Optimizing Treatment of Chronic Obstructive Pulmonary Diseas

The American Journal of Medicine (2007) Vol 120 (8A), S4 –S13 Optimizing Treatment of Chronic Obstructive Pulmonary Disease: An Assessment of Current Therapies Robert A Wise, MD,a and Donald P Tashkin, MDb a Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and Division of Pulmonary, Critical Care Medicine, and Hospitalists, David Geffen School of Medicine at UCLA, University of California–Los Angeles, Los Angeles, California, USA b ABSTRACT Bronchodilators are the mainstay of chronic obstructive pulmonary disease (COPD) therapy Inhaled short-acting ␤2-agonists generally have a more rapid onset of effect and shorter duration of action than short-acting anticholinergic agents, and are usually prescribed as “rescue” medication to relieve acute bronchospasm For patients with persistent symptoms, maintenance therapy with inhaled long-acting ␤2-agonists is preferable to short-acting ␤2-agonists because long-acting ␤2-agonists provide more predictable, longer-lasting improvements in lung function Long-acting anticholinergic agents can provide similar prolonged improvement in lung function with once-daily dosing Inhaled corticosteroids reduce the frequency of acute exacerbations and are recommended for patients with severe COPD and frequent exacerbations Combining different classes of bronchodilators or combining a bronchodilator with a corticosteroid provides greater improvements in lung function and symptoms than the individual agents given alone Nonpharmacologic interventions, including pulmonary rehabilitation, oxygen therapy, and surgery, can benefit patients at various stages of disease A treatment algorithm that combines both pharmacologic and nonpharmacologic interventions for the management of COPD is presented © 2007 Elsevier Inc All rights reserved KEYWORDS: Chronic obstructive pulmonary disease; Combination therapy; Inhaled bronchodilators; Inhaled corticosteroids; Oxygen therapy; Pulmonary rehabilitation In the United States, chronic obstructive pulmonary disease (COPD) affects an estimated 24 million adults,1 and is the fourth leading cause of death.2– Cigarette smoking is the main risk factor for COPD; however, other forms of tobacco smoking and passive exposure to cigarette smoke or inhalants are also risk factors.4 In addition to smoking, occupational exposure to dust and chemicals increases the risk for COPD.4 The hallmark of COPD is airflow limitation that is progressive and not fully reversible.5,6 However, COPD also affects other organ systems Many patients experience weight loss and decreased exercise capacity and are at Requests for reprints should be addressed to Robert A Wise, MD, Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine at the JHU Asthma and Allergy Center, 5501 Hopkins Bay View Circle, Room 4B.74, Baltimore, MD 21224 E-mail address: rwise@welchlink.welch.jhu.edu 0002-9343/$ -see front matter © 2007 Elsevier Inc All rights reserved doi:10.1016/j.amjmed.2007.04.007 increased risk for comorbidities, such as cardiovascular disease, respiratory infections, osteoporosis, and fractures.7,8 Progression of COPD together with these damaging consequences diminishes the patient’s quality of life (QOL).9 Unlike heart disease, cancer, and stroke, the death rate from COPD is increasing dramatically.3 Effective treatment of COPD can prevent disease progression and complications, relieve symptoms, improve exercise tolerance and overall health status, and prevent and reduce exacerbations.6 Current guidelines for the diagnosis and management of COPD recommend the use of spirometry to detect patients in the early stages of the disease.5,6 Smoking cessation is an integral part of the overall management of COPD, and has been shown to slow the rate of decline in lung function.10,11 This review discusses both pharmacologic and nonpharmacologic strategies for treating all stages of COPD, including Wise and Tashkin Optimizing Treatment of COPD: An Assessment of Current Therapies acute exacerbations Different treatment strategies may decrease morbidity and mortality associated with COPD, and may improve the QOL for patients To effectively manage the disease, it is important to raise awareness of COPD among physicians and patients PHARMACOTHERAPY FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: EVIDENCE BASED ON CLINICAL STUDIES Bronchodilators are the mainstay of COPD therapy.6,12 A variety of bronchodilating agents are available for the treatment of COPD, including short- and long-acting ␤2-agonists and short- and long-acting anticholinergic agents (Table 1).13–29 Inhaled drugs are preferred over oral agents because of their faster onset of action, greater effectiveness, and lower risk of side effects The choice of a ␤2-agonist or an anticholinergic agent depends on availability, as well as the symptom relief and side effects experienced by the individual patient.6 Bronchodilators can be prescribed for use as needed to relieve persistent or worsening symptoms, or for regular use to prevent or reduce symptoms.6 In patients with COPD, constriction of airways and loss of lung elasticity lead to impaired lung function.2,12 Bronchodilators relax airway smooth muscle and improve emptying of the lungs10 and may improve exercise capacity.6,12 Currently, there are long-acting inhaled bronchodilators available in the United States: the ␤2-agonists salmeterol and formoterol, and the anticholinergic agent tiotropium The bronchodilator effects of the long-acting inhaled ␤2-agonists last for Ն12 hours, and these agents remain effective overnight when taken in the evening and when used regularly.10,17,18,20 With the long-acting anticholinergic agent tiotropium, the bronchodilator effect is maintained for 24 hours, regardless of whether the once-daily drug is administered in the morning or in the evening.20 ␤2-Agonists ␤2-Agonists stimulate ␤2-receptors, leading to an increase in cyclic adenosine monophosphate, increased smooth muscle relaxation and improved lung emptying or decreased air trapping during tidal breathing.2,5 Inhaled short-acting ␤2agonists generally have a more rapid onset of effect and shorter duration of action than short-acting anticholinergic agents, and thus are more often prescribed as “rescue” medications to relieve acute bronchospasm.2 The long-acting ␤2-agonists salmeterol and formoterol and an extendedrelease oral tablet formulation of albuterol all have a duration of effect of up to 12 hours.14,17,18 Stimulation of ␤2receptors can produce resting sinus tachycardia and can potentially trigger disturbances of cardiac rhythm in very susceptible individuals, although this is rarely seen with inhaled therapy.10 Older patients treated with higher doses of ␤2-agonists may experience exaggerated somatic tremor, which may limit their use.10 Long-acting ␤2-agonists, which became available several years ago, are currently used for maintenance therapy to S5 provide more predictable and longer-lasting improvement in lung function than that produced by use of short-acting ␤2-agonists.30 As part of a recent review of randomized controlled trials with Ն3 months’ follow-up, Sin and colleagues30 assessed the effects of long-acting ␤2-agonists compared with placebo on the frequency of exacerbations and health-related QOL (HRQOL) using meta-analyses The trials that provided data on the relative risk (RR) of exacerbations with long-acting ␤2-agonists or placebo showed a 21% reduction in COPD exacerbation rates (pooled RR, 0.79; 95% confidence interval [CI], 0.69 to 0.90) with use of either salmeterol or formoterol in patients with moderate-to-severe COPD (Figure 1).30 Additionally, of these trials evaluated improvements in QOL using the St George’s Respiratory Questionnaire (SGRQ), a wellstandardized, validated patient self-rating tool used to quantify the extent of COPD-related physical and psychological impairments, and to assess the effects of specific interventions on overall functioning.31 These studies showed that, compared with placebo, use of salmeterol or formoterol improved HRQOL for patients with COPD.30 Anticholinergic Agents Anticholinergic agents induce smooth muscle relaxation of the airways by antagonism of acetylcholine at the M3muscarinic receptors on airway smooth muscle.2,10 Following inhalation, the short-acting anticholinergic agent ipratropium has a slower onset of action than the short-acting ␤2-agonists and a slightly longer duration of action.2 Because ipratropium, as well as the long-acting anticholinergic agent tiotropium, are poorly absorbed, the systemic side effects seen with atropine are limited.10 Some of the reported side effects of anticholinergic agents include worsening signs and symptoms of narrow-angle glaucoma and prostatic hyperplasia or bladder-neck obstruction.19,20 The long-acting anticholinergic agent tiotropium has a sustained action over 24 hours when taken once daily in the morning.20,32 Two randomized, double-blind, doubledummy, parallel-group studies evaluated health outcomes over year in patients with moderate-to-severe COPD who received either tiotropium 18 ␮g once daily (n ϭ 356) or ipratropium 40 ␮g times daily (n ϭ 179).32 At the end of year, tiotropium-treated patients showed significantly greater improvements in lung function (as measured by predose forced expiratory volume in second [FEV1] and morning and evening expiratory flow rates) and dyspnea (measured by the Transition Dyspnea Index focal score), and used significantly fewer doses of rescue medication per week compared with ipratropium-treated patients.32 HRQOL (as measured by the SGRQ total score) improved initially in both treatment groups, and was sustained over year in the tiotropium group but not in the ipratropium group.32 The number of exacerbations per patient per year was 24% lower in patients receiving tiotropium than in those treated with ipratropium, and the times to the first exacerbation and the first COPD-related hospitalization S6 The American Journal of Medicine, Vol 120 (8A), August 2007 Table Bronchodilators commonly used in treatment of chronic obstructive pulmonary disease* Generic Name (by Drug Class) Short-acting ␤2-agonist Albuterol Trade Name Proventil† Proventil† Proventil HFA† Ventolin HFA‡ Volmax§ Pirbuterol Levalbuterol ProAirʈ Maxair¶ Xopenex# — 60–90 60 50–55 56 — Duration of Effect (hr) 3–4 3–4 12 47 30–60 90 3–6 5–8 5–10 76–78 3–4 30–48 180 60–180 12 12 15 60–120 2–4 15–30 60–120 4–5 Spiriva** 30 180 24 Combivent** 15 60 4–5 90 30–60 180 12 15 180 12 Serevent Diskus§ Foradil† Atrovent HFA** Atrovent** Long-acting anticholinergic Tiotropium Combinations Ipratropium-albuterol 15 Inhalation Peak Effect (min) 10–17 Xopenex HFA# Long-acting ␤2-agonist Salmeterol Formoterol Short-acting anticholinergic Ipratropium Onset of Action (min) DuoNeb†† Fluticasone-salmeterol Advair Diskus‡ Budesonide-formoterol Symbicort‡‡ — Dosage Formulation MDI; 90 ␮g/puff Nebulized solution 0.083% (3-mL vial); 2.5 ␮g/ dose MDI (aerosol); 90 ␮g/puff MDI (aerosol); 90 ␮g/puff Extended-release oral tablets; 4.0 or 8.0 mg HFA MDI; 120 ␮g/puff MDI; 200 ␮g/puff Nebulized solution (premixed vials); 0.13, 0.63, or 1.25 mg MDI; 45 ␮g/puff (2 puffs/ dose) DPI; 50 ␮g/dose DPI; 12 ␮g/dose HFA or CFC MDI; 21 ␮g/ puff Nebulized solution 0.02% (2.5-mL vial); 500 ␮g DPI; 18 ␮g/dose MDI; ipratropium 18 ␮g ϩ albuterol sulfate 90 ␮g/ puff Nebulized solution (premixed vial); 3-mL vial, 0.5 mg ipratropium ϩ 3.0 mg albuterol DPI; fluticasone 100, 250, or 500 ␮g ϩ salmeterol 50 ␮g MDI; budesonide 80 or 160 ␮g ϩ formoterol 4.5 ␮g/puff CFC ϭ chlorofluorocarbon; DPI ϭ dry-powder inhaler; HFA ϭ hydrofluoroalkane *Information provided per manufacturer prescribing information.13–29 † Schering Corporation, Kenilworth, NJ ‡ GlaxoSmithKline, Research Triangle Park, NC § Muro Pharmaceutical, Inc., Tewksbury, MA ʈ IVAX Laboratories, Inc., Miami, FL ¶ 3M Pharmaceuticals, Northridge, CA # Sepracor Inc., Marlborough, MA **Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT †† Dey, Napa, CA ‡‡ AstraZeneca, Wilmington, DE were also significantly longer in tiotropium-treated patients.32 A recent Cochrane Review report of randomized controlled trials comparing tiotropium with placebo and the short-acting anticholinergic agent ipratropium or the longacting ␤2-agonist salmeterol in patients with COPD found additional studies in which the effect of treatment on QOL was evaluated using the SGRQ.33 In this analysis, tiotropium produced better health outcomes compared with ipratropium or salmeterol.33 The mean change in SGRQ with tiotropium was larger than with placebo (weighted mean difference [WMD], –3.3; 95% CI, – 4.6 to – 0.8) and ipra- Wise and Tashkin Optimizing Treatment of COPD: An Assessment of Current Therapies Figure Long-acting ␤2-agonists reduce the risk for exacerbations in placebo-controlled studies of patients with chronic obstructive pulmonary disease *Formoterol study; †Salmeterol study (Adapted with permission from JAMA.30) S7 In a recent review of the literature, Alsaeedi and colleagues37 identified placebo-controlled, randomized trials of inhaled corticosteroids given to patients with stable COPD for Ն6 months Use of inhaled corticosteroids led to about a 30% reduction in the total number of exacerbations.37 A more recent systematic review of 13 studies by Gartlehner and associates43 reached a similar conclusion Further studies are needed to confirm the reduction in COPD exacerbations seen in these trials of inhaled corticosteroids, to establish effects on mortality, and to identify adverse effects associated with long-term use.37 In this regard, it may be noted that the recent Towards a Revolution in COPD Health (TORCH) study, which is discussed in detail below, has demonstrated mortality benefit with combination therapy using a long-acting ␤2-agonist and a corticosteroid.44 Combination Therapies tropium (WMD, –3.3; 95% CI, –5.6 to –1.0) A smaller, nonsignificant difference was observed for tiotropium compared with salmeterol (WMD, –1.4; 95% CI, –3.2 to 0.4).33 The impact of anticholinergics on mortality is unclear, although a recent systematic review has suggested an improvement with this class of drug.34 Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT), a large, prospective controlled study of tiotropium, will examine this as an important secondary end point.35 Corticosteroids Corticosteroids act at multiple points in the inflammatory process, although their effects in patients with COPD are less evident than in those with asthma In patients with stable COPD, administration of inhaled corticosteroids produces a small increase in postbronchodilator FEV1 and a small reduction in bronchial reactivity.5 Side effects seen with inhaled corticosteroids include skin bruising, oropharyngeal candidiasis, and voice alterations.36 –38 Although dry-powder inhaler (DPI) and inhalation aerosol formulations containing beclomethasone dipropionate (Qvar inhalation aerosol; 3M Pharmaceuticals, Northridge, CA), fluticasone (Flovent Diskus and Flovent HFA inhalation aerosol; GlaxoSmithKline, Research Triangle Park, NC), triamcinolone (Azmacort inhalation aerosol; Kos Pharmaceuticals, Inc., Cranbury, NJ), and budesonide (Pulmicort Turbuhaler; AstraZeneca LP, Wilmington, DE), are approved in the United States for the maintenance treatment of asthma, they are not approved for use as single agents in patients with COPD.38 – 42 Nevertheless, guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend the addition of inhaled corticosteroids to a maintenance regimen of inhaled bronchodilator therapy for symptomatic patients with an FEV1 Ͻ 50% predicted, i.e., stage III COPD (severe) and stage IV COPD (very severe) and repeated exacerbations (e.g., exacerbations in the past years).6 Because of the differences in mechanisms and durations of action, combining drugs from different classes may increase the degree of bronchodilation and provide greater improvements in lung function and symptoms.5,6 For example, because of differences in their modes of action, a combination of a ␤2-agonist and an anticholinergic agent has additive bronchodilator effects.2,45 A combination of the short-acting anticholinergic agent ipratropium and the short-acting ␤2agonist albuterol is available in the United States for inhalation, and another is available for delivery via a nebulizer (Table 1) The duration of effect with the combination is to hours, and the recommended dosing is times daily A long-acting isomer of formoterol (arformoterol tartrate; Brovana, Sepracor Inc., Marlborough, MA) has been recently approved for nebulized administration.46 As noted earlier, a combination of the corticosteroid fluticasone propionate and the long-acting ␤2-agonist salmeterol is also available in the United States, and its duration of effect permits twice-daily administration (Table 1) Two combination products, one with salmeterol and fluticasone and the other with budesonide and long-acting ␤2-agonist formoterol, are available in the United States as DPIs.6,23,24 The combination of the short-acting anticholinergic agent ipratropium and the short-acting ␤2-agonist albuterol delivered by metered-dose inhaler (MDI) as a single aerosol improves lung function more than either agent alone In a 12-week, prospective, double-blind, randomized, parallelgroup study, patients with moderately severe COPD were treated with ipratropium, albuterol, or the combination administered by MDI times daily As shown in Figure 2,47 on all test days, the overall mean percentage change in FEV1 was statistically significantly greater (P Ͻ 0.01 to P ϭ 0.04) with the combination of ipratropium and albuterol than with the individual agents, particularly during the first hours after administration The mean peak percentage increases in FEV1 over baseline on the test days were 31% to 33% with the combination, 24% to 25% with ipratropium alone, and 24% to 27% with albuterol alone.47 S8 Figure Chest.47) The American Journal of Medicine, Vol 120 (8A), August 2007 Improved lung function with combination ipratropium-albuterol versus single-agent therapy (Reprinted with permission from Figure Improved lung function with combination tiotropium-formoterol versus single-agent therapy FEV1 ϭ forced expiratory volume in second (Reprinted with permission from Eur Respir J.48) Enhanced improvement in lung function was also demonstrated with a combination of the long-acting anticholinergic agent tiotropium plus the long-acting ␤2-agonist formoterol compared with either agent given alone.48 In a randomized, double-blind, 3-way crossover study with three 6-week treatment periods, patients with moderate-to-severe COPD (mean FEV1, 37% of predicted) received tiotropium 18 ␮g once daily, formoterol 12 ␮g twice daily, or both administered once daily in separate devices The 24-hour FEV1 profiles for the treatments are shown in Figure 3.48 Compared with the individual agents alone, the combination of tiotropium and formoterol administered once daily in the morning provided significantly greater bronchodilation during the first 12 hours after dosing, as well as sustained improvements during the nighttime Thus, the combination of tiotropium and formoterol provided an additive bronchodilator effect throughout the 24-hour dosing interval.48 A combination of the corticosteroid fluticasone and the long-acting ␤2-agonist salmeterol delivered together via a DPI also provides enhanced improvement of lung function compared with the single agents given alone As shown in Figure 4,49 all active treatments, fluticasone 250 ␮g, salmeterol 50 ␮g, and fluticasone 250 ␮g plus salmeterol 50 ␮g, increased the morning predose FEV1 over the 24-week treatment period At week 1, the increase in predose FEV1 with fluticasone-salmeterol was statistically significantly greater than that observed with either salmeterol alone (P ϭ 0.026) or placebo (P Ͻ0.001), and these differences were sustained throughout the 24-week treatment period.49 At the end point, the increase in FEV1 after treatment with fluticasone-salmeterol was 16.6% more than baseline, which was statistically significantly greater compared with both salmeterol alone (P Ͻ0.001) and placebo (Figure 4) The increase in predose FEV1 at end point for fluticasone alone was 11%, which was statistically significantly greater than that with placebo (P Ͻ0.001) With the exception of an increase in the incidence of oropharyngeal candidiasis in groups receiving fluticasone, the incidence of adverse effects was low and similar across treatment groups.49 Recently, the TORCH study, a 3-year, multicenter, double-blind, placebo-controlled, randomized clinical trial involving 6,112 patients with COPD and a mean 44% predicted postbronchodilator FEV1, compared twice-daily treatment with salmeterol 50 ␮g (n ϭ 1,521), fluticasone Wise and Tashkin Optimizing Treatment of COPD: An Assessment of Current Therapies S9 Figure Improved lung function with combination fluticasone (FP)-salmeterol (SALM) versus single-agent therapy FEV1 ϭ forced expiratory volume in second *FP ϩ SALM, P Ͻ0.001 vs placebo; FP ϩ SALM, P ϭ 0.012 vs SALM; FP vs placebo at end point, P Ͻ0.001 (Reprinted with permission from Chest.49) 500 ␮g (n ϭ 1,534), salmeterol 50 ␮g plus fluticasone 500 ␮g (n ϭ 1,533), or placebo (n ϭ 1,524).44 Preliminary results demonstrated that treatment with combination salmeterol-fluticasone decreased the risk of all-cause mortality over the 3-year period by 17.5% compared with placebo (P ϭ 0.052).44 The mortality benefit seen with the combination was supported by superior improvements compared with the individual active agents and placebo in health status (SGRQ total score), postbronchodilator FEV1, and the frequency of exacerbations.44 A recent large controlled trial in a high-risk population of patients with severe COPD compared a high-dose fluticasone (500 ␮g) plus salmeterol (50 ␮g) combination with salmeterol 50 ␮g, both given twice daily The study authors documented incremental benefit in exacerbation reduction (the primary end point) with the combination therapy.50 THERAPY FOR ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Acute exacerbations of COPD are usually defined as “a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.”51 Acute exacerbations are characterized by an increase of Ն1 chronic symptom, including shortness of breath, cough, sputum production, sputum purulence, and sputum tenacity.52 Approximately 80% of acute exacerbations of COPD are caused by infection with aerobic gram-positive and gramnegative bacteria (40% to 50%), respiratory viruses (30%), or atypical bacteria (5% to 10%) Infection due to Ͼ1 pathogen occurs in 10% to 20% of patients.52 Acute exacerbations of COPD are serious and require prompt, effective intervention by healthcare providers Exacerbations are associated with mortality rates of 2.5% among hospitalized patients in general beds and of up to 25% among patients admitted to intensive care units.53–55 Of patients treated in emergency departments, 22% to 32% relapse after treatment and return after being discharged.56,57 Frequent exacerbations also lead to significant impairment in QOL and more rapid decline in lung function in patients with moderate COPD.58 Most patients with COPD are treated with antibiotics for acute exacerbations A systematic review of randomized controlled trials compared patients with acute COPD exacerbations who received either an antibiotic (for a minimum of days) or placebo In patients whose exacerbations were defined as increased cough and sputum purulence, antibiotic therapy reduced the risks of short-term mortality by 76% (RR, 0.24; 95% CI, 0.10 to 0.57) and of treatment failure by 49% (RR, 0.51; 95% CI, 0.38 to 0.69).59 In addition, antibiotic therapy successfully reduced sputum purulence at end of treatment by 48% (RR, 0.52; 95% CI, 0.37 to 0.72).59 Oral corticosteroids also benefit patients with acute exacerbations of COPD, and should be considered for patients whose baseline FEV1 is Ͻ50% of predicted.10 As shown in Figure 5,60 for patients with uncomplicated acute exacerbations, treatment options include the macrolides, doxycycline, second- or third-generation cephalosporins, or a respiratory quinolone The macrolides azithromycin and clarithromycin possess activity in vitro against Haemophilus influenzae, which is prevalent in active smokers and those with more advanced disease Among the respiratory quinolones, levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, and telithromycin are active against penicillin-resistant Streptococcus pneumoniae, and ciprofloxacin and levofloxacin have enhanced antipseudomonal activity.60 For patients with complicated acute exacerbations who are not at risk of pseudomonal infection, a respiratory quinolone or amoxicillin-clavulanate is an appropriate choice For those at increased risk for infection due to Pseudomonas, however, treatment with an antipseudomonal quinolone (i.e., ciprofloxacin or levofloxacin) is warranted.60 S10 The American Journal of Medicine, Vol 120 (8A), August 2007 Figure Algorithm for the treatment of acute exacerbations of COPD (AECOPD) C pneumoniae ϭ Chlamydia pneumoniae; FEV1 ϭ forced expiratory volume in second; H influenzae ϭ Haemophilus influenzae; H parainfluenzae ϭ Haemophilus parainfluenzae; M catarrhalis ϭ Moraxella catarrhalis; S pneumoniae ϭ Streptococcus pneumoniae (Adapted with permission from Expert Rev Anti Infect Ther.60) NONPHARMACOLOGIC TREATMENT MEASURES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE A variety of nonpharmacologic interventions are also available for patients with COPD, including pulmonary rehabilitation, oxygen therapy, and lung volume reduction surgery.5,6 Pulmonary Rehabilitation Pulmonary rehabilitation can benefit patients at all stages of COPD and should be considered particularly for those with moderate-to-very severe disease (GOLD stages II to IV), who are more likely to have problems such as exercise deconditioning, relative social isolation, altered mood states (e.g., depression), muscle wasting, and weight loss.10 Pulmonary rehabilitation consists of a comprehensive individualized management program that includes medical evaluation and treatment, exercise training, education and collaborative self-management, psychological counseling, and nutritional counseling.5,10 A minimum of months is recommended for pulmonary rehabilitation, although the longer the program continues, the better the results.6 In a randomized, controlled trial, significantly greater improvements in walking distance and QOL were observed in patients assigned to a 6-week multidisciplinary rehabilitation program than in those assigned to standard medical care.61 The magnitude of these effects has been supported by a Wise and Tashkin Optimizing Treatment of COPD: An Assessment of Current Therapies S11 Figure Clinical algorithm for the treatment of chronic obstructive pulmonary disease by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage Clinical stages are defined symptomatically (Reprinted with permission from BMJ.45) systematic review of the literature.62 Combination therapy including pulmonary rehabilitation and tiotropium suggests synergistic effects on exercise capacity.63 surgery in patients with upper lobe–predominant emphysema and high exercise capacity, exercise capacity and QOL were improved.64 Oxygen Therapy Oxygen therapy is usually recommended for patients with very severe COPD (GOLD stage IV) who have arterial oxygen pressure (PaO2) Ͻ55 mm Hg (or oxygen saturation Ͻ 88%) In these individuals, therapy is used to preserve the function of vital organs by increasing the PaO2 to Ն60 mm Hg and the oxygen saturation to Ն90%.6 Longterm administration of oxygen (Ͼ15 hr/day) increases survival and improves hemodynamics, hematologic characteristics, exercise capacity, motor speed, hand grip, and general alertness; the data are less clear about the patient’s emotional state and QOL.10 The role of oxygen therapy in patients with mild hypoxemia remains controversial Surgery Several surgical options are available for patients with very advanced COPD (GOLD stage IV), including lung volume reduction surgery and lung transplantation.6 An updated analysis (4.3 years vs 2.4 years median follow-up) of the National Emphysema Treatment Trial found that patients who underwent bilateral lung volume reduction surgery experienced improved mortality compared with patients treated with medical therapy Furthermore, patients with upper-lobe emphysema and low exercise capacity after pulmonary rehabilitation had particularly impressive long-lasting improvements in survival, exercise capacity, and symptoms after lung volume reduction surgery Although no survival benefit was observed after lung volume reduction TREATMENT ALGORITHM ACCORDING TO GOLD GUIDELINES The GOLD guidelines recommend stepped-care therapy at each stage of COPD, based on the need for symptomatic control.6 The treatment algorithm shown in Figure 645 provides an evidence-based rationale for the appropriate use of specific long-acting bronchodilators in COPD The pathways for inhaled therapy progress from as-needed, short-acting bronchodilators alone in mild COPD (GOLD stage I) to a single long-acting bronchodilator plus a short acting-bronchodilator used as needed in moderate disease (GOLD stage II) The final treatment step for patients with frequent exacerbations or inadequate control of symptoms, despite optimal bronchodilator therapy (GOLD stages III to IV), is a long-acting ␤2-adrenergic agent in combination with a long-acting anticholinergic agent, with or without the addition of inhaled corticosteroids.45 With regard to nonpharmacologic therapy, risk factor avoidance (mainly smoking cessation) and influenza vaccination are recommended for patients with normal spirometry and chronic symptoms, and those with GOLD stages I through IV COPD.6 As noted previously, pulmonary rehabilitation can benefit patients at all but the mildest stages of COPD.10 Oxygen therapy is usually recommended for patients with very severe COPD, and lung volume reduction surgery may benefit patients with upper lobe–predominant S12 emphysema and poor exercise capacity despite rehabilitation.6,10 SUMMARY Bronchodilators are the mainstay of COPD therapy.6,12 Short-acting bronchodilators can be used as needed to relieve persistent or worsening symptoms, whereas long-acting agents can be taken regularly to prevent or reduce symptoms.6 Bronchodilators relax airway smooth muscle and improve emptying of the lungs, and may also improve exercise capacity.12,65 Different bronchodilators with different modes of action and duration of effects are available, including short-acting and long-acting ␤2-agonists and short-acting and long-acting anticholinergic agents Among the ␤2-agonists, salmeterol and formoterol and an extendedrelease oral formulation of albuterol have a duration of effect of up to 12 hours.14,17,18 Clinical trials have shown that these agents reduce the risk for COPD exacerbations and improve QOL in patients with moderate-to-severe disease.30 Currently, the only long-acting anticholinergic agent available is tiotropium, which has a sustained action over 24 hours when taken once daily in the morning.32 Compared with the short-acting anticholinergic agent ipratropium, tiotropium is associated with significantly greater improvements in lung function and dyspnea, a greater reduction in the frequency of exacerbations, and greater improvement in QOL.32,33 Because of their different modes of action, combinations of different agents can have additive therapeutic effects A combination of a ␤2-agonist and an anticholinergic agent has additive bronchodilator effects.2 Clinical studies have shown that the combination of ipratropium and albuterol, as well as tiotropium plus formoterol, are associated with greater improvements in lung function than the individual agents taken alone.47,48 Likewise, a combination of the corticosteroid fluticasone and the long-acting ␤2-agonist salmeterol improves lung function, and preliminary results from a large 3-year clinical trial in patients with severe COPD indicate that this combination improves survival compared with placebo.44,49 Nonpharmacologic treatment modalities can benefit patients at all stages of COPD Pulmonary rehabilitation is particularly beneficial for selected patients who have poor exercise tolerance, nutritional depletion, or social isolation, because it can improve exercise capacity and help them cope with their illness.10 Oxygen therapy is usually recommended for patients with very severe hypoxemia, and it has been shown to increase survival.10 In selected patients with very severe disease, lung volume reduction surgery may provide additional benefit.6,10 For patients at all stages of COPD, a management program that combines both pharmacologic and nonpharmacologic treatment approaches will provide the greatest clinical benefit The American Journal of Medicine, Vol 120 (8A), August 2007 References Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC Chronic obstructive pulmonary disease surveillance—United States, 19712000 MMWR Surveill Summ 2002;51:1–16 Tashkin DP, Cooper CB The role of long-acting bronchodilators in the management of stable COPD Chest 2004;125:249 –259 Jemal A, Ward E, Hao Y, Thun M Trends in the leading causes of death in the United States, 1970-2002 JAMA 2005;294:1255–1259 National Heart, Lung, and Blood Institute, National Institutes of Health Chronic obstructive pulmonary 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medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group Ann Thorac Surg 2006;82:431– 443 65 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, 2006 Available at: http://www goldcopd.org/Guidelineitem.asp?l1ϭ2&l2ϭ1&intIdϭ989 Accessed January 31, 2007  ... magnitude of these effects has been supported by a Wise and Tashkin Optimizing Treatment of COPD: An Assessment of Current Therapies S11 Figure Clinical algorithm for the treatment of chronic obstructive. .. stable chronic obstructive pulmonary disease Cochrane Database Syst Rev 2005;(2):CD002876 34 Salpeter SR, Buckley NS Systematic review of clinical outcomes in chronic obstructive pulmonary disease:... survival in chronic obstructive pulmonary disease N Engl J Med 2007;356:775–789 45 Cooper CB, Tashkin DP Recent developments in inhaled therapy in stable chronic obstructive pulmonary disease BMJ