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Old Westbury, NY
Dr. Marcus is affiliated with the New York College of Osteopathic Medicine.
Correspondence to: Philip Marcus, MD, MPH, FCCP, 233 East Shore Rd, Great Neck, NY 11023; e-mail: PMarcus{at}nyit.edu
Inhaled corticosteroids have been available in the United States for the treatment of asthma since 1976. At the present time, five different inhaled corticosteroids have been marketed, and two new compounds are expected to be approved for use in the near future. When initially introduced, inhaled corticosteroids were prescribed routinely for use four times a day. In addition, they were generally used following the use an inhaled ß-agonist bronchodilator, in an effort to bronchodilate first to ensure better steroid deposition. Also, they were used in an effort to reduce oral steroid dosage with a goal of elimination of the oral agent with its associated toxicity. In the last quarter century, we have learned a great deal about the use of inhaled corticosteroids in the management of asthma, and all guidelines1 2 3 4 now place inhaled corticosteroids as the primary therapy for persistent asthma. This is because of their clear efficacy, something that has been shown in numerous studies, compared with other classes of controller agents. The appreciation of the crucial role of inflammation in the pathogenesis of asthma has led to the widespread use of this class of anti-inflammatory agents.5 The use of inhaled corticosteroids has been shown to reduce airway inflammation, to decrease airway hyperreactivity, to improve airflow obstruction, and to decrease symptoms and exacerbations. The use of inhaled corticosteroids also has been shown to reduce the number of hospital readmissions6 and asthma mortality.7
It is well-known that many factors are involved in determining the clinical effectiveness of inhaled corticosteroids. The products are interchangeable within the class, and each individual corticosteroid has unique pharmacokinetic characteristics.8 These include half-life, lipophilicity, dissolution rate, extent and strength of receptor binding, and metabolic fate. Potency and the potential for unwanted systemic effects are also factors to be considered when choosing an individual agent for clinical use. Different inhaled corticosteroid preparations are not equivalent on a per puff or microgram basis.1 In addition, the choice of device often will have even greater influence on the characteristics of the inhaled corticosteroid chosen. The device choices available at this time include breath-activated dry powder inhaler, chlorofluorocarbon-containing metered-dose inhaler (MDI), and hydrofluoroalkane (HFA)-containing MDI. At present, each individual corticosteroid is available only with a specific device or propellant. The characteristics of the delivery device often will influence the risk/benefit ratio of the particular inhaled corticosteroid. Also, budesonide is available as a suspension for nebulization, having particular usefulness in young patients.
Of the currently available inhaled corticosteroids, beclomethasone dipropionate (BDP), the first commercially available agent thought to have topical efficacy,9 has largely fallen into disuse. An HFA preparation of BDP is used clinically with the intent of delivering a greater dose to the smaller airways. Triamcinolone acetonide and flunisolide also have lost popularity among clinicians treating patients with asthma. The majority of inhaled corticosteroid prescriptions are written for fluticasone propionate and budesonide. Each of these compounds has unique characteristics.10 11 Fluticasone propionate is also available in combination with salmeterol, and it is anticipated that budesonide will be marketed in combination with formoterol in the near future. Mometasone furoate and ciclesonide are under development at present.
Questions exist in terms of the dose-response relationship of various inhaled corticosteroids, and it is often difficult to establish a dose-response curve.12 13 Such dose-response characteristics vary between patients, and even within a given patient as the severity of asthma changes.14 The dose frequency of inhaled corticosteroids is another aspect of asthma therapy that has evolved and will continue to evolve further in the future. As noted, dosing of four times daily was the standard regimen for all of the initial agents used. This dosing has evolved into regimens that can be administered less frequently with resultant improved adherence and, thereby, improved asthma control. At the present time, both fluticasone propionate and budesonide are indicated for twice-daily use. However, budesonide also has received the indication for once-daily use in stable patients with asthma, likely based on published studies showing its effectiveness in these situations.15 16 In a recent study,17 budesonide also has been shown to be effective once daily when used as initial therapy for patients with mild asthma to prevent exacerbations.
In this issue of CHEST (see page 1584), Purucker et al report on the results of their evaluations of studies comparing once-daily to twice-daily administration of inhaled fluticasone propionate via the Diskus device. The authors, all employees at the Food and Drug Administration (FDA), have reviewed the evidence for the once-daily use of fluticasone via Diskus device. They have concluded that once-daily use was not associated with results greater than that observed with placebo. In addition, no conclusions could be made as to whether the once-daily regimen was associated with greater safety than the comparative twice-daily administration of the same nominal dose. The data reviewed included six studies submitted to the FDA for licensing of fluticasone propionate in the Diskus device. The authors report that in five of the six studies the same nominal dose given once daily and compared to twice-daily administration was no more effective than placebo. In the remaining study, the once-daily administration of fluticasone was more effective than placebo, but only about half as effective as the same dose given twice daily. Accordingly, the authors have recommended that fluticasone should not be used once daily for the management of asthma. This is in contrast to approval of the inhaled corticosteroid budesonide, which has been found to be effective for once-daily administration15 16 and, accordingly, has received FDA approval. In addition, studies of mometasone furoate18 have suggested that it will be effective for once-daily administration. Also, a published study of fluticasone propionate administered via MDI has shown opposite results, demonstrating efficacy when administered once daily for the management of asthma.19
Why then the disparities between inhaled steroids and inhalation devices? Why the need for once-daily administration compared to twice-daily administration? We are past the need to administer these agents four times daily, something that likely resulted in their not being utilized effectively for the management of asthma. The administration four times daily of compounds such as BDP, triamcinolone acetonide, cromolyn sodium, and nedocromil likely led to many clinical failures because of nonadherence to the regimen prescribed by well-meaning clinicians. As a result, both BDP and triamcinolone acetonide were restudied, and twice-daily regimens were proposed and approved for clinical use. Initially, many clinicians also thought that patients with more severe asthma would benefit from more frequent dosing, and indeed clinical studies have supported this notion.20 21 Does once-daily administration confer benefits over twice-daily dosing? Certainly, this would seem to be intuitive since less frequent administration should improve adherence. However, Purucker and colleagues have reviewed the data submitted in this group of studies and have found that there was no significant difference in adherence between the two regimens. In clinical practice this would likely be true as well.
What about the populations studied? Would patients who are stable on a twice-daily regimen of inhaled corticosteroids do better with a once-daily regimen than patients who were inhaled corticosteroid naïve? This too was evaluated and did not seem to be a determining factor in this published study. This is contrary to the situation observed with budesonide, whereby patients who were stable while receiving a twice-daily regimen of budesonide or another inhaled corticosteroid were switched to once-daily budesonide for the maintenance of asthma control.
The clinical management of patients with asthma remains complex, no matter how simple the guidelines seem to make it. Some decisions are straightforward. What agent should be prescribed for a patient with persistent asthma? The answer for almost all patients appears to be an inhaled corticosteroid. Which corticosteroid to use and how to most effectively use the agent chosen are somewhat more complex questions. All contemporary versions of the guidelines for asthma management1 2 3 4 present a dosing table for inhaled corticosteroids indicating what would be considered low, moderate, and high doses for each of the available agents. Until more evidence to support the widespread use of any inhaled corticosteroid once daily is available, these agents should be used no less frequently than twice daily in patients who have received new diagnoses of persistent asthma or in patients who no longer fit the criteria for intermittent asthma. However, as noted, there is evidence that budesonide can be used once daily in patients whose asthma is under good control on a twice-daily regimen. Perhaps newer formulations of fluticasone propionate (eg, HFA-MDI) will confer different properties and therefore will allow for once-daily use for initial treatment. Last, the Diskus device that was reviewed by the authors has not been marketed for use with fluticasone propionate, and the conclusions made are referable only to the combination of fluticasone propionate and the Diskus device. Clinicians must always remember that both the device and the inhaled corticosteroid agent itself together determine clinical efficacy and safety in asthma management.
References
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