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Clinical Updates on the Management of Asthma
Suzanne Bollmeier, PharmD, BCPS, AE-C
Advancements in Asthma Therapy and Their Impact on Managed Care

Clinical Updates on the Management of Asthma

Suzanne Bollmeier, PharmD, BCPS, AE-C
Table 11,19 lists the standard regimens for managing patients with asthma. However, not all patients with asthma respond to standard treatment options, such as a high-dose inhaled corticosteroid (ICS) plus a long-acting beta-agonist (LABA). Approximately 5% to 10% of patients with asthma are classified as having severe asthma.20 Currently, there are many unmet needs with respect to the management of severe asthma; thus, many new approaches to treatment are being attempted.20 Many of the options discussed in the following sections are targeted toward patients suffering from severe asthma who have not gained control of their disease with standard treatment regimens. Of note, many of the medications discussed in the following section are not currently listed in the guidelines, but future options for updated guidelines are discussed.

FDA-approved Treatments

Bronchodilators

ULTRA–LONG-ACTING BETA2-AGONISTS

Beta-agonists are one of the cornerstone therapies of asthma management. They act as bronchodilators by stimulating beta2-receptors to relax smooth muscle. In addition to use of a short-acting beta-agonist (SABA) as rescue therapy in all patients, current guideline recommendations include daily use of the LABAs, salmeterol or formoterol, in combination with an ICS, for long-term control in moderate or severe persistent asthma.1 Results from SMART (Salmeterol Multicenter Asthma Research Trial) showed a significant increase in asthma-related deaths in patients receiving salmeterol alone compared with placebo.21 This study resulted in labeling changes for LABAs; the use of LABAs without an ICS in asthma is now contraindicated. Additionally, the FDA conducted a meta-analysis of data and concluded that LABAs increased the risk of severe exacerbations of asthma symptoms (driven by the number of asthma-related hospitalizations).22 Combination therapy should only be employed as long-term therapy and only if the patient’s asthma is not well controlled.

Traditionally, LABAs last more than 12 hours, providing for twice-daily dosing. Newly approved ultra–long-acting beta2-agonists have entered the market and provide for once-daily dosing, with higher selectivity for beta2-receptors. Currently, the only FDA-approved ultra–long-acting beta-agonist for use in asthma is a combination product of vilanterol with fluticasone. However, there are numerous phase 2 and 3 clinical trials that have assessed the use of each of these agents in asthma. Table 21,19 provides a comparison of the ultra–long-acting beta2-agonists currently approved for use in asthma or chronic obstructive pulmonary disease (COPD).

In clinical trials, fluticasone/vilanterol resulted in significant improvement in pulmonary function and reduced exacerbations compared with placebo or equivalent doses of fluticasone alone.23,24 This combination has also shown similar efficacy compared with fluticasone/salmeterol in patients with persistent asthma.25 A clinical trial comparing the combination of fluticasone/vilanterol to the combination of fluticasone/salmeterol or budesonide/formoterol is currently underway (www.clinicaltrials.gov; identifier NCT02446418).

Compared with placebo, indacaterol resulted in significant improvements in forced expiratory volume in 1 second (FEV1), with good tolerability and safety.26-28 A study comparing indacaterol versus salmeterol and salbutamol concluded that indacaterol resulted in significant improvements in FEV1 compared with placebo or salbutamol with few adverse events (AEs).29

Olodaterol resulted in significant improvements in FEV1 compared with placebo in 2 phase 2 dose-finding studies.30,31 Doses of up to 20 mcg daily were used compared with placebo, with no significant AEs reported.30,31

LONG-ACTING MUSCARINIC ANTAGONISTS

Antimuscarinic agents, such as ipratropium, have previously been used for asthma as a quick-relief medication option if patients did not respond to initial SABA therapy. Muscarinic antagonists inhibit muscarinic cholinergic receptors and reduce the intrinsic vagal tone of the airway.1 Ipratropium bromide is the short-acting antimuscarinic used in combination with a SABA or as an alternative if a patient does not tolerate a SABA. Tiotropium bromide is a once-daily inhaled muscarinic antagonist first utilized in COPD, but it is now approved by the FDA for use in patients with asthma in the Respimat device (Table 31,19). It is currently the only long-acting muscarinic antagonist (LAMA) approved for use in asthma.

A systematic review published in Chest concluded that tiotropium was noninferior to salmeterol in patients with moderate to severe asthma who were not adequately controlled by an ICS or ICS/salmeterol.32 Additionally, tiotropium was found to improve lung function and increase the time to severe exacerbations. As such, the GINA 2016 guidelines now recommend it as add-on therapy for step 4 treatment in patients at least 12 years old with a history of asthma exacerbations (Table 11,19).19

Beyond tiotropium, other LAMAs are currently available (Table 31,19). Aclidinium has shown promising effects in patients suffering from COPD; study results have shown significant improvements in FEV1 compared with placebo.33,34 However, there are currently no data to support its use in asthma. Similarly, glycopyrrolate is approved as a bronchodilator in COPD. A phase 2 study of glycopyrrolate as add-on therapy in adults with mild to moderate asthma was recently completed, but results have yet to be published (www.clinicaltrials

.gov; identifier NCT02296411).

Umeclidinium is also only currently approved for use in COPD. In a double-blind crossover study in patients with asthma, umeclidinium led to modest improvements in FEV1, which did not appear to be related to the dose. Therefore, the authors were unable to confirm the therapeutic benefit of umeclidinium monotherapy in patients with asthma not requiring ICS treatments.35 However, in a double-blind crossover study in patients with asthma on an ICS, improvements in FEV1 and both morning and evening peak expiratory flows were observed following combination therapy with fluticasone/umeclidinium.36 Future long-term clinical trials with all LAMAs, as monotherapy or combination, will provide further insight into their utility in the management of asthma.

Combination Products for Long-term Control

ICSs and beta2-agonists are often used together to increase efficacy outcomes. Glucocorticoids increase the number of beta2-receptors on the cell surface, protecting against the downregulation of beta2-receptors, which can be a consequence of long-term use.37 Beyond increased efficacy, to try and prevent the unintentional use of a LABA alone, combination inhalers are often developed for use in asthma. GINA guidelines recommend the use of combination therapy as early as step 3.19 There are combination inhalers currently available that allow for the potential to improve adherence rates, increase efficacy, and even lower costs (due to 1 co-pay vs 2). However, patients can be prescribed individual inhalers.

Currently, the only long-term, once-daily combination product approved by the FDA for asthma is fluticasone furoate/vilanterol. Compared with fluticasone furoate alone, the combination product resulted in significant improvements in FEV1 and more rescue-free and symptom-free days, with similar AEs.38 Table 439-47 lists combination products that are currently approved by the FDA and whether or not they are approved for use in asthma. Because tiotropium is the only LAMA approved for use in asthma, and it is only available as a single inhaler, combination therapies containing a LAMA are currently not approved for use in asthma. It is anticipated, however, that these products will be utilized in patients with asthma, as GINA guidelines now recommend combining ICS/LABA/LAMA agents.19

In clinical trials in patients with COPD, the combination therapies listed in Table 439-47 that are currently approved for use in COPD led to greater increases in FEV1 compared with their single components.48-50 In addition, the combination product glycopyrrolate/indacaterol led to decreases in dyspnea and use of rescue medications.51 A combination product containing aclidinium/formoterol is currently approved for use in Europe, the United Kingdom, and Canada. There are also ongoing clinical trials in Italy assessing the use of a combination product containing beclomethasone, formoterol, and glycopyrrolate (www.clinicaltrials.gov; identifiers NCT02676076 and NCT02676089). Further clinical trial data are necessary before these combination therapies can be recommended for use in asthma.

Immunotherapy

Allergic rhinitis is often seen in patients with asthma. Asthma symptoms may improve in some patients by controlling their allergies. Allergen immunotherapy creates tolerance to specific antigens (eg, dust mites) by decreasing the immune system’s response to them over time.52 Both subcutaneous and sublingual immunotherapy (in as little as 12 months) can improve asthma symptoms and reduce the need for medications.53 Patients with uncontrolled symptoms, despite the use of pharmacotherapy, and with evidence of allergic disease (ie, positive skin prick testing, elevated serum IgE) are candidates for immunotherapy.52

Eligible patients should consult with their providers to select the best delivery system for them; sublingual tablets require daily dosing and subcutaneous injections require travel to the provider office for administration. As anaphylactic reactions are possible, pharmacists should ensure that patients on either form of immunotherapy are prescribed injectable epinephrine and are educated on its proper use and administration.

Bronchial Thermoplasty

 
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