Asthma Control & Rescue

Should we consider combination therapy for dual purposes?

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Asthma is a chronic inflammatory lung disease characterized by intermittent obstruction of airflow due to airway hyperresponsiveness to external and internal triggers.1 Infiltration of the airway tissues by inflammatory mediators results in hyperplasia of bronchial smooth muscle, bronchoconstriction, increased mucus secretion and airway edema - all of which worsen during acute exacerbations. Permanent airway remodeling occurs over time as a result of this chronic inflammation.1

The Centers for Disease Control and Prevention reports that approximately 19 million adults and 7 million children in the United States now have asthma.2 The treatment of patients with asthma must focus on controlling chronic symptoms and effectively managing acute exacerbations when they occur.3 Effective asthma management improves quality of life for patients, reduces asthma-related morbidity and mortality and decreases associated healthcare costs.3


Current Guidelines

Current best practice guidelines for asthma focus on two things: control of asthma symptoms and prevention of exacerbations.4,5 The Global Initiative for Asthma (GINA) and the National Heart Lung and Blood Institute's National Asthma Education and Prevention Program recommend a step-wise approach to asthma management.4,5 This approach requires the patient and healthcare provider to work collaboratively to classify each patient's asthma severity based on specific measures of asthma control. These measures include the frequency of asthma symptoms, the number of nighttime awakenings per month, the frequency of short-acting beta-agonist (SABA) use, the degree to which symptoms interfere with normal activity, and pulmonary function.4,5

Pulmonary function is evaluated using spirometry, which measures forced expiratory volume (FEV1) and FEV1 in relation to forced vital capacity (FVC). FEV1 is the volume of air forcefully expired over 1 minute, and FVC is the total amount of air that can be expired from the lungs after a maximum breath. The ratio of FEV1 to FVC indicates the presence and degree of airway obstruction. Spirometry performed before and after administration of a short-acting beta-agonist helps determine whether airway obstruction is reversible, which is a key finding in asthma that helps differentiate it from other obstructive pulmonary diseases.1 Spirometry requires equipment that is only available in a healthcare setting. Therefore, assessment of asthma control is based primarily on subjective patient report, which may be skewed and inaccurate. In-office spirometry provides only a snapshot of the patient's overall asthma control.

Several validated instruments for assessing asthma control are available, including the Asthma Therapy Assessment Questionnaire (ATAQ), the Asthma Control Questionnaire (ACQ; http://www.qoltech.co.uk/acq.html) and the Asthma Control Test (ACT; www.asthma.com). These tools measure asthma control based on the frequency of symptoms, severity of symptoms, the degree to which symptoms interfere with daily activities, and the need for rescue medication.

Once asthma severity has been determined, pharmacologic therapy should be initiated based on current guidelines (http://www.nhlbi.nih.gov/guidelines/asthma/).5 In general, pharmacologic therapy for asthma involves a stepwise approach using an as-needed bronchodilator for emergency treatment of exacerbations and controller medications including inhaled steroids, long-acting bronchodilators and medications to control inflammatory mediators - all aimed at preventing asthma exacerbations. After initiating new medication, response to therapy should be evaluated using the same tool originally used to assess asthma severity. Evaluation of therapy effectiveness should then be performed on a regular basis to determine the need for step-up or step-down therapy.5


Primary Drug Categories

Inhaled corticosteroids (ICSs), delivered alone or in combination with long-acting beta-agonists (LABAs), are a key component in the management of persistent asthma.4,5 ICSs decrease airway edema by reducing mucosal granulocytes, diminishing airway hyperresponsiveness and reducing mucus production in the bronchi. In addition, ICSs cause an increase in the production of cell surface beta receptors (upregulation) and improve the beta-receptor response to beta-agonists.6,7

ICSs are the only medications for asthma symptom prevention that decrease the risk of dying from asthma.8 Because ICSs may cause a temporary reduction in growth velocity when used in children and are associated with osteopenia, cataracts and adrenal suppression at high doses, the lowest effective dose should be used to control asthma symptoms.

It is important to note that response to ICS therapy is typically not immediate. This therapy reaches maximum benefit at approximately 4 weeks. Therefore, step-down to lower-dose ICS therapy should only occur after maximum benefit has been achieved following an appropriate treatment period.9

LABAs are also an important tool for controlling persistent asthma symptoms. Formoterol and salmeterol are the only two commercially available LABAs approved for asthma treatment in the United States. Use of these medications as monotherapy is contraindicated, because they can cause a decrease in the production of cell surface beta receptors (downregulation) and subsequent beta-agonist tolerance.10 When co-administered with LABAs, ICSs provide protection against this beta-agonist tolerance and actually cause upregulation of beta-2 receptors.11,12 Similarly, LABAs augment the activity of the glucocorticoid receptor, and in combination with ICSs, they decrease bronchial smooth muscle proliferation.13


Achieving Synergy

The synergistic activity between LABAs and ICSs provides significant benefit to asthma patients whose symptoms are not controlled on an ICS and SABA regimen. These patients require a step-up in treatment to achieve control. Patients may receive prescriptions for both a LABA inhaler and an ICS inhaler. However, this may be inconvenient and confusing for patients and may result in decreased adherence to dosing recommendations.

Combination ICS-LABA inhalers are available. These may improve the likelihood that patients will adhere to their medication regimen. Fluticasone-salmeterol, mometasone-formoterol and budesonide-formoterol are the only three combination ICS-LABA inhalers approved in the United States.14 Each is available in variable concentrations of the ICS component and a fixed concentration of LABA.14

Current guidelines recommend that therapy be initiated based on asthma severity, then titrated up or down based on response. The goal is to provide the minimal effective total dose of ICS to prevent symptoms. Patients who receive prescriptions for ICS-LABA inhalers (or individual ICS and LABA inhalers) still require a SABA inhaler for use as a rescue medication. It is important that they receive thorough instruction about its appropriate use as part of an asthma action plan. Frequent use of SABA in the setting of daily ICS-LABA inhaler use is an indication of poor adherence or the need for an increased concentration of ICS.5


To the Rescue?

Poor adherence and incorrect usage of inhalers are a major cause of poorly managed asthma symptoms, regardless of whether patients receive prescriptions for individual ICS and LABA inhalers or ICS-LABA combination products.15 Poor patient adherence occurs for a variety of reasons, including difficulty using inhaler devices, medication cost, fear of side effects and misunderstanding of the dosing schedule.4 Educating patients about control of environmental factors that trigger asthma is critical. Environmental control requires patients to reduce their exposure to indoor allergens, including cigarette smoke, animal dander, mites and cockroaches. Outdoor allergens and respiratory irritants such as air pollution, dust and pollens should be avoided as well.1,4

Healthcare providers should work with patients to develop a written personalized asthma action plan, which helps patients make small adjustments to their treatment plan (i.e., increasing ICS dose or starting OCS treatment) based on their symptoms and PEF rate, which can be measured at home using an inexpensive handheld PEF meter. This guided self-management can decrease hospitalizations, emergency rooms trips and missed days of work.4

Given that patients who control their asthma using ICS-LABA combination products also require an additional SABA rescue inhaler, the question of whether ICS-LABA combinations might also be effectively used as rescue inhalers is a reasonable one. This could potentially reduce the number of inhalers required to only one, thereby improving adherence.

Many clinical trials have compared single inhaler therapy (budesonide-formoterol combination inhalers used as both maintenance and rescue therapy) with standard therapy (maintenance ICS-LABA and a SABA used as a rescue inhaler). Single-inhaler therapy is based on the presumption that an early increase in total ICS and LABA doses at the first sign of increased asthma symptoms would prevent progression to more serious asthma exacerbations, since it allows a quicker decrease in inflammation.16

Studies evaluating rescue use of ICS-LABA combination inhalers have focused primarily on those containing budesonide and formoterol. Although these trials varied somewhat in design, in general patients were instructed to use their budesonide-formoterol inhalers not only according to their daily prescribed maintenance regimen (typically one or two inhalations twice daily), but also to take additional inhalations at the first sign of increased symptoms, in lieu of their usual SABA rescue inhaler.

The success of this experimental regimen across multiple trials ultimately led to the approval of this strategy for use in adults in the European Union in 2006, as well as its inclusion in the 2006 GINA guidelines.4,17 But a 2013 Cochrane Review that assessed 13 trials including more than 13,000 adult asthma patients found that although single-inhaler therapy did decrease the number of asthma exacerbations requiring oral corticosteroids (OCSs) in comparison to standard therapy (daily ICS-LABA with as-needed SABA), it did not necessarily affect the incidence of hospitalization, death or life-threatening problems. In addition, a review of three large studies that enrolled more than 10,000 patients found that although single inhaler therapy was more effective than standard therapy for preventing exacerbations, patients who followed this regimen did not demonstrate an overall improvement in asthma control as defined by practice guidelines.18

The unique pharmacologic profiles of formoterol and budesonide are likely responsible for their efficacy in reducing time to severe exacerbation when used together as both maintenance and reliever medications. Formoterol is faster acting and longer lasting than salmeterol, and as a full agonist (versus salmeterol, a partial agonist) at the beta-receptor, it is more effective at increasing doses than salmeterol. 19 Formoterol does not appear to be the sole contributor of benefit when budesonide-formoterol is used in single-inhaler therapy. In a study of more than 3,000 asthma patients, the budesonide-formoterol combination was more effective in increasing the time to severe exacerbation when used as reliever therapy versus formoterol alone.20

The FDA has not approved single-inhaler therapy with budesonide-formoterol. Many of the single-inhaler studies have used the dry-powder inhaler form of budesonide-formoterol, which is available in Europe, Australia, Canada and elsewhere. The metered-dose inhaler (MDI) form of formoterol results in greater systemic absorption than the dry powder inhaler form, raising concern for formoterol toxicity.21 Further research is needed to determine the potential benefit of intermittent rescue use of budesonide-formoterol MDIs available in the United States.


Looking Ahead

Appropriate management of asthma is imperative for the millions of Americans affected by this disease. Failure to provide adequate and prompt treatment increases the risk for disease-related complications leading to reduced quality of life, increased morbidity and mortality, and increased healthcare costs. Studies suggest that use of budesonide-formoterol as single-inhaler therapy simplifies asthma treatment and reduces the number of asthma exacerbations requiring systemic corticosteroids. This is desirable given the unfavorable side effect profile associated with systemic steroid use. Single-inhaler studies have not, however, demonstrated a reduction in asthma-related hospitalization, life-threatening complications and death.

Further investigation is needed to clearly define the role of single-inhaler therapy in routine asthma management, and to explore the risk/benefit profile of the MDI formulation of budesonide-formoterol available in the United States. If the risk of formoterol toxicity is acceptable given the potential benefit of single-inhaler therapy, use of the budesonide-formoterol MDI may prove to be a valuable addition to current asthma treatment guidelines.


Danielle Kempton is an assistant professor in the physician assistant program at Midwestern University in Glendale, Ariz. Jennifer Hastings is the assistant director of clinical education for the program. The authors have completed disclosure statements and report no relationships related to this article.



1. McPhee SJ, et al, eds. Current Medical Diagnosis & Treatment. New York, NY: McGraw Hill; 2012.

2. Centers for Disease Control and Prevention. Asthma's Impact on the Nation. http://www.cdc.gov/asthma/impacts_nation/

3. Pederson S, O'Byrne PM. Combination inhaled corticosteroids and long acting β2-agonist use and severe asthma exacerbations. J Allergy Clin Immunol. 2012;129(5):1280-1282.

4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. http://ginasthma.org/documents/4

5. US Department of Health and Human Services, National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. http://www.nhlbi.nih.gov/guidelines/asthma/

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21. Peters S, et al. Treatment of moderate persistent asthma in adolescents and adults. UptoDate. http://www.uptodate.com/contents/treatment-of-moderate-persistent-asthma-in-adolescents-and-adults


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