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Combination Therapy for Chronic Obstructive Pulmonary Disease

Clinical Aspects

Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to James F. Donohue, M.D., Pulmonary & Critical Care Medicine, University of North Carolina School of Medicine, 4125 Bioinformatics Building, CB#7020, Chapel Hill, NC 27599–7020. E-mail: jdonohue{at}med.unc.edu

	ABSTRACT

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Anticholinergics and ß-agonists reduce bronchoconstriction through different mechanisms, and there is a long history of combination therapy with short-acting agents in these classes for chronic obstructive pulmonary disease. Such combinations may allow lower doses and thereby improve safety. Oral theophylline has also been combined with short-acting bronchodilators for many years. Most studies, however, show only mild improvements in bronchodilation at the expense of increased adverse effects. Professional society guidelines recommend that as the symptoms of chronic obstructive pulmonary disease progress, the patient should receive regular treatment with one or more long-acting bronchodilators, and an inhaled corticosteroid if the patient has repeated exacerbations. The combination of a short-acting anticholinergic with a long-acting ß-agonist, or the combination of a long-acting anticholinergic with a short- or long-acting ß-agonist, has been shown in most studies to improve lung function versus monotherapy with the individual components. Systematic reviews have concluded that fluticasone and salmeterol, and budesonide and formoterol, are superior to placebo and lead to clinically meaningful improvements in lung function, exacerbation rate, and quality of life. Effects on survival are less clear. Some of the other issues to be resolved are the safety of combination therapy, its pharmacoeconomic impact, and the role of newer agents.

Key Words: anticholinergic • ß-agonist • inhaled corticosteroid • theophylline

The goals of therapy for chronic obstructive pulmonary disease (COPD) are to prevent disease progression, relieve symptoms, improve health status, prevent and treat complications and exacerbations, reduce morbidity, and prevent or minimize adverse effects from treatment (1). This article addresses how well combination pharmacologic therapy accomplishes these goals.

Two combination schemes widely used for the treatment of COPD are a short-acting anticholinergic plus a short-acting ß-agonist (SABA), and an inhaled corticosteroid (ICS) plus a long-acting ß-agonist (LABA). The two combinations approved by the Food and Drug Administration for COPD, ipratropium and albuterol, and fluticasone and salmeterol, are respective examples. This article summarizes the research on such combinations and the many other types of combinations that have been tried, including theophylline plus short-acting bronchodilator or LABA, short-acting anticholinergic plus LABA, and long-acting anticholinergic plus SABA or LABA.

The American Thoracic Society/European Respiratory Society guidelines (2) and the Global Initiative for Chronic Obstructive Lung Disease guidelines (1) recommend that as COPD symptoms progress, the patient should receive regular treatment with one or more long-acting bronchodilators, and an ICS if the patient has repeated exacerbations. Nonpharmacologic interventions, offered concurrently with combination therapy, are essential to the management of COPD at all stages of the disease. These include smoking cessation, avoidance of indoor and outdoor pollutants and allergens, and avoidance of occupational exposure to allergens.

	SHORT-ACTING ANTICHOLINERGIC PLUS SABA

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Anticholinergics and ß-agonists reduce bronchoconstriction through different mechanisms, and there is a long history of combination therapy with these drug classes. The use of combinations may allow lower doses and thereby improve safety. A number of lower-dose combinations of short-acting anticholinergics and SABAs have been developed, using ipratropium or oxitropium as the anticholinergic and albuterol, metaproterenol, fenoterol, or terbutaline as the ß-agonist. These agents have been combined in pressurized metered dose inhalers and aerosol solutions. Sin and coworkers pooled data from trials of short-acting anticholinergic and SABA combinations that were at least 3 mo in duration and collectively involved 1,399 patients (3). Combination therapy resulted in a 32% (95% confidence interval [CI], 9–49%) reduction in exacerbations compared with monotherapy, but there was no difference in mortality.

Pressurized Metered Dose Inhalers
The first inhaled combination therapy introduced in the United States was Combivent (Boehringer-Ingelheim, Ridgefield, CT), the combination of ipratropium, 21 µg, and albuterol, 120 µg, given as two puffs of a pressurized metered dose inhaler four times daily. An 85-d multicenter trial of 534 COPD patients compared the combination with either agent alone (4). The combination was superior in peak effect, in the effect during the first 4 h after dosing, and in the total area under the FEV₁ response-time curve (FEV₁ AUC) (Figure 1). The mean peak percentage increases over baseline were 31 to 33% for the combination, 24 to 25% for ipratropium alone, and 24 to 27% for albuterol alone. Symptom scores did not change over time. The advantage of the combination over its individual components became apparent mostly in the first 4 h after administration. As shown in Figure 1, however, combination therapy was as short-acting as monotherapy; improvement in FEV₁ fell to below 15% by 5 h after administration of all three regimens.

View larger version (16K): [in this window] [in a new window]   Figure 1. Short-acting bronchodilatory effect of ipratropium and albuterol in patients with COPD. Reprinted by permission from reference 4.

Combination therapy with ipratropium and albuterol may have a pharmacoeconomic advantage. Friedman and coworkers concluded that compared with ipratropium alone or albuterol alone, ipratropium and albuterol improved FEV₁ and the FEV₁ AUC and reduced exacerbations and length of hospital stay, thereby reducing overall costs (9).

Fenoterol, a SABA not approved in the United States, has been combined with ipratropium (Duovent [ipratropium, 80 µg, and fenoterol, 200 µg]; Boehringer Ingelheim, Ingelheim, Germany) with increased bronchodilator effects. Numerous studies comparing ipratropium and fenoterol with monotherapy with each agent have noted the superior bronchodilator efficacy of the combination. Usually the combination has a substantial bronchodilator effect over the first 3 to 4 h, and one study found that the duration of action was 7 h, versus 6 h for albuterol plus fenoterol, with no increase in adverse effects (10). Huhti and Poukkula observed that subjective adverse effects were more common with fenoterol, 400 µg, than with Duovent or 80 µg ipratropium alone (11). When compared with albuterol, 200 µg, in 24 patients with COPD, ipratropium, 40 µg, plus fenoterol, 100 µg, produced a similar maximal increase in FEV₁ (32 versus 31% with albuterol) and a similar decrease in specific airway resistance (24 versus 21% with albuterol) (12). At 8 h, ipratropium and fenoterol was significantly better than placebo, and in patients responsive to ipratropium at baseline, fenoterol added more bronchodilation (12). In a study of 20 patients with COPD, Grassi and coworkers found that ipratropium, 40 µg, plus fenoterol, 100 µg, was superior to terbutaline, 250 µg, by inhalation at Days 7 and 14 in terms of persistence of bronchodilation (13). Like other ß-agonists, fenoterol mildly stimulates ventilation during exercise, but its effects on heart rate and oxygen uptake are no different from those of placebo, whether at rest or during submaximal or maximal exercise (14).

Another possible use of combination therapy in COPD is for bronchodilator reversibility testing. In two multicenter, 3-mo, randomized controlled trials, 1,067 patients were evaluated for response to ipratropium, albuterol, or the combination (15). Retrospective analysis showed that, using a 12 or 15% increase in FEV₁ to denote a positive response, the combination was superior (p < .05) to the individual agents, and <80% of patients responded to the combination within 30 min. More studies of these outcomes are necessary to determine the value of add-on therapy. Because chlorofluorocarbon-containing pressurized metered dose inhalers are being phased out as a result of environmental safety concerns, studies must be repeated with the new dry powder inhalers and hydrofluoroalkane-containing pressurized metered dose inhalers.

	COMBINATION THERAPY VERSUS MAXIMAL DOSE OF A SINGLE AGENT

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Although maximal bronchodilation can be achieved with a high dose of a single agent, combining two classes of bronchodilators allows the use of lower doses, with the same efficacy results and fewer adverse effects (Table 1). Serra and coworkers studied gradually increasing doses of fenoterol (cumulative doses 100, 200, 400, 800, and 1600 µg), ipratropium (40, 80, 160, 320, and 640 µg), and the combination (100/40, 200/80, and so forth) in nine patients with partially reversible airway obstruction (16). On average, with all three products, the bronchodilatory effect showed a linear correlation with the logarithm of the dose given. Adverse effects, particularly tremor, were less with the combination than with fenoterol alone. The three dose–response curves revealed that in terms of improvement in FEV₁, one puff of ipratropium and fenoterol 100/40 equaled two puffs of fenoterol (200 µg) and four puffs of ipratropium (160 µg). Combining agents made it possible to maintain bronchodilator effects while improving the therapeutic index.

	AEROSOL SOLUTIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Ipratropium and albuterol is also available in an inhalational solution that provides benefits over each separate component with no increase in adverse effects. With this combination there was an increase in acute spirometric response and evening PEF rate in patients with COPD on Day 1, and the improvements persisted for 85 d, longer than the benefits of the individual components (18). In another 12-wk comparison, in 652 patients with COPD, the combination increased peak FEV₁ by 26% over albuterol alone, 28% over ipratropium alone, and the FEV₁ AUC increased over ipratropium alone and albuterol alone (p < .001) (19). Surprisingly, in a study of patients with acute exacerbations of COPD, there was no benefit of nebulized ipratropium and albuterol over albuterol alone with respect to spirometric values or mean length of hospital stay (20).

Ipratropium has also been combined with metaproterenol nebulized inhalant solution, producing similar changes in FEV₁ (21). In a study of 213 patients with COPD, the mean FEV₁ AUC and mean peak responses for FEV₁ and FVC were significantly higher with ipratropium and metaproterenol than with metaproterenol alone on Test Days 1, 43, and 85, and there was no increase in adverse effects. Duration of action was significantly longer for the combination therapy on Test Days 1 and 43. Neither regimen, however, had an appreciable effect on morning PEF rate, respiratory symptoms, or quality of life.

	COMPOUNDED AEROSOL SOLUTIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Recently, there has been an increase in compounding of aerosol solutions (formulation of off-brand products) by pharmacies and other companies, which particularly target patients with COPD who are enrolled in Medicare. This practice is being driven in part by direct-to-consumer advertising on television and by the home health care industry. Strict manufacturing guidelines must be followed, because the pH, osmolarity, and stability of an ipratropium and albuterol mixture must fall within narrow parameters. The quality of the agents produced by unregulated compounding companies has been questioned, especially because some combinations are not manufactured under sterile conditions, and some contain undisclosed solvents or untested mixtures. The Food and Drug Administration has sent stern warning letters to some of the companies. A Food and Drug Administration–approved ipratropium and albuterol formulation, DuoNeb (Dey LP, Napa, CA), is available, and in one study it resulted in 24% greater improvement in peak FEV₁ than was seen with albuterol alone (p < .001), and 37% greater than was seen with ipratropium alone (p < .001) (22). In terms of the FEV₁ AUC, DuoNeb resulted in 30% more improvement than was seen with albuterol alone (p < .001), and 32% more than was seen with ipratropium alone (p < .001). These results are similar to findings from the pivotal trials of Combivent. Physicians caring for patients with COPD need to follow closely the statements on compounding from the Food and Drug Administration and professional societies to ensure that patients receive safe combination aerosol therapy.

	ORAL THEOPHYLLINE PLUS SHORT-ACTING BRONCHODILATOR

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Oral theophylline, a long-acting bronchodilator, has been combined with SABAs or short-acting anticholinergics in the treatment of COPD for many years. The effects of theophylline on exacerbations and mortality are controversial, because most of the older studies were not adequately powered to evaluate these end points. Theophylline does increase FEV₁ and improve arterial blood gases, but it increases nausea sevenfold (3, 23). Anticholinergics are more potent bronchodilators than theophylline in COPD, increasing FEV₁ 31 versus 17% for theophylline (24).

Ram and coworkers (23) recently completed a systematic review of the efficacy of oral theophylline in COPD. FEV₁ and FVC improved with theophylline (weighted mean difference 0.10 L, 95%CI, 0.04–0.16; and weighted mean difference 0.21 L; 95%CI, 0.10–0.32, respectively). There are benefits to theophylline that could be additive.

In a crossover study, 16 patients with severe COPD received high-dose albuterol followed by high-dose theophylline, and the opposite regimen (25). The increase in FEV₁ with albuterol alone was 24% of the baseline value, versus 17% with theophylline alone. The responses to the two agents were additive regardless of which drug was given first. Interestingly, patients with reversibility to albuterol showed a large increase in FEV₁ when theophylline was added (32% of baseline), whereas those with poorly reversible obstruction showed no additional benefit when theophylline was added. These observations raise the question of the risk-benefit ratio of theophylline therapy for patients with poorly reversible obstruction. Others have recommended the opposite: that theophylline be reserved for patients with bronchodilator irreversibility (26).

In a crossover study of 21 patients with COPD, ipratropium and theophylline produced greater increases in FEV₁, maximal oxygen consumption, maximal minute ventilation, and several dyspnea ratios than placebo (27). A parallel-group study of 236 patients with COPD showed that oxitropium, and oxitropium and theophylline, were more effective than theophylline alone in improving FEV₁, PEF rate, and total score and symptom score on the St. George's Respiratory Questionnaire, an instrument for evaluating health status and quality of life (28). The differences were not statistically significant except for evening PEF rate. Nishimura and coworkers added theophylline to ipratropium and albuterol treatment of 24 patients with stable COPD (29). Theophylline had a small bronchodilatory effect at 60 min but did not improve symptoms, although eight patients did experience subjective benefit with theophylline. Karpel and coworkers compared ipratropium alone, theophylline and albuterol, and all three agents in 48 patients with COPD (30). The triple combination was superior in bronchodilatory effect to the other two regimens, but the triple combination and albuterol and theophylline significantly increased peak heart rate compared with ipratropium alone.

Most of the studies of regimens that include theophylline show only mild improvements in bronchodilation at the expense of increased adverse effects. Perhaps more promising is the potential of theophylline to reduce ICS resistance by histone deacetylation inhibition (31).

	COMBINATIONS INCLUDING A LABA OR LONG-ACTING ANTICHOLINERGIC

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Long-acting anticholinergics (glycopyrrolate, which may work for up to 24 h in current formulations, and tiotropium) and LABAs (salmeterol and formoterol) have been combined with short-acting and long-acting agents from other classes.

Short-Acting Anticholinergic plus LABA
Salmeterol, when added to existing anticholinergic therapy in a 6-month trial involving 408 COPD patients, significantly improved trough FEV₁ compared with placebo at 4, 8, and 16 wk (32). The salmeterol group also showed significant improvement in morning PEF rate over 24 wk, and fewer patients in the salmeterol group had exacerbations of COPD compared with the placebo group. In a single-dose trial of 144 patients, salmeterol produced a significant increase in FEV₁ (peak of 7% predicted), and ipratropium and salmeterol elicited a greater bronchodilator response (11% increase) than salmeterol alone during the first 6 h after inhalation (33). Cazzola and coworkers found in a small study that after pretreatment with salmeterol, a low dose of ipratropium produced no further effect, but a high dose of oxitropium (600 µg) given 2 h later increased FEV₁ by 0.152 L (95% CI, 0.124–0.180 L) (34).

Formoterol has also been combined with short-acting anticholinergics. After pretreatment with formoterol, a high dose of oxitropium (600 µg) increased FEV₁ by 0.082 to 0.087 L (35). Ipratropium and formoterol boosted FEV₁ by 335.2 ml (SE 24.6), more improvement than with ipratropium alone (p < .05) (36). Separately, ipratropium and formoterol was significantly more effective than ipratropium and albuterol in 172 patients who remained symptomatic on ipratropium alone, with respect to improving morning PEF rate (p < .0003), FEV₁ AUC (p < .0001), and mean total symptom score (p < .0042) (37).

Long-Acting Anticholinergic plus ß-Agonist
Glycopyrrolate has been compared with metaproterenol alone and in combination. In a study of 11 patients with COPD, the bronchodilating effect of glycopyrrolate was about equal to that of metaproterenol but lasted longer (8 h versus 5 h) (38). The effect of glycopyrrolate and metaproterenol was greater than that of monotherapy (the mean peak percentage improvement in FEV₁ over baseline was 35% for the combination versus 25% for either drug alone). In an urban emergency room, the combination of glycopyrrolate and albuterol was more effective than albuterol alone for patients with COPD with exacerbations (56 versus 19% improvement in FEV₁ from pretreatment value, p = .008) (39).

Cazzola and coworkers compared tiotropium, salmeterol, and the combination in a crossover study of 20 patients with COPD (40). The mean maximal increase in FEV₁ was 0.165 L (95% CI, 0.098–0.232) for tiotropium; 0.241 L (95% CI, 0.151–0.332) for salmeterol; and 0.290 L (95% CI, 0.228–0.353) for the combination. At 12 h the mean increases in FEV₁ from the predosing values were 0.071 L (95% CI, 0.001–0.141; p = .047) for tiotropium; 0.069 L (95% CI, 0.018–0.120; p = .010) for salmeterol; and 0.108 L (95% CI, 0.047–0.170; p = .001) for the combination. The FEV₁ AUCs for 0 to 12 h and 0 to 24 h favored the combination. These clinical changes are small, however, and salmeterol still needed to be dosed twice daily. In contrast, conference abstracts presented on two separate trials of tiotropium and formoterol by van Noord and coworkers found more substantial, statistically significant additive effects on both FEV₁ and FVC (41, 42).

Even when combined with tiotropium, the LABAs provide additional bronchodilatory effects. Whether once-daily administration is sufficient is unclear at this time. That issue may become moot, because new ultra-LABA, such as carmoterol, indacaterol, and R-R' formoterol, are far along in development. These agents should make dosing more convenient and reduce breakthrough symptoms when compared with short-acting agents.

Theophylline plus LABA
Theophylline has been combined with salmeterol in two studies of COPD patients. When theophylline and salmeterol was compared with the individual components, all three groups improved, but the combination produced greater improvement in lung function and decreased symptoms without much increase in adverse effects (43). Compared with fluticasone and salmeterol, however, theophylline and salmeterol resulted in less improvement in FEV₁ (44).

ICS plus LABA
ICS were initially combined with LABAs in the treatment of patients with asthma (45). Compared with monotherapy with the individual components, such combinations provide a significant improvement in all FEV₁ parameters, including peak effect, mean effect, AUC, and trough or predose effect. In asthma, ICS-LABA combinations are not inferior to doubling the ICS dose (46) or possibly even quadrupling the dose (47).

In patients with COPD, the combination of fluticasone and salmeterol increases trough FEV₁, peak FEV₁, mean FEV₁, and the FEV₁ AUC compared with monotherapy (48–50). The combination of fluticasone, 500 µg, and salmeterol, 50 µg, led to improvement on the Transitional Dyspnea Index (50), but it did not increase FEV₁ to a greater extent than fluticasone, 250 µg, and salmeterol, 50 µg (49), so there does not seem to be a dose-response relationship. ICS in high doses, when added to bronchodilator, improved health status without significant improvement in lung function (51). Dal Negro and coworkers reported a marked decrease in exacerbations in patients with COPD previously treated with theophylline who were switched to either fluticasone and salmeterol, salmeterol alone, or placebo (52). The combination works rapidly, with improvement in PEF and breathlessness by Day 2 with salmeterol and the combination versus placebo (53).

Formoterol can be used as a rescue medication, because its onset of action is as rapid as that of albuterol. It has dose–response properties, so higher doses or more frequent doses can be given if patients worsen (54). This principle of flexible or adjustable maintenance dosing has made budesonide and formoterol a popular option for combination therapy delivered by Turbuhaler or pressurized metered dose inhalers in asthma. In patients with COPD, Szafranski and coworkers observed a slight improvement in FEV₁ with the combination over budesonide alone, but the difference was not statistically significant (55). A study by Calverley and coworkers confirmed these findings (56). The two trials differed in that the Calverley study involved treatment with prednisone (30 mg OD) and formoterol for 2 wk before randomization and was larger.

Systematic Reviews of ICS and LABA
Nannini and coworkers performed a systematic review of six studies, collectively involving 4,118 participants with COPD, which compared budesonide and formoterol or fluticasone and salmeterol against monotherapy with the individual components and placebo (57). They determined that both combinations were superior to placebo and led to clinically meaningful improvements in lung function, mean exacerbation rate, and quality of life. Sin and colleagues arrived at similar conclusions when analyzing three of the trials (2,951 patients) (3).

Specifically, in terms of lung function, both combinations led to small but significant differences when compared with monotherapy with the ICS (3, 57). Fluticasone and salmeterol produced a small improvement over salmeterol alone, but budesonide and formoterol was no better than formoterol alone (3, 57). Combination therapy was more effective in improving trough FEV₁ than placebo (101 ml/yr; 95% CI, 76–126 ml/yr); LABA monotherapy (34 ml/y; 95% CI, 11–57 ml/yr); or ICS monotherapy (50 ml/yr; 95% CI, 26–74 ml/yr) (3). The minimal clinically important difference for trough FEV₁ has not been established, but a review suggests that 100 ml correlates with improvement in dyspnea and exacerbations and is in the range of the values found with all Food and Drug Administration–approved long-acting agents (8).

Nannini and coworkers found that exacerbations were less frequent with the combinations than with placebo or LABA alone, but not when compared with ICS alone. The clinical impact was that prevention of one full exacerbation required 2 to 4 yr of combination therapy (57). Sin and coworkers concluded that the ICS and LABA combinations were associated with significantly lower exacerbation rates compared with LABA monotherapy or placebo, but compared with ICS monotherapy there was only a trend toward statistical significance (3).

The Nannini meta-analysis concluded that comparison of fluticasone and salmeterol with fluticasone alone produced conflicting data on quality of life, whereas there was no difference when fluticasone and salmeterol was compared with salmeterol (57). Budesonide and formoterol improved symptoms versus budesonide monotherapy but not formoterol monotherapy, and the comparisons produced conflicting data on quality of life (Table 2). In two studies pooled by Sin and coworkers, the mean improvement in St. George's Respiratory Questionnaire score with combination therapy, compared with placebo, was –2.4 points (95% CI, –3.4 to –1.4), which is below the minimal clinically important difference for this instrument, –4 points (3).

Effect of ICS and LABA on survival.
ICS do not influence the annual decline in FEV₁ that is typical of COPD. Some retrospective observational studies based on administrative data have shown an effect on survival, however, whereas others have not (65, 66). Suissa has proposed that the apparent survival benefit from ICS in COPD is caused by an "immortal time bias," where incident-free periods can be attributed merely to the definitions used in the study, not to the drug itself (65, 66).

Whether ICS-LABA combinations have a survival benefit is even less clear. Sin and coworkers concluded that the effects of both combinations on mortality are uncertain (relative risk versus placebo, 0.52; 95% CI, 0.20–1.34) (3). Using data from the UK General Practice Research Database, Soriano and coworkers showed that survival at Year 3 was more likely for patients with COPD using fluticasone and salmeterol than for those using fluticasone alone or salmeterol alone (64). The more prescriptions of fluticasone or fluticasone and salmeterol that a patient filled, the greater the likelihood of survival. There is controversy about retrospective review of administrative databases, however, so it will be interesting to see survival data from the ongoing TORCH study (toward a Revolution in COPD Health, a prospective comparison of fluticasone, salmeterol, and the combination) (67).

Cardiovascular disease is still the leading cause of death in patients with COPD. Inflammation in COPD and its relationship to coronary plaque instability by circulating cytokines and other markers has recently been investigated. C-reactive protein was a moderate predictor of coronary heart disease (odds ratio, 1.45) in a large nested case-control study conducted in Iceland (68). In a short-term study, fluticasone and prednisone reduced C-reactive protein about 30 to 40% in 41 patients with COPD (69). Using C-reactive protein as a surrogate for coronary risk, fluticasone and salmeterol is being prospectively studied in a large Canadian trial.

	OTHER TWO-DRUG COMBINATIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Because airflow obstruction in COPD is multifactorial, it is logical to investigate drug classes besides bronchodilators and antiinflammatory agents. N-acetylcysteine is a pharmacologic antioxidant that influences various aspects of oxidative stress, including mucus hypersecretion. This agent was combined with inhaled terbutaline in a crossover study of 22 patients with COPD (70). Seventeen of the patients had fewer coughs, less difficulty in raising sputum, and general improvement when they used N-acetylcysteine and terbutaline than when they used placebo and terbutaline. Changes in FEV₁, however, were minimal. In a recently completed 3-yr trial, the addition of N-acetylcysteine apparently did not change the annual rate of decline in FEV₁ or reduce exacerbations in patients with COPD on ICS, but did reduce exacerbations in those not on ICS (71).

The combination of an oral antiinflammatory, such as a phosphodiesterase 4 inhibitor, with a LABA or a long-acting anticholinergic theoretically offers advantages. Little additional benefit is obtained, however, when leukotriene antagonists are added to LABAs (72). Celik and coworkers found slight improvements in pulmonary function tests, dyspnea, and quality of life when montelukast was added to ipratropium and formoterol (73).

	THREE-DRUG COMBINATIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
Many experts have proposed triple-drug therapy for patients with advanced COPD and frequent exacerbations. Three-drug regimens have been tested in asthma, but leukotriene modifiers added little to ICS-LABA combinations (74). In a 12-wk pilot trial of 40 patients with COPD, Yildiz and coworkers added high-dose budesonide to ipratropium and formoterol, which had been used for the prior 3 mo (51). There were no significant changes in spirometry values or arterial blood gases. The proportion of patients achieving the minimal clinically important difference on a Turkish version of the St. George's Respiratory Questionnaire, however, was 70% in the triple-therapy group and 22% in the group that continued on ipratropium and formoterol without ICS.

A small trial of fluticasone, salmeterol, and tiotropium for 1 week resulted in greater improvement in FEV₁ with the triple combination than with fluticasone and either tiotropium or salmeterol (preinhalation FEV₁ 1.32 [0.56]L, [p < 0.03 in both comparisons]; postinhalation FEV₁ 1.49 [0.68] L, [p <.001 in both comparisons]) (75).

The ongoing Canadian Optimal Therapy of COPD Trial, funded by the Canadian Institutes of Health, includes a triple-drug treatment arm and is the first study to compare fluticasone and salmeterol with tiotropium (76). This 1-year randomized, double-blind, placebo-controlled trial is powered to discover whether combinations of inhaled medications reduce exacerbations and optimize disease-specific quality of life. The three treatment arms are tiotropium plus fluticasone and salmeterol, tiotropium and salmeterol, and tiotropium and placebo.

	COMPARISONS OF DIFFERENT COMBINATIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
ICS and LABA versus Short-Acting Anticholinergics and SABA
In a comparison of three different inhaled combinations, Kerstjens and coworkers evaluated ipratropium and terbutaline, beclomethasone ipratropium, and placebo and terbutaline (77). Beclomethasone and terbutaline, but not ipratropium and terbutaline, substantially reduced morbidity, hyperresponsiveness, and airway obstruction. It should be noted, however, that the study population comprised both individuals with asthma and patients with COPD, and 56% had allergies.

Donohue and coworkers compared ipratropium and albuterol given four times daily with twice-daily fluticasone and salmeterol in a 4-wk double-blind study of 352 patients with COPD (78). As shown in Figure 2A, the mean change in FEV₁ favored fluticasone and salmeterol. Improvement in the Transitional Dyspnea Index was a robust 2.7 U with fluticasone and salmeterol versus 1.2 U with ipratropium and albuterol (Figure 2B). The number of patients achieving a change of 1 U, the minimal clinically important difference on the Transitional Dyspnea Index, was 64% for fluticasone and salmeterol versus 44% for ipratropium and albuterol. The findings of this study have been replicated with a similar study and, regardless of baseline characteristics, such as reversibility, smoking status, age, and lung function, the increases in Transitional Dyspnea Index and FEV₁ were greater with fluticasone and salmeterol than with ipratropium and albuterol (79). This probably indicates an advantage of twice-daily fluticasone and salmeterol in stable outpatients over ipratropium and albuterol given four times daily. Frequently in the United States, however, both combinations are prescribed for the same patient, with fluticasone and salmeterol used as the maintenance combination and ipratropium and albuterol used as rescue medication. No studies of concurrent use of the two combinations are available.

View larger version (20K): [in this window] [in a new window]   Figure 2. Comparison of fluticasone, 250 µg, and salmeterol, 50 µg, with ipratropium and albuterol in patients with COPD. (A) Mean change from baseline on 6-hour serial FEV1. *p 0.002 ipratropium and albuterol versus FP/SAL 250/50. p < 0.001 FP/SAL 250/50 versus ipratropium and albuterol. (B) Mean change from baseline on the Transitional Dyspnea Index (TDI). Mean TDI score expressed at end point. *p < 0.001 FP/SAL versus ipratropium and albuterol. Clinically meaningful difference between treatments: 1 unit. Reprinted by permission from reference 78.

In a study of asthma control, there were no differences in efficacy between fixed-dose fluticasone and salmeterol, fixed-dose budesonide and formoterol, and adjustable-dose budesonide and formoterol during a 4-wk double-blind period (81). In the 6-mo open-label extension, there were fewer exacerbations and less need for reliever medication with adjustable-dose budesonide and formoterol. A second 1-yr multicenter trial from Canada, however, reported that the fixed dose of fluticasone and salmeterol, 250 and 50 µg, resulted in fewer exacerbations than the adjustable maintenance dose (82). It will be interesting to make these comparisons in COPD.

	SPECIAL ISSUES IN COMBINATION THERAPY

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Concurrent Versus Sequential Use
One relevant question is whether bronchodilator combinations are less effective than two agents given sequentially. For many years in asthma therapy, a rapid-onset SABA was given first, followed by an ICS to "open up" the airways. In contrast, in treating patients with COPD, an anticholinergic was given before the ß-agonist, because anticholinergics were reputed to have greater central airway bronchodilator effects that enable ß-agonists to be deposited deeper in the lungs. As an example, a 1979 publication by Douglas and coworkers reported the effects of albuterol given 3 h after ipratropium (83). The two agents were similar in improving spirometry values in patients with severe bronchitis, but the combination was superior to either alone.

More recently, Newnham and coworkers administered two different sequences of high and low doses of terbutaline and ipratropium to patients with COPD (84). When terbutaline was given first, there was a significant difference between mean FEV₁ responses to low and high doses of terbutaline, but when ipratropium was given first, there was no difference in response to high-dose versus low-dose terbutaline. The researchers concluded that when ipratropium is given first, there is no benefit of adding a high dose of terbutaline. In contrast, in a study of 16 patients with stable COPD, giving formoterol, 24 µg, followed by oxitropium, 200 µg, 180 min later was more effective than giving oxitropium before formoterol (85). The differences were small: the maximal change in FEV₁ was 28.8% with formoterol followed by oxitropium versus 20.9% with the reverse sequence. There is no compelling evidence that there are benefits to sequencing bronchodilators, and simultaneous use is preferred because it is more convenient.

One Inhaler Versus Separate Inhalers
Using a United Healthcare dataset, Chrischilles and coworkers analyzed the records of 428 patients who used ipratropium and a ß-agonist in one inhaler and those of 658 patients who used separate inhalers (86). They found that use of a two-in-one inhaler was associated with a significantly lower risk of an emergency department visit or hospitalization (relative risk, 0.58; 95% CI, 0.36–0.94); lower mean monthly health care charges (p = .015); shorter hospital stays (2.05 versus 4.61 d, p = .040); and greater likelihood of compliance (odds ratio, 1.77; 95% CI, 1.46–2.14). In a study limited to patients with COPD, Benayoun and coworkers reviewed 1 yr of administrative data on 641 individuals and found that the overall cost of ipratropium and ß-agonist therapy was lower with a two-in-one inhaler than with separate inhalers, even though patients prescribed the combination inhaler used more drug (87). In patients with asthma, one puff of fluticasone and salmeterol through the Advair diskus device (GlaxoSmithKline, Research Triangle Park, NC) resulted in a small increase in morning PEF rate compared with the use of separate inhalers (88). The researchers speculate that delivery of two agents from one device results in better codeposition and hence increased opportunity for synergistic interaction. More studies are needed in COPD, because combination inhalers in asthma are more convenient to use, ensure that the ICS is not discontinued when a bronchodilator is used, and are cost-effective (89).

Effect of Type of Device
Kassner and coworkers recently summarized the pivotal studies of the Respimat Soft Mist Inhaler, a propellant-free inhaler (90). At the time of their report, two phase II studies and two phase III studies in patients with asthma, and a phase III study in patients with COPD had evaluated the efficacy and safety of delivering an ipratropium and fenoterol combination (Berodual; Boehringer Ingelheim, Ingelheim, Germany) by Respimat or by a chlorofluorocarbon-containing pressurized metered dose inhaler. The new device enabled a reduction in the nominal dose of ipratropium and fenoterol because of improved lung deposition. In a separate report, Kilfeather and coworkers describe the results of a similar study, which involved 892 patients with moderate to severe COPD (91). At Day 85, the efficacy and safety of Berodual were similar whether it was delivered by Respimat or a chlorofluorocarbon-containing pressurized metered dose inhalers, and switching from pressurized metered dose inhalers to Respimat was well tolerated.

A study of 38 patients with COPD demonstrated the therapeutic equivalence of Berodual inhaled as a dry powder or by pressurized metered dose inhalers. (92).

Effect of Route of Administration
Recent biopsy evidence of persistent inflammation and obstruction in the small airways of patients with COPD (93) raises the question of systemic delivery of bronchodilators. In patients with more severe disease, more aerosol drug is deposited by impaction in larger airways and less by sedimentation in the peripheral small bronchi. In an early crossover study, the bronchodilator efficacy of oral therapy with aminophylline (400 mg) and terbutaline (5 mg) was compared with that of inhaled albuterol in 17 patients with COPD (94). By 30, 60, and 120 min after administration, albuterol improved FEV₁ significantly more from baseline than did oral therapy. Adverse effects were noted in 13 of the 17 patients after oral therapy and in no patient after albuterol. In 14 patients, maximal bronchodilation was achieved by albuterol alone; the addition of oral therapy produced no further benefit. When using bronchodilators in COPD, the inhaled route is preferred over oral dosing because of greater efficacy and safety. Orally administered agents have not as yet demonstrated any superiority except for patients who cannot use inhalers. Smaller particles, as in the new hydrofluoroalkane-containing pressurized metered dose inhalers, theoretically are deposited more peripherally, but this has not been confirmed because of difficulties in studying the small airways.

Effect of Gender
Women have greater susceptibility to COPD progression than men, with greater hyperresponsiveness to methacholine, more deaths, and greater annual decline in FEV₁ if persistently smoking. Nevertheless, few studies have explored sex differences in response to COPD therapy. Vestbo and coworkers did evaluate the effect of sex on response to fluticasone and salmeterol in the TRISTAN (TRial of Inhaled STeroids ANd long-acting ß₂-agonists) study (95). Compared with placebo, combination therapy improved pretreatment FEV₁ by 152 ml (95% CI, 95–208) in women and by 127 ml (95% CI, 94–159) in men; reduced exacerbation rates by 31% (95% CI, 9–48%) in women and by 23% (95% CI, 8–35%) in men; and improved health status, changing the St. George's Respiratory Questionnaire score by –2.3 points (95% CI, –4.6 to –0.1) in women versus –2 points (95% CI, –3.5 to –0.8) in men. Fluticasone and salmeterol was effective in both sexes. There was no difference between sexes in the incidence of adverse effects.

Annual Decline in FEV₁
Few data are available so far about the effect of combination therapy on the annual rate of decline in FEV₁, because studies 3 yr or longer in duration are required. Smoking cessation reduces the rate of decline from 60 to 30 ml/yr (96). Ipratropium, ICS, and N-acetylcysteine do not influence the rate of decline (96). The effects of augmentation with ₁-antitrypsin therapy have been inconclusive, with the nonrandomized National Heart, Lung and Blood Institute Registry showing an effect, whereas the results of a controlled study were negative (97). Tiotropium is presently being compared with placebo in a 3-yr trial (UPLIFT) (98). The ongoing TORCH study will provide important information about the effect of fluticasone and salmeterol on FEV₁. (66).

	CONCLUSIONS

TOP ABSTRACT SHORT-ACTING ANTICHOLINERGIC... COMBINATION THERAPY VERSUS... AEROSOL SOLUTIONS COMPOUNDED AEROSOL SOLUTIONS ORAL THEOPHYLLINE PLUS SHORT... COMBINATIONS INCLUDING A LABA... OTHER TWO-DRUG COMBINATIONS THREE-DRUG COMBINATIONS COMPARISONS OF DIFFERENT... SPECIAL ISSUES IN COMBINATION... CONCLUSIONS REFERENCES

 
It is known that combining drug classes, especially the bronchodilators, is useful in the treatment of COPD. Combinations of bronchodilators improve effectiveness, improve compliance, and reduce costs without increasing adverse effects. In addition, ICS-LABA combinations seem to be superior to placebo with respect to lung function, exacerbations, and quality of life. There are conflicting results, however, when ICS-LABA combinations are compared with the individual components, except in terms of lung function. More studies are needed that compare higher doses and different classes, such as ICS-LABA versus anticholinergic and theophylline, and ICS-LABA versus anticholinergic and phosphodiesterase 4 inhibitor.

More data are also needed about:

• The safety of combination therapy
  
• The effects of combinations on outcomes that are meaningful to patients, such as dyspnea caused by hyperinflation
  
• Whether the beneficial effects of ICS-LABA are restricted to older patients with more severe disease (e.g., FEV₁ <50% predicted), as one study has shown (99), or those with frequent exacerbations
  
• Whether there is an optimal combination (e.g., anticholinergic and LABA, ICS-LABA, anticholinergic-ICS-LABA, ICS and theophylline, anticholinergic and LABA and phosphodiesterase 4 inhibitor
  
• The role of newer agents (e.g., ciclesonide, R*R1, formoterol, QAB149) in combination therapy
  
• The comparison of two-in-one inhalers versus separate administration of two drugs
  
• The effect of combination therapy on survival
  
• The effects of combination therapy on airway inflammation, including the small airways
  
• The long-term benefits of combination therapy
  
• The pharmacoeconomic impact of combination therapy
  

Research into combination therapy for COPD is a dynamic area that has caused a great deal of interest and enthusiasm, and clinicians can look forward to many more developments in the near future.

	FOOTNOTES

 
Conflict of Interest Statement: J.F.D. has received $2000 from DEY for serving on an Advisory Board in 2004; $4,000 in 2003 and $4,000 in 2004 from AstraZeneca for serving on an Advisory Board; $8,000 from Boehringer Ingelheim Pharmaceuticals and Pfizer for serving on an Advisory Board; $8,000 yearly for lectures from Boehringer Ingelheim; and $8,000 yearly 3 years from GlaxoSmithKline for serving as a consultant and serving on their Advisory Board. The University of North Carolina has research contracts with each of these entities and Dr. Donohue serves as principal investigator.

(Received in original form May 9, 2005; accepted in final form July 13, 2005)

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