Redefining Treatment in COPD Management: New Directions in Bronchodilator Therapy

The recently published Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines characterize chronic obstructive pulmonary disease (COPD) by airflow limitation that is not fully reversible. COPD is progressive and associated with an abnormal inflammatory response of the lung to noxious particles and gases. It is the fourth leading cause of death in the United States. Importantly, however, it is the only one of the first four that continues to increase, having risen 163% between 1965 and 1998. It is estimated that in 2000, there were 2.74 million deaths due to COPD throughout the world and approximately 114,000 in the United States alone. COPD is overwhelmingly but not exclusively a disease of smokers. As more women smoke, the historical gap between the genders in the incidence of COPD gradually closes. 

This program was supported by an unrestricted educational grant from Novartis Pharmaceuticals.

GOLD Guidelines for Diagnosing COPD

A diagnosis of COPD should be considered for any individual who has symptoms of cough, sputum production or dyspnea and/or a history of exposure to risk factors for the disease. The diagnosis is confirmed by spirometry, in part because there is an imperfect relationship between the degree of airflow limitation and the presence of symptoms. Mitchell Friedman, MD, FCCP (Tulane University) presented the disease stages and diagnostic criteria. As a progressive disease, COPD typically leads to biochemical and cellular alterations a decade or more prior to the development of symptoms. 

The treatment of COPD is primarily symptom-driven, with inhaled bronchodilating agents—principally b₂-adrenergic agonists (henceforth “b-agonists”), anticholinergics, or combinations of the two—serving as the central therapy. Inhalation permits the deposition of active drug molecules on the airway surface, resulting in significant bronchodilation and few side effects due to minimal systemic exposure. Inhaled bronchodilators improve venti-latory impairment, increase baseline FEV₁, decrease the frequency of exacerbations, improve the quality of life (QOL) by relieving dyspnea, and reduce overall healthcare costs associated with COPD. The GOLD treatment guidelines recommend that short-acting bronchodilators be used as needed in mild (stage I) disease. For moderate (stage II) and severe (stage III) disease, however, regular treatment with one or more long-acting bronchodilators and respiratory rehabilitation constitute the recommended regimen. Short-acting bronchodilators may be added for management of acute symptoms. Inhaled glucocorticosteroids are indicated, however, only in cases of significant symptoms and a lung function response to these drugs or in cases of repeated exacerbations. 
 
 

Assessment of Clinical Response to Bronchodilators in COPD

It might seem paradoxical that bronchodilators are the backbone of treatment for COPD when they have only limited ability to reverse lung function and improve airway obstruction. Reversibility by usual spirometric criteria to single doses of a bronchodilator correlates poorly with steady-state responses, symptoms, QOL, or subjective benefit. There is also a poor correlation between the degree of bronchodilation and the extent of clinical improvement. Roger Menendez, MD, FCCP (Allergy and Asthma Research Center, El Paso, TX) observed that the apparent benefit from these agents may be less from bronchodilation than from other actions directed at the complex pathophysiology of COPD. Bronchodilators relax airway smooth muscle, increase mucociliary clearance, and reduce the volume and viscosity of tracheobronchial secretions. 

Designing and selecting clinical endpoints for evaluating bronchodilators is challenging, primarily because changes in FEV₁ correlate poorly with clinical improvement. Clinical studies include both single-dose trials, designed to characterize the extent of bronchodilation as well as the onset and duration of action, and multi-dose trials, designed to determine whether or not the agent induces a sustainable effect on airway smooth muscle. Short-term clinical trials focus on measuring parameters of lung function that reflect ventilatory pump performance and usually also include symptoms, lung function (FEV₁), and lung volumes. Medium-term assessments focus mainly on more subjective measures such as QOL and patient satisfaction with treatment. The primary endpoints in long-term trials are changes in rates of decline and mortality. 

Ultimately, the goal of clinical trials is to correlate some measurable physiologic parameter with quality of life. Despite the standard use of spirometry, both absolute FEV₁ and FEV₁ change from baseline are unreliable for this purpose. There is increasing evidence, however, that the area under the curve (AUC) for the FEV₁ versus time may correlate reasonably well with improvement in QOL based on standard QOL assessment instruments: the Chronic Respiratory Questionnaire (CRQ), St. George’s Respiratory Questionnaire (SGRQ), and of the Health-Related Quality of Life (HRQOL) assessment tool. 

Since this relationship was first observed 6 years ago (Jones PW. Chest. 1995;107:187S), it has been replicated in a trial that compared the long-acting b-agonists formoterol with ipratropium, a short-acting anticholinergic agent, and in a trial of salmeterol and theophylline. In the formoterol trial, patients were randomized to formoterol twice daily, ipratropium four times daily, or placebo after baseline FEV₁ levels were established. After 12 weeks, AUC FEV₁ was significantly greater in the formoterol group than in the ipratropium group. Also, FEV₁ was significantly higher in the formoterol group at most time points (Figure 1.) Interestingly, significant overall improvement in symptom scores occurred only among patients treated with formoterol, suggesting a reasonable correlation between AUC FEV₁ and perceptible symptom relief (Dahl R et al. Am J Respir Crit Care Med. 2001; 164:778). In the salmeterol/theophylline trial, combination therapy improved lung function (AUC FEV₁) more than either agent alone, and the improvements were positively but weakly correlated with improvements in QOL and dyspnea (ZuWallack RL et al. Chest. 2001; 119:1661). 

Another potentially reliable endpoint for clinical trials of bronchodilators is dynamic lung volume. Destruction of lung parenchyma leads to hyperinflation which, in turn, results in increased airway obstruction and neuromechanical dissociation. Reduction of hyperinflation may improve dyspnea, regardless of the change in either the absolute FEV₁ or the FEV₁ change from baseline. 

Bronchodilator Therapy with b-Agonists

In 1987, Anthoninsen and colleagues published results of the first large (N=985), independent trial designed to assess the response of patients with COPD to bronchodilators based on FEV₁ evidence. The trial drug was isoproterenol, a short-acting b-agonist. On an absolute scale, the mean improvement was from 4% to 6%. Although this was small, the 20% relative improvement from baseline may have been significant for individuals with severe respiratory compromise. The results for long-acting b-agonists are very different, as is evidenced by the salmeterol/theophylline and formoterol trials discussed by 
Dr. Menendez. These agents induce durable symptom relief that permits the convenience of twice-daily administration with effective bronchodilation throughout the day and night. Short-acting bronchodilators are now used almost exclusively for short-term relief and for rescue. 

Stephen I. Rennard, MD, FCCP (University of Nebraska) observed that because b-agonists increase cAMP in the smooth muscle of the airway, they cause smooth muscle relaxation and improve airflow in nearly all individuals. In normal individuals, the resulting increase of 200 to 300 mL has little significance, but in patients with COPD, the same degree of bronchodilation can result in dramatic improvements in function. This allows for greatly increased activity, less anxiety, and improved QOL. Based on a recent study of formoterol using AUC FEV₁, formoterol is more effective than theophylline for improving lung function in both reversible and poorly reversible COPD (Kristufek P et al. 96th International Conference of the American Thoracic Society, 2000). It has a rapid onset of action and a lengthy duration of therapeutic activity.

In addition to relaxing respiratory smooth muscle, long-acting b-agonists improve lung volumes. In a trial comparing salmeterol with ipratropium and placebo, salmeterol provided similar maximal bronchodilation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Improvement in forced vital capacity (FVC) correlated with improvement in dyspnea (Rennard S et al. Am J Resp Crit Care Med. 2001;163: 1087).

Long-acting b-agonists have an acceptable safety profile. The most common side effects of salmeterol are placebo-like incidences of headache and upper respiratory tract infection, and slightly higher frequencies of sore throat and diarrhea. Formoterol was safe and well tolerated in two studies of COPD patients, with the frequencies of cough, bronchitis, rhinitis, and nausea either equal to or less than placebo. Because virtually all patients with COPD are (or were) smokers and many have concurrent heart disease including arrhythmias, b-agonist therapy has sometimes been considered risky. However, in a study in which 813 patients underwent 24-hour monitoring at baseline and in weeks 4, 8 and 12, there was a trend toward fewer episodes of nonsustained ventricular tachycardia (NSVT) in salmeterol patients during the trial compared with ipratropium and placebo, even though salmeterol patients had a higher incidence of NSVT at baseline. The incidents that did occur were brief and all were asymptomatic. 

Weiner and colleagues recently published a sequential study in which COPD patients were randomized to long-acting b-agonists or placebo following establishment of baseline FEV₁ levels. Patients receiving pharmacotherapy showed improvements in lung function. Subsequent exercise and inspiratory muscle training provided no significant additional improvement in FEV₁. However, when treated patients were given exercise training in the second phase of the study, there was a marked increase in the 6-minute walking distance compared to the placebo group, and a slight additional increase was associated with subsequent inspiratory muscle training. Interestingly, the subsequent inspiratory muscle training enabled the treated patients to generate much higher maximum inspiratory pressures than the group of untreated patients. (Weiner et al. Chest. 2000;118: 672). These findings suggest that the optimal management program for COPD may be sequential rehabilitation built on optimized physiologic function with long-acting bronchodilators. 

Glucocorticoid agents have only limited application in COPD. In a randomized and placebo-controlled study completed by 912 patients, treatment with budesonide induced a slight improvement in lung function for 6 months compared with placebo, but thereafter treated patients declined at roughly the same pace as did the control (Pauwels et al. N Engl J Med. 1999;340:1948). It is clear, therefore, that glucocorticoids do not affect the natural history of COPD as measured by FEV₁. They do, however, induce an improvement of approximately 50 mL of air compared with placebo, an amount that may bring perceptible relief to patients with severe pulmonary compromise. 

Bronchodilator Therapy with Anticholinergic Agents

Anticholinergic agents used in the management of COPD have no therapeutic activity other than bronchodilation. Nicholas J. Gross, MD, PhD (Loyola University) explained that when inhaled in the form of a nonabsorbable molecule, these drugs rest on the airway surface and exert a topical effect, thus avoiding the potentially serious side effects of systemic exposure. Anticholinergics inhibit muscarinic receptors in the airway to diminish bronchomotor tone. Secondarily, they suppress airway reflexes associated with a wide range of stimuli. They do not affect mucus secretion or inhibit mucociliary transport. Anticholinergics have a longer onset of action than short-acting b-agonists, taking an hour or more to reach peak therapeutic activity. Their duration of action, however, is approximately an hour longer. These agents have limited use in asthma, but they are widely used for treatment of bronchitis and emphysema. 

Adrenergic agents such as metaproterenol may transiently decrease arterial PO2, but the decrease is rarely of clinical significance. It has been shown that increasing the dose by as much as a factor of four induces improved bronchodilation without introducing adverse effects. Even at higher doses, however, anticholinergic agents do nothing more than relieve symptoms; they have no effect on the natural history of COPD. Whether or not this will change with future approval of long-acting anticholinergics remains to be determined. 

The lung expresses three muscarinic receptor subtypes. The M1 and M3 subtypes appear to mediate bronchoconstriction by promoting transfer of the action potential down from the autonomic nervous system to airway smooth muscle. The M2 subtype, in contrast, appears to be an auto-regulator that turns off further secretion of acetylcholine from the nerve terminal. Anticholinergic agents such as atropine and ipratropium are non-selective with respect to these receptor subtypes, thus inhibiting all of them. Ideally, an anticholinergic bronchodilator would be specific for the M1 and M3 subtypes but would spare M2. Tiotropium, a long-term agent with this specificity, is currently in development. It has been shown in placebo-controlled trials to have residual bronchodilator activity for 32 hours and as many as 48 hours. 

Currently, ipratropium is considered first-line therapy for COPD, and studies have shown that when used in combination with other agents such as salmeterol of formoterol, there are additive benefits. 
 

The Pharmacoeconomics of Bronchodilator Usage in COPD

Most of the $14.7 billion dollar annual direct cost of COPD in the United States is attributable to hospitalizations and to visits to clinicians. Expenses for pharmaceuticals and home care are considerably less. In 1987, the retrospective National Medical Expenditure Study calculated the mean annual expense of COPD to be $6,500, 68% of which was for hospitalizations. It is estimated that in 1995, there were 500,000 COPD-related hospitalizations in the United States. Dr. Friedman began his discussion of pharmacoeconomics by saying that because most hospitalizations result from exacerbations, preventing them is the key to controlling the cost of managing COPD. 

In a 5-year prospective study of 400 patients with COPD, Friedman and Hilleman identified all healthcare costs associated with lung disease ( Hilleman DE et al. Chest. 2000;118:1278).

They found that direct cost was a function of disease severity, and that median healthcare costs remained stable over the 5-year period for each degree of severity. The major cost driver was exacerbations. Of the total study population, 47% of patients had a single exacerbation over 24 months, but 25% had between three and seven. Frequency was associated with both severity of symptoms and reduction of FEV₁. In an earlier study of 173 COPD patients, the mean frequency of exacerbations was 8.5 months with an average of 13 days (Anthoninsen NR et al. Ann Intern Med. 1987;106:196). 

Dr. Friedman hypothesized that maintenance therapy based on inhaled bronchodilators can reduce exacerbations in COPD. He reviewed data from clinical trials indicating that anticholinergics and long-acting b-agonists, individually or in combination, do reduce the frequency (as much as 40%), duration, and cost of hospitalization (Friedman M et al. Chest. 1999;115: 635). From these data and the average wholesale price of bronchodilating agents, he calculated the cost/benefit of maintenance therapy and the overall direct cost savings associated with it (Friedman M et al. Pharmacoecon. 2001;19:245). The total annualized healthcare cost dropped by an average of 29% (range: 12 to 44%) or $277 to $388 for all three regimens compared with albuterol: ipratropium, salmeterol, and albuterol plus ipratropium. Formoterol was not available at the time at which the study was conducted. 

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