. 2004;69(5):1107-1114.

Global Strategy for the Diagnosis, Management and Prevention of COPD. http://www.goldcopd.org/other-resources-gold-teaching-slide-set.html. Accessed August 20, 2013.

Agusti A, Calverley PM, Celli B, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122.

Tsiligianni IG, van der Molen T, Moraitaki D, et al. Assessing health status in COPD. A head-to-head comparison between the COPD Assessment Test (CAT) and the clinical COPD questionnaire (CCQ). BMC Pulm Med. 2012;12:20.

Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J. 1959;2(5147):257-266.

Hurst JR, Vestbo J, Anzueto A, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138.

Garcia-Aymerich J, Serra Pons I, Mannino DM, Maas AK, Miller DP, Davis KJ. Lung function impairment, COPD hospitalisations and subsequent mortality. Thorax. 2011;66(7):585-590.

Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994;272(19):1497-1505.

Larzelere MM, Williams DE. Promoting smoking cessation. Am Fam Physician. 2012;85(6):591-598.

Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006(1):CD002733.

Walters JA, Smith S, Poole P, Granger RH, Wood-Baker R. Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2010(11):CD001390.

Nici L, Lareau S, ZuWallack R. Pulmonary rehabilitation in the treatment of chronic obstructive pulmonary disease. Am Fam Physician. 2010;82(6):655-660.

Sestini P, Renzoni E, Robinson S, Poole P, Ram FS. Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2002(4):CD001495.

Appleton S, Jones T, Poole P, et al. Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2006(2):CD001387.

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(5):1411-1419.

Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2005(2):CD002876.

Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) [published correction appears in Eur Respir J. 1997;10(7):1696]. Eur Respir J. 1997;10(4):815-821.

Calverley PM, Anderson JA, Celli B, et al.; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.

Kerwin EM, Gotfried MH, Lawrence D, Lassen C, Kramer B. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥ 40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther. 2011;33(12):1974-1984.

McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks of FDA-approved long-acting β₂-adrenergic receptor agonists. Pediatrics. 2011;128(5):e1147-e1154.

Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2012(9):CD009157.

Aaron SD, Vandemheen KL, Fergusson D, et al.; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555.

van Noord JA, Aumann JL, 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(2):214-222.

Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis [published correction appears in JAMA. 2009;301(12):1227–1230]. JAMA. 2008;300(12):1439-1450.

Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP 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(10):948-955.

Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with ipratropium bromide in COPD. Chest. 2010;137(1):13-19.

Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA INSPIRE Investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;177(1):19-26.

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(8):741-750.

Grimes GC, Manning JL, Patel P, Via RM. Medications for COPD: a review of effectiveness. Am Fam Physician. 2007;76(8):1141-1148.

Ram FS, Jardin JR, Atallah A, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med. 2005;99(2):135-144.

Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials [published correction appears in Lancet. 2010;376(9747):1146]. Lancet. 2009;374(9691):685-694.

Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al.; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703.

Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139-1147.

Albert RK, Connett J, Bailey WC, et al.; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD [published correction appears in N Engl J Med. 2012;366(14):1356]. N Engl J Med. 2011;365(8):689-698.

Walters JA, Walters EH, Wood-Baker R. Oral corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2005(3):CD005374.

Bradley JM, O'Neill B. Short-term ambulatory oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. ;2005(4):CD004356.

Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;93(3):391-398.

Celli BR, MacNee W ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper [published correction appears in Eur Respir J. 2006;27(1):242]. Eur Respir J. 2004;23(6):932-946.

Sanchez PG, Kucharczuk JC, Su S, Kaiser LR, Cooper JD. National Emphysema Treatment Trial redux: accentuating the positive. J Thorac Cardiovasc Surg. 2010;140(3):564-572.

National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med. 2001;345(15):1075-1083.

Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-1012.

American College of Physicians/American College of Chest Physicians/American Thoracic Society/European Respiratory Society guideline⁵
FEV₁ = 60% to 80% predicted: inhaled bronchodilators may be used
FEV₁ < 60% predicted: long-acting anticholinergic or long-acting beta₂ agonist recommended; combination therapy may be used (long-acting anticholinergic, long-acting beta₂ agonist, or inhaled corticosteroid)
Global Initiative for Chronic Obstructive Lung Disease guideline³
Patient group A*: short-acting anticholinergic or short-acting beta₂ agonist as needed
Patient group B*: long-acting anticholinergic or long-acting beta₂ agonist
Patient group C or D*: long-acting anticholinergic or combination of long-acting beta₂ agonist plus inhaled corticosteroid
National Institute for Health and Care Excellence guideline⁴
Patients with breathlessness and exercise limitation: short-acting beta₂ agonist or short-acting anticholinergic as needed
Patients with persistent breathlessness and exacerbations despite therapy above:
	FEV₁ ≥ 50% predicted: long-acting anticholinergic or long-acting beta₂ agonist
	FEV₁ < 50% predicted: long-acting anticholinergic or combination of long-acting beta₂ agonist and inhaled corticosteroid
Patients with persistent breathlessness or exacerbations despite therapy above:
	FEV₁ ≥ 50% predicted: long-acting beta₂ agonist plus inhaled corticosteroid, or combination of long-acting anticholinergic, long-acting beta₂ agonist, and inhaled corticosteroid
	FEV₁ < 50% predicted: long-acting anticholinergic, long-acting beta₂ agonist, and inhaled corticosteroid

In patients with FEV₁/FVC < 0.70:
	GOLD 1 (mild): FEV₁ ≥ 80% predicted
	GOLD 2 (moderate): 50% ≤ FEV₁ < 80% predicted
	GOLD 3 (severe): 30% ≤ FEV₁ < 50% predicted
	GOLD 4 (very severe): FEV₁ < 30% predicted