A Retrospective Study Evaluating Asthma Control in Patients on Fluticasone Propionate/Salmeterol Proactive Regular Dosing with a History of Uncontrolled Asthma

Asthma is a chronic heterogeneous disease of the lower airways characterized by chronic inflammation and airway hyperreactivity, which can lead to cough, wheezing, difficulty breathing, and chest tightness [1]. Globally, it is estimated that over 260 million people have poorly controlled asthma, with a high count of disabilities and premature deaths across many low- and middle-income countries (LMICs) [2, 3]. In Malaysia, asthma is prevalent in 8.9–13% of children and adolescents and 6.3% of the adult population, with a substantially high incidence of poor asthma control [4‐6]. According to the National Health and Morbidity Survey 2023 by the Ministry of Health, Malaysia, over 1.4 million adults were diagnosed with asthma, with 3 out of 10 patients remaining undiagnosed. The survey indicated that 22% of patients reported 1–3 attacks, while 8% had experienced more than 3 asthma attacks in the past 12 months [7]. Poor asthma control is associated with a substantial disease burden in terms of impaired quality of life and significant healthcare resource utilization with frequent emergency visits and hospitalization [8‐11].

Mild asthma is common, and is often neglected. It is important to emphasize that patients with mild asthma are at high risk of experiencing acute asthma exacerbations [12]. According to a large multicenter, observational, cross-sectional study conducted at 15 primary and specialty care centers in Malaysia, around half of the patients with mild asthma treated at primary care settings with Global Initiative for Asthma (GINA) step 1 and 2 treatments still had uncontrolled/partially controlled disease, and about 46% had at least one severe exacerbation in the past year [13]. It is imperative that healthcare practitioners identify these patients and adjust their treatment to achieve asthma control and reduce future risk of exacerbations [14].

The long-term goal of asthma management should be to achieve effective symptom control and minimize asthma-related problems such as mortality, exacerbations, and drug-related adverse effects such as long-term side effects of oral corticosteroids [15]. The GINA recommendations propose a reliever-based two-track treatment approach for patients with asthma: Track 1 is a variable-dose regimen utilizing inhaled corticosteroid (ICS)/formoterol as needed (pro re nata [PRN]) for patients with mild asthma (steps 1–2), followed by maintenance and reliever therapy (MART) for steps 3 and beyond, whereas Track 2 recommends ICS and short-acting beta-agonist (SABA) taken together PRN at step 1, and employs regular fixed-dose ICS or ICS/long-acting beta-agonist (LABA) with SABA PRN at steps 2 and beyond [15‐17]. Across the five steps, treatment may be stepped up or down within a track or switched between tracks according to the patient's needs and preferences [15]. While GINA has recommended Track 1 as the preferred track, many other national asthma guidelines continue to advocate regular maintenance dosing for optimal management of patients with asthma [18‐28].

The PRN strategy depends on the patient accurately perceiving symptoms and triggering the medication intake for asthma control and exacerbation reduction. However, most patients with asthma tend to underestimate their symptoms and overestimate their level of control [16, 17]. A proactive regular dosing (PRD) regimen, on the other hand, reduces reliance on self-driven symptom tracking and may effectively eliminate the potential risks associated with over- or under-medication [29‐31].

There are limited real-world data in evaluating treatment step-up for patients with uncontrolled asthma on PRN to a PRD regimen. Thus, MERIT, a real-world retrospective observational study, aimed to evaluate asthma control in patients with uncontrolled asthma with either of the two PRN treatments—ICS/formoterol or ICS whenever SABA was taken—and were stepped up to proactive regular dosing of fluticasone propionate/salmeterol (FP/SAL PRD). This study examined the safety and effectiveness of FP/SAL PRD in terms of asthma control and exacerbations.

This study highlights the effectiveness and safety of proactive regular dosing of a combination of fluticasone propionate (FP)/salmeterol (SAL) as a step-up approach for patients with uncontrolled asthma with PRN treatment regimes in a real-world setting. This retrospective study in a Malaysian cohort showed that patients with uncontrolled asthma on a PRN regimen achieved significantly improved asthma control after stepping up to FP/SAL PRD. Similar improvements were observed regardless of prior PRN regimen (BUD/FOR PRN or ICS whenever SABA was used). This was accompanied by a notable decrease in patients experiencing moderate and severe exacerbations. Moreover, there was a significant reduction in the number of patients who reported needing systemic corticosteroids, visits to the emergency department, and/or hospitalization due to asthma. In addition, the study showed no reports of adverse drug events following the step-up to the FP/SAL PRD combination, suggesting that this treatment regimen has a well-tolerated safety profile.

Overreliance on reliever medication like SABA is evidenced in real-world practice [13], including patients who were put on GINA Track 1 with ICS/formoterol PRN or MART therapy [16, 17]. In our study, we found that despite being on BUD/FOR PRN, about 42% of patients on this regimen were also prescribed an additional SABA, which shows a poor understanding of PRN strategy with Track 1 anti-inflammatory relievers. Some patients may prefer SABA for faster symptom relief. We further analyzed the patient-reported use of rescue medication based on the ACT questionnaire response. Our results showed that with FP/SAL PRD, there was a statistically significant reduction in the patient-reported use of rescue medication, with the greatest improvement seen in the patients with prior BUD/FOR PRN and SABA use. It has been reported in real-world practice that patients receiving an appropriate amount of ICS tend to demonstrate reduced inappropriate or excessive SABA use [37]. Regular ICS dosing encourages appropriate SABA use by managing airway inflammation, improving asthma control, and reducing the need for symptom relief. Similarly, our results showed that FP/SAL PRD effectively achieved symptom control and reduced the need for reliever medications.

Although GINA has recommended Track 1 as the preferred track, many other national asthma guidelines continue advocating regular maintenance dosing for optimal management of patients with asthma [18‐28]. In SYGMA [Symbicort Given as Needed in Mild Asthma] studies, patients who received BUD/FOR PRN had significantly lower levels of control, lung function, and quality of life than those receiving regular fixed daily ICS despite showing similar exacerbation prevention. In addition, there are challenges with the PRN strategy, which assumes that asthma control will be accurately guided by patient perception of symptoms [38, 39]. However, asthma control is frequently over- and underestimated by both physicians and patients, as shown previously [9, 16, 17, 40]. The Asthma Insights and Reality in Asia–Pacific (AIRIAP 1 and 2) studies revealed that the severity of symptoms varies in different regions, management of patients with asthma is suboptimal, and international recommendations are not followed. In the Asia–Pacific region, patients with asthma often overestimated their level of symptom control, possibly due to difficulties in accurately assessing the severity of their condition [41, 42]. Similarly, the Asthma Insight and Management (AIM) survey reported that 56% of Malaysian respondents perceived their asthma as “well controlled” or “controlled,” while the actual data were as low as 6% [43]. Self-management of asthma can place a burden of responsibility on patients and may increase anxiety related to symptom perception. Both over-perception and under-perception of asthma by patients pose serious risks, potentially leading to iatrogenic adverse events or life-threatening delayed treatments [44]. Undertreatment of inflammation causes a decline in lung function, worsening of asthma control, increased risk of exacerbation, and airway remodeling [45, 46]. This highlights the importance of controlling inflammation, especially in patients with mild persistent asthma, where regular treatment often proves more effective than on-demand therapy [45].

Results from this study underscore the importance of proactive regular dosing of ICS/LABA as a practical step-up approach that may mitigate the risks associated with patients overestimating or underestimating symptom severity. It is essential to recognize that asthma is a heterogeneous condition, and pharmacological treatment should be tailored to the individual rather than following a one-size-fits-all approach. In addition, biomarker identification and phenotyping can help in identifying the severity of asthma and designing personalized treatment approaches [47]. To the best of our knowledge, this is the first study highlighting the effectiveness of the PRD treatment approach with FP/SAL in patients with uncontrolled asthma with PRN in a Malaysian cohort. Findings from this study add to the body of randomized controlled trials and real-world studies, affirming the long-term safety and effectiveness of the FP/SAL in asthma control [27‐29, 44, 45] and improved health-related quality of life (HRQoL) of patients with asthma [40]. In addition to effectively managing the visible symptoms, regular dosing of ICS/LABA also positively impacts bronchial inflammation and airway remodeling and controls eosinophilic infiltration in sputum as compared with the MART approach [48‐50]. Singh et al., in 2022, reported a favorable benefit–risk ratio for regular dosing of FP/SAL (in terms of high airway efficacy and low systemic activity) compared with BUD/FOR PRN dosing in mild asthma or BUD/FOR MART in patients with moderate and moderate-to-severe asthma. In addition, such a difference may be associated with corticosteroid-specific properties, which vary between inhaled corticosteroids [51, 52]. Fluticasone has a high binding affinity to lung glucocorticoid receptors as compared with budesonide. Fluticasone also has high plasma protein binding and rapid clearance, reducing the risk of systemic side effects. This translates to higher potency and superior clinical outcomes [22, 51]. Fluticasone is known to significantly improve asthma control in terms of the percentage of symptom-free days, days without resorting to bronchodilator, > 10% increase in peak expiratory flow (PEF), and shorter exacerbations with faster resolution time compared with budesonide [53].

The results from the present study have several clinical implications. Firstly, there are challenges and divergences in how patients and healthcare professionals perceive asthma severity [16, 17, 43, 54]. Our study underscores the importance of assessing asthma control routinely with validated tools and adjusting the treatment for attaining asthma control. ACT is a validated, short, easy-to-use tool for assessing asthma control and guides physicians in making informed decisions regarding the treatment plan. Stepping up to FP/SAL PRD among patients with asthma with uncontrolled disease identified by ACT score showed significant symptom improvement and exacerbation reductions. In addition, with the high prevalence of mild asthma, many patients diagnosed with mild asthma relying on PRN treatment could potentially be underestimating their asthma symptoms and should be recategorized as having moderate instead of mild asthma. Secondly, there was notable use of systemic corticosteroids and emergency department visits and/or hospitalization among the patients on the PRN regimen. Asthma management is associated with high healthcare resource use. It was estimated that the cost of acute exacerbation management in the emergency department and hospitalization events in Malaysia suburban public hospitals was $13.50 (RM43.46) and $552.13 (RM1777.86), respectively [8]. A regular dosing approach with FP/SAL significantly reduces the proportion of patients using systemic corticosteroids, and emergency department visits and/or hospitalization may represent a cost-effective approach to asthma management.

Real-world evidence is integral to patient-driven decision-making and offers important value in adding complementary evidence to traditional randomized controlled trials [55]. Our study shows that FP/SAL PRD can effectively improve asthma control and reduce exacerbations in patients with uncontrolled asthma on PRN in local clinical settings. The study had several limitations consistent with those of a retrospective and observational study. First, the study utilized medical records from multiple participating sites, with challenges in the availability and quality of medical records from multiple study sites. However, standardized data collection tools (eCRFs) with online data entry methods were used across the sites to harmonize data from various sites and to minimize manual biases and variability. Second, the follow-up duration of this study was relatively short (between 3 and 6 months). Third, the study lacks a comparator group, and baseline data were used to compare and interpret clinical endpoints. Future studies should include a comparator group and longer follow-ups to better understand the long-term adverse events profile and the potential cost implications. Additionally, a prospective study that compares regular dosing of ICS/LABA and ICS/FOR MART or fixed dosing regimen as stepping-up strategies should also be considered in the future to evaluate the effectiveness of these different treatment approaches.

This study highlights the effectiveness of the PRD treatment approach in patients with uncontrolled asthma on a PRN treatment regimen. PRD FP/SAL is a practical step-up approach to manage asthma control and attenuate exacerbations in patients with uncontrolled asthma on PRN regimes. Results from MERIT provide valuable clinical evidence and can help healthcare providers make informed treatment decisions for patients who are not responding well to PRN regimens. It can guide them in considering a shift to a PRD approach. Further clinical studies in larger populations are required to validate these results and ensure the reliability and generalizability of the findings.