From Pages to Practice
You have followed Gaele, a 20-year-old college student, for the past 2 years. She has mild persistent asthma with infrequent symptoms, except for worsening during the spring. However, this past year she experienced three off season severe exacerbations warranting emergency care. She was prescribed as-needed albuterol and daily budesonide, but finds it challenging to remember to take the daily inhaler between assignment deadlines and college schedules. When she feels symptoms worsening, especially in the spring, she increases her albuterol use and feels some symptom relief for a few hours, but her exacerbations have remained poorly controlled. Would an as-needed controller glucocorticoid be a potential option for Gaele when she encounters the onset of worsening symptoms?
Up to 75% of patients with asthma present with mild disease. However, patients with mild asthma can experience severe exacerbations and even death. Severe exacerbations represent 30%–40% of asthma exacerbations leading to emergency care in those with mild asthma. Asthma management guidelines recommend strategies to control symptoms, prevent exacerbations, and reduce loss of life and lung function, balanced with strategies to avoid treatment-related side effects. This usually includes daily treatment with an anti-inflammatory inhaled corticosteroid (ICS) or the combination of an ICS and long-acting beta-agonist (LABA) to reduce symptoms, exacerbations, and airway remodeling, plus an as-needed short-acting beta-agonist (SABA) to provide short-term symptomatic relief. Maintenance therapy with an ICS, such as budesonide, is the current standard of care, and the most effective treatment for reducing symptoms and exacerbations. However, adherence to maintenance ICS is poor (<35%), further increasing the risk of exacerbations.
In this week’s issue of NEJM, two international randomized studies examined alternative treatment approaches. The Symbicort Given as Needed in Mild Asthma (SYGMA) 1 and 2 trials examined whether on-demand use of the LABA formoterol and the ICS budesonide improved outcomes in patients requiring Global Initiative for Asthma [GINA] Step 2 treatment for uncontrolled asthma with as-needed inhaled SABA or well-controlled asthma with maintenance low-dose ICS or leukotriene-receptor antagonist plus as-needed SABA.
In the SYGMA 1 trial, 3849 patients were randomized to receive twice-daily placebo plus as-needed SABA (terbutaline, 0.5 mg), twice-daily placebo plus as-needed budesonide (200 µg) and formoterol (6 µg), or twice-daily budesonide (200 µg) plus as-needed terbutaline (0.5 mg) for 52 weeks. Electronic diaries were used to record morning and evening peak expiratory flow, asthma symptoms, night-time awakenings due to asthma, and to prompt the use of the blinded maintenance inhaler. The primary outcome was a composite measure of asthma control (the percentage of weeks with well-controlled asthma).
As-needed budesonide and formoterol was superior to as-needed terbutaline for asthma symptom control and prevention of exacerbations (64% lower rate of severe exacerbations), and was similar to maintenance budesonide for prevention of exacerbations (with prolonged interval to first exacerbation), inferior for asthma control, and associated with an 83% lower cumulative dose of ICS.
In the SYGMA 2 trial, 4215 patients were randomized to treatment with twice-daily placebo plus as-needed budesonide and formoterol (200 μg and 6 μg, respectively) or twice-daily budesonide plus as-needed terbutaline (0.05 mg) for 52 weeks in a more pragmatic, less intensively monitored fashion. As-needed budesonide/formoterol was noninferior to budesonide maintenance for the prevention of exacerbations, with 75% lower median daily ICS dose. However, symptom control, quality of life, and pre-bronchodilator FEV1 were better with budesonide maintenance.
These two studies demonstrate that as-needed treatment with budesonide and formoterol prevented exacerbations and loss of lung function, significantly reduced median daily ICS dose, but was less effective than the other treatments for symptom control.
In an accompanying editorial, Dr. Stephen C. Lazarus, Professor, Pulmonary and Critical Care, UCSF, notes that along with reduced glucocorticoid side effects and improved acceptability for steroid-averse patients, as-needed budesonide and formoterol also has the potential to reduce drug costs dramatically, by close to 1 billion dollars per year. Dr. Jeffrey Drazen, Editor-in-Chief of NEJM and an asthma researcher adds, “these studies show that on-demand glucocorticoid and LABA treatment can prevent exacerbations at a cost of less-than-great symptom control. Many people will think this is a reasonable tradeoff.”
The SYGMA authors argue, that given the spectrum of asthma phenotypes, treatment should aim for symptom control or exacerbation prevention, tailored to patient behavior, preferences, and possibly biomarkers. A patient like Gaele, with mild or infrequent symptoms, might prefer an as-needed option. The use of an as-needed anti-inflammatory reliever might also reduce the over-reliance on and misuse of SABAs for asthma control, which is associated with worse asthma exacerbations. Ongoing pragmatic trials will address patient experiences, attitudes, and preferences.