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A Review of the GOLD Guidelines for the Diagnosis and Treatment of Patients With COPD: Pharmacologic Treatment in the Management of COPD


Pharmacologic Treatment in the Management of COPD

Management of Stages I–IV COPD

Bronchodilator therapy is a key component of treatment for patients with stage I to stage IV COPD. Bronchodilators include anticholinergics, β2-adrenergic receptor agonists and methylxanthines. These agents increase FEV1 by relaxing the smooth muscle in the airways and are given as needed for persistent or worsening symptoms or routinely to prevent or reduce symptoms.[1,34,35] Although treatment with bronchodilators can improve emptying of the lungs, reduce hyperinflation and dyspnoea, and improve the patient's ability to exercise, it cannot ameliorate the decline in lung function or improve the patient's prognosis. For patients with stage I COPD, bronchodilator therapy may be administered as needed to relieve acute, intermittent symptoms.[1] Short-acting bronchodilators, such as albuterol and ipratropium, are appropriate, and may be administered either as monotherapy or together as combination bronchodilator therapy. These drugs typically are used to provide relatively immediate relief of symptoms.[1,36]

Patients with more severe stages of COPD can be expected to exhibit more frequent and persistent symptoms as the disease follows its normal course. Shortness of breath is one of the more readily apparent symptoms of COPD but may not be present in stage I. It is also important for healthcare providers to recognise that the development and/or worsening of dyspnoea may be masked in a patient who modifies his or her daily physical activities to avoid this symptom and accommodate the growing limitations on physical activity.[28] As COPD progresses, patients may benefit from the introduction of long-acting bronchodilator therapy to prevent or reduce symptoms and maintain normal levels of physical activity. Long-acting agents have become the recommended first-line choice for maintenance pharmacotherapy for symptomatic COPD.[1,37] Adverse events associated with inhaled formulations of bronchodilators are pharmacologically predictable and dose dependent. Although oral formulations may be used for the treatment of COPD, inhaled formulations of bronchodilators are preferred.[1] The selection of bronchodilator therapy or the decision to administer combination therapy should be based on the patient's response to treatment and should take into consideration the availability of the medications and cost to the patient. Figure 2 illustrates one suggested strategy for the stepwise introduction of pharmacotherapy based on the clinical staging of COPD.[36]

Figure 2. (click image to zoom) Suggested treatment algorithm for patients with chronic obstructive pulmonary disease (COPD). Reused with permission from the British Medical Journal[36]

Inhaled Anticholinergics. Inhaled anticholinergic medications, which are frequently used in the treatment of symptomatic COPD, decrease bronchoconstriction by reducing smooth muscle tone and glandular mucus.[38] The anticholinergics inhibit the interaction of acetylcholine with cholinergic M1 and M3 receptors in the airway smooth muscle and glands that control bronchoconstriction and mucus secretion.[38] Administration of short-acting inhaled anticholinergics, such as ipratropium, usually results in maximum bronchodilation in approximately 1–2h[39] and this effect can be maintained for approximately 4h.[39] Administration of tiotropium, a long-acting inhaled anticholinergic, results in prolonged bronchodilation for 24h or more, with peak bronchodilation occurring within 3 to 4h.[40] Treatment with tiotropium has also been shown to significantly improve lung function, improve dyspnoea and health-related QoL (HRQL) scores, reduce the incidence of COPD exacerbations and rescue medication use compared with either placebo[41] or ipratropium treatment.[42] Because the prolonged duration of effect of tiotropium allows a once-daily dosing regimen, this therapeutic option may be more convenient for, and preferred by, patients compared with the multidose regimens required when treating with short-acting inhaled anticholinergics.

Although inhaled anticholinergics are generally well tolerated, caution should be used in patients with prostate symptoms and glaucoma.[34] Adverse events are relatively uncommon following inhaled anticholinergic therapy, with approximately 10–14% of patients reporting drug-related dry mouth.[43] Nevertheless, dry mouth is generally well tolerated by patients with COPD, and the benefits outweigh the risks with this group of agents.

β2-Adrenergic Receptor Agonists. β2-adrenergic receptor agonists induce bronchodilation by acting on the β2-adrenergic receptors located in the smooth muscle of the airways.[38] Stimulation of these receptors increases the production of cyclic adenosine monophosphate (AMP), which in turn inhibits bronchoconstriction.[44] Inhaled formulations are recommended over oral formulations because oral agents have a slower onset of action and are associated with a greater incidence of treatment-related adverse events.[1] Short-acting β2-adrenergic receptor agonists (SABAs), such as terbutaline and albuterol are often used on an as-needed basis to relieve symptoms because they elicit a rapid onset of action,[1] achieve maximum bronchodilatory effects shortly after administration,[39] and provide effective bronchodilation for approximately 4–6h.[39] Terbutaline at high doses has also been shown to improve bronchodilation in patients with severe COPD[45] and to improve dyspnoea in patients with irreversible COPD.[46]

Long-acting β2-adrenergic receptor agonists (LABAs), such as formoterol and salmeterol, are recommended in the 2006 GOLD guidelines as maintenance therapies for the long-term prevention and reduction of COPD-related symptoms.[1] They also have a greater duration of effect compared with SABA treatment (>12 vs. 4–6h).[1] Their relatively long half-lives allow for twice-daily dosing, which may provide continuous daytime and nighttime bronchodilation and symptom control, as well as greater convenience for patients. This helps to protect patients from breathlessness during their normal daytime activities and can also be important for patients who have significant nighttime symptoms. Compared with short-acting bronchodilators, treatment with LABAs results in greater improvement of symptoms, including dyspnoea, fewer number of exacerbations, a reduction in the need for rescue medications and improvements in overall health status in patients with COPD.[36]

In addition to providing prolonged bronchodilation in patients with COPD, treatment with formoterol is associated with a rapid onset of action, usually within 5min of administration, that is comparable with that of albuterol[47,48] and faster than that of salmeterol.[49,50] Peak bronchodilation with formoterol is achieved within 60–120min after administration, and the duration of action is more than 12h.[51] Clinical studies have shown that treatment with formoterol significantly improves airflow obstruction, decreases SABA use, and improves QoL compared with ipratropium or oral theophylline treatment.[52,53]

Treatment with salmeterol has also been shown to significantly improve and maintain bronchodilation,[54] as well as improve airway obstruction, decrease the use of rescue medication, and improve QoL in patients with COPD.[55] Salmeterol is associated with a slower onset of action than formoterol (approximately 10–15min vs. <5min respectively),[49] and peak bronchodilation is achieved within approximately 2h after administration.[49,55]

Treatment with β2-adrenergic receptor agonists is generally well tolerated.[1,51] Adverse events appear to be dose related and occur more frequently with oral formulations than with inhaled formulations.[1] Adverse events may include tachycardia, palpitations, supraventricular arrhythmias, tremors, sleep disturbance (primarily following LABA treatment), hypokalemia and immediate hypersensitivity reactions (e.g. urticaria, angioedema, rash and bronchospasm).[1,35,56,57] The possibility of cardiac effects, especially in elderly patients who have pre-existing heart disease, should be considered when choosing medications to treat COPD.[37,56,57]

It should also be noted that results from a clinical trial designed to evaluate salmeterol for the treatment of asthma, the Salmeterol Multicentre Asthma Research Trial, found a small, but statistically significant, increase in the number of asthma-related deaths in patients treated with salmeterol compared with those receiving placebo.[58] Furthermore, small clinical studies have shown a higher incidence of serious asthma exacerbations associated with high-dose (24μg/day) formoterol treatment when compared with the incidence in patients receiving placebo,[59] although no studies of adequate size have been conducted to determine whether formoterol treatment results in an increased rate and risk of asthma-related death. These results prompted the Food and Drug Administration to mandate label warnings for formoterol and salmeterol concerning the possibility of an increase in risk for serious asthma exacerbations and asthma-related deaths in patients with asthma who receive regular treatment with LABAs.[56,57] It is important to note that no label changes are required for LABAs with regard to the treatment of COPD.

Methylxanthines. Methylxanthines, such as aminophylline and theophylline, can also be used to treat stage I to stage IV COPD, and can also be used for treating exacerbations of COPD. The efficacy of slow-release preparations of theophylline has been demonstrated in patients with COPD,[1] and theophylline continues to be used in the treatment of COPD primarily because of its low cost.[60] However, use of these agents is considered controversial because of well-documented treatment-associated adverse events, and theophylline is generally considered to be a third-line treatment option after inhaled β2-agonists and anticholinergic agents because of the frequency, severity and types of adverse events and its limited clinical efficacy.[37,60] Concerns regarding theophylline treatment centre around its small therapeutic window, wide range of dose-related toxic effects and the need for close monitoring of plasma concentrations during treatment.[1,37] Adverse events associated with methylxanthine treatment include possible fatal atrial and ventricular arrhythmias, convulsions, headaches, insomnia, nausea and heartburn.[1]

Bronchodilator Combination Therapy. Combined treatment with a β2-adrenergic receptor agonist, an anticholinergic agent, and/or theophylline have been shown to provide additional improvements in lung function and health status compared with single-agent therapy for COPD.[1,61-64] The combination of agents with different mechanisms and durations of action seem to provide better bronchodilation and improved safety profiles.[1] The fixed dose combination of ipratropium and albuterol, 2 short-acting bronchodilators, has been used for many years to treat patients with COPD. This combination may prove advantageous for patients with intermittent symptoms who need medications on an as-needed basis.[65] Studies have found that concurrent treatment with the long-acting anticholinergic agent tiotropium and formoterol or salmeterol is more effective than treatment with the individual agents used alone.[62,66]

Results of a study conducted by van Noord et al.[64] demonstrated that combination therapy with formoterol plus tiotropium improved pulmonary function, as assessed by several lung function parameters (e.g. FVC and FEV1), more than improvements achieved with either component alone. The beneficial results were particularly evident during daytime hours when patients were active. Improvement in FVC may be indicative of reduced hyperinflation. Because hyperinflation is more directly related to functional activity, dyspnoea and exercise capacity than airflow, improvements in FVC with combination therapy may be more representative of a patient's response to treatment with regard to functional capacity than improvements in FEV1.[67] In the study by van Noord et al.,[64] patients receiving combination therapy also experienced a significant decrease in the use of as-needed rescue medication, especially during the daytime, which is also indicative of the better symptomatic benefit available with combination therapy when compared with monotherapy. The study investigators concluded that optimisation of bronchodilation with combination therapy may potentially lead to significant improvements in patients' ability to undertake physical activities and better QoL for patients and thus warrants further investigation.[64] In another study, Rabe et al.[68] compared the benefits of two combination therapies in patients with moderate COPD: formoterol plus tiotropium vs. salmeterol plus fluticasone, an ICS. Both treatment combinations were well tolerated. However, the combination of formoterol and tiotropium resulted in significantly better improvements in objective measures of lung function compared with the improvements observed in patients receiving salmeterol plus fluticasone.

Stage III to stage IV COPD

Oral corticosteroids (OCS) and ICS are used as add-on therapy in very specific situations in the management of stable COPD.[1] Although a short course of OCS (e.g. 2weeks) has been used in COPD to evaluate a patient's potential response to long-term therapy with oral or ICS, the 2006 GOLD guidelines do not support this practice, as there is a growing body of evidence to suggest that this is an unreliable predictor of long-term response to corticosteroid treatment.[1] Additionally, long-term maintenance treatment with OCS is not recommended, primarily because of limited evidence demonstrating clinical benefit, in addition to the well-documented adverse events and dependency associated with prolonged OCS treatment.[1]

The place for ICS in the management of COPD has been controversial because of conflicting results from studies. Use of ICS agents may result in some improvements in lung function for a few months in patients with COPD,[69] although a number of studies have shown that ICS treatment does not improve the long-term progressive decline in lung function seen in patients with COPD, especially patients with mild-to-moderate disease (stages I and II).[69-71] However, the recent trial Towards a Revolution in COPD Health (TORCH) was the first to show that combined ICS and LABA therapy significantly reduced the decline in lung function over the 3-year study period.[72,73] The 2006 GOLD guidelines recommend ICS therapy with agents such as beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate and triamcinolone acetonide for the treatment of patients with advanced COPD (FEV1<50% predicted) who experience repeated exacerbations.[1]

In a study performed to assess the effects of long-term ICS therapy in patients with severe COPD (stages III and IV), Burge et al.[69] found that treatment with inhaled fluticasone propionate resulted in significant increases in FEV1, decreases in the number of exacerbations, and a significantly slower decline in health status compared with treatment with placebo. Their findings support the addition of ICS therapy to treatment plans for patients with severe COPD. Although it has been suggested that treating patients with COPD with an ICS reduces the rate of all-cause mortality, the TORCH trial did not find a statistically significant reduction of all-cause mortality in COPD patients treated with combined fluticasone propionate plus salmeterol.[72]

In patients with severe to very severe COPD, the addition of an ICS to a LABA has been shown in several studies to provide better improvements in objective clinical measures of lung function and health status than monotherapy with an ICS or a LABA.[74–77] In one of these studies, Kardos et al.[76] assessed the effect of combination therapy with salmeterol and fluticasone propionate compared with salmeterol alone on the numbers of moderate and severe exacerbations in patients with severe COPD and a history of exacerbations. They found that combination therapy reduced the frequency of exacerbations in patients, as well as, the need for rescue medication when compared with outcomes in patients receiving salmeterol alone. Combination therapy also resulted in an increase in the time to first exacerbation and improved lung function and HRQL for patients. Similarly, Calverley et al.[77] demonstrated that when budesonide and formoterol were administered together to patients with severe COPD, lung function, as assessed by FEV1, improved and was maintained throughout the study. In contrast, maintenance of improvements in lung function was not sustained in patients who received either agent alone. Time to first exacerbation was also delayed with the combination of budesonide and formoterol compared with monotherapy with either agent. While all treatment groups showed some level of improvement in HRQL, patients in the combined treatment group experienced the greatest benefits.

General Recommendations for Stage I to Stage IV COPD

In addition to the stepwise approach to treatment of patients with COPD, there are a number of general recommendations in the 2006 GOLD guidelines that should be integrated into treatment strategies. The GOLD guidelines recommend that all patients with COPD receive an annual influenza vaccination.[1] The influenza vaccine has been shown to reduce serious illness for patients with COPD by as much as 50%.[78] Pneumococcal vaccine is also recommended for patients >65years old and has been shown to reduce pneumococcal pneumonia in patients with COPD,[79] and community acquired pneumonia in general in patients <65years old with severe airway obstruction (i.e. FEV1<40% of predicted).[1,80]