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Quick Test posted on 3.6.12:
| Pharmacotherapy of Chronic Obstructive Pulmonary Disease (COPD)
| Pharmacologic Therapy
Results from numerous recent clinical trials have improved insight and understanding about the respective roles of various medications used in chronic COPD management; yet, some controversies still exist related to both effectiveness and safety. In contrast to the survival benefit conferred by supplemental oxygen therapy, there is no medication available for the treatment of COPD that has been shown to modify the progressive decline in lung function or prolong survival. There is limited evidence that chronic treatment with long-acting inhaled β-agonists, inhaled corticosteroids, or the combination can reduce the rate of decline in spirometry in a subset of patients with more severe disease. Currently, the primary goal of pharmacotherapy is to control patient symptoms and reduce complications, including the frequency and severity of exacerbations and improving the overall health status and exercise tolerance of the patient.
International guidelines recommend a stepwise approach to the use of pharmacotherapy based on disease severity, which is determined by the extent of airflow limitation and degree of symptoms. The impact of recurrent exacerbations on accelerating disease progression is increasingly recognized as an important factor to be considered. The primary goals of pharmacotherapy are to control symptoms (including dyspnea), reduce exacerbations, and improve exercise tolerance and health status. Currently, there is inadequate evidence to support the use of more aggressive pharmacotherapy early in the course of disease because of the lack of a disease modifying benefit. Because of the progressive nature of COPD, pharmacotherapy tends to be chronic and cumulative and step down approaches in stable patients are not successful. Patients exhibit variable responses to available therapies and the treatment approach should be individualized.
Pharmacotherapy of COPD typically involves the use of inhaled medications, requiring patient knowledge, understanding, and skills using the various inhalation devices. Several delivery devices are available (e.g., metered-dose inhalers, dry powder inhalers, nebulizers, and ancillary devices such as holding chambers), and the instructions about proper use vary. Comorbidities that are common for patients with COPD, including physical and mental conditions, can have a significant effect on the patient's ability to use the devices. Periodic and frequent reinforcement and observation by the clinician is required for the patient's benefit.
Pharmacotherapy focuses on the use of bronchodilators to control symptoms. Bronchodilators relax bronchial smooth muscle, improve lung emptying, reduce thoracic hyperinflation at rest and during exercise, and improve exercise tolerance. These effects can be seen in the absence of objective improvements on spirometry. There are several classes of bronchodilators to choose from, and no single class has been proven to provide superior benefit over other available agents. The initial and subsequent choice of medications should be based on the specific clinical situation and patient characteristics. Medications can be used as needed or on a scheduled basis depending on the clinical situation, and additional therapies should be added in a stepwise manner depending on the response and severity of disease. Considerations should be given to individual patient response, tolerabilility, adherence, and economic factors. A stepwise approach to the management of COPD has been proposed based on the stage of disease severity (Fig. 34-3).
|  | | Figure 34–3. Recommended therapy of stable COPD. (FEV1, forced expiratory volume in the first second of expiration; FVC, forced vital capacity.) |
| First-Line Treatment
Systemic chemotherapy with a taxane and platinum regimen following optimal surgical debulking is the standard of care for treatment of epithelial ovarian cancer (Fig. 141–3). Table 141–1 summarizes the chemotherapeutic regimens used as the initial treatment of newly diagnosed epithelial ovarian cancer. More than 60 randomized, controlled clinical trials have evaluated combination chemotherapy regimens for the treatment of advanced ovarian cancer, and a meta-analysis of these trials confirmed the efficacy of platinum and taxane regimens over other regimens.
| According to the guidelines, patients with intermittent symptoms should be treated with short-acting bronchodilators. When symptoms become more persistent, long-acting bronchodilators should be initiated. For patients with an FEV1 less than 50% and who experience frequent exacerbations, inhaled corticosteroids should be considered. Short-acting bronchodilators relieve symptoms and increase exercise tolerance. Long-acting bronchodilators relieve symptoms, reduce exacerbation frequency, and improve quality of life and health status. Patients have a variety of choices in using inhalational therapies, including metered dose inhalers (MDI), dry powder inhalers (DPI), or nebulizers. There is not a clear advantage of one delivery method over another, and it is recommended that patient-specific factors and preferences should be considered in selecting the device.
| Bronchodilators
Bronchodilator classes available for the treatment of COPD include β2-agonists, anticholinergics, and methylxanthines. There is no clear benefit to one agent or class over others, although inhaled therapy generally is preferred. In general, it can be more difficult for patients with COPD to use inhalation devices effectively compared with other populations owing to advanced age and the presence of other comorbidities. Clinicians should advise, counsel, and observe patient technique with the devices frequently and consistently.
Bronchodilators generally work by reducing the tone of airway smooth muscle (relaxation), thus minimizing airflow limitation. For patients with COPD, the clinical benefits of bronchodilators include increased exercise capacity, decreased air trapping in the lungs, and relief of symptoms such as dyspnea. However, use of bronchodilators may not be associated with significant improvements in pulmonary function measurements such as FEV1. In clinical studies, regular use of a long-acting inhaled bronchodilator (LABA or Anticholinergic) or ipratropium are associated with improved health status. Regular use of tiotropium also reduces exacerbation rates. In general, side effects of bronchodilator medications are related to their pharmacologic effects and are dose dependent. Because COPD patients are older and more likely to have comorbid conditions, the risk for side effects and drug interactions is higher compared with patients with asthma.
| Short-Acting Bronchodilators
The initial therapy for COPD patients who experience symptoms intermittently are short-acting bronchodilators. Among these agents, the choices are a short-acting beta2 agonist or an anticholinergic. Either class of agents has a relatively rapid onset of action, relieves symptoms, and improves exercise tolerance and lung function. In general, both classes are equally effective.
| Short-Acting Sympathomimetics (β-Agonists)
A number of sympathomimetic agents are available in the United States. They vary in selectivity, route of administration, and duration of action. In COPD management, sympathomimetic agents with β2-selectivity, or β2-agonists, should be used as bronchodilators. β2-Agonists cause bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). cAMP is responsible for mediating relaxation of bronchial smooth muscle, leading to bronchodilation. In addition, they may improve mucociliary clearance. Although shorter-acting and less selective β-agonists are still used widely (e.g., metaproterenol, isoetharine, isoproterenol, and epinephrine), they should not be used owing to their shorter duration of action and increased cardiostimulatory effects. Short-acting, selective β2-agonists such as albuterol, levalbuterol, and pirbuterol are preferred for therapy.
Sympathomimetics are available in inhaled, oral, and parenteral dosage forms. The preferred route of administration is by inhalation. The use of oral and parenteral β-agonists in COPD is discouraged because they are no more effective than a properly used metered-dose inhaler (MDI) or dry-powder inhaler (DPI), and the incidence of systemic adverse effects such as tachycardia and hand tremor is greater. Administration of β2-agonists in the outpatient and emergency room settings via inhalers (MDIs or DPIs) is at least as effective as nebulization therapy and usually favored for reasons of cost and convenience. Chapter 33 includes a complete description of the devices used for delivering aerosolized medication and a comparison β2-agonist therapies.
Albuterol is the most frequently used β2-agonist. It is available as an oral and inhaled preparation. Albuterol is a racemic mixture of (R)-albuterol, which is responsible for the bronchodilator effect, and (S)-albuterol, which has no therapeutic effect. (S)-Albuterol is considered by some clinicians to be inert, whereas others believe that it may be implicated in worsening airway inflammation and antagonizing the response to (R)-albuterol. Levalbuterol is a single-isomer formulation of (R)-albuterol. A retrospective evaluation of levalbuterol versus albuterol use for patients with asthma and COPD concluded that levalbuterol offered significant advantages over albuterol for hospitalized patients. Other clinicians feel that there are no significant differences between the products and that the use of levalbuterol is not justified owing to its higher acquisition cost. The effects of a single dose of levalbuterol have been compared with those of albuterol and ipratropium plus albuterol for patients with COPD. No significant differences in pulmonary function improvements or adverse effects were noted.
In COPD patients, β2-agonists exert a rapid onset of effect, although the response generally is less than that seen in asthma. Short-acting inhaled β2-agonists cause only a small improvement in FEV1 acutely but may improve respiratory symptoms and exercise tolerance despite the small improvement in spirometric measurements. Patients with COPD can use quick-onset β2-agonists as needed for relief of symptoms or on a scheduled basis to prevent or reduce symptoms. The duration of action of short-acting β2-agonists is 4 to 6 hours.
Inhaled β2-agonists are generally well tolerated. They can cause sinus tachycardia and rhythm disturbances in predisposed patients, but these are rarely reported. Skeletal muscle tremors can occur initially but subside as tolerance develops.
| Short-Acting Anticholinergics
When given by inhalation, anticholinergics such as ipratropium or atropine produce bronchodilation by competitively inhibiting cholinergic receptors in bronchial smooth muscle. This activity blocks acetylcholine, with the net effect being a reduction in cyclic guanosine monophosphate (cGMP), which normally acts to constrict bronchial smooth muscle. Muscarinic receptors on airway smooth muscle include M1, M2, and M3 subtypes. Activation of M1 and M3 receptors by acetylcholine results in bronchoconstriction; however, activation of M2 receptors inhibits further acetylcholine release.
Ipratropium is the primary short-acting anticholinergic agent used for COPD in the United States. Atropine has a tertiary structure and is absorbed readily across the oral and respiratory mucosa, whereas ipratropium has a quaternary structure that is absorbed poorly. The lack of systemic absorption of ipratropium greatly diminishes the anticholinergic side effects such as blurred vision, urinary retention, nausea, and tachycardia associated with atropine. Ipratropium bromide is available as an MDI and a solution for inhalation. The MDI was recently reformulated with an HFA propellant and delivers 17 mcg per puff. Ipratropium is also available as an MDI in combination with albuterol and as a solution for nebulization at 200 mcg/mL. It provides a peak effect in 1.5 to 2 hours and has a duration of effect of 4 to 6 hours. Ipratropium has a slower onset of action and a more prolonged bronchodilator effect compared with standard β2-agonists. Because of the slower onset of effect (15 to 20 minutes compared with 5 minutes for albuterol), it may be less suitable for as-needed use; however, it is often prescribed in that manner. The role of inhaled anticholinergics in COPD is well established. However, results from the Lung Health Study showed that treatment with ipratropium did not affect the progressive decline in lung function. Studies comparing ipratropium with inhaled β2-agonists have generally reported similar improvements in pulmonary function. Others report a modest benefit with ipratropium, including a lower incidence of side effects such as tachycardia.
Although the recommended dose of ipratropium is 2 puffs four times a day, there is evidence for a dose-response, so the dose can be titrated upward often to 24 puffs a day. Ipratropium has been shown to increase maximum exercise performance in stable COPD patients with doses of 8 to 12 puffs prior to exercise but not with doses of 4 puffs or less. During sleep, ipratropium also has been shown to improve arterial oxygen saturation and sleep quality. Ipratropium is well tolerated. The most frequent patient complaints are dry mouth, nausea, and an occasional metallic taste.
Clinicians differ about preference in choosing the initial short-acting bronchodilator therapy for the patient with COPD. Both a short-acting β2-agonist and ipratropium represent reasonable choices for initial therapy.
| Long-Acting Bronchodilators
For patients with moderate to severe COPD who experience symptoms on a regular and consistent basis, or in whom short-acting therapies do not provide adequate relief, long-acting bronchodilator therapies are the recommended treatment. Long-acting inhaled bronchodilator therapy can be administered as an inhaled β2-agonist (LABA) or an anticholinergic. Long-acting, inhaled bronchodilator therapy is more convenient and effective, compared with short-acting agents, for patients with chronic symptoms. There are superior outcomes in lung function as measured by spirometry, symptoms including dyspnea, and, importantly, reductions in exacerbation frequency and improved quality of life.
| Long-Acting Inhaled β-Agonists (LABAs)
LABAs offer the convenience and benefit of a long duration of action for patients with persistent symptoms. Each of the currently available agents, salmeterol, formoterol, and arformoterol is dosed every 12 hours and provides sustained bronchodilation. Arformoterol and formoterol has an onset of action similar to albuterol (less than 5 minutes), whereas salmeterol has a slower onset (15 to 20 minutes); however, neither agent is recommended for acute relief of symptoms. There is no dose titration for any of these agents; the starting dose is the effective and recommended dose for all patients. The clinical benefits of long-acting inhaled β2-agonists compared with short-acting therapies include similar or superior improvements in lung function and symptoms, as well as reduced exacerbation rates in some studies. The use of the long-acting agents should be considered for patients with frequent and persistent symptoms. When patients require short-acting β2-agonists on a scheduled basis, LABAs are more convenient based on dosing frequency but are also more expensive. Salmeterol and formoterol are available in dry powder inhalation devices, and formoterol and arformoterol as solutions for nebulization. An ultra-long-acting agent, indacaterol, which requires once daily dosing is in phase 3 and 4 clinical trials in 2009.
LABAs are also useful to reduce nocturnal symptoms and improve quality of life. When compared with short-acting bronchodilators or theophylline, both salmeterol and formoterol improve lung function, symptoms, exacerbation frequency, and quality of life. These benefits are apparent even for patients with poorly reversible lung function and are related to improvements in inspiratory capacity. Both salmeterol and formoterol have been compared with ipratropium. In separate studies, each agent improved FEV1 compared with ipratropium and, in addition, the LABA was more effective for other selected outcomes (e.g., prolonged time to exacerbation for salmeterol while formoterol reduced symptoms and rescue inhaler use).
| Long-Acting Anticholinergics
Tiotropium bromide, a long-acting quaternary anticholinergic agent, has been available in the United States since 2004. This agent blocks the effects of acetylcholine by binding to muscarinic receptors in airway smooth muscle and mucus glands, blocking the cholinergic effects of bronchoconstriction and mucus secretion. Tiotropium is more selective than ipratropium at blocking important muscarinic receptors. Tiotropium dissociates slowly from M1 and M3 receptors, allowing prolonged bronchodilation. The dissociation from M2 receptors is much faster, allowing inhibition of acetylcholine release. Binding studies of tiotropium in the human lung show that it is approximately 10-fold more potent than ipratropium and protects against cholinergic bronchoconstriction for greater than 24 hours.
When inhaled, tiotropium is minimally absorbed into the systemic circulation and results in bronchodilation within 30 minutes, with a peak effect in 3 hours. Bronchodilation persists for at least 24 hours, allowing for a once daily dosing. There is no titration of tiotropium dose; a regimen of 18 mcg inhaled once daily is recommended for all patients. In the United States, it is delivered via the HandiHaler, a single-load, dry-powder, breath-actuated device. Because it acts locally, tiotropium is well tolerated, with the most common complaint being a dry mouth. Other anticholinergic side effects that are reported include constipation, urinary retention, tachycardia, blurred vision, and precipitation of narrow-angle glaucoma symptoms.
The benefits of tiotropium have been evaluated in numerous trials of patients with COPD. Similar to long-acting β-agonists, tiotropium improves lung function and dyspnea, exacerbation frequency, and health-related quality of life. In this study, tiotropium improved FEV1 by an average of 12% to 22% compared with placebo. The tolerance that is demonstrated with chronic use of β-agonists does not occur with tiotropium therapy, as improvements in lung function are sustained with long-term therapy.
There is a large body of evidence supporting the use of tiotropium as a long acting bronchodilator for COPD patients. Benefits have been demonstrated compared with placebo and to ipratropium. Tiotropium therapy is associated with a decreased risk of exacerbations compared with placebo or ipratropium, and equal or superior efficacy compared with LABAs in various studies.
As a long-acting bronchodilator, tiotropium is an option to consider in addition to long-acting inhaled β2-agonists for COPD management. Once-daily tiotropium has been compared with twice-daily salmeterol in two placebo-controlled trials of 6 months duration. Tiotropium reduced asthma exacerbations and hospital admissions and improved quality of life, whereas both active treatments improved lung function and reduced dyspnea. In another 6-month randomized, controlled trial of patients with COPD, patients were randomized to receive either tiotropium once daily by DPI, salmeterol twice daily by MDI, or placebo. Patients receiving tiotropium had greater improvements in trough FEV1 and dyspnea scores than those receiving salmeterol. Patients also were more likely to have improvements in quality-of-life indicators with tiotropium than with salmeterol. However, no differences in frequency of exacerbations were noted among the three groups.
The most notable study involving the use of tiotropium in recent years for patients with COPD was the Understanding Potential Long-term Impacts on Function with Tiotropium(UPLIFT) trial. This was a randomized, double-blind study of 4 years duration. A total of 5,993 subjects received either tiotropium 18 mcg daily inhaled via a HandiHaler device or a matching placebo. All other COPD therapies were allowed except for other anticholinergic therapies (e.g., ipratropium). The mean postbronchodilator FEV1 among subjects was 1.32 L, and the primary outcome was the rate of decline in FEV1 on spirometry. The results showed that tiotropium treatment resulted in prebronchodilator FEV1 improvement of 87 to 103 ml, and postbronchodilator improvement of 47 to 65 mL, both of which were statistically significant. However, the rate of decline in the mean FEV1 result was not statistically significant between the groups. Tiotropium-treated subjects benefited from treatment as reflected in improved quality-of-life scores, reduced exacerbation rates, fewer hospitalizations, and instances of respiratory failure. Tiotropium was associated with a lower overall risk of mortality, including deaths from respiratory and cardiac causes.
The safety of tiotropium documented in the UPLIFT trial is reassuring. Recently, retrospective analysis have reported an increased risk of cardiovascular events associated with ipratropium and tiotropium use. However, the UPLIFT study, which was a prospective trial over 4 years, did not report an increased cardiovascular risk associated with tiotropium use.
| Combination Anticholinergics and β-Agonists
Combination regimens of bronchodilators are used often in the treatment of COPD, especially as the disease progresses and symptoms worsen over time. Combining bronchodilators with different mechanisms of action allows the lowest possible effective doses to be used and reduces potential adverse effects from individual agents. Combinations of both short- and long-acting β2-agonists with ipratropium have been shown to provide added symptomatic relief and improvements in pulmonary function. A combination of albuterol and ipratropium (Combivent) is available as an MDI in the United States for chronic maintenance therapy of COPD. This product offers the obvious convenience of two classes of bronchodilators in a single inhaler.
Although clinical practice guidelines recommend that combinations of long-acting bronchodilators are appropriate for patients who do not receive adequate benefit from a single agent, data to support the use of these combinations have been lacking. These approaches have been the focus of more recent research. Future combination inhalation products may contain long-acting β2-agonists with tiotropium to reduce the need for frequent dosing. In a preliminary single-dose study, the combination of tiotropium and formoterol resulted in a faster and greater improvement in FEV1 compared with either treatment alone. In another trial, 95 subjects received either tiotropium 18 mcg or tiotropium plus formoterol 12 mcg either once or twice daily. All patients received each therapy for 2 weeks each in an open label, crossover design. Both combination regimens improved lung function and reduced rescue therapy use compared with tiotropium alone.
| Methylxanthines
Methylxanthines, including theophylline and aminophylline, have been available for the treatment of COPD for at least five decades and at one time were considered first-line therapy. However, with the availability of long-acting inhaled β2-agonists and inhaled anticholinergics, the role of methylxanthine therapy is significantly limited. Inhaled bronchodilator therapy is preferred for COPD. Because of the risk for drug interactions and the significant intrapatient and interpatient variability in dosage requirements, theophylline therapy generally is considered for patients who are intolerant or unable to use an inhaled bronchodilator. Theophylline is still an alternative to commonly used inhaled therapies partially due to the potential for multiple mechanisms (bronchodilation and antiinflammatory) and the possible benefit that systemic administration may exert on peripheral airways.
The methylxanthines may produce bronchodilation through numerous mechanisms, including (1) inhibition of phosphodiesterase, thereby increasing cAMP levels, (2) inhibition of calcium ion influx into smooth muscle, (3) prostaglandin antagonism, (4) stimulation of endogenous catecholamines, (5) adenosine receptor antagonism, and (6) inhibition of release of mediators from mast cells and leukocytes.
Chronic theophylline use for patients with COPD has been shown to exert improvements in lung function, including vital capacity (VC), FEV1, minute ventilation, and gas exchange. Subjectively, theophylline has been shown to reduce dyspnea, increase exercise tolerance, and improve respiratory drive in COPD patients. Other nonpulmonary effects of theophylline that may contribute to improved overall functional capacity for patients with COPD include improved cardiac function and decreased pulmonary artery pressure.
Although theophylline is available in a variety of oral dosage forms, sustained-release preparations are most appropriate for the long-term management of COPD. These products have the advantages of improving patient compliance and achieving more consistent serum concentrations over rapid-release theophylline and aminophylline preparations. However, caution must be used in switching from one sustained-release preparation to another because there are considerable variations in sustained-release characteristics. Aside from intravenous aminophylline, there is no need to use any of the various salts forms of theophylline.
Regular use of methylxanthines has not been shown to have either a beneficial or a detrimental effect on the progression of COPD. However, methylxanthines may be added to the treatment plan of patients who have not achieved an optimal clinical response to ipratropium and an inhaled β2-agonist. Studies suggest that adding theophylline to a combination of albuterol and ipratropium provides added benefit for stable COPD patients, supporting the hypothesis that there is a synergistic bronchodilator effect. The efficacy of combination therapy with salmeterol and theophylline for patients with COPD was reported to improve pulmonary function and reduce dyspnea better than either treatment alone. Combination treatment also was associated with a reduced number of exacerbations only when compared with the theophylline group, suggesting that the salmeterol component was responsible for this beneficial effect.
As is the case with other bronchodilator therapy, parameters other than objective measurements, such as FEV1, should be monitored to assess efficacy of theophylline in COPD. Subjective parameters, such as perceived improvements in symptoms of dyspnea and exercise tolerance, become increasingly important in assessing the acceptability of methylxanthines for COPD patients. Although objective improvement may be minimal, patients may experience an improvement in clinical symptoms, and thus benefit to the individual may be meaningful.
The role of theophylline in COPD is as maintenance therapy in the nonacutely ill patient. Therapy can be initiated at 200 mg twice daily and titrated upward every 3 to 5 days to the target dose. Most patients required daily doses of 400 to 900 mg. Dosage adjustments generally should be made based on serum concentration results. Traditionally, the therapeutic range of theophylline was identified as 10 to 20 mcg/mL; however, because of the frequency of dose-related side effects and the relatively minor benefit of higher concentrations, a more conservative therapeutic range of 8 to 15 mcg/mL often is targeted. This is especially preferable for the elderly. When concentrations are measured, trough measurements are most appropriate.
Once a dose is established, serum concentrations should be monitored once or twice a year unless the patient's disease worsens, medications that interfere with theophylline metabolism are added to therapy, or toxicity is suspected. The most common side effects of theophylline therapy are related to the gastrointestinal system, the cardiovascular system, and the central nervous system. Side effects are dose-related; however, there is overlap in side effects between the therapeutic and toxic ranges. Minor side effects include dyspepsia, nausea, vomiting, diarrhea, headache, dizziness, and tachycardia. More serious toxicities, especially at toxic concentrations, include arrhythmias and seizures.
Factors that decrease theophylline clearance and lead to reduced maintenance-dose requirements include advanced age, bacterial or viral pneumonia, left or right ventricular failure, liver dysfunction, hypoxemia from acute decompensation, and use of drugs such as cimetidine, macrolides, and fluoroquinolone antibiotics. Factors that may enhance theophylline clearance and result in the need for higher maintenance doses include tobacco and marijuana smoking, hyperthyroidism, and the use of such drugs as phenytoin, phenobarbital, and rifampin.
In summary, there are decades of experience with theophylline and other methylxanthine products in the management of patients with COPD. However, inhalation therapy is currently preferred based on superior efficacy and safety, as well as ease of use by the clinician. Theophylline is a challenging medication to dose, monitor, and manage due to the significant intrapatient and interpatient variability in pharmacokinetics and the potential for drug interactions and toxicities.
| Corticosteroids
Corticosteroid therapy has been studied and debated in COPD therapy for half a century; however, owing to the poor risk-to-benefit ratio, chronic systemic corticosteroid therapy should be avoided if possible. Because of the potential role of inflammation in the pathogenesis of the disease, clinicians hoped that corticosteroids would be promising agents in COPD management. However, their use continues to be debated, especially in the management of stable COPD.
The antiinflammatory mechanisms whereby corticosteroids exert their beneficial effect in COPD include (1) reduction in capillary permeability to decrease mucus, (2) inhibition of release of proteolytic enzymes from leukocytes, and (3) inhibition of prostaglandins. Unfortunately, the clinical benefits of systemic corticosteroid therapy in the chronic management of COPD are often not evident, and the risk of toxicity is extensive and far-reaching. Currently, the appropriate situations to consider corticosteroids in COPD include (1) short-term systemic use for acute exacerbations and (2) inhalation therapy for chronic stable COPD.
The role of oral steroid use in chronic stable COPD patients was evaluated in a metaanalysis over a decade ago. Investigators concluded that only a small fraction (10%) of COPD patients treated with steroids showed clinically significant improvement in baseline FEV1 (increase of 20%) compared with those treated with placebo. While a small number of COPD patients are considered responders to oral steroids, many of these patients actually may have an asthmatic, or reversible, component to their disease. The best predictors for response to oral steroids are the presence of eosinophils on sputum examination (≥3%) and a significant response to sympathomimetics on pulmonary function tests. Both the presence of eosinophils in sputum and the responsiveness to sympathomimetics suggest an asthmatic component to the disease process and thus may explain the clinical benefit seen with steroids.
Long-term adverse effects associated with systemic corticosteroid therapy include osteoporosis, muscular atrophy, thinning of the skin, development of cataracts, and adrenal suppression and insufficiency. The risks associated with long-term steroid therapy are much greater than the clinical benefits. If a decision to treat with long-term systemic corticosteroids is made, the lowest possible effective dose should be given once per day in the morning to minimize the risk of adrenal suppression. If therapy with oral agents is required, an alternate-day schedule should be used.
Previously, a common clinical practice was to administer a short course (2 weeks) of oral corticosteroids as a trial to predict which patients would benefit from chronic oral or inhaled corticosteroids. There is now sufficient evidence suggesting that this practice is not effective in predicting a long-term response to inhaled corticosteroids and should not be recommended.
The use of chronic inhaled corticosteroid therapy has been of interest for the past decade. Their use has been common despite the lack of firm evidence about significant clinical benefit until recently. Inhaled corticosteroids have an improved risk-to-benefit ratio compared with systemic corticosteroid therapy. Using the model for asthma, it was hoped that the inhalation of potent corticosteroid would result in high local efficacy and limited systemic exposure and toxicity. In the latter part of the 1990s, several large international trials were initiated to evaluate the effect on inhaled corticosteroids in COPD. Unfortunately, the results of these major clinical trials failed to demonstrate any benefit from chronic treatment with inhaled corticosteroids in modifying long-term decline in lung function that is characteristic of COPD. Therefore, the role of inhaled corticosteroids in COPD continues to be debated in the literature, unlike in asthma, where their use is clearly advocated. Much of the debate centers on the appropriate outcome measures in this population of patients.
During the last decade, several studies of inhaled corticosteroids in COPD were designed to detect a benefit on slowing the progressive loss of lung function, but the results were disappointing. None of the large national or international trials were able to demonstrate a benefit of high-dose inhaled corticosteroid therapy on this primary outcome. However, inhaled corticosteroids have been associated with other important benefits in some patients, including a decrease in exacerbation frequency and improvements in overall health status. Clinicians continue to debate the most appropriate and relevant outcome measure to evaluate in COPD studies. Based on the results of clinical trials, consensus guidelines suggest that inhaled corticosteroid therapy should be considered for symptomatic patients with stage III or IV disease (FEV1 <50%) who experience repeated exacerbations. These are the patients who demonstrated benefit in clinical trials and in whom a trial of inhaled corticosteroid therapy is warranted. There are also data from epidemiologic studies that suggest that chronic treatment with inhaled corticosteroids is associated with a lower risk of rehospitalization for a broader group of patients with COPD. Thus the debate about the appropriate role for this antiinflammatory therapy continues.
A metaanalysis evaluating randomized clinical trials involving inhaled corticosteroids for patients with COPD indicated that treatment was associated with a relative risk reduction in exacerbation frequency of 33%. The report indicated that 12 patients would require treatment for 20.8 months to prevent one exacerbation episode. The benefit was evident for patients with moderate to severe COPD. This metaanalysis did not detect a mortality benefit.
Other investigators have reported a reduction in mortality for patients with COPD who were treated with inhaled corticosteroids. In an epidemiologic study of a Canadian database, patient mortality 3 months to 1 year following a hospitalization for a COPD exacerbation was evaluated for patients who received inhaled corticosteroids in the first 3 months compared with those who did not. For patients over 65 years of age, inhaled corticosteroid therapy reduced mortality by 25%. Much of the mortality reduction was reflected in deaths due to cardiovascular causes. Conversely, patients who received only bronchodilator therapy trended toward higher mortality rates, although not significant. A pooled analysis of seven large trials also concluded that inhaled corticosteroids reduced all-cause mortality in COPD patients.
Currently, the recommended role of inhaled corticosteroid therapy is for COPD patients with moderate to severe airflow obstruction (FEV1 <50% predicted) and who experience frequent exacerbations despite bronchodilator therapy. Repeated exacerbations are described as 3 in 3 years. The initial hope that treatment with inhaled corticosteroids would prevent or slow the progressive decline in FEV1 remains unproven; however, it is often argued that additional important outcomes for patients with COPD include relief of symptoms, fewer and less severe exacerbations, and improved quality of life. Inhaled corticosteroids (ICs) do not prolong survival in COPD patients and there is good evidence to suggest that treatment with ICs increases the risk of pneumonia for patients with COPD.
Although a dose-response relationship for ICs has not been demonstrated in COPD, the major clinical trials employed moderate to high doses for treatment. Side effects of ICs are relatively mild compared with the toxicity from systemic therapy. Hoarseness, sore throat, oral candidiasis, and skin bruising have been reported in the clinical trials. Severe side effects, such as adrenal suppression, osteoporosis, and cataract formation, have been reported less frequently than with systemic corticosteroids, but clinicians should monitor patients who are receiving high-dose chronic therapy.
There is evidence supporting a dose relationship between inhaled corticosteroid use and the risk of fractures. In a cohort of over 1,600 subjects with a diagnosis of asthma or COPD (mean age 80 years), the risk of a fracture was 2.53 times higher (CI, 1.65-3.89) in those receiving a mean daily dose of inhaled corticosteroid of 601 mcg or greater. However, the data are conflicting about this issue. A metaanalysis found no evidence supporting an increased risk of fractures or decreased bone mineral density with chronic inhaled corticosteroid use. It appears prudent to suggest that, to minimize the risk of fracture, patients should be treated with the lowest effective dose of ICs. It may also be helpful to recommend adequate intake of calcium and vitamin D and possibly periodic bone mineral density testing.
| Combination Therapy: Bronchodilators and Inhaled Corticosteroids
Following the disappointing results of chronic inhaled corticosteroid studies and the progressive decline in lung function, investigators became interested in the combination of potent antiinflammatory therapies and long-acting bronchodilators. Subsequently, several studies have shown an additive benefit with long-acting bronchodilators. In various studies, combination therapy with salmeterol plus fluticasone or formoterol plus budesonide was associated with greater improvements in clinical outcomes such as FEV1, health status, and frequency of exacerbations compared with ICs or long-acting bronchodilators alone. The availability of combination inhalers (e.g., salmeterol plus fluticasone and budesonide plus formoterol) makes administration of both ICs and long-acting bronchodilators more convenient for patients and decreases the total number of inhalations needed daily. An inhaled corticosteroid combined with a long acting β-agonist is superior to the individual components in reducing exacerbations, improving lung function and overall health status. Therefore, there is growing evidence that inhaled corticosteroid and long-acting β-agonist combinations improve lung function, as well as reduce symptoms of dyspnea and exacerbation frequency.
The combination of a long-acting β-agonist and inhaled corticosteroid has been compared with the long-acting β-agonist therapy alone. In a study involving nearly 1,000 patients with severe but stable COPD, subjects received either salmeterol 50 mcg/fluticasone 500 mcg twice daily or salmeterol 50 mcg twice daily for 44 weeks. Exacerbation frequency was significantly lower in the combination group (334 vs 464 episodes), which corresponded to a 35% reduction in the annualized rate. The time to the first exacerbation was also delayed with the combination therapy. One finding of concern reported in this trial was the increased number of pneumonia cases for patients receiving combination therapy compared with salmeterol alone. There were 23 cases reported compared with 7 in the salmeterol group. An increase in the risk for pneumonia was also reported in the Towards a Revolution in COPD Health (TORCH) study described below.
The largest prospective study to date is referred to as the Towards a Revolution in COPD Health (TORCH) study. This trial consisted of 6,112 patients who received one of four treatments for three years. Treatment groups were placebo, salmeterol 50 mcg twice daily, fluticasone 500 mcg twice daily, or the combination of salmeterol and fluticasone in a single inhaler. The primary outcome was death from any cause and secondary outcomes were exacerbation rates, lung function, and health status. None of the active treatments differed significantly from placebo, although the combination of salmeterol and fluticasone trended toward fewer deaths (P = .052). The combination also reduced exacerbation rates, and improved lung function and health status compared with the other treatments. Exacerbation rates were also significantly reduced with combination therapy compared with either single agent alone. Both treatment groups that included fluticasone had higher rates of pneumonia. Although this study did not reflect a mortality benefit, the authors indicated the risk of death was reduced by 17.5% with the combination and that the number needed to treat for 1 year to provide a benefit was 4.
For patients with an FEV1 of less than 60% predicted, the individual agents and the combination decreased the rate of spirometry decline.
In a head-to-head trial, a large study comparing a combination of salmeterol and fluticasone to tiotropium alone showed no difference in the exacerbation rates between the groups, although the combination therapy was associated with a higher study completion rate.
| Combinations of Long-Acting Bronchodilators Compared with Long-Acting Bronchodilators Plus Inhaled Corticosteroids
The combination of salmeterol and tiotropium has also been evaluated in a short-term crossover study involving only 22 subjects who received either salmeterol (50 mcg twice daily) plus fluticasone (500 mcg twice daily), fluticasone plus tiotropium (18 mcg once daily), or fluticasone, salmeterol, and tiotropium for 1 week. The triple combination provided a significant benefit of improved lung function compared with either of the dual treatments in subjects with moderate to severe COPD. The benefit of triple therapy was evaluated in a 1 year randomized, double-blind, placebo control study involving 449 subjects with moderate to severe COPD. Treatment consisted of either tiotropium, tiotropium plus salmeterol, or tiotropium, salmeterol, and fluticasone. There was no difference between treatments for the primary outcome of percentage of patients experiencing an exacerbation requiring systemic corticosteroids or antibiotics. The triple-drug regimen improved lung function, quality of life, and reduced hospitalization compared with tiotropium alone, while two-drug therapy did not offer any benefit in lung function improvement or hospitalization rates compared with the single agent. Another small study evaluated the addition of tiotropium for 1 month to a regimen of an inhaled corticosteroid and a long-acting β-agonist. The addition of tiotropium improved lung function and quality-of-life scores, apparently by improving dynamics of lung capacity (inspiratory capacity). These effects were reversed when tiotropium therapy was discontinued. These data involving combinations of long acting bronchodilators are limited and preliminary. More research is required and should include other outcome parameters including relief of symptoms, exacerbation rates, and quality of life. Larger sample sizes and longer durations will provide insight into the value of combinations.
A retrospective cohort study of 42,090 patients in the Veterans Affairs healthcare system evaluated outcomes for patients with COPD who received tiotropium as part of a COPD regimen compared with a cohort of COPD patients who did not receive the medication. Patients who received tiotropium with ICs plus a long-acting β-agonist exhibited a 40% reduction in mortality compared with patients treated with ICs plus a long-acting β-agonist alone (95% CI of 0.45-0.79). Triple therapy patients also significantly reduced exacerbations and hospitalization rates. However, this same study demonstrated that tiotropium combined with two other medications (various) increased mortality and morbitity risks. |
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