Abstract: Although smoking cessation is still the most impor- tant intervention in chronic obstructive pulmonary disease (COPD), a variety of pharmacologic therapies are available to help manage symptoms. Short-acting ß2-agonists and/or ipratropium should be taken as needed, and the use of additional therapies is based on the severity of disease. Patients with moderate or severe COPD should regularly take 1 or more long-acting bronchodilators. The long-acting ß2-agonists salmeterol and formoterol have been demonstrated to improve health-related quality of life. Newer therapies include the long-acting anticholinergic tiotropium and a salmeterol-fluticasone combination. These agents improve forced expiratory volume in 1 second and may reduce the rate of acute exacerbations. For patients with moderate to very severe COPD, participation in a pulmonary rehabilitation program can improve health status, quality of life, and exercise tolerance. (J Respir Dis. 2005;26(7):284-289)
Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death and the second leading cause of disability (behind heart disease) in the United States.1,2 However, unlike heart disease, which kills more men than women each year, the COPD mortality rate among women surpassed that of men in 2000.2 Unfortunately, the mortality rates for both men and women with COPD are continuing to rise at an alarming rate (Figure 1). COPD is projected to be the third lead- ing cause of death worldwide by 2020.3
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines were developed through a collaboration of the World Health Organization and the National Heart, Lung, and Blood Institute and are the result of a worldwide effort to develop evidence-based guidelines for COPD.4 The 4 main components of the GOLD guidelines include how to:
Assess and monitor the disease.
Reduce risk factors.
Treat patients who have stable COPD.
In a 2-part article, I will use the principles contained in the GOLD guidelines to provide practical information for managing the most important problems that are associated with COPD. In part 1, I will discuss assessment and treatment options for stable COPD. In a second article, to be published in a coming issue of The Journal of Respiratory Diseases, I will review the management of acute exacerbations of COPD.
ASSESSING AND MONITORING COPD
The first step in successfully managing COPD involves correctly diagnosing the condition. COPD has been classically defined as 1 of 2 conditions: emphysema (a pathologic diagnosis, consisting of destroyed alveoli) and chronic bronchitis (a clinical definition, consisting of a productive cough in which sputum is produced on most days for 3 months for 2 consecutive years and other causes of chronic cough have been excluded).
Most patients with COPD have a mixture of these 2 conditions and are not likely to present as a typical "pink puffer" (a patient with pure emphysema) or a typical "blue bloater" (a patient with pure chronic bronchitis). In fact, most patients with COPD have some elements of both emphysema and chronic bronchitis and cannot be identified by their physical appearance. Most patients appear normal and frequently do not complain of many respiratory symptoms until their disease is very advanced.
It is important to screen patients for COPD, particularly those 40 years or older who have risk factors for the disease, such as a history of smoking. Because the diagnosis is only suggested by symptoms and the patient's physical appearance is often normal, the GOLD guidelines (as well as guidelines by the American Thoracic Society and the European Respiratory Society) state that the diagnosis of COPD must be confirmed by spirometry.4,5
The currently accepted definition of COPD is airflow limitation that is not fully reversible, confirmed by spirometry.4,5 This airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious stimuli (predominantly cigarette smoke).
In the past, the airflow limitation was described as "irreversible"; however, we now know that this is not correct. Some investigators have found that as many as 70% of patients with COPD have a significant degree of reversibility at some point when tested repeatedly with pre- and post-bronchodilator challenges.6 However, the lung function of patients with COPD does not return to normal after bronchodilator challenge, as it does in many patients with asthma. Therefore, the airflow limitation in COPD is said to be "not fully reversible."
The severity of COPD is based on the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC).4 Patients with COPD classified as stage 0 have a normal FEV1 and a normal FEV1:FVC, but they have respiratory symptoms and risk factors (such as smoking). Patients with COPD classified as stage I, II, III, or IV have an FEV1:FVC of less than 70%, and staging is based on the FEV1. The FEV1 cutoff points are used for simplicity but have not been clinically validated. FEV1 does not consistently predict disability or mortality among patients with COPD, but it is useful for guiding therapy.4
Patients with very severe COPD (stage IV with an FEV1 of less than 30% of predicted) should be screened for the need for long-term supplemental oxygen therapy.4
The number one risk factor for COPD is tobacco smoking. Cigarette smoke is associated with more than 90% of cases of COPD in the United States. Other risk factors, which are more common in other countries, involve exposure to wood-burning stoves; smoke from repeatedly burning trash; and cer-tain pollutants, occupational dusts, chemicals, and infections.4
The best-documented genetic risk factor associated with COPD is a1-antitrypsin deficiency. The extent and severity of emphysema and the rate of decline in lung function are highly variable among patients with this hereditary condition. However, smoking considerably increases the risk and severity. The most common characteristics of a1-antitrypsin deficiency are early age at onset (usually younger than 40 years) and the presence of lower lobe bullae.
TREATING PATIENTS WITH STABLE COPD
The long-term management of COPD is focused on improving symptoms and preventing complications. COPD not only affects the lungs but also produces significant systemic consequences. Although the management of COPD is largely based on disease severity, there are some points that should be applied to all patients.
First, all patients with COPD, regardless of severity, should receive counseling on either smoking cessation (for active smokers) or the importance of remaining abstinent (for former smokers).4 Smoking cessation is the most effective way to reduce the natural decline in pulmonary function that occurs with aging.
Since successfully quitting smoking is so difficult, many clinicians have a nihilistic attitude about talking with their patients about smoking cessation. However, approximately 5% of patients will quit smoking simply because their health care provider tells them that it is the best thing that they can do for their health.7
One method that can be used to help motivate patients to quit smoking involves explaining the graph from the 1977 Fletcher and Peto8 article (Figure 2). I first explain that FEV1 is the amount of air that a person blows out in the first second during a "breathing test." I further explain that this number gives us a general idea of how well the lungs are working.
The patient may be significantly more motivated to quit smoking once he or she understands the following points: all persons, regardless of smoking status, lose lung function starting at the age of about 25 years; a patient with COPD who continues to smoke loses lung function at 2 to 3 times the rate of a nonsmoker; and most importantly, as soon as he quits smoking, this decline in lung function slows and returns to about the rate of decline of a nonsmoker. Therefore, I emphasize that for a smoker with COPD, it is never too late to quit smoking and that smoking cessation is the single most important intervention to slow the rate of decline in lung function.8,9
In addition to smoking cessation, influenza vaccination is recommended for all patients with COPD, regardless of severity. The influenza vaccine may reduce serious morbidity and death in these patients.4,10 Although the data are much weaker regarding the benefits of the pneumococcal vaccine, most pulmonologists recommend that all patients with COPD receive this vaccine as well (this recommendation is not included in the GOLD guidelines because of insufficient evidence).
Similar to the recommendations for the management of asthma, COPD should be managed in a stepwise fashion by adding therapies as the severity increases and as symptoms worsen (Table 1).4
Stage I (mild COPD): Patients with stage I disease often do not have respiratory symptoms. When respiratory complaints are present, short-acting bronchodilators (ß2-agonists and anticholinergics such as ipratropium bromide) should be prescribed as needed to help reduce symptoms and improve exercise tolerance.4 However, these agents have not been shown to modify the clinical course, the rate of decline in pulmonary function, or survival in patients with COPD.4,9,11,12
Stage II (moderate), stage III (severe), and stage IV (very severe): Patients with stage II, III, or IV COPD should be given one or more long-acting bronchodilators to be taken regularly, in addition to the as-needed short-acting bronchodilator(s).4
Long-acting inhaled medications
Unlike the short-acting bronchodilators, which can be taken as needed, the long-acting inhaled medications should be taken on a scheduled basis to produce optimal effects.
Long-acting ß2-agonists: These agents were introduced several years ago to provide longer-lasting bronchodilation and more effective improvement in lung function than the short-acting bronchodilators (Table 2). Salmeterol and formoterol are both approved by the FDA for bronchodilation in COPD. The dosage for salmeterol is 50 µg bid. The dosage for formoterol is 12 to 24 µg bid.
Salmeterol and formoterol have been shown in clinical trials to improve health-related quality of life, but not mortality, in patients with COPD. Nine placebo-controlled clinical trials involving these agents demonstrated an overall 21% reduction in acute exacerbations of COPD.
Inhaled corticosteroids: The GOLD guidelines state that inhaled corticosteroids (ICS) may be used for patients with frequent acute exacerbations of COPD and severe or very severe disease.4 This recommendation is based on the combined results of several clinical trials that suggest a reduction of acute exacerbations of COPD in patients treated with ICS.12 However, these trials were not designed or powered to study acute exacerbations as a primary end point; therefore, the FDA does not consider this evidence conclusive enough to approve any of the ICS as a single agent for the management of COPD.
Long-acting ß2-agonists plus ICS: The FDA has approved a combination of salmeterol and fluticasone for bronchodilation, but only in patients with chronic bronchitis, because chronic bronchitis was one of the inclusion criteria in the sentinel study.13 This does not necessarily mean that the combination agent is ineffective in COPD patients who do not have chronic bronchitis. This agent has been shown to improve FEV1 by an average of 150 to 200 mL above placebo, but it does not alter the rate of decline in FEV1.12,13 Three clinical trials (involving 2951 patients) demonstrated that the combination of a long-acting ß2-agonist and ICS is associated with lower exacerbation rates compared with monotherapy with a long-acting ß2-agonist or with placebo.12 The recommended dosage is 250 µg of fluticasone and 50 µg of salmeterol bid.
Long-acting anticholinergic: Tiotropium is an anticholinergic agent that has a very long half-life and, therefore, is given only once a day. The dosage is 18 µg daily. This agent has been shown in clinical trials to improve FEV1 significantly more (by a mean of approximately 150 to 200 mL) than either placebo or ipratropium at the end of 6 months to 1 year.12 A meta-analysis of 5 published clinical trials (3574 patients with moderate to severe COPD) has uniformly demonstrated that tiotropium reduces acute exacerbation rates compared with either placebo or ipratropium.12
In addition, a large placebo-controlled trial of veterans with COPD by Niewoehner and associates14 demonstrated a significant reduction (about 25%) in acute exacerbations in those who received tiotropium. Although tiotropium has not yet been approved by the FDA for this indication, it is approved for bronchodilation in patients with COPD.
Pulmonary rehabilitation: Patients with stage II disease and higher (moderate to very severe COPD) have been shown to benefit from participation in a pulmonary rehabilitation program.12,15 Although these pulmonary rehabilitation programs have not been demonstrated to improve survival or reduce hospitalization rates, these programs do improve health status, quality of life, and exercise tolerance in patients with moderate to very severe COPD.
Supplemental oxygen: As noted above, patients with stage IV COPD (FEV1 of less than 30% of predicted) should be screened for the need for supplemental oxygen.4 Supplemental oxygen has been convincingly demonstrated to improve survival in COPD patients who have chronic hypoxemia at rest.16,17 The most important thing to emphasize to these patients is that to obtain the survival benefit, they must use supplemental oxygen for more than 15 to 18 hours per day.16,17
Although the qualifying criteria for home oxygen therapy may differ slightly from one area to another, the Medicare criteria include at least 1 of the following: resting pulse oximetry of 88% or less; exercise pulse oximetry that falls by at least 4% and is 88% or less; resting PaO2 of less than 55 mm Hg; or resting PaO2 of less than 60 mm Hg with evidence of pulmonary hypertension, peripheral edema (suggesting congestive heart failure), or polycythemia (with a hematocrit value greater than 55%).
Surgery: Patients with very severe COPD may benefit from surgical intervention. Three well-conducted clinical trials (involving 1321 patients) demonstrated that lung volume reduction surgery (LVRS) improves health-related quality of life and exercise tolerance in patients who have an FEV1 of less than 30% of predicted.12
The short-term mortality rate is higher in patients who undergo LVRS than in those who receive only medical therapy, and the 5-year mortality rate is not significantly different between the 2 groups.12 However, based on the results of the recently completed National Emphysema Treatment Trial, LVRS may be considered in carefully selected patients with heterogeneous lung disease (upper lobe bullae) who do not significantly improve with an intensive pulmonary rehabilitation program (low exercise capacity).18
Lung transplantation is another potential surgical intervention for patients with very severe COPD who do not have significant comorbidities. It is important for clinicians and patients to understand that lung transplantation does not prolong life, but it has the potential to significantly improve the quality of life in patients with very severe COPD who have an extremely limited functional status because of dyspnea with minimal exertion.19
[Editor's note: In a coming issue of The Journal of Respiratory Diseases, Dr Adams will discuss the management of acute exacerbations of COPD.]
1. National Institutes of Health. National Heart, Lung, and Blood Institute. Morbidity and mortality: 2002 chart book on cardiovascular, lung and blood diseases. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002.
2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance--United States, 1971-2000.
3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study.
4. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med.2001;163:1256-1276.
5. 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. Eur Respir J. 2004; 23:932-946.
6. Calverley PM, Burge PS, Spencer S, et al. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax.2003; 58:659-664.
7. Lindholm LH, Ekbom T, Dash C, et al. The impact of health care advice given in primary care on cardiovascular risk. CELL Study Group. BMJ.1995;310:1105-1109.
8. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977;1: 1645-1648.
9. 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;272:1497-1505.
10. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med.1994;331:778-784.
11. Rennard SI, Calverley P. Rescue! Therapy and the paradox of the Barcalounger. Eur Respir J. 2003;21:916-917.
12. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA. 2003;290:2301-2312.
13. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest.2003;124:834-843.
14. Niewoehner D , Rice K, Cote C, et al. Reduced COPD exacerbations and associated health care utilization with once-daily tiotropium (TIO) in the VA Medical System. Am J Respir Crit Care Med. 2004;169:A207.
15. Ries AL. Position paper of the American Association of Cardiovascular and Pulmonary Rehabilitation. Scientific basis of pulmonary rehabilitation. J Cardiopulm Rehabil.1990;10: 418-441.
16. Global Initiative for Chronic Obstructive Lung Disease. GOLD teaching slide kit. Available at: http://www.goldcopd.com. Accessed June 6, 2005.
17. Report of the Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet.1981;1:681-686.
18. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med.2003;348: 2059-2073.
19. Hosenpud JD, Bennett LE, Keck BM, et al. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet.1998;351:24-27.