Treatment of the Stable Patient with Chronic Obstructive Pulmonary Disease

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Chapter 42 Treatment of the Stable Patient with Chronic Obstructive Pulmonary Disease

Bartolome R. Celli

The airflow obstruction of chronic obstructive pulmonary disease (COPD), as defined by the forced expiratory volume in 1 second (FEV₁), is thought to be only partially irreversible. This physiologic fact has been perpetuated over the years and has generated an unjustified negativist therapeutic attitude in many health care providers. The evidence suggests that the airflow obstruction of COPD does reverse with therapy, and that therapies aimed at the extrapulmonary manifestations of the disease do improve patient outcomes. An optimistic attitude toward these patients helps relieve fears and misconceptions. In contrast to many other diseases, some forms of intervention in COPD improve survival, such as smoking cessation, long-term oxygen therapy in hypoxemic patients, lung volume reduction surgery in certain patients with inhomogeneous upper lobe emphysema, and even pharmacologic therapy. Other interventions, such as pulmonary rehabilitation, lung transplantation, and bronchodilator therapy, improve symptoms and the quality of a patient’s life once the diagnosis of COPD has been established.

Box 42-1 summarizes the available therapeutic options for patients with COPD. This chapter reviews medical management of COPD that centers on three goals: (1) prevent deterioration in lung function, (2) alleviate symptoms, and (3) treat complications as they arise. Once diagnosed, patients with COPD should be encouraged to participate actively in their management; collaborative management improves their self-reliance and self-esteem. All patients should be encouraged to lead a healthy life and exercise regularly. Preventive care is extremely important, and all patients should receive immunizations, including pneumococcal vaccine every 5 years and yearly influenza vaccine. Figure 42-1 provides an algorithm detailing this comprehensive approach.

Figure 42-1 Algorithm describing the comprehensive management of patients with chronic obstructive pulmonary disease. FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; BODE, body mass index, degree of airflow obstruction and dyspnea, and exercise capacity; BMI, body mass index; MMRC, Modified Medical Research Council Scale; 6MWD, 6-minute walking distance.

Multicomponent Disease

Increasing evidence shows that independent of the degree of airflow limitation, the lung volumes are important in the development of symptoms in patients with more advanced COPD. Studies have demonstrated that dyspnea perceived during exercise, including walking, more closely relates to development of dynamic hyperinflation than to changes in FEV₁. Further, the improvement in exercise brought about by several therapies, including bronchodilators, oxygen, lung reduction surgery, and even rehabilitation, is more closely related to delaying dynamic hyperinflations than by changing the degree of airflow obstruction. Hyperinflation, expressed as the ratio of inspiratory capacity to total lung capacity, was shown to predict survival better than the FEV₁. This not only provides new insights into pathogenesis, but also opens the door for novel ways to alter lung volumes and perhaps impact COPD progression.

The association between COPD and important systemic manifestations in patients with more advanced disease is now accepted. Because of a persistent systemic inflammatory state or other, yet-unproven mechanisms (e.g., imbalanced oxidative stress, abnormal immunologic or reparative response), many patients with COPD may have decreased fat-free mass (FFM), impaired systemic muscle function, anemia, osteoporosis, depression, pulmonary hypertension, and cor pulmonale, all of which are important determinants of outcome. Indeed, dyspnea measured with a simple tool such as the UK Modified Medical Research Council (MMRC) scale, the body mass index (BMI; kg/m²), and the 6-minute walking distance (6MWD) are all better predictors of mortality than the FEV₁. The incorporation of these variables into the multidimensional BODE index (BMI, airflow obstruction, dyspnea, exercise capacity) predicts survival even better. The BODE index is also responsive to exacerbations and, more importantly, acts as a surrogate marker of future outcome after interventions, thus providing clinicians with a useful tool to help determine the comprehensive severity of the disease. Other multidimensional indices (e.g., age, dyspnea, and obstruction [ADO]; dyspnea, obstruction, smoking, and exacerbation [DOSE]), have also shown important outcome predictive capacity and could be used to test novel forms of therapy.

Based on the multidimensional nature of COPD and the availability of multiple effective therapies, the approach shown in Figure 42-1 may more accurately help clinicians evaluate patients and choose therapies than the current approach, using primarily the FEV₁ percentage from reference values.

Treatable Disease

Current evidence suggests that besides smoking cessation, long-term oxygen therapy in hypoxemic patients, mechanical ventilation in acute respiratory failure, and lung volume reduction surgery for patients with upper lobe emphysema and poor exercise capacity improve survival. The TORCH study (Towards a Revolution in COPD Health) in more than 6000 patients showed not only that the combination of salmeterol and fluticasone improved lung function and health status, but also that the relative mortality risk over the 3 years of the study decreased by 17.5%. This is not exclusive of this drug combination; the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study also observed a decrease in mortality risk over 4 years in patients taking tiotropium, a long-acting anticholinergic. Other therapies, such as pulmonary rehabilitation and lung transplantation, improve symptoms and quality of life (QOL) once the diagnosis has been established.

Respiratory Manifestations

Once diagnosed, the patient with COPD should be encouraged to participate in disease management, confident that if not cured, COPD can certainly be treated.

Smoking Cessation and Smoke Pollutants

Smoking is the major cause of COPD, and thus smoking cessation is the most important component of therapy for patients who still smoke. Because secondhand smoke is known to damage lung function, limitation of exposure to involuntary smoke, particularly in children, should be encouraged.

Many factors cause patients to smoke, including the addictive nature of nicotine, conditional responses to stimuli surrounding smoking, psychosocial problems such as depression, poor education and low income, and forceful advertising campaigns. Therefore, smoking cessation programs should also involve multiple interventions. The clinician should always participate in the treatment of smoking addiction, because a physician’s advice and the appropriate medications (nicotine patch, gum, or inhalers; bupropion; varenicline) help obtain successful results.

Decreased Exposure to Biomass Fuel

The significant burden of COPD in patients exposed to biomass fuel in certain areas of the world should improve by changing to more efficient and less polluting sources of energy.

Pharmacologic Therapy of Airflow Obstruction

Most patients with COPD require pharmacologic therapy. This should be organized according to the severity of symptoms, the degree of lung dysfunction, and the tolerance of the patient to specific drugs. A stepwise approach similar to that developed for systemic hypertension may be helpful, because medications alleviate symptoms, improve exercise tolerance and QOL, and may decrease mortality. Tables 42-1 and 42-2 summarize the evidence supporting the effect of individual and combined therapies on outcomes of importance in patients with COPD. Because most patients with COPD are elderly, care must be taken when prescribing drugs for this population. Comorbidities are frequently present in patients with COPD, mandating caution to ensure that therapy takes these into account.

Table 42-1 Effect of Single Pharmacologic Agents on Important Outcomes in Chronic Obstructive Pulmonary Disease Patients

Table 42-2 Effect of Combined Pharmacologic Agents on Important Outcomes in Chronic Obstructive Pulmonary Disease Patients

Bronchodilators

Several important concepts guide the use of bronchodilators. In some patients, changes in FEV₁ may be small, and the symptomatic benefit may result from other mechanisms, such as a decrease in hyperinflation of the lung. Some older COPD patients cannot effectively activate metered dose inhalers (MDIs), and clinicians should work with the patient to achieve mastery of the MDI. If this is not possible, use of a spacer or nebulizer to facilitate inhalation of the medication will help achieve the desired results. Mucosal deposition in the mouth will result in local side effects (e.g., thrush with inhaled steroids) or general absorption and its consequences (e.g., tremor after β₂-agonists). The inhaled route is preferred over oral administration, and long-acting bronchodilators are more effective than short-acting agents. The currently available bronchodilators are described next.

Beta₂-Agonists

The β₂-adrenoceptor agonists increase cyclic adenosine monophosphate (cAMP) within many cells and promote airway smooth muscle relaxation. Other nonbronchodilator effects have been observed, but their significance is uncertain. In the minority of COPD patients with mild intermittent symptoms, it is reasonable to initiate drug therapy with an MDI of a short-acting β₂-agonist as needed for relief of symptoms. Patients with persistent symptoms should receive long-acting β₂-agonists twice daily or once daily if the new ultra-long-acting agents are available. These prevent nocturnal bronchospasm, increase exercise endurance, and improve QOL. The safety profile of salmeterol in the TORCH trial and formoterol fumarate in the SUN and SHINE studies, as well as that of the longer-acting indacaterol, is reassuring to clinicians, who frequently prescribe selective long-acting β₂-agonists for their patients with COPD.

Anticholinergics

Anticholinergic drugs act by blocking muscarinic receptors known to be functional in COPD. The appropriate dosage of the short-acting ipratropium bromide is 2 to 4 puffs three or four times daily, but some patients require and tolerate larger doses. The therapeutic effect is a decrease in exercise-induced increased lung inflation or dynamic hyperinflation. The long-acting tiotropium (Spiriva) is effective in inducing prolonged bronchodilation and decreasing lung volume in patients with COPD. In addition, tiotropium improves dyspnea, decreases exacerbations, and improves health-related QOL compared with placebo and even ipratroprium. The results of the large UPLIFT trial confirmed the effectiveness of tiotropium as a disease-modifying agent in that it improved QOL, decreased exacerbation rate, and provided more bronchial dilation when used with regular treatment. These results place tiotropium as a good first-line agent for COPD patients with persistent symptoms. Other new long-acting anticholinergic agents, such as aclidinium bromide and glycopyrrolate, are being developed and will become available to clinicians worldwide.

Phosphodiesterase Inhibitors

Theophylline is a nonspecific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle. The bronchodilator effects of these drugs are best seen at high doses, which also carry a higher risk of toxicity. Theophylline’s potential for toxicity has led to a decline in its popularity. Theophylline is of particular value for less compliant or less capable patients who cannot use aerosol therapy optimally. The previously recommended therapeutic serum levels of 15 to 20 mg/dL are too close to the toxic range and are frequently associated with side effects. Therefore, a lower target range of 8 to 13 mg/dL is safer and still therapeutic in nature. Some research suggests that theophylline could help reestablish the corticosteroid sensitivity that appears to be absent in patients with COPD.

The specific phosphodiesterase E4 (PDE4) inhibitor roflumilast has antiinflammatory and bronchodilator effects, with minimal gastrointestinal irritation. Roflumilast has proved useful in decreasing exacerbations in COPD patients with cough and sputum production.

Other Antiinflammatory Therapy

In contrast to their value in asthma management, antiinflammatory drugs have not been documented to have a significant role in the routine treatment of patients with stable COPD. Cromolyn and nedocromil have not been established as useful agents, although they could possibly be helpful if the patient has associated respiratory tract allergy. One study using monoclonal antibodies against interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) failed to detect a response. However, patients were selected according to the degree of airflow obstruction, not the presence or level of the specific targeted molecule. The groups of leukotriene inhibitors useful in asthma have not been adequately tested in COPD, so a conclusion about their potential use cannot be drawn.

Corticosteroids

Glucocorticoids act at multiple points within the inflammatory cascade, although their effects in COPD appear to be more modest compared with bronchial asthma. In outpatients, COPD exacerbations necessitate a course of oral steroids, as discussed later, but it is important to wean patients quickly; older COPD patients are susceptible to complications such as skin damage, cataracts, diabetes, osteoporosis, and secondary infections. These risks do not accompany standard doses of inhaled corticosteroid aerosols, which may cause thrush but pose a negligible risk for other outcomes, such as cataract and osteoporosis.

Several large multicenter trials evaluated the role of inhaled corticosteroids (ICS) in preventing or slowing the progressive course of symptomatic COPD. The results of these earlier studies showed minimal, if any, benefits in the rate of decline of lung function. On the other hand, in the one study that evaluated it, inhaled fluticasone decreased exacerbations and the rate of loss of health-related QOL. Recent retrospective analysis of large databases suggesting a possible effect of ICS on improving survival was not confirmed in the TORCH trial, in which the ICS-only arm did not show improved survival compared with placebo, whereas the combination arm was significantly more effective than ICS alone. In TORCH the combination was superior in terms of all outcomes evaluated. Along with the more frequent development of pneumonia in the patients receiving ICS, this suggests that ICS should not be prescribed alone but rather with a long-acting β₂-agonist (LABA).

Combination Therapy

All the studies on combinations of agents show significant improvements over single agents alone, and clinicians should now consider combination therapy as first-line therapy. Initially, the combination of inhaled ipatroprium and albuterol proved effective in the management of COPD. More recently, the combination of tiotropium and formoterol, even when administered once daily, was almost as effective as tiotropium once daily added to the recommended twice-daily dose of formoterol. Similarly, the combination of theophylline and salmeterol was significantly more effective than either agent alone.

The TORCH study showed better effects of the salmeterol-fluticasone combination on survival, FEV₁

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