June 11, 2018
Treating Patients When Asthma Symptoms Worsen
In four trials, investigators examined novel ways to use inhaled corticosteroids to augment asthma control.
From March through May 2018, the New England Journal of Medicine published results of four industry-sponsored, randomized trials in which researchers examined novel ways to use inhaled corticosteroids (ICS) to treat patients whose asthma symptoms worsen, with the goal of preventing major exacerbations. Because these regimens probably are unfamiliar to most primary care clinicians, I will briefly outline the findings and suggest how they might be incorporated into current practice.
Quadruple-Dose Inhaled Steroids for Worsening Symptoms
Despite little evidence of efficacy, some asthma guidelines and asthma action plans recommend quadrupling the dose of ICS to prevent exacerbations in patients with early worsening asthma symptoms. In two randomized trials, researchers examined such regimens, started at the earliest sign of worsening symptoms, in patients with mild-to-moderate asthma who were treated with daily ICS. The results were disappointing: Quadruple-dose or quintuple-dose ICS was ineffective in children and only marginally effective at preventing exacerbations in adults, despite exposing patients to a systemic steroid level similar to that of an oral corticosteroid burst (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:891 and 902). Based on these studies, I no longer use short-term quadruple doses of ICS to prevent asthma exacerbations. Instead, I usually supply patients with 5-day courses of oral corticosteroids, to be started for exacerbations according to an asthma action plan.
As-Needed Inhaled Corticosteroids Without Daily Maintenance Therapy
For many years, a cornerstone of asthma therapy has been managing persistent asthma with daily ICS to reduce inflammation and improve symptoms, prevent exacerbations, and perhaps prevent loss of lung function. But two additional new studies — which involved about 8000 patients with mild persistent asthma — call this conventional wisdom into question. As-needed use of inhalers that combine an ICS (i.e., budesonide) plus a long-acting β-agonist (LABA) with quick onset of action (i.e., formoterol) — without daily ICS maintenance therapy — was compared with a conventional maintenance regimen (daily ICS plus as-needed short-acting β-agonist as rescue therapy). Although the regimen with only as-needed ICS/LABA was not as effective as daily-maintenance therapy for day-to-day asthma control, it was just as effective in preventing exacerbations, and total annual ICS exposure was dramatically lower (NEJM JW Gen Med Jul 1 2018 and N Engl J Med 2018; 378:1877 and 1865).
These studies were done with Symbicort Turbohaler dry powder (200 μg of budesonide plus 6 μg of formoterol), which is not available in the U.S. The budesonide/formoterol combination in the U.S. (Symbicort) is available in metered-dose inhalers that are not FDA-approved for as-needed rescue treatment. Nevertheless, I have started using as-needed budesonide/formoterol in selected patients with mild persistent asthma who do not want to take daily ICS and who are not bothered by mild increases in day-to-day symptoms. In a real-world setting, many patients with mild persistent asthma do not use daily ICS consistently anyway.
Single Maintenance and Reliever Therapy (“SMART”)
So-called SMART (Single Maintenance and Reliever Therapy) also is worth mentioning. SMART refers to use of combination inhalers (low-dose ICS plus long-acting bronchodilator with quick onset) for both daily maintenance and as-needed rescue therapy, without use of an as-needed short-acting β-agonist, such as albuterol. In an April 2018 meta-analysis, SMART lowered the incidence of asthma exacerbations, although it didn't improve day-to-day symptoms (NEJM JW Gen Med Jun 1 2018 and JAMA 2018; 319:1473). SMART should be reserved for patients with moderate-to-severe asthma who require daily therapy (in contrast, the two studies discussed above involved as-needed ICS without daily maintenance therapy for patients with mildasthma). Although SMART is not FDA approved in the U.S., I have used it in patients with moderate-to-severe asthma who have symptoms and exacerbations despite daily ICS/LABA therapy and in whom tiotropium (Spiriva) was not helpful and biologics were not an option.
Wrap-Up
In summary, the 2018 studies provide little support for quadrupling ICS doses in patients whose symptoms worsen while they are using daily ICS therapy. But the studies do support use of as-needed ICS/LABA in selected patients. Keep in mind that these currently are off-label uses in the U.S., and clinicians should make that clear in discussions with patients. Although European asthma guidelines currently recommend using SMART for patients with moderate-to-severe asthma, whether the next National Asthma Education and Prevention Program guidelines will endorse these as-needed regimens as treatment options remains to be seen.
