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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