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CLINICAL CARE: RESPIRATORY
from CCC-0322
by ensembleiq
Asthma Update
New guidelines and studies aim to improve asthma control
In 2020, for the first time in 13 years, there was a significant change in asthma-treatment recommendations. The 2020 Focused Updates to the Asthma Guidelines included a new recommendation to replace separate inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) inhalers with a single combination device that would be used daily for both prevention and rescue therapy.1,2 This recommendation was based on multiple studies showing that single maintenance and reliever therapy (SMART) offers better asthma control for patients ages 5 and older with moderate persistent asthma that is not well controlled. Combining asthma medications into a single inhaler is more effective and easier to use.2
The Promise of Triple Therapy
The new guidelines also recommended—for the first time—using a bronchodilator called a long-acting muscarinic antagonist (LAMA) in certain situations.2 Although a LAMA is not a preferred treatment in the current guidelines, there is a growing body of research that suggests it might play a bigger role in future guidelines. That role would be as a third addition to a single inhaler that would include an ICS, LABA, and LAMA for people with moderate to severe asthma.3,4
There have been several trials of this triple therapy. Two studies in 2019, both published in the journal Lancet, have had the most influence: • The TRIMARAN trial included 1,155 adults who had at least one serious asthma exacerbation per year, despite being on a moderate-dose ICS. This was a randomized, double-blind study conducted in 16 countries. Patients
were randomly assigned to receive triple therapy with ICS, LABA, and LAMA in a single inhaler, or a single inhaler with just ICS and LABA. The researchers followed the patients for one year.5 • The TRIGGER study had a similar number of patients and was also international. In this randomized, double-blind trial, patients with at least one severe asthma exacerbation per year despite treatment with a high-dose ICS were randomly assigned to three groups. One group used a single inhaler with ICS and LABA. One group used a single inhaler with ICS and LABA, along with a second LAMA inhaler. The final group used ICS, LABA, and LAMA in a single inhaler.4
In both studies, patients treated with triple therapy had fewer exacerbations, better lung function, and the time between exacerbations was longer than patients in the ICS- and LABA-only group. Triple therapy was the same in the single inhaler group as in the group that added an inhaler for the LAMA.4
In May 2021, a systematic review and meta-analysis published in JAMA confirmed the findings of prior studies comparing
At-a-Glance
• The 2020 Focused Updates to the Asthma Guidelines included a new recommendation to replace separate inhaled corticosteroid and long-acting beta-agonist inhalers with a single combination device for both prevention and rescue therapy.
• In the stepwise approach to managing long-term asthma, a step-up in treatment occurs whenever asthma is not well controlled.
• Triple therapy with a long-acting muscarinic antagonist can reduce asthma exacerbations, improve lung function, and increase the time between exacerbations.
Classes of Asthma Medications 1,2
ABBREVIATION DRUG TYPE ACTION ICS inhaled corticosteroid anti-inflammatory reduces swelling and tightening of the airway USE most effective for long-term control
EXAMPLE DRUGS fluticasone (Flovent), budesonide (Pulmicort)
LABA long-acting beta-agonist bronchodilator
LAMA long-acting muscarinic antagonist, long-acting bronchodilator acts through enhancement of 2 receptors, opens airways, and reduces swelling for at least 12 hours
blocks acetylcholine receptors but not used without an ICS used for moderate to severe asthma, not used alone, may trigger an asthma attack if not combined with an ICS fluticasone and salmeterol (Advair Diskus); or budesonide and formoterol (Symbicort)
frequently used to treat COPD, but have not been routinely used for asthma tiotropium bromide (Respimat)
1. US Department of Health and Human Services. National Institutes of Health. Asthma Care Quick Reference: Diagnosing and Managing Asthma. Accessed November 23, 2021. https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf
2. Agusti A, Fabbri L, Lahousse L, Singh D, Papi A. Single inhaler triple therapy (SITT) in asthma: Systematic review and practice implications. Allergy. 2021.doi: 10.1111/all.15076. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/34478578/
triple-drug therapy to current guideline therapy. Canadian researchers led by a team from McMaster University wanted to answer the question: Does adding a LAMA to ICS and LABA improve clinical outcomes in patients with moderate to persistent asthma? They included 20 randomized trials, involving close to 12,000 patients, ranging in ages from 9 to 71.6 They found, with high certainty, a significant reduction of severe exacerbations and better asthma control in the triple-therapy patients compared with the ICS and LABA patients.
Adding LAMA did not increase serious adverse events due to treatment. The lead author of the analysis concluded that the benefit of triple-drug therapy outweighs the risks, and suggested a revision of the current guidelines, noting that optimal control with triple therapy will avoid the use of oral steroids, which have significant side effects, and the use of biologics that are significantly more expensive.3
Different Mechanism of Action
In September 2021, the European Journal of Allergy and Clinical Immunology published a systematic review of triple therapy in a single inhaler for uncontrolled asthma in patients treated with an ICS and a LABA. They noted that up to 40% of patients remain uncontrolled despite the use of ICS and LABA.6 Because LAMAs act to block acetylcholine receptors and LABAs act through enhancement of 2 receptors, combination therapy is additive and may be synergistic. The research team reviewed all randomized phase 3 studies comparing triple therapy to other therapy through
Take a Stepwise Approach
Picking the best long-term management plan for asthma is complex because it depends on a patient’s age and the severity level of their asthma. The stepwise approach to managing long-term asthma was developed to help guide those decisions. In this approach, a step-up in treatment occurs whenever asthma is not well controlled.1,2 Well-controlled asthma refers to symptoms, nighttime awakenings, or the need for a rescue medication occurring on two or fewer days per week. There should also be no interference with daily activity and no more than one exacerbation requiring systemic corticosteroids per year.1 An asthma exacerbation is defined as progressive worsening of symptoms that include shortness of breath, wheezing, cough, or chest tightness that results in decreased expiratory airflow.2
Step 1 for all ages refers to intermittent asthma, and the preferred treatment is a shortacting beta-agonist (SABA) used as a rescue medication.
Steps 2 though 6 apply to persistent asthma that requires daily treatment. In step 2, the preferred treatment for all ages is a low-dose ICS. Step 3 introduces SMART inhalers with ICS and a LABA as the preferred treatment. The guidelines vary by age, but for ages 12 and over, step 3 includes a low-dose ICS and LABA or a medium-dose ICS.
Step 4 employs a medium-dose ICS and a LABA. Step 5 moves to a high-dose ICS and LABA, and consideration of the oral biologic omalizumab (Xolair) for patients with allergies.
Step 6 includes a high-dose ICS and LABA, as well as oral steroids or omalizumab for patients with allergies.
1. U.S. Department of Health and Human Services. National Institutes of Health. Asthma Care Quick Reference: Diagnosing and Managing Asthma. Accessed November 23, 2021. https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf
2. U.S. Department of Health and Human Services. National Institutes of Health. 2020 Focused Updates to the Asthma Management Guidelines: Clinician’s Guide. Accessed November 23, 2021. https://www.nhlbi.nih.gov/sites/default/files/ publications/AsthmaCliniciansGuideDesign-508.pdf
February 2021, including the TRIMARAN, TRIGGER, and 27 other studies.6 They concluded that triple therapy is a safe and effective alternative for patients with uncontrolled asthma.
Better Medication Compliance
The researchers also commented that triple therapy may help patients comply with their treatment because it reduces the number of inhaler devices and instructions. This may eliminate confusion and reduce dosing and handling errors. This is a significant advantage because studies show that 50% to 75% of asthma patients fail to take their medications as directed. They concluded that the optimum place for triple therapy needs to be properly established within the existing guidelines.6
Current Guidelines and LAMA
For now, the recommendation is to consider adding a LAMA to ICS if asthma is not controlled by ICS alone and a LABA is not tolerated. Although it is not a preferred treatment, the guidelines say that if a patient is not controlled with ICS and LABA, triple therapy is conditionally recommended as an option. Current guidelines say that triple therapy may offer a small potential benefit.
The guidelines do not recommend adding LAMA for anyone under age 12, and LAMA should not be used for anyone at risk of urinary retention or with a diagnosis of glaucoma.1,2 C
