Case 1: Importance of Asthma Treatment Guidelines and Role of New Pharmacologic Agents (CE)

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Case 1: Importance of Asthma Treatment Guidelines and Role of New Pharmacologic Agents

Aidan A. Long, MD

Clinical Director, Allergy and Immunology

Massachusetts General Hospital

Boston, Massachusetts

Aidan A. Long, MD has disclosed expert testimony for GlaxoSmithKline.The planning staff from the University of Cincinnati, The American Journal of Managed Care, and the Pharmacy Times Office of Continuing Professional Education have no relevant financial relationships to disclose.

Activity Overview

Asthma still exacts a severe national burden through patient morbidity and mortality, rising healthcare costs, and employee absenteeism. There is a need to improve the management of asthma to improve outcomes and alleviate the burden on the patient and healthcare system. There are a multitude of therapies currently available and being researched that can help to achieve better outcomes in patients with asthma. This activity will provide managed care healthcare professionals an overview of the unmet needs in asthma, discuss current and emerging therapies and their role in the treatment paradigm, and identify strategies that can help improve patients and providers achieve asthma control.

Please note the case presentation and supporting material have been created to be an engaging CE activity, and as such the case and questions will appear throughout. These questions are provided for your reference to be able to relate material presented back to a patient case presentation, and are not answerable on the case page. To answer the questions you will need to go to the posttest section, which will again reiterate the questions and provide you the opportunity to answer them.How to Obtain Credit

To receive your CE certificate, participants must view the entire activity online, complete the online 10‐ question posttest with a score of 70% or better, and complete the evaluation form. After successful completion of the online posttest and evaluation form, participants may immediately print their certificates.

Release Date: April 8, 2011

Expiration Date: April 8, 2012

Estimated time to complete: 1 hour

Type of Activity: Application

Targeted Audience

This activity is designed for medical directors, pharmacy directors, and other managed care professionals who oversee the care of patients with asthma.

Educational Objectives

After completing this activity, the participant should be able to:

  • Describe the significance of unmet needs among people with asthma and elucidate contributing factors to poor asthma control
  • Examine new and emerging therapies for asthma and assess their role in the treatment of asthma
  • Identify strategies for improving asthma control


Control of asthma is likely accomplished by implementing the guidelines developed by the National Asthma Education and Prevention Program (NAEPP).1 These evidence-based guidelines provide a solid foundation to help clinicians in practice and in managed care organizations develop treatment plans to control asthma. If adequate control is delayed, it can impede future efforts to control symptoms. Poor asthma control can also impact medical costs through excess utilization and decreased health-related quality of life.2,3 Proper adherence to evidence-based guidelines is a key factor in obtaining asthma control.

Review of Asthma Treatment Guidelines

The most recent version of the NAEPP guidelines was written in 2007, and it is commonly referred to as the Expert Panel Report 3 (EPR-3).1 The EPR-3 lists 4 components of asthma management: (1) assessment and monitoring; (2) education; (3) controlling environmental and comorbid conditions; (4) pharmacologic therapy. Clinicians, as well as practitioners evaluating medical policies, can contribute to these 4 components, which are all equally important.

Assessment and Monitoring


Assessment and monitoring tools can be used to determine the patient’s asthma severity, their control of the condition, and responsiveness to treatment. Asthma severity and asthma control are determined clinically through assessment of impairment (ie, symptom severity and functional limitations), lung function, and future risk of exacerbations. Severity is best determined if the patient has not begun long-term treatment; otherwise, it can be inferred from the least amount of treatment required to maintain control. After the patient has been started on medication appropriate for the asthma severity, they should be seen on a regular basis to assess control. For assessment of asthma control, patient-centric questionnaires such as the Asthma Control Test,4 the Childhood Asthma Control Test,5 the Asthma Control Questionnaire,6 and the Asthma Therapy Assessment Questionnaire control index7 can be used. Lung function and asthma control can vary over time; therefore, if asthma control begins to falter, clinical reassessment should be performed prior to any treatment adjustments (ie, step-up or step-down therapy).

Assessment should evaluate both impairment and risk of asthma. The impairment domain encompasses how the patient has been bothered by asthma over the past several weeks. Specific considerations include: how asthma has limited the patient's ability to lead a normal life, how often they use rescue medication for symptom control, and how often they awake from sleep with asthma symptoms. The risk domain encompasses how likely the patient is to experience a complication in the future, such as an exacerbation, adverse event from a medicine, or an accelerated decline in lung function. A medical history may help ascertain the patient’s risk. For example, patients without a good asthma action plan, or those with a history of recent exacerbations requiring emergency department visits, hospitalization, or intensive care unit admission, generally are at greater risk of future exacerbations.8-10

Monitoring asthma control is important, as it can determine if the patient was prescribed appropriate therapy and if he or she is adhering to the treatment regimen. Selecting the proper treatment program (including appropriate and directed environmental modification, recognition and management of comorbid conditions, and careful choice of pharmacotherapy) is essential to improve asthma control.11 Assessment and monitoring of treatment should include a discussion on the environment the patient inhabits (Table).

Table. Precipitating and Aggravating Factors Associated With Asthma1

  • Viral respiratory infections
  • Environmental allergens, indoor (eg, mold, house-dust mite, cockroach, animal dander, or secretory products) and outdoor (eg, pollen)
  • Characteristics of home including age, location, cooling and heating system, wood-burning stove, humidifier, carpeting over concrete, presence of molds or mildew, characteristics of rooms where patient spends time (eg, bedroom and living room with attention to bedding, floor covering, stuffed furniture)
  • Smoking (patient and others in home or daycare)
  • Exercise
  • Occupational chemicals or allergens
  • Environmental change (eg, moving to new home; going on vacation; and/or alterations in workplace, work processes, or materials used)
  • Irritants (eg, tobacco smoke, strong odors, air pollutants, occupational chemicals, dusts and particulates, vapors, gases, and aerosols)
  • Emotions (eg, fear, anger, frustration, hard crying or laughing)
  • Stress (eg, fear, anger, frustration)
  • Drugs (eg, aspirin; and other nonsteroidal anti-inflammatory drugs, beta-blockers including eye drops, others)
  • Food, food additives, and preservatives (eg, sulfites)
  • Changes in weather, exposure to cold air
  • Endocrine factors (eg, menses, pregnancy, thyroid disease)
  • Comorbid conditions (eg, sinusitis, rhinitis, gastroesophageal reflux disease)

Adapted from National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 2007. Accessed March 2, 2011.

Patient Education

Most asthma treatment is self-administered. Therefore, patients should be familiar with the pathophysiology of asthma and educated on the importance of proper treatment adherence. Managed care professionals should ensure that asthma and other respiratory-related disease management programs include an allotment of time for clinicians and pharmacists to educate patients. This education should be repeated and reinforced often.

Control of Environmental Factors and Comorbid Conditions

It is well established that asthma is associated with an immune response. As such, patients need to be informed on methods to reduce exposure to known allergens. They should also be familiar with other factors that can aggravate symptoms (Table). This aspect of the treatment plan can easily be overlooked by all parties involved. Comorbid conditions can also complicate the presentation and treatment of asthma. Effective monitoring and management of comorbidities is important because it may improve overall asthma control and reduce the need for certain asthma medications.

The central goal of optimal asthma care is to control asthma with the least amount of medication necessary. Therefore, medical care and education must focus on the avoidance of environmental triggers and the recognition and management of comorbidities and complications.

Pharmacologic Therapy

Asthma medications are classified as long-term controller medications or quick-relief medications. Long-term controller medication classes include inhaled corticosteroids (ICSs), long-acting beta2-agonists (LABAs), cromolyn sodium and nedocromil, sustained-release theophyllines, leukotriene modifiers, and anti-immunoglobulin E (IgE) agents.

ICSs are the most potent and effective anti-inflammatory medications currently on the US market. ICSs block late-phase reactions to allergens, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. Clinical studies have shown that ICSs have numerous benefits in patients with asthma, including reduction in severity of symptoms, improvement in asthma control and quality of life, improvement in peak expiratory flow and spirometry, diminished airway hyperresponsiveness, prevention of exacerbations, and reduction in systemic corticosteroid requirements, emergency department care, hospitalizations, and deaths (due to asthma).1 LABAs are often used in combination with ICSs for control of symptoms, especially nighttime symptoms. LABAs act as bronchodilators. They are not recommended as monotherapy, but the ICS + LABA combination is often used for step 3 or 4 in the step-up treatment regimen recommended by the NAEPP (Figure).1 Omalizumab is a monoclonal antibody (anti-IgE) used as add-on therapy for severe, persistent asthma (ie, step 5 or 6). It has been shown to reduce exacerbations and improve symptoms.

Quick-relief medications consist of short-acting beta2-agonists (SABA), anticholinergics, and oral corticosteroids. SABAs are the therapy of choice for relief of acute asthma symptoms and prevention of exercise-induced bronchospasm.

Figure. Step‐Wise Approach to Treatmenta,1


A 35-year-old female with a 20-year history of severe asthma visited her clinician to ask for a change in treatment. For the past 5 years, her asthma was under adequate control with daily use of an ICS plus a LABA (fluticasone propionate 115 μg [medium-dose ISC] and salmeterol 21 μg).Using that regimen, a SABA rescue inhalant was only necessary 2 or 3 times a week. Recently, her symptoms have worsened, and she is reporting use of the SABA 3 to 5 times a day to avoid or manage exacerbations.

1) The combination of an ICS plus a LABA has worked well in the past, but is no longer effective. The clinician should immediately:

a) Prescribe omalizumab

b) Increase the dose of ICS

c) Reassess lung function

d) All of the above

2) Inadequate asthma control includes the use of a SABA _____ times a week.

a) 0

b) 1

c) 2

d) 3

3) Among the components of asthma management proposed by the NAEPP guidelines, which of the following is considered the most important?

a) Assessment and monitoring

b) Patient education

c) Pharmacologic treatment

d) All are equally important

4) This patient may have fewer exacerbations with a step-up regimen that includes:

a) The addition of omaluzimab

b) Higher dose of LABA

c) Switching from ICS plus LABA to high dose ICS monotherapy

d) Any of the above

Emerging Treatment Options for Asthma

New treatment options are needed to improve outcomes in some patients, including those with refractory or difficult to control asthma who often require urgent care. If treatment options listed in the guidelines are not effective or are contraindicated in some patients, newer options may be available soon.

Many medications in combination with ICSs have shown promise in clinical trials. For example, the leukotriene inhibitor montelukast, normally recommended for patients with mild asthma, may be effective for some patients with severe asthma when combined with an ICS. 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.12 At the end of the study, Asthma Control Test scores showed 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.

The combination of tiotropium plus an ICS may be another option for patients with uncontrolled asthma.1 Currently, this anticholinergic drug is approved only for the treatment of chronic obstructive pulmonary disorder. In a double-blind, triple-dummy, crossover study, tiotropium, in combination with an ICS, was comparable to other standard asthma treatments (ie, doubling the ICS dose or an ICS plus a LABA) in patients with uncontrolled asthma on standard ICS therapy (n = 210).13 In this study, 3 different treatment options were examined [(1) doubling the dose of the ICS (beclomethasone 160 μg twice daily); (2) normal dose ICS (beclomethasone 80 μg twice daily) plus the LABA salmeterol xinafoate (50 μg twice daily); or (3) normal dose ICS (beclomethasone 80 μg twice daily) plus tiotropium bromide (18 μg each morning)]. Each of the treatment approaches provided some benefits, but the tiotropium and LABA additions had consistently better improvements in overall asthma control than doubling the dose of the ICS, as assessed by morning and evening peak expiratory flows (PEF), forced expiratory volume in 1 second (FEV1), and daily symptom scores.

Patients may also benefit from the combination of an ICS plus the monoclonal anti-IgE agent omalizumab. A recent analysis by Rodrigo et al14 showed that the addition of omalizumab can significantly reduce asthma exacerbation rates (37.6 per 100 patient-years in the omalizumab group vs 69.9 in the placebo group). 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.

Various cytokine inhibitors are being studied as monotherapy for asthma. These include the interleukin (IL)-5 antagonist mepoluzimab for patients with eosinophilic asthma;15 daclizumab, a monoclonal antibody that binds to IL-2, for moderate-to-severe asthma;16 and the tumor necrosis factor antagonists (TNF) etanercept17 and infliximab.18

Many of these medications are showing great promise in clinical trials. For example, Haldar et al performed a randomized, double-blind, placebo-controlled, parallel-group study in patients (n = 61) with refractory eosinophilic asthma and a history of recurrent severe exacerbations.15 At the end of this year-long study, patients who received monthly infusions of mepolizumab (750 mg; n = 29) had significantly fewer severe exacerbations compared with those receiving placebo (n = 32) (mean exacerbations per subject, 2.0 vs 3.4, respectively; relative risk= 0.57; 95% confidence interval [CI], 0.32-0.92; P = .02). Asthma Quality of Life Questionnaire (AQLQ) scores were also better in the group receiving mepolizumab (mean increase from baseline, 0.55 vs 0.19; mean difference between groups, 0.35; 95% CI, 0.08-0.62; P = .02).15

The clinical results for daclizumab, a monoclonal antibody that binds to the α chain of the high-affinity IL-2 receptor, indicate that it may be effective as add-on therapy. Busse et al performed a small, randomized, double-blinded, placebo-controlled study in adults with moderate-to- severe persistent asthma who required ICS treatment for asthma control.16 During the first 12 weeks of the study, all patients were maintained on a stable dose of an ICS and received daclizumab (2 mg/kg loading dose, 1 mg/kg maintenance dose; n = 88) or placebo (n = 27) every 2 weeks. Over the next 8 weeks of the study, efforts were made to taper the ICS dose. Patients were followed for an additional 16 weeks without therapy as a washout period. During the first 12 weeks of the study, there was a small but significant increase in FEV1 in the daclizumab group (daclizumab, 4.4 % vs placebo, 1.5 %; P = .05), along with reduced daytime asthma symptoms (P = .018) and SABA use (P = .009). Daclizumab treatment did not allow ICS tapering, but did prolong the time to the first asthma exacerbation (P = .024).

TNF antagonists may also be effective. TNF plays an important role in chronic inflammatory disorders involving the Th1 immune response and neutrophils. Morjaria et al performed a randomized, double-blind, placebo-controlled parallel group study that compared etanercept (50 mg administered by subcutaneous injection once weekly for 12 weeks) with placebo in 39 patients with severe corticosteroid-refractory asthma.17 Etanercept was associated with a significant decrease in Asthma Control Questionnaire scores compared with placebo (-1.11 [95% CI -1.56 to -0.75] and -0.52 [95% CI -0.97 to -0.07], respectively; P = .037), but there were no significant differences among the treatment groups with respect to AQLQ scores, PEF, and bronchial hyperresponsiveness. Another TNF antagonist, infliximab, may also help some patients. Erin et al performed a double-blind, placebo-controlled, parallel-group design study in 38 patients with moderate asthma who were symptomatic despite treatment with ICSs. Patients received infliximab (5 mg/kg intravenously at weeks 0, 2, and 6) or placebo.18 At the end of the study, there was no significant difference in the primary end point (the change in morning PEF at end of study compared with end of run-in phase), but significantly fewer patients given infliximab had exacerbations compared with those given placebo (29% vs 78%, respectively; P = .01).

Another class of drugs that may prove effective is phosphodiesterase type 4 inhibitors. Bateman et al conducted a double-blind, parallel-group, phase 2/3 study in which patients with asthma (n = 693) were randomized to receive 100, 250, or 500 μg of roflumilast or placebo and they observed increases in FEV1 that were dose dependent.19 Further, Bousquet et al compared roflumilast (500 μg once daily) with inhaled beclomethasone dipropionate (BDP) (200 μg twice daily) in a double-blind, double-dummy, randomized, noninferiority study in patients with persistent asthma (n = 499).20 At the end of the 12-week study, both medications significantly improved FEV1 (roflumilast, 12% increase; BDP, 14% increase) and forced vital capacity (roflumilast, 270 mL increase; BDP, 330 mL increase).

Finally, oligonucleotides may prove to be an effective treatment option. Oligonucleotides cover a broad range of drugs and can be either RNA-targeting agents such as antisense, small interfering RNA, deoxyribozymes, and microRNA, or protein-targeting agents such as RNA decoy, immunostimulatory sequence drugs, and aptamers. At present, most studies are in animal models of asthma but some clinical studies have been conducted. For example, a phase 2 crossover study by Gauvreau et al assessed the safety and efficacy of TPI ASM8, which consists of 2 modified phosphorothioate antisense oligonucleotides that may attenuate the allergic inflammation response by targeting C-C chemokine receptor type 3 and the beta chain of IL-3, IL-5, and granulocyte macrophage colony-stimulating factor receptors.21A total of 17 patientswith mild atopic asthma were randomized to inhale 1500 μg TPI ASM8 or placebo by nebulizer once daily for 4 days. On day 3, subjects underwent an allergen inhalation challenge. Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% and blunted the increase in total cells (63%) after the allergen challenge. Additional studies are under way.

CASE STUDY (continued)

The patient is a mother of an 8-year old autistic child, and she recently quit her job to focus more of her attention on managing her child’s medical and educational needs. Two months ago, the family (she, her husband, and the child) moved into the basement of her parents’ house to save money. Her symptoms worsened shortly after they moved into the basement, but she insists that the basement is very clean and remarked that it is even cleaner than her old apartment. The patient is very knowledgeable about asthma treatment options and has asked the doctor whether or not she is now a “step 5 patient” and is in need of additional medication such as omalizumab.

5) A new environment, regardless of its cleanliness, can impact asthma symptoms.

a) True

b) False

6) The patient’s new residence may be clean, but another factor that may aggravate her asthma is:

a) Heating/cooling system in the residence

b) Geographic region

c) Type and age of carpeting over the concrete basement floor

d) All of the above

7) The stress the patient has been under to help her child, quit her job, and move to a new residence are likely very intense, but probably did not aggravate her asthma.

a) True

b) False

8) If further assessment reveals she has eosinophilic asthma, she may eligible to enter a clinical trial with:

a) Roflumilast

b) Mepoluzimab

c) Etanercept

d) An oligonucleotide

9) Tiotropium is approved for asthma treatment.

a) True

b) False

10) Which of the following is not a cytokine inhibitor?

a) Daclizumab

b) Etanercept

c) Roflumilast

d) Infliximab

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The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information including treatments, drugs, and dosage regimens is accurate and conforms to the standards accepted at the time of publication. However, healthcare professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently.


After reading “Case 1: Importance of Asthma Treatment Guidelines and Role of New Pharmacologic Agents,” select the 1 best answer to each of the posttest questions.

A statement of continuing education hours will be provided to those physicians and pharmacists who successfully complete and return the answer form and program evaluation and receive a passing grade of 70% or higher.




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