Introduction

See Section 1, "Overall Methods Used To Develop This Report," for the literature search strategies and tallies of results used to update each class of medication discussed in this section. Evidence Tables were prepared for: 11, Inhaled Corticosteroids: Combination Therapy; 12, Inhaled Corticosteroids: Dosing Strategies; 13, Immunomodulators: Anti-IgE; 14, Leukotriene Receptor Antagonists: Monotherapy/Effectiveness Studies; 15, Bronchodilators: Safety of Long-Acting Beta₂-Agonists; 16, Bronchodilators: Levalbuterol.

Pharmacologic therapy is used to prevent and control asthma symptoms, improve quality of life, reduce the frequency and severity of asthma exacerbations, and reverse airflow obstruction. Recommendations in this "Component 4: Medications," reflect the scientific concepts that asthma is a chronic disorder with recurrent episodes of airflow limitation, mucus production, and cough and that the severity of the underlying asthma may vary over time. Asthma medications are categorized into two general classes: long-term control medications taken daily on a long-term basis to achieve and maintain control of persistent asthma (these medications are also known as long-term preventive, controller, or maintenance medications) and quick-relief medications taken to provide prompt reversal of acute airflow obstruction and relief of accompanying bronchoconstriction (these medications are also known as reliever or rescue medications). Patients who have persistent asthma require both classes of medication. Figures 3-22 and 3-23 present summaries of the indications, mechanisms, potential adverse effects, and therapeutic issues for currently available long-term control and quick-relief medications. The discussion in this component includes the following: an overview of asthma medications—both long-term control and quick-relief—and an overview of complementary alternative medicine strategies.

Figure 3-22

LONG-TERM CONTROL MEDICATIONS

Figure 3-23

QUICK-RELIEF MEDICATIONS

Overview of the Medications

LONG-TERM CONTROL MEDICATIONS

The Expert Panel recommends that long-term control medications be taken daily on a long-term basis to achieve and maintain control of persistent asthma. The most effective long-term-control medications are those that attenuate the underlying inflammation characteristic of asthma (Evidence A).

Long-term control medications include ICSs, inhaled long-acting bronchodilators, leukotriene modifiers, cromolyn, theophylline, and immunomodulators. Because eosinophilic and lymphocytic inflammation is a constant feature of the mucosa of the airways in asthma, the most effective long-term control medications are those that attenuate inflammation (Haahtela et al. 1991; Kerrebijn et al. 1987; Van Essen-Zandvliet et al. 1992). The Expert Panel defines anti-inflammatory medications as those that cause a reduction in the markers of airway inflammation in airway tissue or airway secretions (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, and cytokines; or ECP and tryptase; or extravascular leakage of albumin, fibrinogen, or other vascular protein) and thus decrease the intensity of airway hyperresponsiveness. Because many factors contribute to the inflammatory response in asthma, many drugs may be considered anti-inflammatory. It is not yet established, however, which anti-inflammatory actions are responsible for therapeutic effects, such as reduction in symptoms, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, or prevention of airway wall remodeling.

Inhaled Corticosteroids

Mechanism

The Expert Panel concludes that ICSs are the most potent and consistently effective long-term control medication for asthma (Evidence A). The broad action of ICSs on the inflammatory process may account for their efficacy as preventive therapy. Their clinical effects include reduction in severity of symptoms; improvement in asthma control and quality of life; improvement in PEF and spirometry; diminished airway hyperresponsiveness; prevention of exacerbations; reduction in systemic corticosteroid courses, ED care, hospitalizations, and deaths due to asthma; and possibly the attenuation of loss of lung function in adults (Barnes et al. 1993; Barnes and Pedersen 1993; Dahl et al. 1993; Fabbri et al. 1993; Gustafsson et al. 1993; Haahtela et al. 1991; Jeffery et al. 1992; Kamada et al. 1996; Pauwels et al. 2003; Rafferty et al. 1985; Suissa et al. 2000; Van Essen-Zandvliet et al. 1992).

Which of these clinical effects depend on specific anti-inflammatory actions of corticosteroids is not yet clear. Corticosteroids suppress the generation of cytokines, recruitment of airway eosinophils, and release of inflammatory mediators. These anti-inflammatory actions of corticosteroids have been noted in clinical trials and analyses of airway histology (Booth et al. 1995; Busse 1993; Djukanovic et al. 1992; Duddridge et al. 1993; Laitinen et al. 1991, 1992; Levy et al. 1995; McGill et al. 1995). The anti-inflammatory effects of corticosteroids are mediated through receptors that modulate inflammatory gene expression.

ICSs do not have the same bioavailability as oral systemic corticosteroids; hence, the risk of potential side effects is substantially reduced with ICSs.

Inhaled Corticosteroid Insensitivity

The Expert Panel concludes that sensitivity and consequently clinical response to ICS can vary among patients (Evidence B).

Variation in sensitivity to ICS therapy may be related to high levels of inflammation, corticosteroid-insensitive pathways, or structural changes refractory to corticosteroid therapy (Leung and Bloom 2003). Corticosteroid responsiveness is decreased in smokers (Chalmers et al. 2002; Chaudhuri et al. 2003) and persons who have asthma with predominantly neutrophilic inflammation (Gauvreau et al. 2002; Green et al. 2002). Also, African American children who have poor control of their asthma appear to have an increased risk for corticosteroid insensitivity; this could be related to diminished glucocorticoid responsiveness at the cellular level, specifically T lymphocytes (Chan et al. 1998; Federico et al. 2005).

Efficacy of Inhaled Corticosteroids as Compared to Other Long-Term Control Medications as Monotherapy

The Expert Panel concludes that studies demonstrate that ICSs improve asthma control more effectively in both children and adults than LTRAs or any other single long-term control medication (Evidence A).

For the EPR—3: Full Report 2007, the evidence of the efficacy of ICS therapy compared to other single daily long-term control medications in patients ≥5 years of age was obtained from nine randomized trials, most of which compared ICS to LTRA; five of these trials had placebo control groups (Garcia-Garcia et al. 2005; Ostrom et al. 2005; Szefler et al. 2002, 2005; Zeiger et al. 2006). These studies confirm findings discussed in EPR—Update 2002. Patients who have mild or moderate persistent asthma and are treated with ICS, compared to other single long-term control medications, demonstrate greater improvements in prebronchodilator FEV₁; reduced airway hyperresponsiveness, symptom scores, exacerbation rates, and symptom frequency; as well as less use of supplemental SABA, fewer courses of oral systemic corticosteroids, and less use of hospitalization. The evidence does not suggest, however, that ICS use is associated with improved long-term postbronchodilator FEV₁ (CAMP 2000).

Studies comparing ICS to cromolyn or theophylline are limited, but available evidence shows that neither of these long-term control medications appears to be as effective as ICS in improving asthma outcomes.

Efficacy of Inhaled Corticosteroid and Adjunctive Therapy (Combination Therapy)

The Expert Panel recommends that when patients ≥12 years of age require more than low-dose ICS alone to control asthma (i.e., step 3 care or higher), a therapeutic option is to add LABA to ICS (Evidence A). Alternative, but not preferred adjunctive therapies include LTRA (Evidence B), theophylline (Evidence B), or, in adults, zileuton (Evidence D). (See Evidence Table 11, Inhaled Corticosteroids: Combination Therapy.) For children 0–11 years of age, LABA, LTRA, and, in children 5–11 years of age, theophylline may be considered as adjunctive therapies in combination with ICS (Evidence B, based on extrapolation from studies in older children and adults; see also section 4, "Managing Asthma Long Term" for recommendations on adjunctive therapies at different steps of care for different age groups in children).

Although numerous studies have examined adjunctive therapy in adults, adjunctive therapy has not been studied adequately in children 5–11 years of age, and it has not been evaluated at all in children less than 4 years of age. An extensive review of the literature on this topic, conducted for the EPR—Update 2002, concluded that strong evidence in adults and older children indicates that the combination of ICS and LABA leads to improvements in lung function and symptoms and reduced need for quick-relief SABA. Adding an LTRA or theophylline to ICS or doubling the dose of ICS also was shown to improve outcomes, but the evidence was not as substantial as with the addition of LABA (EPR—Update 2002).

The current review of the evidence supports this conclusion. The 2006 evidence review included studies comparing the combination of ICS and LABA to either baseline dose of ICS (two articles) or increasing doses of ICS (eight articles); comparing the combination of ICS and LTRA to baseline doses of ICS (three articles) or increasing doses of ICS (one article); comparing the combination of ICS and LABA to ICS and LTRA (seven articles); and comparing the combination of ICS and one LABA to another LABA (two articles), as well as three Cochrane Review meta-analyses (See Evidence Table 11, Inhaled Corticosteroids: Combination Therapy for complete citations.). The weight of the evidence reviewed continues to demonstrate that the addition of LABA to ICS leads to greater improvement in lung function, symptoms, and less use of SABA than increasing the dose of ICS or using LTRA as adjunctive therapy. Studies on the addition of LTRA to ICS have limitations that preclude conclusions, although the studies reveal a trend showing that LTRA improved lung function and some but not all trials report improvements in some measures of asthma control (See also the section below on "Leukotriene Modifiers."). Recent data indicate potential risks that need to be considered for uncommon but life-threatening exacerbations associated with the daily use of LABAs (See the section below on "Safety of Inhaled Long-Acting Beta₂-Agonists."). See also section 4 on "Managing Asthma Long Term" for a discussion of issues to consider regarding combination therapy compared to increasing the dose of ICS.

Dose-Response and Delivery Device

The Expert Panel concludes that dosages for ICSs vary, depending upon the specific product and delivery devices. (See figure 3-24 for issues on delivery devices; see figures 4-4b, and 4-8b in section 4, "Managing Asthma Long Term," for comparative ICS dosages.) For all ICS preparations, the dose-response relationship appears to flatten in patients who have mild or moderate asthma for most clinical parameters and lung function in the low- to medium-dose range (Evidence C).

Figure 3-24

AEROSOL DELIVERY DEVICES

Although most of the benefits of treatment are achieved with a low dose, the dose-response to ICS may vary, based on the response measured (e.g., improvement in lung function, prevention of exacerbations, or improvement in bronchial hyperresponsiveness, individual variability in response to ICS, and disease severity). Several studies show that for patients who have mild or moderate persistent asthma, use of higher doses improves asthma control modestly if at all (Bousquet et al. 2002; Holt et al. 2001; Kemp et al. 2000; Masoli et al. 2004a; Nayak et al. 2000; Powell and Gibson 2003; Szefler and Eigen 2002). However, the dose-response continued to improve at a higher dose for patients who have severe asthma (Masoli et al. 2004b). This efficacy of low-dose ICS therapy may account for the success of once-per-day treatment of patients who have mild or moderate persistent asthma, using several ICS preparations—both ICS alone (Casale et al. 2003; Jonasson et al. 2000; Jones et al. 1994; Noonan et al. 2001; Pincus et al. 1995) and in combination with LABA (Buhl et al. 2003). This efficacy may also account for the finding that mild and moderate asthma are as well controlled by starting treatment with a low, standard dose of an ICS as by starting with a high dose (Chanez et al. 2001; Reddel et al. 2000). These generalizations may not apply to patients who have more severe, uncontrolled asthma or to patients who have frequent, severe exacerbations. In these patients, twice-daily therapy with a higher dose may be necessary (Noonan et al. 1995; Pauwels et al. 1997), although control is achieved in a higher proportion of patients, and at a lower ICS dose, when it is given in combination with a LABA (Bateman et al. 2003, 2004).

Variability in Response and Adjustable Dose Therapy

The Expert Panel recommends that, given the variations over time in the severity of the pathophysiologic processes underlying asthma, it may be useful to adjust anti-inflammatory therapy accordingly (Evidence B). (See Evidence Table 12, Inhaled Corticosteroids: Dosing Strategies.)

Several studies have shown that, for most patients whose asthma has been well controlled for at least 2 months by a high dose of an ICS alone, a 50 percent reduction in dose does not lead to loss of control (Aalbers et al. 2004; Hawkins et al. 2003; Leuppi et al. 2003; Thoonen et al. 2003). This finding does not mean, however, that treatment with an ICS can be stopped altogether, for studies show that asthma control in most patients can worsen within a few weeks when treatment is discontinued (CAMP 2000; Dahl et al. 2002). Trials are now focusing on clinical features or "biomarkers" to distinguish between those patients who need continued treatment and those in whom it can be reduced or discontinued (Deykin et al. 2005; Leuppi et al. 2003).

Whether ICS treatment should be increased temporarily in response to some index of worsening asthma is also being examined. The effectiveness of this adjustable dose approach may be a function of timing or of dose. When asthma symptoms have worsened to the point of qualifying as an asthma exacerbation (See section 5 on "Managing Exacerbations of Asthma" for definition.), simply doubling the regular maintenance dose of ICS treatment does not appear to be effective (FitzGerald et al. 2004; Harrison et al. 2004). Studies that have shown benefit to patients from treatment with an adjustable dose regimen have employed greater increase in the dose of ICS (e.g., fourfold) and/or have made this adjustment earlier, at the first appearance of worsening symptoms (Aalbers et al. 2004; Boushey et al. 2005; Foresi et al. 2000; Harrison et al. 2004; Ind et al. 2004; Leuppi et al. 2003; Reddel and Barnes 2006; Thoonen et al. 2003). An interesting application of this approach was made possible by the development of an inhaler containing both budesonide (an ICS) and formoterol (a LABA with a rapid onset of action). Although this product does not have approved labeling for use as an acute quick-relief medication, one study has shown that use of a low dose of budesonide from this combination inhaler twice daily (maintenance therapy) plus additional use for relief of symptoms (adjustable therapy) was associated with a lower rate of asthma exacerbations and a lower cumulative dose of budesonide than was twice daily treatment with a fourfold greater dose of budesonide alone (Bisgaard et al. 2006; O'Byrne et al. 2005; Rabe et al. 2006).

Another approach to adjustable therapy with an ICS is to link the dose adjustments to measurement of a biomarker of airway inflammation. Three biomarkers have been examined: bronchial reactivity to methacholine (Sont et al. 1999), sputum eosinophils (Green et al. 2002), and the concentration of nitric oxide in exhaled air (FeNO) (Smith et al. 2005). In these studies, biomarker-adjusted therapy reduced the rate of asthma exacerbations. In two of the studies (Green et al. 2002; Smith et al. 2005), the cumulative dose of ICS was reduced as well as in comparison to standard maintenance therapy alone.

Safety of Inhaled Corticosteroids

KEY POINTS: SAFETY OF INHALED CORTICOSTEROIDS

• ▪ ICSs are the most effective long-term therapy available for mild, moderate, or severe persistent asthma; in general, ICSs are well tolerated and safe at the recommended dosages (Evidence A).
• ▪ The potential but small risk of adverse events from the use of ICS treatment is well balanced by their efficacy (Evidence A).
• ▪ The dose-response curve for ICS treatment begins to flatten for many measures of efficacy at low to medium doses, although some data suggest that higher doses may reduce the risk of exacerbations. Most benefit is achieved with relatively low doses, whereas the risk of adverse effects increases with dose (Evidence B).
• ▪ To reduce the potential for adverse effects, the following measures are recommended:

  • — Spacers or valved holding chambers (VHCs) used with non-breath-activated MDIs reduce local side effects (Evidence A), but there are no data on use of spacers with ultra fine particle hydrofluoroalkane (HFA) MDIs.
  • — Advise patients to rinse their mouths (rinse and spit) after inhalation (Evidence B).
  • — Use the lowest dose of ICS that maintains asthma control. Evaluate patient adherence and inhaler technique as well as environmental factors that may contribute to asthma severity before increasing the dose of ICS (Evidence B).
  • — To achieve or maintain control of asthma, consider adding a LABA to a low or medium dose of ICS rather than using a higher dose of ICS (Evidence A).
  • — For children, monitor growth (Evidence A). See "Key Points: Inhaled Corticosteroids and Linear Growth in Children."
  • — In adult patients, consider supplements of calcium (1,000–1,500 mg per day) and vitamin D (400–800 units a day), particularly in perimenopausal women (Evidence D). Bone-sparing therapy (e.g., bisphosphonate), where appropriate, may be considered for patients on medium or high doses of ICS, particularly for those who are at risk of osteoporosis or who have low bone mineral density (BMD) scores by dual energy x ray absorptiometry (or DEXA) scan (Evidence C). In children, age-appropriate dietary intake of calcium and exercise should be reviewed with the child's caregivers (Evidence D).

The Expert Panel concludes that ICSs are the most effective long-term therapy available for patients who have persistent asthma and, in general, ICSs are well tolerated and safe at the recommended dosages (Evidence A). Systemic activity has been identified, particularly at high doses (See figures 4-4b and 4-8b.), for a definition of high-, medium-, and low-dose ICSs), but their clinical significance remains unclear (Leone et al. 2003). Furthermore, there may be interindividual variations in dose-response effects; thus, some patients may experience effects at lower doses. See Key Points, above, for a summary of recommendations to minimize the potential for adverse effects. In general, the potential for adverse effects must be weighed against the risk of uncontrolled asthma; to date, evidence supports the use of ICS, especially at low and medium doses (Barnes et al. 1993; CAMP 2000; EPR—Update 2002; Leone et al. 2003; Tinkelman et al. 1993; Van Essen-Zandvliet et al. 1992).

The Expert Panel recommends the following actions to minimize potential adverse effects of ICS. Specific recommendations and evidence rank are presented under "Prevention and Treatment."

Local Adverse Effects

Oral candidiasis (thrush) is one of the most common adverse effects of ICSs. Positive throat cultures of Candida can be identified in about 45–58 percent of patients, whereas clinical thrush is diagnosed in only 0–34 percent of patients (Rinehart et al. 1975; Shaw and Edmunds 1986; Toogood et al. 1980). With lower dosages of ICS, candidiasis is uncommon (5 percent) (Rinehart et al. 1975), although it is more frequent in adults than in children. Prevention and Treatment: Use a spacer or VHC with a non-breath-activated MDI to reduce the incidence of colonization and clinical thrush; rinse mouth with water after inhalation (Selroos and Halme 1991). No data are available on the use of spacers or VHCs with ultrafine-particle-generated HFA MDIs. Administer ICS less frequently (bid versus qid). Topical or oral antifungal agents should be used to treat active infections (EPR—2 1997).

Dysphonia is reported in 5–50 percent of patients who use an ICS and is associated with vocal stress and increasing dosages of ICS (Toogood et al. 1980). Prevention and Treatment: Use a spacer or VHC with a non-breath-activated MDI, temporarily reduce dosage, or rest for vocal stress (EPR—2 1997).

Reflex cough and bronchospasm. Prevention and Treatment: These effects can be reduced by slower rates of inspiration and/or use of a spacer or valved holding chamber or by pretreatment with SABA. There is no convincing evidence that the routine use of a SABA before each dose of ICS increases intrapulmonary delivery of the ICS or reduces dosage requirement (EPR—2 1997).

Systemic Adverse Effects

Linear growth

A reduction in growth velocity may occur in children or adolescents as a result of inadequate control of chronic diseases such as asthma or from the use of corticosteroids for treatment. Overall, however, the available cumulative data about children suggest that, although low or medium doses of ICS may have the potential of decreasing growth velocity, the effects are small, nonprogressive, and may be reversible (CAMP 2000; Guilbert et al. 2006; Leone et al. 2003). Furthermore, studies of early intervention with low- or medium-dose ICS showed significantly improved asthma outcomes, despite a small reduction in growth velocity (Guilbert et al. 2006; Pauwels et al. 2003).

The long-term prospective studies on growth involved budesonide, the retrospective analyses included studies on beclomethasone, and several shorter term studies have been performed on a variety of moieties, but the results have been generalized to include all ICS preparations. Although different preparations and delivery devices may have a systemic effect at different doses, all short-term studies on numerous preparations suggest that the effect of ICS on growth is a drug-class effect. When high doses of ICS are necessary to achieve satisfactory asthma control, the use of adjunctive long-term control therapy should be initiated to reduce the dose of ICS and thus minimize possible dose-related long-term effects on growth. Prevention and Treatment: Physicians should monitor the growth of children and adolescents who are taking corticosteroids by any route and should weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression or delay if a child's or an adolescent's growth appears slowed (Evidence D).

KEY POINTS: INHALED CORTICOSTEROIDS AND LINEAR GROWTH IN CHILDREN

In the opinion of the Expert Panel:

• ▪ The potential risks of ICSs are well balanced by their benefits.
• ▪ Growth rates are highly variable in children. Short-term evaluations may not be predictive of final adult height attained.
• ▪ Poorly controlled asthma may delay growth in children.
• ▪ In general, children who have asthma tend to have longer periods of reduced growth rates before puberty (males more than females).
• ▪ The potential for adverse effects on linear growth from ICS appears to be dose dependent. In treatment of children who have mild or moderate persistent asthma, low- to medium-dose ICS therapy may be associated with a possible, but not predictable, adverse effect on linear growth. The clinical significance of this potential systemic effect has yet to be determined. High doses of ICS have greater potential for growth suppression.
• ▪ Use of high doses of ICS by children who have severe persistent asthma has significantly less potential than use of oral systemic corticosteroids for having an adverse effect on linear growth.
• ▪ Studies in which growth has been carefully monitored suggest the growth-velocity effect of ICS occurs in the first several months of treatment and is generally small and nonprogressive.
• ▪ In general, the efficacy of ICSs is sufficient to outweigh any concerns about growth or other systemic effects. However, ICSs, as with any medications, should be titrated to as low a dose as needed to maintain good control of the child's asthma.

Bone mineral density

Low and medium doses of ICS appear to have no serious adverse effects on BMD in children (CAMP 2000; Roux et al. 2003). A small, dose-dependent reduction in BMD may be associated with ICS use in patients older than 18 years of age (Ip et al. 1994; Israel et al. 2001), but the clinical significance of these findings is not clear. A large observational study of older patients (>65 years of age) with prolonged use of ICS showed that, at <2,000 mcg/day of beclomethasone or equivalent, there was no increase in the risk of fractures (Suissa et al. 2004). Data in adults suggest a cumulative dose relationship to the effects of ICS on BMD (Wong et al. 2000). Prevention and Treatment: In patients who have risk factors for osteoporosis or low BMD scores, consideration can be given to bone-protecting therapies (e.g., bisphosphonates), although data are mixed in supporting the use of these therapies specifically in asthma patients who are taking ICS (Campbell et al. 2004; Kasayama et al. 2005) (Evidence C). Measuring BMD may be considered every 1–2 years, depending on duration and dose of ICS and oral corticosteroid treatment as well as previous BMD scores (Evidence D).

Disseminated varicella

Although high doses of ICS theoretically present risks similar to those of systemic corticosteroid treatment, the reports of disseminated varicella in patients receiving only ICS are rare, causality is not clear, and there is no evidence that recommended doses of the ICSs are immunosuppressive. Cases have been reported of children who have severe persistent asthma, and are taking immunosuppressive doses of systemic corticosteroids, developing fatal disseminated disease from varicella infection (Kasper and Howe 1990; Silk et al. 1988). Other case reports indicate complications for patients who have Strongyloides or tuberculosis and who take high doses of systemic corticosteroids. Prevention and Treatment of Varicella: Children who require episodic therapy with systemic corticosteroids and who have not had clinical varicella should receive the varicella vaccine (EPR—2 1997). The vaccine should not be administered to patients who are receiving immunosuppressive doses of systemic corticosteroids (2 mg/kg or more of prednisone equivalent or 20 mg/day of prednisone for more than 1 month), unless this dosage is discontinued for at least 1 month. Children who have completed a short prednisone course may receive varicella vaccine without delay (American Academy of Pediatrics 1995; CDC 1994). Children and adults on treatment with immunosuppressive doses of corticosteroids who have not been immunized against varicella and are exposed to varicella infection are candidates for oral antiviral therapy (e.g., valacyclovir). If they develop clinical varicella, intravenous antiviral therapy should be given (EPR—2 1997).

Dermal thinning and increased ease of skin bruising

These effects have been observed in patients treated with ICS. The effect is dose dependent, but the threshold dose is variable (Capewell et al. 1990).

Ocular effects

In children, low- and medium-dose ICS therapy appears to have no significant effects on the incidence of subcapsular cataracts or glaucoma (CAMP 2000). In adults, high cumulative lifetime exposure (greater than 2,000 mg of beclomethasone dipropionate or equivalent) to ICS may increase the prevalence of cataracts, as suggested in three retrospective studies of adult and elderly patients (Evidence C) (Cumming et al. 1997; Garbe et al. 1998; Jick et al. 2001). A retrospective, case-control study showed an association between long-term ICS use and the development of glaucoma (Garbe et al. 1997). A subsequent cross-sectional, retrospective study in adults reported an association between elevated intraocular pressure and glaucoma in patients who had a family history of glaucoma and used ICS, particularly at higher doses (defined in this study as more than 4 puffs per day). There was no increase in risk in ICS users who did not have a family history of glaucoma (Mitchell et al. 1999). Prevention and Treatment: These data suggest the advisability of periodic assessments and treatments, if indicated, for increased intraocular pressures in asthma patients who use ICS, particularly at higher doses, and have a family history of glaucoma (Evidence C).

Hypothalamic-pituitary-adrenal axis function

The available evidence indicates that, on average, children may experience only clinically insignificant, if any, effects of low- or medium-dose ICS on the hypothalamic-pituitary-adrenal (HPA) axis (Leone et al. 2003). Rarely, however, some individuals may be more susceptible to the effects of ICS even at conventional doses.

Glucose metabolism

In a study of children, ICS at dosages from 400 to 1,000 mcg/day (budesonide) did not affect fasting glucose or glycosolated hemoglobin. At 1,000 mcg/day, a significantly greater rise in fasting serum insulin levels and glucose during a glucose tolerance test was noted, but results remained within normal limits (Turpeinen et al. 1991).

Oral Systemic Corticosteroids

The Expert Panel recommends that chronic administration of oral systemic corticosteroids as a long-term-control medication be used only for the most severe, difficult-to-control asthma because of well-documented risk for side effects (EPR—2 1997).

The Expert Panel recommends that, because the magnitude of adverse effects is often related to the dose, frequency of administration, and the duration of corticosteroid use (Evidence A), every consideration should be given to minimize systemic corticosteroid doses and maximize other modes of therapy (Evidence D). It is necessary, therefore, to monitor for the development and progression of adverse effects and to take appropriate steps to minimize the risk and impact of adverse corticosteroid effects (Evidence D).

Oral systemic corticosteroids suppress, control, and reverse airway inflammation. However, side effects with chronic administration include adrenal suppression, growth suppression, dermal thinning, hypertension, Cushing's syndrome, cataracts, and muscle weakness. Chronic corticosteroid use can also result in immunologic attenuation with loss of delayed-type hypersensitivity, diminished immunoglobulin G (IgG) levels without change in functional antibody response, potential for reactivation of latent tuberculosis infection, and possible increased risk for infection, especially the development of severe varicella (Spahn et al. 2003).

Cromolyn Sodium and Nedocromil

Cromolyn and nedocromil are alternative, not preferred, medications for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment before exercise or unavoidable exposure to known allergens (EPR—2 1997). Although cromolyn and nedocromil have distinct properties (Clark 1993), they have similar anti-inflammatory actions. The mechanism of cromolyn and nedocromil appears to involve the blockade of chloride channels (Alton and Norris 1996) and modulate mast cell mediator release and eosinophil recruitment (Eady 1986). The two compounds are equally effective against allergen challenge (Gonzalez and Brogden 1987), although nedocromil appears to be more potent than cromolyn in inhibiting bronchospasm provoked by exercise (de Benedictis et al. 1995; Novembre et al. 1994), by cold dry air (Juniper et al. 1987), and by bradykinin aerosol (Dixon and Barnes 1989).

Dosing recommendations for both nedocromil and cromolyn are for administration four times a day, although nedocromil has been shown to be clinically effective with twice-daily dosing (Creticos et al. 1995; EPR—2 1997).

Cromolyn sodium and nedocromil have been shown to provide symptom control greater than placebo in some but not all clinical trials (Konig 1997; Petty et al. 1989; Tasche et al. 2000) and to confer protection against exacerbations of asthma leading to hospitalization, particularly in children (Donahue et al. 1997), and ED visits (Adams et al. 2001). These results, along with the excellent safety profile, justify consideration of cromolyn and nedocromil as treatment options. However, a systematic review (van der Wouden et al. 2003) concluded that insufficient evidence existed to conclude that cromolyn had a beneficial effect on maintenance treatment of childhood asthma. Compared to placebo, nedocromil reduces both urgent care visits as well as the need for prednisone, which are meaningful clinical outcomes. However, nedocromil is no different than placebo on all other outcome measures (CAMP 2000). Overall, nedocromil is significantly less effective than ICS in improving outcomes measures (CAMP 2000). Nedocromil has not been studied adequately in children younger than 5 years of age. As a result of these disparate findings (i.e., some, but limited, effectiveness and strong safety profile), the Expert Panel's opinion is that cromolyn for children of all ages and nedocromil for children ≥5 years of age could be considered in the treatment of persistent asthma for children of all ages, but they are not preferred therapies. The Expert Panel's review of the literature in 2006 found that no new studies have been published that would change these conclusions.

Immunomodulators

Many different pharmaceutical agents have been tested for their ability to provide long-term control and/or steroid-sparing effects. These agents are loosely defined as immunomodulators. New information is available and discussed here on methotrexate, soluble interleukin-4 (IL-4) receptor, anti-IL-5, recombinant IL-12, cyclosporin A, intravenous immunoglobulin (IVIG), clarithromycin, omalizumab (anti-IgE), and others. For discussion of immunotherapy as an asthma management strategy, see "Component 3: Control of Environmental Factors and Comorbid Conditions That Affect Asthma."

Omalizumab

The Expert Panel recommends that omalizumab may be considered as adjunctive therapy in step 5 or 6 care for patients who have allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA (Evidence B). (See Evidence Table 13, Immunomodulators: Anti-IgE.)

Omalizumab, a recombinant DNA-derived humanized monoclonal antibody to the Fc portion of the IgE antibody, binds to that portion preventing the binding of IgE to its high-affinity receptor (FcεRI) on mast cells and basophils. The decreased binding of IgE on the surface of mast cells leads to a decrease in the release of mediators in response to allergen exposure. Omalizumab also decreases FcεRI expression on basophils and airway submucosal cells (Djukanovic et al. 2004; Lin et al. 2004). That study also showed significant decreases in sputum and bronchial eosinophils as well as in CD3+, CD4+, and CD8+ T cells in bronchial biopsy (Djukanovic et al. 2004). The vast majority of patients in clinical trials of omalizumab had moderate or severe persistent asthma incompletely controlled with ICS (Walker et al. 2004); all had atopy and IgE ≥30 IU/mL. Adding omalizumab to ICS therapy generally produced a significant reduction in asthma exacerbations (Busse et al. 2001a; Soler et al. 2001; Vignola et al. 2004) but not always (Holgate et al. 2004; Milgrom et al. 2001). (See Evidence Table 13, Immunomodulators: Anti-IgE.) Omalizumab, added to ICS, was associated with a small but significant improvement in lung function (Busse et al. 2001a; Soler et al. 2001). In two trials, one open-label, in patients who had severe persistent asthma inadequately controlled on ICS plus LABAs, omalizumab reduced asthma exacerbations and ED visits (Ayres et al. 2004; Humbert et al. 2005). Omalizumab appears to have a modest steroid-sparing effect, allowing a median reduction of 25 percent over that of placebo in the trials (Busse et al. 2001a; Holgate et al. 2004; Milgrom et al. 2001; Soler et al. 2001). Omalizumab has not been compared in clinical trials to the other adjunctive therapies for moderate persistent asthma (LABAs, leukotriene modifiers, and theophylline), all of which improve outcomes and allow reduction of ICS dose. Omalizumab is the only adjunctive therapy, however, to demonstrate added efficacy to high-dose ICS plus LABA in patients who have severe persistent allergic asthma (Humbert et al. 2005). In studies of patients who have severe persistent asthma, omalizumab resulted in clinically relevant improvements in quality-of-life scores in significantly more patients (approximately 60 percent) than did placebo (approximately 43 percent) (Holgate et al. 2004; Humbert et al. 2005).

Omalizumab is approved for patients 12 years and older who have proven sensitivity to aeroallergens: studies have been done in patients who have sensitivity to dust mite, cockroach, cat, or dog. One study of omalizumab in children 6–12 years of age demonstrated nonsignificant reductions in exacerbations and no improvement in lung function but did show small but significant reduction in ICS dose compared to placebo (Milgrom et al. 2001).

Urticaria and anaphylactic reactions have been reported in 0.1 percent of cases (Berger et al. 2003; FDA 2003; Holgate et al. 2004; Lanier et al. 2003). Postmarketing surveys have identified anaphylaxis in an estimated 0.2 percent of treated patients, which resulted in an FDA alert (FDA 2007). Most of these reactions occurred within 2 hours of the omalizumab injection, and after the first, second, or third injections. However, reactions have occurred after many injections and after many hours. Therefore, clinicians who administer omalizumab are advised to be prepared and equipped for the identification and treatment of anaphylaxis that may occur, to observe patients for an appropriate period of time following each injection (the optimal length of the observation is not established), and to educate patients about the risks of anaphylaxis and how to recognize and treat it if it occurs (e.g., using prescription auto injectors for emergency self-treatment, and seeking immediate medical care) (FDA 2007).

Adverse effects reported from omalizumab in the trials have also included injection-site pain and bruising in up to 20 percent of patients (Holgate et al. 2004). In the trials reported to the FDA, twice as many patients receiving omalizumab had malignancies (20 of 48,127, or 0.5 percent) as did those receiving placebo (5 of 2,236, or 0.2 percent), but there were no trends for a specific tumor type.

Antibiotics

In the opinion of the Expert Panel, the data at present are insufficient to support a recommendation about the use of macrolide in chronic asthma.

Some, but not all, data—including a recent controlled trial—have shown an effect of the macrolide antibiotic, clarithromycin, in the treatment of asthma (Kostadima et al. 2004; Kraft et al. 2002). Although it has been shown that clarithromycin can interfere with the clearance of methylprednisolone (Fost et al. 1999), this did not appear to be the mode of action. Preliminary data suggest that clarithromycin may enhance glucocorticoid effect on lymphocyte activation (Spahn et al. 2001).

Recent evidence suggesting that telithromycin may provide benefit in recovery from acute exacerbations has not linked the benefit with antibiotic activity of the drug (Johnston et al. 2006). Macrolide antibiotics, however, have potential risk for liver toxicity.

Others

The Expert Panel concludes that current evidence does not support the use of methotrexate, soluble IL-4 receptor, humanized monoclonal antibody against IL-5 or IL-12, cyclosporin A, IVIG, gold, troleandomycin (TAO), or colchicine for asthma treatment (Evidence B).

For methotrexate, the evidence from a new meta-analysis does not support use of the treatment, given the side effects of the drug (Aaron et al. 1998; Davies et al. 2000).

Use of soluble IL-4 receptor gave promising initial results on moderate to severe asthma (Borish et al. 1999), but subsequent trials were less successful, and it is unlikely to be marketed (Borish et al. 2001).

A humanized monoclonal antibody directed against IL-5 depleted eosinophils from blood and induced sputum but had no effect on airway hyperresponsiveness, on the late asthmatic reaction to inhaled allergen, or in patients who have severe persistent asthma (Flood-Page et al. 2003; Kips et al. 2003; Leckie et al. 2000). Recombinant IL-12 also reduced blood and sputum eosinophils, but it had no significant effects on airway hyperresponsiveness or the late asthmatic reaction to allergen (Bryan et al. 2000). These findings suggest that neither biological will be useful in clinical asthma.

Despite further interesting studies on the mechanism of action of cyclosporin A (Khan et al. 2000), data from controlled trials are not convincing (Evans et al. 2001); given the toxicity of the drug, the data make it difficult to recommend.

Data from open-label trials of IVIG have shown clinical and biomarker benefit in steroid-dependent asthma (Landwehr et al. 1998; Mazer and Gelfand 1991; Spahn et al. 1999). Two controlled trials, however, have failed to establish a clinical benefit of IVIG in such patients (Kishiyama et al. 1999; Niggemann et al. 1998) and showed significant adverse effects. The Expert Panel concludes, from available data, that the use of IVIG in asthma is not recommended.

Trials have suggested limited or no usefulness for oral gold (Bernstein et al. 1996), TAO (Nelson et al. 1993), and colchicine (Fish et al. 1997; Newman et al. 1997).

Leukotriene Modifiers

The Expert Panel recommends that LTRAs are an alternative, not preferred, treatment option for mild persistent asthma (Step 2 care) (Evidence A). LTRAs can also be used as adjunct therapy with ICS, but for youths ≥12 years of age and adults they are not the preferred, adjunct therapy compared to the addition of LABAs (Evidence A). A 5-lipoxygenase inhibitor (zileuton) is an alternative treatment option that is less desirable than LTRAs due to more limited efficacy data and the need for liver function monitoring (Evidence D). (See Evidence Table 14, Leukotriene Receptor Antagonists: Monotherapy/Effectiveness Studies.)

Leukotrienes are potent biochemical mediators—released from mast cells, eosinophils, and basophils—that contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells in the airways of patients who have asthma (Henderson 1994).

Three leukotriene modifiers—montelukast, zafirlukast, and zileuton—are available as oral tablets for the treatment of asthma. Leukotriene modifiers comprise two pharmacologic classes of compounds: 5-lipoxygenase pathway inhibitors (e.g., zileuton), and LTRAs (e.g., montelukast and zafirlukast, which block the effects of the CysLT1 receptor). Only montelukast (for children as young as 1 year of age) and zafirlukast (for children as young as 7 years of age) are approved for use in children.

Leukotriene receptor antagonists

The LTRAs have been demonstrated to provide statistically significant but modest improvement in lung function when used as monotherapy in both adults and children as young as 5 years of age as well as in asthma control outcomes other than lung function in patients as young as 2 years of age (Bisgaard et al. 2005; Bleecker et al. 2000; Busse et al. 2001b,c; Garcia-Garcia et al. 2005; Jenkins et al. 2005; Ostrom et al. 2005; Pearlman et al. 2000; Szefler et al. 2005; Zeiger et al. 2005, 2006) (see Evidence Table 14). In general, these studies included patients who had either mild or moderate persistent asthma, although the classification of severity was not always clear in the studies, nor was it consistently applied. When comparing overall efficacy of LTRA to ICS in both children and adult patients who have persistent asthma, most outcome measures (e.g., reduction in exacerbations, improvements in symptom-free days and FEV₁) significantly and clearly favored ICS (Busse et al. 2001b,c; Ducharme et al. 2003; Garcia-Garcia et al. 2005; Jenkins et al. 2005; Ostrom et al. 2005; Sorkness et al. 2007; Zeiger et al. 2006). See Evidence Table 14: Leukotriene Receptor Antagonists: Monotherapy/Effectiveness Studies.

Three randomized, controlled, double-blind studies in children 5–15 years of age demonstrated the greater effectiveness of ICS (fluticasone) compared to montelukast (Garcia-Garcia et al. 2005; Ostrom et al. 2005; Sorkness et al. 2007). All three reported significantly greater improvements in lung function and total symptom scores as well as reduction in exacerbations; one demonstrated that montelukast was not inferior to fluticasone in rescue-free days (defined in the study as any day without asthma rescue medication and with no asthma-related resource use) (Garcia-Garcia et al. 2005), but the other two showed superiority of fluticasone compared to montelukast for percentage of rescue-free days.

A randomized, cross-over, double-blind study of 140 children 6–17 years of age, in which children received either ICS or LTRA (montelukast) for 8 weeks followed by 8 weeks of the other medication, examined what factors might predict individual variation in response to different medications. The study suggests that children who have higher levels of eosinophilic/allergic airway inflammation (nitric oxide, IgE levels, total eosinophil levels) or low pulmonary function (measured by FEV₁/FVC or FEV₁) are more likely to respond favorably to ICS than to LTRA. Children who do not have these markers appeared to respond equally to treatment with ICS or LTRA (Szefler et al. 2005; Zeiger et al. 2006).

LTRAs have been demonstrated to attenuate EIB (Mastalerz et al. 2002; Moraes and Selvadurai 2004).

LTRAs may be considered as an alternative treatment option for patients whose response to ICSs may be compromised. For example, a controlled trial noted that active cigarette smoking impairs the efficacy of short-term ICS treatment in adults who had mild asthma (Chalmers et al. 2002). However, patients who smoke should be advised to quit smoking. See "Component 3: Control of Environmental Factors and Comorbid Conditions That Affect Asthma" and "Component 2: Education for a Partnership in Care."

Zafirlukast, an LTRA, has been demonstrated to attenuate the late response to inhaled allergen and post-allergen-induced bronchial responsiveness (Dahlen et al. 1994; Taylor et al. 1991). A study comparing zafirlukast to placebo in patients who have mild or moderate asthma demonstrated that patients treated with zafirlukast experienced modest improvement in FEV₁ (mean improvement of 11 percent above placebo), had improved symptom scores, and reduced albuterol use (average decline of 1 puff/day) (Spector et al. 1994). Zafirlukast can cause a significant increase in the half-life of warfarin. Consequently, for those individuals receiving zafirlukast and warfarin, it will be necessary to closely monitor prothrombin times and adjust doses of warfarin accordingly. Cases of hepatic dysfunction have occurred with zafirlukast. Although most patients improved with discontinuation of zafirlukast, some have gone on to fulminate hepatic failure resulting in receiving a transplant or in death. Patients should be advised to be alert for signs and symptoms of hepatitis (anorexia, abdominal pain, nausea, jaundice, and pruritis); if these occur, they should discontinue zafirlukast and have liver enzymes (ALT) monitored.

The use of LTRA as adjunctive therapy in moderate or severe asthma has not been studied adequately in children 5–11 years of age and has not been studied at all in children less than 4 years of age. Limitations in the studies comparing addition of LTRA to a fixed dose of ICS (i.e., adding LTRA when patients are not adequately controlled with ICS alone) preclude definitive conclusions, although they reveal a trend showing that LTRA improved lung function and some but not all measures of asthma control (Laviolette et al. 1999; Robinson et al. 2001; Simons et al. 2001; Vaquerizo et al. 2003). One study in adults compared the combination of LTRA and ICS to increasing the dose of ICS and reported similar outcomes for the two approaches (Price et al. 2003). In a 24-week trial in patients who had poorly controlled asthma, the addition of theophylline or montelukast led to small improvement in lung function but did not improve episodes of poor asthma control, symptoms, or quality of life (American Lung Association Asthma Clinical Research Centers 2007). Studies comparing LTRA to LABA as adjunctive therapy in adults show significantly greater improvement in lung function and other asthma control measures with the LABA adjunctive therapy (EPR—Update 2002; Ram et al. 2005).

5-lipoxygenase inhibitor

Zileuton has not been studied in patients less than 12 years of age. It has been demonstrated to provide immediate and sustained improvements in FEV₁ (mean increase of 15 percent above placebo) in placebo-controlled trials in patients who have mild or moderate asthma (Israel et al. 1993, 1996). Compared to placebo, the patients who had moderate asthma treated with zileuton experienced significantly fewer exacerbations requiring oral systemic corticosteroids (Israel et al. 1996), thus suggesting anti-inflammatory action. Zileuton is capable of attenuating bronchoconstriction from exercise (Meltzer et al. 1996) and from aspirin in aspirin-sensitive individuals (Israel et al. 1993). One large, randomized, open label, study in adults who had asthma (Lazarus et al. 1998) and one small cross-over study in aspirin-sensitive adults who had asthma (Dahlen et al. 1998) demonstrated clinical benefits to adding zileuton to existing therapy; the large trial also reported elevated liver enzymes. Because liver toxicity has been found in some subjects receiving zileuton, it is recommended that hepatic enzymes (ALT) be monitored in patients who take this medication. Furthermore, zileuton is a microsomal cytochrome P450 enzyme inhibitor that can inhibit the metabolism of warfarin and theophylline; doses of these drugs should be monitored accordingly. Due to the limited efficacy data and the need for liver function monitoring, zileuton is a less desirable alternative than LTRAs.

Inhaled Long-Acting Beta₂-Agonists

The principal action of beta₂-agonists is to relax airway smooth muscle by stimulating beta₂-receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstriction. Due to their increased lipophilicity prolonging retention in lung tissue, the LABAs have a duration of bronchodilation of at least 12 hours after a single dose (Kips and Pauwels 2001). The LABAs effectively block EIB for 12 hours after a single dose; however, with chronic regular administration, this effect does not exceed 5 hours (Ramage et al. 1994; Simons et al. 1997).

The Expert Panel concludes the following regarding the use of LABAs:

• ▪ LABAs are used as an adjunct to ICS therapy for providing long-term control of symptoms (Evidence A). Of the adjunctive therapies available, LABA is the preferred treatment to combine with ICS in youths ≥12 years of age and adults (Evidence A).
• ▪ LABAs are not recommended for use as monotherapy for long-term control of persistent asthma (Evidence A).
• ▪ Use of LABA is not currently recommended to treat acute symptoms or exacerbations of asthma (Evidence D). Studies are underway examining the potential use of formoterol in acute exacerbations and in adjustable-dose therapy in combination with ICS; see the discussion below in the section on "Quick-Relief Medications" and on "Inhaled Short-Acting Beta₂-Agonists."
• ▪ LABA may be used before exercise to prevent EIB (Evidence B), but frequent and chronic use of LABA for EIB may indicate poorly controlled asthma which should be managed with daily anti-inflammatory therapy.
• ▪ Safety issues have been raised regarding LABAs. The Expert Panel reviewed the safety data provided to the FDA Pulmonary and Allergy Drugs Advisory Committee as well as the extensive accumulation of clinical trials and meta-analyses on the use of LABA, both as monotherapy and in conjunction with ICS. The Expert Panel concluded that LABAs should not be used as monotherapy as long-term control medication in persistent asthma but that LABAs should continue to be considered for adjunctive therapy in patients ≥5 years of age who have asthma that requires more than low-dose ICS. For patients inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the addition of a LABA. For patients who have more severe persistent asthma (i.e., those who require step 4 care or higher), the Expert Panel continues to endorse the use of a combination of LABA and ICS as the most effective therapy. The basis of this opinion is discussed below. (See Evidence Table 15, Bronchodilators: Safety of Long-Acting Beta₂-Agonists.)

Safety of Long-Acting Beta₂-Agonists

KEY POINTS: SAFETY OF INHALED LONG-ACTING BETA₂-AGONISTS

• ▪ The addition of LABA (salmeterol or formoterol) to the treatment of patients whose asthma is not well controlled on low- or medium-dose ICS improves lung function, decreases symptoms, and reduces exacerbations and use of SABA for quick relief in most patients (EPR—Update 2002; Greenstone et al. 2005; Masoli et al. 2005).
• ▪ A large clinical trial comparing daily treatment with salmeterol or placebo added to usual asthma therapy (Nelson et al. 2006) resulted in an increased risk of asthma-related deaths in patients treated with salmeterol (13 deaths out of 13,176 patients treated for 28 weeks with salmeterol versus 3 deaths out of 13,179 patients with placebo). In addition, increased numbers of severe asthma exacerbations were noted in the pivotal trials submitted to the FDA for formoterol approval, particularly in the higher dose formoterol arms of the trials (Mann et al. 2003). Thus the FDA determined that a Black Box warning was warranted on all preparations containing a LABA.
• ▪ The Expert Panel recommends that the established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with ICS alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with the daily use of LABAs.
• ▪ Therefore, the Expert Panel has modified its previous recommendation (EPR—Update 2002) and has now concluded that, for patients who have asthma not sufficiently controlled with ICS alone, the option to increase the ICS dose should be given equal weight to the option of the addition of a LABA to ICS.
• ▪ Daily use of LABA generally should not exceed 100 mcg salmeterol or 24 mcg formoterol.
• ▪ It is not currently recommended that LABA be used for treatment of acute symptoms or exacerbations.
• ▪ LABAs are not to be used as monotherapy for long-term control. Patients should be instructed not to stop ICS therapy while taking salmeterol or formoterol even though their symptoms may significantly improve.

General Safety

LABAs induce sustained relaxation of airway smooth muscle that allows twice-daily administration. The two LABAs currently available for the treatment of asthma are salmeterol and formoterol. They have slightly different properties in that salmeterol is a partial agonist and formoterol is a full agonist, but the only clinically relevant difference is that formoterol has a more rapid onset of bronchodilation (similar to albuterol) (Kips and Pauwels 2001). Both are highly selective beta₂-adrenergic receptor agonists that produce clinically relevant cardiovascular effects (tachycardia, QTc interval prolongation, and hypokalemia) at doses approximately 4–5 times those recommended (Guhan et al. 2000; Ostrom 2003; Palmqvist et al. 1999). Other dose-dependent sympathomimetic effects include tremor and hyperglycemia. Because the LABAs are devoid of any clinically apparent anti-inflammatory activity (Currie et al. 2003; Lazarus et al. 2001), they should not be used as monotherapy for long-term control of persistent asthma. Discontinuation of ICS therapy following initiation of LABA results in an increase in asthma exacerbations (Lemanske et al. 2001). Of greatest concern have been the reports of an increased risk of severe asthma exacerbations, both life-threatening and fatal, associated with regular LABA use (Mann et al. 2003; Nelson et al. 2006) that has resulted in a Black Box Warning label for products in the United States containing either salmeterol or formoterol.

Early recognition of the potential dangers of LABAs followed a large, randomized, prospective postmarketing study in approximately 25,000 patients in the United Kingdom. The study reported an increased (although not statistically significant) number of deaths in patients treated with salmeterol (42 mcg/day) versus albuterol (180 mcg four times/day) added to usual asthma therapy (12 of 16,787 patients taking salmeterol versus 2 of 8,393 patients on albuterol) (Castle et al. 1993). However, an observational, prescription-event monitoring program in the United Kingdom evaluating 15,407 patients taking salmeterol found no evidence that salmeterol contributed to the death of any of the patients (Mann et al. 1996). Similarly, a retrospective review of a large, health insurance claims database in the United States, comparing a cohort of 2,708 patients receiving salmeterol to 3,825 recipients of sustained release theophylline, found no increase in ED visits, hospitalizations, or ICU admissions among those receiving salmeterol during the year following initiation of therapy (Lanes et al. 1998).

Due to the concerns generated by the initial United Kingdom study, a large, randomized, placebo-controlled, 28-week trial of salmeterol versus placebo added to usual care in adults who had asthma was performed to assess the safety of salmeterol (Nelson et al. 2006). The goal was to enroll approximately 60,000 patients, and the primary outcome variable was combined respiratory-related deaths or respiratory-related, life-threatening experiences; secondary end points included all-cause deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences. A planned interim analysis of more than 26,000 patients found no increase in the primary outcome but did find an increased risk of asthma-related deaths and combined asthma-related death or life-threatening experiences in the total population. Although the study was not designed to assess subgroups, a subgroup analysis reported that African Americans, who were 18 percent of the total population, experienced a significant increased risk for the primary end point as well as combined asthma-related death or life-threatening experiences. In addition, an analysis of serious asthma exacerbations in the pivotal trials submitted to the FDA for marketing approval of formoterol revealed an increased number of these events in patients receiving formoterol, particularly at the higher dose of 48 mcg daily that exceeds current labeling (Chowdhury 2005; Mann et al. 2003). A followup analysis of the same data reiterated the potential risks (Salpeter et al. 2006). The data from the Salmeterol Multicenter Asthma Research Trial (SMART), Chowdhury, and Mann and colleagues prompted the FDA to convene a meeting of the Pulmonary and Allergy Drugs Advisory Committee (www.fda.gov/cder/drug/advisory/LABA.htm) (FDA 2005). This group, in conjunction with the FDA, determined that these data represented a serious safety concern for the use of LABAs but that the significant benefit provided by these agents to a large number of patients, particularly in conjunction with ICS therapy, warranted continued use of LABA as adjunctive therapy for patients who have asthma that is not well controlled with ICS alone.

A meta-analysis of trials, performed for the EPR—Update 2002, reported greater benefit in measures of asthma control with the addition of a LABA compared to doubling the dose of ICS (EPR—Update 2002). A Cochrane Library systematic review of 85 RCTs (60 studies with salmeterol and 25 studies with formoterol) comparing LABA with a placebo in chronic asthma (Walters et al. 2003) reported a decrease in severe asthma exacerbations (defined as requiring intervention other than as-needed SABA) associated with LABA use. Additional meta-analyses showed that the addition of LABA compared to increasing the ICS dose improved lung function and symptom control (Ni et al. 2005), reduced exacerbations (Masoli et al. 2005), and did not increase serious asthma exacerbations or participant withdrawals due to worsening asthma. A recent case-control study of 532 asthma patients who died from asthma did not find a positive association between LABA use and death (Anderson et al. 2005). A more recent large, postmarketing study (2,085 patients) of adding formoterol, either 24 mcg or 12 mcg twice daily, to usual care (65 percent receiving concomitant anti-inflammatory therapy) failed to detect an increase risk of serious asthma exacerbations (Wolfe et al. 2006).

A mechanism for a direct effect of LABAs in producing exacerbations has not been established. The primary hypotheses for LABAs' increasing the risk of severe, life-threatening asthma exacerbations include: (1) a direct adverse effect of LABA on bronchial smooth muscle, resulting in more severe obstruction following any bronchoconstrictive stimulus, or (2) maintenance of lung function in the face of worsening underlying inflammation, leading either to a catastrophic increase in obstruction or to patients' delaying seeking appropriate medical attention for a severe exacerbation. Clinical trials clearly demonstrate that, in patients who have persistent asthma, discontinuation of ICS after starting LABA results in increased markers of inflammation and increased risk of exacerbations (Lazarus et al. 2001; Lemanske et al. 2001; Mcivor et al. 1998). In patients who have mild asthma, the increase in exacerbations occurs despite benefits in measures of daily asthma control such as symptoms, as-needed use of SABA, and PEFs (Lazarus et al. 2001). Unlike regular use of SABA, the regular daily administration of LABA has not produced an increase in bronchial hyperresponsiveness (Cheung et al. 1992; Lazarus et al. 2001; Simons 1997; Van Schayck et al. 2002; Walters et al. 2003).

Genetic studies assessing the role of the polymorphism at codon 16 of the beta₂-adrenergic receptor gene have produced inconclusive results. A cross-over study by Taylor and coworkers (2000) reported that, during 24 weeks of treatment with placebo, albuterol, and salmeterol, the number of major exacerbations was significantly increased for homozygous Arg-16 subjects (only 17 subjects) during albuterol treatment compared with placebo but not during salmeterol treatment. In addition, researchers found no adverse effect of salmeterol on morning peak flow in the homozygote Arg-16 subjects compared with placebo or compared to homozygous Gly-16 subjects. More recently, Wechsler and colleagues (2006) reported that homozygote Arg-16 subjects (n = 8) who were taking salmeterol and an ICS had lower FEV₁, increased symptom scores, and increased use of SABA compared with Gly/Gly subjects (n = 22) taking the same combination therapy. On the other hand, Bleecker (2006) reported that, in a study of patients receiving LABA and ICS (N = 183), there were no differences in clinical response between Arg/Arg or Gly/Gly genotypes.

Studies assessing the qualitative nature of exacerbations have shown no difference in the rapidity of onset or severity of obstruction, reporting of symptoms, or use of SABA whether patients who had asthma were receiving LABA or not (Matz et al. 2001; Tattersfield et al. 1999). However, the patients in these studies were all receiving ICS as well as LABA. No studies have specifically addressed whether patients who take LABA delay seeking medical attention for deterioration of asthma, but this effect would be difficult to assess.

What ameliorative role, if any, the concomitant administration of ICS has on the potential for severe asthma exacerbations associated with LABA use has not been studied adequately. In a meta-analysis, the addition of LABA to ICS produced a significant reduction in severe exacerbations, but only a borderline significant decrease occurred in studies of patients who were not receiving ICS (Walters et al. 2003). In large clinical trials of at least 1 year duration, with severe exacerbations as a primary end point, LABA added to low- to medium-dose ICS significantly reduced the number of severe exacerbations in patients who had moderate asthma (O'Byrne et al. 2001; Pauwels et al. 1997) and reduced the number of patients who withdrew from the study because of an excessive number of exacerbations (Tattersfield et al. 1999). These results have been confirmed in a recent meta-analysis (Masoli et al. 2005). Although the study was not designed to assess subgroups or to assess concomitant medication use during the trial, no increase in the primary outcome of asthma deaths or life-threatening experiences was seen in association with salmeterol in the 12,265 patients who self-reported taking ICS at baseline in the SMART trial; however, this finding should not be considered conclusive (Nelson et al. 2006).

On the other hand, there did not appear to be a protective effect of ICS in the number of serious exacerbations reported in the formoterol pivotal trials. Although not statistically significant, an increased number of exacerbations were observed in the formoterol group (Chowdhury 2005). Thus, while the data do not necessarily support an increased risk of severe or serious exacerbations in patients who are taking LABA and are receiving concomitant ICS, data are also insufficient to establish definitively that ICS therapy completely obviates the risk. Further research is urgently needed to clarify this issue.

Methylxanthines

The Expert Panel recommends that sustained-release theophylline is an alternative but not preferred treatment for mild persistent asthma (Step 2 care) (Evidence A); it may also be used as alternative but not preferred adjunctive therapy with ICS (Evidence B). Theophylline, the principally used methylxanthine, provides mild or moderate bronchodilation in persons who have asthma. Theophylline is a nonselective phosphodiesterase inhibitor; as such, it has exhibited mild anti-inflammatory activity according to some but not all studies (Jaffar et al. 1996; Kidney et al. 1995; Page et al. 1998).

Theophylline produces minimal to no effect on airway reactivity and significantly less control of asthma than low-dose ICS does (Dahl et al. 2002; Reed et al. 1998). The addition of theophylline to ICS produces a small improvement in lung function similar to doubling the dose of ICS (Evans et al. 1997; Lim et al. 2000; Suessmuth et al. 2003). In a 24-week randomized, placebo-controlled trial in patients who had poorly controlled asthma, the addition of theophylline or montelukast led to small improvement in lung function but did not improve episodes of poor asthma control, symptoms, or quality of life (American Lung Association Asthma Clinical Research Centers 2007). Thus, the main use of theophylline is as adjunctive therapy to ICS. Sustained-release theophylline may be considered as a nonpreferred alternative long-term preventive therapy when issues arise concerning cost or a patient's aversion to inhaled medication. Monitoring serum concentrations of theophylline is essential to ensure that toxic concentrations are avoided. For sustained-release theophyllines, the serum concentration is obtained in the middle of the dosing interval, at least 3–5 days after initiation of theophylline and then at least 2 days after initiation of any factor known to affect theophylline clearance significantly. If patients experience signs and symptoms of toxicity (e.g., severe headache, tachycardia, nausea and vomiting), theophylline should be discontinued and a serum concentration obtained.

Tiotropium Bromide

Tiotropium bromide is a new, long-acting inhaled anticholinergic indicated once daily for COPD; this drug has not been studied in the long-term management of asthma (Gross 2004), and it has not received FDA-approved labeling for use in treating asthma. Ipratropium bromide, a short-acting anticholinergic, also has not demonstrated effectiveness in long-term management of asthma (Kerstjens et al. 1992).

Complementary and Alternative Medicine

Alternative healing methods are not substitutes for recommended asthma management strategies (i.e., pharmacologic therapy, environmental control measures, or patient education). Although alternative healing methods may be popular, clinical trials that adequately address safety and efficacy are limited, and their scientific basis has not been established.

The most widely known complementary and alternative medicine methods are acupuncture, homeopathy, herbal medicine, and Ayurvedic medicine (which includes transcendental meditation, herbs, and yoga).

Because complementary and alternative medicine is reported to be used by as much as one-third of the U.S. population (Eisenberg et al. 1993), it is important to inquire about all the medications and interventions a patient uses and advise the patient accordingly (See "Component 2: Education for a Partnership in Asthma Care.").

References

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