Introduction

Asthma is a heterogeneous disease characterized by variable expiratory airflow restriction and chronic airway inflammation, presenting with respiratory symptoms of varying severity over time, such as wheezing, shortness of breath, chest tightness, and cough. The primary treatment for asthma is inhaled medication, and therefore, the correct inhalation technique and regular patient follow-up and education significantly impact treatment outcomes. Consequently, the selection of an inhaler device that delivers the medication to the lungs, tailored to the patient’s characteristics, preferences, and abilities, is as critical to treatment success as the choice of pharmacological agents. Appropriate treatment of patients can largely control the disease and prevent exacerbations.^1-3

In asthma treatment, metered-dose inhalers (pMDI) or dry powder inhalers (DPIs) can be used. Both classes are effective and safe when used with the correct technique. Capsule-based DPIs are devices in which the medication is presented in a single-dose gelatin capsule. After the capsule is punctured inside the DPI device, the medication is delivered to the lungs by the dispersion and aerosolization of particles by the patient’s inspiratory stream. Their portability and the ability to provide confirmation with auditory feedback during dose administration are practical advantages. On the other hand, the need for sufficient inspiratory flow and multiple steps are drawbacks of this device.² pMDIs aerosolize the medication with a propellant gas and deliver a constant dose independent of the inspiratory stream. This feature makes pMDIs particularly useful in patients with low airflow capacity.^1,4,5 Simultaneous breathing with triggering and inability to hold one’s breath after inhalation are common usage errors with pMDIs and should be ensured to be eliminated by implementing structured training.^1,4,5 Selection of the inhaler device to be used in the patient’s treatment should not be based on a general concept of the best inhaler device, but rather on the patient’s inspiratory flow, hand-eye coordination, cognitive status, and preferences. In recent years, environmental impact has also been included in device selection: while the hydrofluorocarbon propellants of current pMDIs have a high global warming potential, DPIs have a much lower carbon footprint.^6,7

Inhaler adherence is usually impaired for two reasons: unintentional forgetting and the patient’s own failure to use the medication.¹ Patients may refrain from using their inhalers regularly due to reasons such as the use of multiple inhalers, concerns about side effects, and disease perception.¹ In asthmtic subjects, high adherence to treatment is crucial for disease control. Low or variable inhaler adherence significantly increases the risk of severe exacerbations and poor disease control.⁸

This study aimed to retrospectively evaluate the efficacy of fluticasone-salmeterol combination treatment via a capsule-based DPI and medication adherence at first and third months of treatment in asthmatic patients.

Material and methods

Study design and ethics committee approval

This study is an observational study that retrospectively examined the clinical data of asthma patients treated with RESPIRO-D capsule inhaler and was carried out at the immunology and allergy clinic of a tertiary chest diseases hospital. There is no comparison group in the study. The primary objective of the study was to statistically examine the changes over time in pulmonary functions, adherence to asthma medication and asthma control in the study population.

All procedures adhered to good clinical practices and the principles outlined in the Declaration of Helsinki. Ethics approval for the study was obtained from the local ethics committee (2024-BÇEK/357, September 10, 2025).

Study population

The study population consisted of adult asthma patients who required inhaled corticosteroid-long-acting beta-agonists combination treatment as maintenance therapy according to stepwise approach of asthma medication based on the GINA recommendations and who were receiving RESPIRO-D therapy.¹ Patients with at least 6 months of regular follow-up data throughout the treatment period were included in the study. Exclusion criteria were incomplete or insufficient data records, pregnancy, subjects under 18 years of age, chronic lung disease other than asthma, and subjects using biological medications for asthma treatment.

Data acquisition and study outcomes

Data of the patients including age, gender, smoking history, body-mass index, comorbid diseases, baseline and follow-up clinical characteristics regarding pulmonary function test (PFT) values, ACT scores, and Morisky Medication Adherence Scale-8 (MMAS-8) scores were obtained by reviewing patient records. Information regarding patients who discontinued medication due to side effects was obtained from patient records. Anonymous data obtained from our hospital’s data system were used in this study.

Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) measured and % predicted values, FEV1/FVC, forced expiratory flow at 25–75% of FVC (FEF25–75%), and FEF25–75% were used to assess pulmonary functions. Asthma control test (ACT) and MMAS-8 were used to assess adherence to asthma medication and asthma control, respectively. Measurements of PFTs, ACT scores, and MMAS-8 at three different time points (baseline, first month, third month) in asthmatic individuals treated with fluticasone–salmeterol capsule inhaler were noted and compared. Patients received brief, hands-on inhaler instruction at each visit, and drug-related side effects were discussed.

Statistical analysis

Statistical analysis was performed using the IBM SPSS Statistics 27 package. Continuous variables were summarized as mean ± standard deviation, while categorical variables were expressed as frequencies and percentages.

Given that the dependent variables were obtained from repeated measurements on the same individuals, repeated measures analysis of variance (ANOVA) was employed to evaluate the effect of the time factor. Prior to analysis, the assumptions of parametric testing were formally assessed. Distributional properties were evaluated using the Shapiro–Wilk test and visual inspection of Q–Q plots. Based on these assessments, the data were considered to be approximately normally distributed. Accordingly, parametric methods were applied, also taking into account their robustness to moderate deviations from normality under adequate sample size conditions, consistent with the Central Limit Theorem.

The sphericity assumption was evaluated using Mauchly’s test of sphericity. When this assumption was violated, Greenhouse–Geisser or Huynh–Feldt corrections were applied to adjust the degrees of freedom. For variables satisfying the sphericity assumption, results based on “assumed sphericity” are reported.

When a significant time effect was detected, pairwise comparisons were conducted using Bonferroni correction to identify differences between measurement time points. The time variable was treated as an ordered factor with equally spaced measurement intervals, allowing for the application of linear and quadratic trend analyses. Effect sizes were quantified using partial eta-squared (η²), and 95% confidence ıntervals were reported for each analysis to support the sensitivity of the findings. A P < 0.05 was considered statistically significant.

Results

In all, 131 subjects were included in the study. Baseline data of the study are demonstrated in Table 1. Regarding comorbidities 24 (18.30%) subjects had hypertension, 8 (6.10%) had diabetes, 14 (10.70%) had cardiovascular disease, and 36 (27.50%) subjects had gastroesophageal reflux disease. Allergic rhinitis accompanied asthma in 75 (57.30%) subjects.

As seen in Table 2, statistically significant increase was seen in all lung functions in spirometric measurements recorded at baseline and at first and third months of treatment. Similarly, baseline ACT scores (17.15 ± 2.29) were increased to 21.34 ± 2.14 at first month of treatment and to 22.36 ± 2.01 at third month of treatment. The increments were both statistically significant (Table 2). The MMAS-8 scores did not change significantly at first and third months of treatment (Table 2). Repeated measures ANOVA demonstrated that the effect of time on pulmonary function parameters and ACT score was statistically significant. Effect sizes, expressed as partial eta-squared (η²), together with their 95% confidence intervals (CIs), indicated a small effect for FVC (η² = 0.040; 95% CI: 0.003–0.096) and a small-to-moderate effect for %FVC (η² = 0.063; 95% CI: 0.015–0.123). In contrast, FEV1 showed a very large effect size (η² = 0.918; 95% CI: 0.894–0.933). The effect sizes were moderate for %FEV1 (η² = 0.145; 95% CI: 0.067–0.227), FEV1/FVC (η² = 0.114; 95% CI: 0.047–0.188), and FEF 25–75 (η² = 0.129; 95% CI: 0.055–0.210), while %FEF 25–75 demonstrated a small-to-moderate effect (η² = 0.077; 95% CI: 0.023–0.143). The ACT score exhibited an extremely large effect size (η² = 0.925; 95% CI: 0.906–0.937), indicating a substantial improvement over time. No significant change was observed in MMAS-8 scores, consistent with a negligible effect. Overall, these findings suggest that while some pulmonary function parameters showed modest improvements, the treatment effect was particularly pronounced for FEV1 and clinical symptom control (ACT score).

None of the patients stopped treatment due to drug-related side effects.

Discussion

In this study, adult asthma patients using fluticasone-salmeterol capsule inhalers showed a significant increase in asthma control levels in the first month compared to baseline, and a gradual increase in the third month. Similarly, a statistically significant increase in pulmonary functions was detected. Moreover, none of the patients stopped treatment due to drug-related side effects, and medication adherence did not change significantly at first and third months of treatment. When interpreting these changes, it should be remembered that achieving an improvement above the smallest clinically significant difference defined for ACT and a shift towards reference values in spirometric values indicate significant clinical gains for the patient.^9,10

Based on stable drug adherence levels, it can be assumed that the improvement observed in the first month with fluticasone-salmeterol will continue into the third month, provided that appropriate technique and good compliance conditions are maintained. In our study, the significant increase in asthma control levels in the first month and the continuation of this increase in the third month show that the control achieved in the early period can be maintained. In clinical practice, the first and third month follow-up appointments are an important opportunity to reinforce both correct inhaler technique and treatment adherence in asthmatics.¹ Also it is noteworthy that pharmacological treatment should be re-evaluated in accordance with stepwise approach of GINA only if control is insufficient despite optimal inhaler technique and treatment adherence.¹

Inhaler technical errors have a strong impact on clinical outcomes. Common errors such as inability to perform a complete exhalation before inhalation, inability to perform sufficiently fast and deep inspiration, and inability to hold one’s breath after inhalation have been shown to be associated with poor asthma control and more frequent exacerbations due to inadequate drug deposition.^4,8 Therefore, relying solely on initial training for technical accuracy is insufficient; repeated and structured training and reinforcement strategies are needed.¹¹ The fact that short, hands-on inhaler training was given at each visit in our study may have played a role in the significant functional and clinical improvement we observed; furthermore, the fact that treatment was not terminated due to drug-related side effects supports the safety aspect of this structured approach.

Meta-analyses in the literature highlight the need for studies supported by long-term follow-up, objective adherence measures, and standardized technical assessments to isolate inhaler device performance from patient-related variables.^11-13 Our study focuses on early (first 3 months) real-world data and reveals the short-term efficacy and safety profile of fluticasone-salmeterol treatment administered with a capsule-based DPI. The MMAS-8 scale, which we used to assess adherence to treatment, has been described as a valid and useful tool in predicting clinical outcomes in asthma.¹⁴ The fact that MMAS-8 scores did not change significantly at 1 and 3 months in our study suggests that adherence, which was already at a certain level in the early period, was maintained. This situation may indicate that the current level of adherence is sufficient for clinical response in most patients, given the significant improvement in symptom control and respiratory function. However, the limited follow-up period and the fact that adherence was assessed only with a self-report scale represent significant limitations in terms of not fully demonstrating the effects on long-term exacerbation risk and disease burden.

Comparative real-world data between different ICS/LABA components and device types are guiding in interpreting our findings. In a real-world cohort study evaluated by Park et al. in 2025, while no clinically significant differences in efficacy and safety were found between different ICS/LABA combinations and device types (pMDI vs DPI) in the first 3 months, it was reported that DPI use could slightly improve compliance.^15,16 Fluticasone–salmeterol is offered with both DPI and pMDI, and the results of the CRITIKAL study showed that pMDI with a spacer may be appropriate in patients with low inspiratory flow, advanced age, or severe obstruction, while DPI offers a practical and environmentally advantageous option in patients with adequate inspiratory flow.¹⁷ However, both the existing literature and our findings suggest that clinical outcomes are determined more by technical accuracy and compliance level than by the device itself. National data studies conducted in Korea have also shown that ICS/LABA treatment is effective in newly diagnosed asthma patients from the early stages to the first year, and that the use of DPIs may provide an additional advantage in terms of compliance in some groups.¹⁶

Although the present study did not include a direct comparison with a branded fluticasone propionate–salmeterol product, the clinical improvements observed in our cohort are in line with the well-established evidence for this combination in asthma management. Previous studies have consistently shown that fluticasone propionate–salmeterol therapy leads to meaningful improvements in symptom control and lung function within a relatively short period of time. In the GOAL study, the addition of salmeterol to inhaled corticosteroid therapy resulted in higher rates of achieving guideline-defined asthma control compared with corticosteroid monotherapy, with improvements becoming evident early during treatment.¹⁸ Similarly, Baumgarten et al. reported that initiation of salmeterol/fluticasone therapy in patients with mild-to-moderate asthma was associated with early increases in peak expiratory flow and significant improvements in FEV₁ over the first weeks of treatment, together with a reduction in the need for rescue medication.¹⁹ Consistent with these findings, Murray et al. demonstrated that the combination provided greater overall asthma control compared with its individual components.²⁰ In addition, real-world data from primary care settings have shown that patients treated with fluticasone propionate–salmeterol experience improvements in symptom burden and clinical outcomes, further supporting the generalizability of these results.²¹ Taken together, these findings suggest that the improvements in asthma control and pulmonary function observed in our study are consistent with the expected clinical effects of this widely used combination therapy.

However, these results should be evaluated within the context of some methodological limitations of our study. The single-center, retrospective design and the absence of a control group are limitations. The limited follow-up period of 3 months prevented the demonstration of effects on exacerbation frequency, hospitalization, long-term FEV₁ course, and healthcare utilization. Furthermore, although inhaler technique was supported by structured training, the lack of quantitative recording of errors using standard scoring systems limited the detailed analysis of the relationship between technical errors and clinical outcomes. Due to the retrospective design of the study, information regarding the need for rescue treatment and hospitalization/emergency visits could not be reliably collected as only data recorded in patients’ files could be evaluated. Therefore, clinically significant benefit was based on asthma control level and pulmonary function available in the file records. Finally, subgroup analyses could not be performed for different phenotypes, different comorbid conditions, or other concomitant inhaler treatments. For these reasons, generalization of these findings to different patient populations should be done cautiously; it should be considered that our results need to be supported by multicenter, prospective, and comparative studies with longer follow-up periods.

In conclusion, this study demonstrates that fluticasone-salmeterol capsule inhaler therapy can significantly improve symptom control and respiratory function in adult asthma patients. Furthermore, it suggests that capsule-based DPI use, when combined with appropriate patient-device matching and regular inhaler technique training, can be a safe and effective option in real-life situations by supporting treatment adherence. A deeper understanding of the interaction between device selection, correct technique, and sustained training in inhaled therapy may provide new perspectives on long-term asthma management and individualized treatment strategies. Since these findings are based on a single-center, retrospective, and short-term (3-month) observation, multicenter and prospective studies including objective adherence measures are needed to more strongly validate the hypothesis and to reveal the long-term effects of fluticasone-salmeterol capsule inhaler therapy on exacerbation risk, FEV₁ course, healthcare use, and quality of life.