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Emerging Therapeutic Options for Asthma
Gene L. Colice, MD
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Jonathan D. Campbell, PhD
Participating Faculty: Improving Asthma Care
Managed Care Opportunities for Improving Asthma Care
Jonathan D. Campbell, PhD
Improving Asthma Care: An Update for Managed Care
Emerging Therapeutic Options for Asthma
Gene L. Colice, MD
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Aidan A. Long, MD
Participating Faculty: Improving Asthma Care
Improving Asthma Care: An Update for Managed Care

Emerging Therapeutic Options for Asthma

Gene L. Colice, MD

Asthma is characterized by eosinophilic airway inflammation and elevated serum immunoglobulin E (IgE) levels. Due to these pathologic features, the foundation of asthma treatment has historically been anti-inflammatory therapy with inhaled corticosteroids (ICSs). Numerous factors in addition to IgE and eosinophils, however, likely play important roles in mediating the airway inflammatory response characteristic of asthma. ICSs are effective therapy for some patients with persistent asthma, but clinical trials have shown that even increasing doses of ICSs under carefully controlled situations does not always result in acceptable asthma control. Consequently, other classes of medications, in addition to ICSs, are recommended in those patients with more severe asthma. The class of medication most commonly used in more severe asthma, along with ICSs, is long-acting inhaled beta2-agonists, but leukotriene modifying agents and anti-IgE monoclonal antibodies may also be used. Agents such as tiotropium, a long-acting inhaled anti-muscarinic agent, and those aimed at inhibiting cytokines, such as mepoluzimab, daclizumab, and etanercept, hold promise in the treatment of asthma. Other agents under investigation include phosphodiesterase type 4 inhibitors and oligonucleotides. Bronchial thermoplasty, a nonpharmacologic option, may also be beneficial in patients with poorly controlled asthma. As our understanding of the complex pathophysiology of asthma increases, it will enable the development of novel therapeutic approaches for patients who are not responding well to traditional treatments. Although more studies are necessary to ensure the efficacy and safety of both pharmacologic and nonpharmacologic approaches, there is future promise for therapeutic advances in severe, persistent asthma.
(Am J Manag Care. 2011;17:S82-S89)

Asthma is usually a relatively straightforward disease to diagnose. Patients typically present with some combination of 4 basic symptoms: cough, wheeze, chest tightness, and shortness of breath.1 These symptoms may be episodic or persistent. Asthma patients often have wheezing on physical examination and some combination of airway obstruction and/or bronchial hyperresponsiveness on physiologic testing. Patients with asthma usually also have a history of eczema and allergic rhinitis. The combination of asthma, eczema, and allergic rhinitis is considered the atopic triad, because these 3 conditions are believed to involve a specific type of inflammatory reaction to extrinsic allergens called atopy. The inflammatory reactions in atopic disease are mediated by immunoglobulin E (IgE) and involve eosinophils. Asthma is characterized by eosinophilic airway inflammation and elevated serum IgE levels.1 Due to these pathologic features, the foundation of asthma treatment has historically been anti-inflammatory therapy with inhaled corticosteroids (ICSs).1 Although the clinical presentation of asthma might be straightforward, we are learning that the pathophysiology of asthma is far more complex than we believed. This is an important point because we are also learning that ICS therapy will not adequately control asthma in all patients.

As shown in the Figure, numerous factors in addition to IgE and eosinophils likely play important roles in mediating the airway inflammatory response characteristic of asthma. Cytokines (eg, interleukins, lymphokines, tumor necrosis factor [TNF], interferons) and other cell types (eg, lymphocytes, mast cells, airway epithelial cells, airway smooth muscle cells) have all been implicated as mediators of airway inflammation.2 Understanding how these inflammatory mediators and cells contribute to the pathophysiology of asthma will be crucial next steps in our approach to better managing asthma, because current pharmacologic treatment approaches do not always ensure asthma control. ICSs are effective therapy for some patients with persistent asthma, but clinical trials have shown that even increasing doses of ICSs under carefully controlled situations does not always result in acceptable asthma control.3 This article is intended to review newer methods of treating asthma, both pharmacologic and nonpharmacologic, as a basis for understanding how these approaches may be used to manage patients not responding to standard treatment with ICSs.

Current Approach to Categorizing Asthma Severity and Treating Asthma

As discussed in the previous article by Dr. Long,4 the Expert Panel Report 3 (EPR3) published by the National Heart, Lung, and Blood Institute recommends a stepwise approach to managing persistent asthma.1 The EPR3 emphasizes that there are 2 goals of this stepwise approach to asthma pharmacotherapy: the first is to achieve asthma control, which is the elimination of daytime and nocturnal symptoms, normalization of lung function, and reduction in the risk of exacerbations; the second is to minimize the likelihood of adverse events and costs related to asthma pharmacotherapy. To achieve these goals, the stepwise approach requires that physicians estimate asthma severity; asthma pharmacotherapy will vary depending upon the severity category. For mild, persistent asthma, recommended therapy consists of low dose ICSs, education, and removal of environmental triggers. For patients with moderate-to-severe persistent asthma, however, treatment is more complex. Increasing doses of ICSs are used in these patients, as well as additive therapy. The class of medication most commonly used in more severe asthma, along with ICSs, is long-acting inhaled beta2-agonists (LABAs), but leukotriene modifying agents (LMAs) and anti-IgE monoclonal antibodies may also be used. Unfortunately, healthcare providers are suboptimally managing asthma. For example, a survey of patients with asthma being treated by primary care physicians in Canada showed that almost 60% did not have well-controlled asthma, and that healthcare providers often did not appreciate the lack of control.5 In this survey, patients with suboptimal asthma control were significantly more likely to need urgent care visits for asthma management (P <.001).

There are 3 important reasons for the lack of success in achieving asthma control. 1) Many patients with asthma simply do not adhere to recommended treatment. In a retrospective database analysis of medical records and pharmacy claims, overall adherence to ICS use by patients with asthma was found to be only 50%. There was a clear relationship between poor adherence with ICS use and worse outcomes, including asthma-related hospitalizations.6 2) Physicians may fail to appreciate asthma severity in the individual patient. To appropriately use the EPR3 step-up approach to asthma pharmacotherapy, physicians must first make the appropriate link between accurately categorizing asthma severity and choosing the appropriate pharmacotherapeutic regimen. Telephone surveys have suggested that the majority of patients with asthma have mild disease.7 However, my colleagues and I found that more than 90% had moderate-to-severe persistent asthma using information obtained from diary cards completed daily by patients not using ICSs.8 Similary, Fuhlbrigge et al found that over three-quarters of asthma sufferers had moderate or severe persistent asthma.9 A prospective, longitudinal study from a managed care consortium showed that physicians often underestimated asthma severity. The consequence of underestimating asthma severity in that study was undertreatment.10 3) There are subsets of patients with persistent asthma who do not respond to ICSs. A recent editorial by Drs Bhat and Calhoun speculated that 10% to 15% of patients with severe persistent asthma may be refractory to the best currently available pharmacotherapy.11 For such patients, newer therapies are needed, and efforts such as those by the Severe Asthma Research Program are helping us determine how to better manage these patients.12

Inhaled Corticosteroids in Combination With Other Drugs

ICSs are the foundation of therapy for patients with persistent asthma.1 ICSs are the most effective anti-inflammatory medications currently available for asthma. They block late-phase reactions to allergens, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation.1 ICSs are the only class of medications which have been proved, by bronchoscopy biopsy studies, to effectively reduce airway inflammation in patients with asthma.13-15 By controlling airway inflammation, the use of ICSs reduces symptoms and improves lung function.16 Regular use of ICSs has been associated with reduced asthma exacerbations17 and possibly decreased asthma mortality.18 However, carefully conducted controlled clinical trials have shown that a substantial minority of patients do not achieve asthma control, even with high-dose ICSs. In the GOAL (Gaining Optimal Asthma controL) study, the use of ICSs alone resulted in well-controlled asthma in only 68% of patients at the end of 1 year of treatment.3

The EPR 3 recognizes that ICSs alone, even at increased doses, may be insufficient to control asthma in all patients, particularly those with moderate-to-severe disease.1 Consequently, they recommend adding other classes of medications to ICSs in those patients with more severe asthma. LABAs are the medication most commonly added to the regimen of patients whose asthma is not controlled by an ICS. The addition of a LABA to an ICS was hypothesized to provide benefits compared with simply increasing the dose of the ICS, by improving lung function and symptom control more rapidly. The GOAL study directly compared the effectiveness of higher doses of an ICS (fluticasone propionate) with the combination therapy of an ICS plus a LABA (salmeterol) in achieving asthma control.3 The combination of the ICS and LABA was associated with patients achieving well-controlled status faster. Also, a significantly higher percentage of patients achieved asthma control with the combination compared with those receiving the ICS alone. The combination approach was also associated with fewer asthma exacerbations. Although the combination of an ICS with a LABA was more effective in this study, it is remarkable to note that only 77% of patients treated with an ICS and a LABA achieved well-controlled asthma status at study end.

Another combination that may be effective for patients poorly controlled by ICSs alone is ICS therapy plus an LMA. Although LMAs are recommended as an alternative to ICSs in patients with mild, persistent asthma, the combination of an LMA plus an ICS may help some patients with more severe symptoms. Virchow et al performed a 6-month open-label study in which patients (n = 1681) were given montelukast (10 mg) in addition to their ICS or ICS plus LABA therapy.19 At the end of the study, there was a dramatic improvement in the patients’ asthma control. Using Asthma Control Test score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 to 17.6% and 21.7%, respectively. Furthermore, the percentage of patients with well-controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 to 47.5% and 11.4%, respectively. Similar improvements were seen in 2 recent Canadian studies.20,21 Although LMAs provide benefits when combined with an ICS, the LABA and ICS combination seems more effective. Nelson et al randomized patients with asthma suboptimally controlled on an ICS alone to additionally receive a LABA or an LMA.22 Patients improved with both combinations, but the addition of a LABA to an ICS resulted in significantly greater improvements in lung function and overall asthma control.

Selected patients may benefit from the combination of an ICS plus the humanized monocloncal anti-IgE antibody omalizumab. Rodrigo et al examined data from 8 placebo-controlled clinical trials that assessed the safety and efficacy of an ICS plus omalizumab in patients with moderate to severe persistent asthma.23 They calculated that the asthma exacerbation rate during the stable phase was almost halved in patients receiving omalizumab compared with placebo (37.6 per 100 patient-years in the omalizumab group vs 69.9 in the placebo group; RR= 0.57, 95% confidence interval [CI], 0.48-0.66). The percentage of patients with at least 1 asthma exacerbation was 17.2% in the omalizumab group versus 30.9% in the placebo group (RR = 0.55, 95% CI, 0.47-0.64). Patients treated with omalizumab were significantly more likely to tolerate ICS reduction. Equally important, the placebo and omalizumab treatment groups had similar safety profiles. There were no indications of increased risk of hypersensitivity reactions, cardiovascular effects, or malignant neoplasms in patients receiving omalizumab. One limitation of therapy with omalizumab is the requirement that elevated IgE levels be documented prior to initiation. Also, because of the risk of immediate hypersensitivity reactions to this product, the US Food and Drug Administration requires careful monitoring of patients during and immediately after administration of omalizumab.

 
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