August 2019

Long-Term Care Updates

Asthma is a chronic respiratory disease characterized by airway inflammation that affects approximately 235 million

people worldwide. Asthma impacts people of all ages and is typically diagnosed at a young age. As of 2017, 7% of adults

aged 65 years and older were affected by asthma. While asthma is considered by many to be a childhood disease, adults

65 years of age and older had the highest asthma death rate in 2016 compared to all other age groups, with 29.2

asthma-related deaths per one million people.1

Asthma is typically underdiagnosed in the elderly due to the belief that dyspnea is a part of the typical aging process. This

belief along with reductions in physical activity and greater comorbidities in elderly patients makes diagnosis and

treatment of asthma more difficult. Additionally, the management of asthma in the elderly is more complex as these

patients are generally excluded from clinical trials and may have functional difficulties with inhalers and comorbidities that

may lead to an increased risk for drug-drug interactions. Asthma treatment is further complicated in older patients who

are or were smokers. These patients are more likely to have an asthma-COPD overlap which is addressed in the Global

Initiative for Asthma (GINA) report.2

The updated GINA report was officially published in June of 2019 and provides an evidence-based strategy for the

management of the asthma. This report is developed from an international perspective. US guidelines on asthma

management from the National Heart, Lung, and Blood Institute (NHLBI) have not been updated since 2007,3 and no

Low dose daily ICSOR

LTRAOR

Low dose daily ICS-LABAMedium dose ICS

ORLow dose daily ICS+LTRA

Medium dose daily ICS-LABAHigh dose ICS

ORConsider add-on LTRA or tiotropium

withphenotypic assessment

ANDConsider add-on therapy

Low dose OCS

Note: Changes from 2018 GINA Report are noted in .

timeframe for updating these guidelines has been announced

(written communication, NHLBI Center for Health

Information, July 16, 2019). Therefore, the GINA guidelines

are the most current, evidence-based guidance available for

patients with asthma and will be the focus of this article

moving forward.

The clinical course of asthma can be reversible and requires

continued reevaluation of the disease and its treatment. This

involves a process of assessing the disease, adjusting therapy, and reviewing the response. The step therapy

recommendations from the 2019 GINA Report are summarized in the Table below. The decision to step up or step down

therapy is dependent on multiple factors including exacerbations, lung function, patient satisfaction, side-effects, and

Allergic bronchopulmonary aspergillosis

Inhaled corticosteroid

Long acting beta 2 agonist

Leukotriene receptor antagonist

Oral corticosteroid

Short acting beta 2 agonist

symptoms. Treatment is generally characterized by a controller medication and a reliever medication. Controller

medications typically include an ICS with or without a LABA medication. Increasing the ICS dose may be necessary in

patients with uncontrolled asthma.2

A number of changes were made in the 2019 GINA Report that have the potential to impact patient care. A review of

these updates and supporting evidence follows:

Per the 2019 GINA Report, SABA inhalers are no longer the preferred reliever for patients with asthma. Instead, an

ICS-formoterol combination is recommended. This is the most highlighted and perhaps controversial change in the

updated report. This recommendation was based on the results of the SYGMA1 study which indirectly demonstrates that

as needed ICS-formoterol therapy is associated with better asthma control and a lower risk of severe exacerbations

compared to as needed SABA. SABA inhalers have long been considered the primary choice for “rescue inhalers” in

patients with asthma, and this update changes the standard to ICS-formoterol.2 It is important to note that as needed

ICS-formoterol would be considered an off-label use in the US.

The SYGMA1 study was a 52-week, double-blind, phase 3 trial that evaluated the safety and efficacy of budesonide-

formoterol (Symbicort) as needed vs. terbutaline as needed vs. maintenance therapy with budesonide twice daily plus

terbutaline as needed. The study included over 3800 patients 12 years of age or older with mild asthma. As needed

budesonide-formoterol was superior to as needed terbutaline with respect to the mean percentage of weeks with

well-controlled asthma per patient (34.4% vs. 31.1%; p=0.046). The odds of having a week with well-controlled asthma

during the 52-week trial period were 14% higher in the budesonide-formoterol group than in the terbutaline group.

Additionally, the annualized rate of severe exacerbations was reduced by 64% with as needed budesonide-formoterol

vs. as needed terbutaline (RR 0.36; 95% CI 0.27 to 0.49). Compared with budesonide-formoterol twice daily

maintenance therapy plus as needed terbutaline, the odds of having a week with well-controlled asthma were 36% lower

with as needed budesonide-formoterol. However, no significant difference in the rate of severe exacerbations between

maintenance therapy and as needed budesonide-formoterol was reported, and patients receiving as needed budesonide-

formoterol vs. budesonide-formoterol maintenance therapy had an 83% lower exposure to the inhaled glucocorticoid

(i.e., budesonide) during the study period.4

The updated GINA Report now notes that patients with persistent symptoms of asthma despite moderate-high dose

ICS and LABA therapy may be candidates for add on azithromycin used off label. This change was based, in part, on

the AMAZES study, which is described below. Azithromycin is reserved for patients in step 5, with patient-specific

characteristics considered before initiating therapy. Additionally, sputum should be screened for atypical

mycobacteria in order to reduce the risk of antimicrobial resistance.2

The AMAZES study was a 48-week, double blind, placebo-controlled trial evaluating the use of azithromycin vs.

placebo in 420 adults with persistent uncontrolled asthma on ICS-LABA therapy. The treatment group received

azithromycin 500 mg three times weekly during the treatment period. The primary endpoint of this study was total

exacerbations over the 48 weeks and asthma-related quality of life. The average age of patients in the treatment and

control groups was 61 years and 60 years, respectively. Azithromycin decreased the rate of asthma exacerbation by

41% compared to placebo, and this outcome remained significant in both eosinophilic and non-eosinophilic patients.

Additionally, asthma-related quality of life scores improved with azithromycin vs. placebo. With respect to adverse

effects, patients receiving azithromycin had a 79% greater risk of diarrhea but a 35% lower risk for antibiotic-treated

respiratory tract infections.5

High dose ICS-LABA, which was previously considered an option for step 4 therapy, has been moved to step 5 only.

The 2019 GINA Report also notes that high dose ICS therapy should only be used for a limited duration due to the

potential long-term adverse effects. High dose ICS is typically used as an indicator for add on therapy if patients

remain symptomatic despite high dose ICS therapy.2

OCSs are no longer a preferred controller medication in patients who reach step 5. They are considered alternative

controller options and may be used based on patient-specific factors. The GINA Report emphasizes the significant

adverse effects associated with OCS use and notes that other add-on therapies may be more appropriate instead of

long-term OCS therapy.2

The 2019 GINA Report added ABPA as a new section to the report. ABPA is a pulmonary disease caused by

hypersensitivity to , a mold found both indoors and outdoors. This condition can occur in patients

with cystic fibrosis or asthma. First-line treatment of this condition is a 4-week tapered OCS course, with itraconazole

is an alternate option if exacerbations continue.2

The 2019 GINA Report’s recommendation that as needed ICS-formoterol be preferred over as needed SABA may

face significant barriers to adoption. First, the ICS-formoterol combination available in the US is not FDA-approved for

as needed use. It is important to note that, per the GINA Report, no specific ICS is preferred, but the preferred LABA

is formoterol due to its faster onset of action. It is also important to note that the specific formulation of budesonide-

formoterol studied in the SYGMA1 study is not available in the US.6 It is also suggested that using an ICS-SABA

combination would be appropriate,2 but this combination is not currently commercially available. Implementing this

recommendation would require the subsequent use of two inhalers, which can be inconvenient and may be difficult

for some patients to manage. A final barrier is that SABA rescue therapy has a long history of use in asthmatic patients,

and providers may be hesitant to change this longstanding approach.6

Updates contained in the 2019 GINA Report have to potential to improve the quality of life in patients with asthma.

Moving from a SABA to ICS-formoterol as the preferred reliever is a significant practice change, but the

implementation of this change may be delayed due to the off-label nature of available products and the long-standing

history of SABA use in asthmatic patients. Other major changes to the GINA Report impact step 5 therapy. These

changes include recommending azithromycin as possible add-on therapy and removing the preferred status of OCSs.

Providers should be aware of these changes and discuss strategies to implement these evidence-based

recommendations into practice.

1. Most recent national asthma data. Centers for Disease Control and Prevention.https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed June 28, 2019.

2. Global Strategy for Asthma Management and Prevention (2019 update). Global Initiative forAsthma. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Accessed June 28, 2019.

3. National Asthma Education and Prevention Program Expert Panel Report 3. Guidelines for the Di-agnosis and Management of Asthma.https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthsumm.pdf. Accessed July 19, 2019.

4. O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide–formoterol asneeded in mild asthma. . 2018; 378:1865-76.https://www.nejm.org/doi/full/10.1056/NEJMoa1715274.

5. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and qualityof life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, place-bo-controlled trial. 2017; 390(10095): 659-68.https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31281-3/fulltext.

6. Holley AB. Medscape(WebMD). https://www.medscape.com/viewarticle/915191. Published Jul 11, 2019. Accessed July19, 2019.

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