Pro: SMART Should be the Preferred Therapy Option in Children with Asthma Aged 6 Years and Older Because it is so Smart

Speaker- Louise Fleming

Single Inhaler for Maintenance and Reliever Treatment (SMART) was designed for children six and older as a comprehensive asthma management approach, utilizing a single inhaler for maintenance and symptom relief. This regimen incorporated inhaled corticosteroids (ICS) and formoterol, combining anti-inflammatory effects with rapid bronchodilation. Patients used the same inhaler for daily maintenance doses and for relieving acute asthma symptoms, ensuring treatment consistency. Formoterol, a key component, acted as both a long-acting beta-agonist (LABA) and a fast-acting bronchodilator, offering quick symptom relief comparable to short-acting beta-agonists (SABAs). The single inhaler system optimized treatment efficacy and patient adherence, demonstrating the potential to simplify asthma management.

The current Global Initiative for Asthma (GINA) treatment guidelines for adolescents and adults outline two tracks. Track 1 utilizes an ICS combined with formoterol as a reliever therapy, while Track 2 provides an alternative option by using a SABA as the reliever. In contrast, for children aged 6 to 11, there is a single treatment track. At Steps 3 and 4, the approach involves maintenance and reliever therapy with a low dose of ICS-formoterol, complemented by a short-acting beta agonist at the same steps. While anti-inflammatory reliever options are available, they are not elaborated upon. The variation in treatment figures between adolescents and younger children reflects the differences in therapeutic strategies required for these age groups.

Starting asthma treatment with SABA is not ideal, as it conditions children to view SABA as their primary asthma therapy. This reliance is reinforced by the rapid symptom relief SABAs provide, their prominent use in emergency departments and hospitals for managing asthma attacks, and their low cost. However, regular and frequent use of SABA is associated with significant adverse effects, creating confusion for children who must switch between the widely recognized blue SABA inhaler and the preferred reliever inhaler. Data from UK primary care prescription records indicate that children prescribed three or more SABA canisters per year had at least double the risk of experiencing an asthma attack. Alarmingly, 30% of children were prescribed only SABA. Among those prescribed ICS, the median coverage was just 33% of days, suggesting that increased SABA use undermines its effectiveness, resulting in a vicious cycle of dependence. Mechanistic evidence also points to increased SABA usage leading to enhanced allergic responses and heightened eosinophilic airway inflammation. This underscores the importance of including ICS in asthma treatment regimens, as it helps modulate pro-inflammatory pathways and mitigates interactions between rhinovirus (RV) and interleukin-6 (IL-6), contributing to asthma exacerbations. 

The use of SABAs alone or their overuse is not without harm, as demonstrated by two key studies. The first study, TREXA, included four treatment arms—three with ICS and one with only SABA. While the primary outcome of time to the first exacerbation showed that the SABA-only group fared worse than those receiving regular ICS, secondary analyses revealed that all ICS-containing arms significantly outperformed the SABA-only arm regarding exacerbation prevention. The second study, Sigma, compared the use of ICS-formoterol on an as-needed basis. Both ICS-containing arms showed a substantial reduction in exacerbations compared to the SABA-only arm, reinforcing the need for regular ICS use in children for effective asthma management. However, despite the clear benefits of ICS, adherence to maintenance therapy remains poor. Primary care prescription data reflect low adherence rates, with many patients failing to follow prescribed regimens consistently. Bruce Bender, an expert on medication adherence, emphasized that 40 years of research indicates that altering patient behavior to comply strictly with treatment guidelines is highly challenging. Patients tend to take medication based on perceived need rather than adhering to a fixed schedule. In light of this, anti-inflammatory reliever therapy offers a safety net, but the fundamental issue of low adherence to maintenance treatment persists.

A meta-analysis of six randomized controlled trials utilizing Budesonide (BUD) and Formoterol within the SMART approach in adolescents demonstrated a significant reduction in asthma attacks and time to exacerbation, approximately 60% compared to other treatment regimens. This effect was particularly pronounced in younger children. In a study by Hans Bisgard, part of a larger investigation, the pediatric cohort was analyzed separately. Participants were randomized into three groups: one receiving SMART with a low dose of ICS, another receiving a fixed combination of ICS and ICS-formoterol with short-acting beta agonist (SABA) as their reliever, and a final group receiving a higher dose of ICS with SABA as the reliever. The findings revealed that those in the very low-dose ICS and SABA group experienced a 70% to 79% reduction in exacerbations compared to the other two groups. These results suggest that the SMART approach can effectively diminish asthma attacks in younger children, even when using a lower dose than standard inhaled corticosteroid treatments. 

The importance of SABAs as a reliever for children is underscored by their entrenched perception as the best option. Concerns exist regarding device compatibility, as not all children can effectively use dry powder inhalers due to environmental factors. Additionally, there are apprehensions about the pharmaceutical industry's influence, particularly the potential push to prescribe ICS and formoterol widely for profit. While SABAs are inexpensive, the motivations behind promoting them versus ICS-formoterol usage remain uncertain. Evidence for the use of ICS-formoterol as needed in children is currently lacking. Still, several ongoing studies in New Zealand and the UK are being conducted to fill this gap. Richard Beasley has led adult studies that implement innovative strategies. In New Zealand, the CARE and SMART CARE studies investigate anti-inflammatory relievers for both as-needed use and as part of maintenance and reliever therapy. Stuart DL is conducting noteworthy research on younger children, while Raphael Masakela in South Africa is exploring ICS-formoterol. These studies aim to address the applicability of findings in low- and middle-income countries, focusing on answering critical questions about asthma management. Overall, there is hope that these investigations will provide valuable insights into the effectiveness of ICS-formoterol as a reliever for children.

In Conclusion, the importance of utilizing a single inhaler for maintenance and reliever treatment in children with asthma is emphasized, as it simplifies the treatment regimen and provides a safety net in cases of poor adherence. The use of ICS in the reliever dose is also highlighted as essential. There is a belief that sufficient evidence supports implementing the SMART approach for children aged six and older. However, it is noted that further evidence is needed to establish the safety and efficacy of using an anti-inflammatory reliever inhaler as a single inhaler for school-aged children, ensuring a logical, safe, and equitable treatment for all asthma patients.

Con: (S)MART is not so Smart in Young Children. Where is the Clinical Evidence and for Whom?

Speaker- Alexander Möller

The concept of SMART therapy in children is examined, with the assertion that its effectiveness does not yet match that observed in adults. Asthma is characterized by symptoms such as reversible airway obstruction, airway inflammation, and hyperresponsiveness. It is emphasized that a one-size-fits-all approach is inadequate, as lung function plays a critical role in management. The significance of the pressurized metered-dose inhaler (pMDI) and the dry powder inhaler (DPI) is also discussed. The primary objective is to illustrate why SMART therapy may be less effective in young children. Additionally, there is an intention to outperform the Swiss team at the European Championships despite a penalty loss by England. The importance of prescribed-as-needed therapy (PRN) and the necessity of continuous ICS therapy is highlighted. Asthma is recognized as a heterogeneous disease, encompassing various phenotypes, endotypes, and inflammatory types. Consequently, a single therapy regimen may not be appropriate for all patients, underscoring the belief that continuous ICS therapy is crucial for effective asthma management.

A large study involving patients aged four to 80 demonstrated that daily inhaled corticosteroid therapy was more effective than regular high-dose Budesonide butazene therapy in reducing exacerbations. Additionally, daily inhaled corticosteroids provided better coverage of daily symptoms. A smaller study by Hans Bisgaard indicated that the SMART approach was associated with reduced exacerbation rates in younger children. Data from the Sigma 1 and Sigma 2 studies revealed no significant difference between the maintenance and SMART approaches; however, the SMART approach utilized a lower dose of ICS, which is particularly relevant in pediatric populations. Nonetheless, it is emphasized that a one-size-fits-all strategy is inadequate due to genetic variations affecting responses to beta mimetics and LABA. Single nucleotide polymorphisms (SNPs), such as Arg16Gly and glu polymorphisms, contribute to different asthma phenotypes. A large study from the Pharmacogenomics in Childhood Asthma (PiCA) consortium found that treatment with ICS plus LABA increased the risk of exacerbations in children with the Arg16 haplotype. However, as this data is cross-sectional, it does not necessarily imply that the SMART approach suits all children.

In an oral presentation by the Dutch group and Elise Lobb, two randomized controlled studies were discussed, focusing on the effectiveness of personalized asthma treatment for children. The Precision Asthma Care Team (PACT) study was conducted in the UK, and the Personalized Use of Frequent Monitoring in Children with Asthma (PUFFIN) study was conducted in the Netherlands, which aimed to assess this approach. The primary outcome was the change in asthma control, while the secondary outcome evaluated the exacerbation rate. These studies centered on a genotype-based strategy, treating children according to their SNPs. In cases involving young children, the mother often plays a pivotal role in guiding treatment decisions. Asthmatic presentations can arise from various triggers, including exercise, emotional stress, colds, and environmental exposures. The challenge lies in the concept of treating a child during symptomatic episodes rather than adhering to a consistent baseline treatment regimen. A Swiss study highlighted the low correlation between reported wheezing and a mother's perception of her child's symptoms. If therapy is guided solely by maternal impressions, unnecessary treatments may occur, leading to inconsistent symptom management in young children, many of whom may be poor communicators regarding their symptoms. Furthermore, when parents are allowed to determine when to administer therapy, treatment decisions may be influenced by their feelings and beliefs, which can hinder consistent adherence to prescribed regimens.

The study by Bisgaard found no significant difference in lung function between SMART therapy and baseline corticosteroid treatment in children and adolescents. However, data from the Sigma 1 and Sigma 2 studies indicated that those receiving baseline corticosteroid treatment exhibited improved lung function. Lung function is critical; tracking this data is essential for helping children achieve optimal respiratory health. A systematic review of SMART therapy suggests that regular inhaled corticosteroid therapy yields better outcomes in lung function. The pMDI, a straightforward corticosteroid delivery device, differs from a dry powder inhaler (DPI) and requires an inspiratory flow of 60 liters per second. Many children under nine years old struggle to achieve this flow rate. However, a study indicated that 66% of experienced children could produce the necessary flow. Many children under nine can correctly use the Turbuhaler device. Compared to the propeller inhaler with the same corticosteroid dosage, pMDI significantly reduced the dose delivered to the lung mass deposition while increasing availability. It remains uncertain whether pMDI data from older children using Budesonide for control therapy can be effectively translated to younger children using this device. Additionally, adherence levels in the Sigma 1 study were alarmingly low, with an overall adherence rate of 70% and only 50% in the Sigma 2 study. Such low adherence rates do not represent real-life scenarios, emphasizing that maintaining adherence is even more crucial in practical applications.

In conclusion, the effectiveness of the SMART approach in young children is limited by a lack of published data on asthma management in this age group. SMART therapy does not demonstrate superiority over traditional ICS maintenance therapy. Furthermore, approximately 50% of children possess the ADRB2 Arg16 haplotype, which can exacerbate responses when an LABA is added. Additionally, lung deposition is lower with pMDI, and young children often struggle to use DPI effectively.

European Respiratory Society Congress 2024, 7–11 September, Vienna, Austria