Abstract
The 2019 GINA recommendations are supported by clinical trials in >10000 mild asthma patients. For any treatment decision, GINA recommends that clinicians should consider individual patient characteristics/risk factors as part of shared decision making. http://bit.ly/2ZqboJ2
From the author:
N.C. Thomson and R. Chaudhuri raise an important issue about treatment recommendations for patients with asthma who have a significant smoking history. The exclusion of such patients from most asthma studies appears to have largely been driven by the requirement by regulators for pure “asthma” and “COPD” populations in pharmacotherapy studies that are designed for obtaining regulatory approval. However, once that is obtained, there is an important need for additional clinical trials to be performed in broader populations, and with more pragmatic designs, to increase the generalisability of evidence to clinical practice. Considering the large number of randomised controlled trials in asthma in the past 20 years, very few studies have included patients with a significant smoking history; N.C. Thomson and R. Chaudhuri are to be commended for their work in this area.
The specific case raised by the authors relates to new recommendations made by the Global Initiative for Asthma (GINA) in 2019 [1]. The most fundamental of these changes is that, for adults and adolescents, treatment of asthma with short-acting β2-agonists (SABA) alone is no longer recommended [2]. This change was possible because of evidence from four randomised controlled trials now totalling more than 10 000 patients, demonstrating the efficacy and safety of as-needed low dose budesonide–formoterol in mild asthma. This regimen provided a 60–64% reduction in severe exacerbations compared with SABA alone [3, 4], and provided similar or greater risk reduction as with maintenance inhaled corticosteroids (ICS) [3–6], thus providing an efficacious alternative option to daily treatment in mild asthma. Given the need for regulatory approval of this regimen (already obtained in several countries) the initial two studies [3, 5] were limited to “pure” asthma populations, but as N.C. Thomson and R. Chaudhuri note, the subsequent two open-label studies [4, 6] allowed a greater smoking history. Of importance, interaction analyses in the latter two studies found no significant interaction between baseline smoking status and differential treatment response for exacerbations, severe exacerbations or symptom control. However, it would be highly desirable for additional studies to be done in mild asthma populations with larger numbers of smokers/ex-smokers and greater tobacco exposure, to give greater discriminatory power for such analyses.
Should GINA have excluded smokers or ex-smokers with a significant smoking history from its new recommendations until randomised controlled trials were available in these specific populations? I believe that the answer is no, because the primary recommendation by GINA was against SABA-only treatment, the concerns about which are not limited to “pure” asthma. Large well-conducted observational studies have shown that patients with diagnoses of both COPD and asthma are significantly more likely to die or be hospitalised if they are initiated on maintenance treatment with bronchodilators alone compared with ICS and long-acting β2-agonists [7, 8]. With such “hard” safety signals, the risks of treating asthma patients without any ICS cannot be ignored, even though the specific underlying mechanisms for this risk are not yet known.
What is the clinician to do, therefore, when a new asthma treatment becomes available, but no specific data are yet available for patient subgroups that may potentially have different responses? Since 2014, GINA has advocated against a one-size-fits-all approach to asthma management. Instead, GINA recommends that for treatment decisions in individual patients, the clinician should take into account not only population-level recommendations about efficacy, effectiveness and safety, but also the individual patient's characteristics or phenotype, noting as examples: “Does the patient have any features that predict differences in their future risk or treatment response compared with other patients (e.g. smoker; history of exacerbations, blood eosinophilia)? Are there any modifiable risk factors or comorbidities that may affect outcomes?” (box 3-3 of the GINA 2019 report [1]). The patient's preferences, and practical issues such as inhaler technique, likely adherence and treatment cost, may also form part of this shared decision-making [1]. Further, once treatment is started, patients who are at higher risk, such as smokers, should be followed up more closely to ensure that their treatment is appropriate. Meantime, for greater precision in treatment, we await the results of studies such as NOVELTY [9] that are investigating the specific mechanisms underpinning the heterogeneity and overlap of “asthma” and “COPD”.
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Footnotes
Conflict of interest: H.K. Reddel reports research grants and personal fees for data monitoring committee work, consultancy, advisory board work and providing education from AstraZeneca, research grants, personal fees for data monitoring committee work, consultancy, advisory board work and providing education and non-financial support (study medication) from GlaxoSmithKline, personal fees for data monitoring committee work from Merck, research grants and personal fees for data monitoring committee work, advisory board work and providing education from Novartis, personal fees for providing education from Teva and Mundipharma, personal fees for advisory board work and providing education from Boehringer Ingelheim, personal fees for advisory board work from Sanofi Genzyme, outside the submitted work; and is Chair of the GINA Science Committee.
- Received January 13, 2020.
- Accepted January 13, 2020.
- Copyright ©ERS 2020