NR= Not Reported.

Latry et al. highlighted the necessity for enhanced education for both prescribers and patients regarding asthma control (15). Lee TAC et al. observed that while adherence and outcomes improved with leukotriene modifiers therapy, this came with higher pharmacy costs (16). Perrin K et al. found that using a combination ICS/LABA inhaler did not significantly boost adherence compared to using separate inhalers (25). On the other hand, Foster et al. demonstrated that better adherence notably improved symptom control (p=0.01) (17). Both Wu AC et al. and Feehan et al. reported generally poor adherence to controller medications (18, 19). Parimi et al. found that patients starting on FF/VI were less likely to discontinue treatment and showed higher adherence compared to those on BUD/FM or BDP/FM (20). Bassam et al. recommended improving treatment access, follow-up care, and education for healthcare providers and patients (21). Sousa-Pinto et al. reported that patients using ICS plus another LABA had better adherence than those using ICS plus F. Additionally, three separate studies by Averell et al. showed that patients starting FF/VI had better adherence and a lower risk of treatment discontinuation compared to those on B/F or FP/SAL (22-24). Overall, adherence to ICS/LABA medications is linked to fewer asthma-related exacerbations, highlighting the impact of medication adherence on asthma management. These results in detail are presented in (Table 4).

LM: leukotriene modifiers; FP: fluticasone dipropionate; ACQ: Asthma Control Questionnaire; AEQ, Asthma Exacerbation Questionnaire; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LTRA = leukotriene antagonist; BDP: beclomethasone dipropionate; FM: formoterol. BUD: budesonide; FF: fluticasone furoate; VI: vilanterol; FP/SAL, fluticasone propionate; SAL: Salmeterol

Discussion

This review evaluated the incidence of adherence to asthma medications, specifically ICS and LABA, and assessed the impact of adherence to these medications. Findings from the included studies on asthma medication adherence reveal that higher adherence rates are linked to improved asthma management and reduced exacerbations. The adherence rates varied widely, with some studies reporting as high as 85% and others as low as 6%. Better adherence generally led to improved quality of life and fewer asthma-related exacerbations. Healthcare utilization costs also varied, with a range from $521 to $836. Barriers to adherence included fear of side effects and forgetfulness. Interventions such as enhanced education for both patients and providers, along with better medication management (particularly with combination inhalers), were suggested to improve adherence. Overall, consistent adherence to asthma medications is crucial for effective symptom control and reducing exacerbation rates.

Similarly, a random-effects meta-analysis of studies involving asthma patients aged 15-30 years who were prescribed ICS reported an overall adherence rate of 28% (95% CI: 20-38%, k=16) in studies providing quantitative adherence data. Adherence rates were notably higher in studies with a mean age under 18 years, reaching 36% (95% CI: 36-37%, k=4). Additionally, studies relying on self-reported adherence data reported higher adherence rates (35%; 95% CI: 28-42%, k=10) compared to those using pharmacy refill records (20%; 95% CI: 9-38%, k=6) (27). In this review, we also observed that self-reported adherence rates were the highest. Results of another meta-analysis indicated that in studies that defined nonadherence as obtaining 50% or less of the prescribed medication, the overall rate of nonadherence was 42.9%. For studies assessing nonadherence on a continuous scale, the weighted average nonadherence was also 42.9% (95% CI 28.2–49.5) (28). Meta-analysis of factors influencing adherence revealed that male patients had a higher likelihood of adherence, with an odds ratio of 2.25. Additionally, higher scores on the Asthma Quality of Life Questionnaire were associated with adherence, showing a mean difference of 0.47 points in adherent patients. Other factors, such as older age, greater knowledge about asthma, and simpler medication regimens, were also linked to better adherence, though these associations were derived from individual studies (28). However, it is noteworthy to mention here that although our incidence of adherence aligns well with these two meta-analyses, the predictors of adherence vary, which may be attributable to differences in intrinsic characteristics of the studies. For instance, differences in study population age, as the majority of our study population were middle-aged.

Furthermore, an analysis of 323 individuals revealed that 40.9% adhered to ICS. Good ICS adherence was associated with perception of asthma as a chronic disease (OR=1.22; 95% CI=1.10-1.35; p<0.001), belief of ICS as an essential medicine (2.67; 1.76-4.06; p<0.001), and fewer concerns about its use (0.39; 0.26-0.60; p<0.001). Patients on combined ICS-LABA medication exhibited a greater adherence rate (2.50; 1.41-4.44; p=0.02) than those on ICS alone (29). Findings from another observational study showed patients with poorly managed asthma had a lower proportion of excellent adherence (FDC ICS/LABA medication possession ratio [MPR] ≥0.8) compared to those with controlled asthma (35.6% [n = 21] vs 46.7% [n = 126]) (30). Additionally, findings from a multi-centre study concluded that treatment with a fixed-dose combination of budesonide/formoterol delivered via the Elpenhaler device was associated with improvements in asthma-related quality of life and lung function over 6 months, which were more pronounced in patients with higher adherence (31). Several studies have demonstrated that low adherence to controller medication is associated with an increase in the incidence of hospitalizations and emergency room visits (32). However, a database study by Vervloet et al. concluded that ICS adherence was not associated with exacerbations, whereas poor adherence (≤50%) has been linked to uncontrolled asthma (33). The most frequently recommended combination of medications to treat asthma, ICS-LABA, has been demonstrated to be the best option for preventing asthma exacerbation. Continuous use of asthma prescription drugs results in a consistent clinical outcome (34). All this evidence from the current literature supports the findings of this review and highlights the significance of adherence, which is associated with reduced exacerbations and improved quality of life, as reported by our results.

Previous research indicates that medication adherence rates among asthma patients typically range from 30% to 40% in real-world settings and can reach up to 70% in well-monitored clinical trials, though adherence often declines over time. Significant reductions in asthma exacerbations were only observed in patients who adhered to more than 75% of their prescribed medication. The challenges patients face in maintaining adherence are multifaceted, and interventions that are effective for one group may not yield the same results in different populations. Recent interventions aimed at improving adherence in asthma patients can be categorized into three main types: patient education programs, strategies to enhance communication between healthcare providers and patients, and the implementation of remote wireless technologies (35). A narrative review highlighted that personality traits, illness perceptions, and beliefs about treatment might play significant roles in predicting adherence (27).

A recent review highlighted that poor adherence is an independent predictor of future asthma exacerbations and persistent airflow limitation. A broad range of factors influence medication adherence, including multiple devices, a complicated treatment schedule i.e. several times per day, forgetfulness, cost, and concerns about adverse effects (36). Similarly, in this review we observed that one study reported fear of side effects and forgetfulness to be associated with medication non-adherence therefore, a study by Brooks et al. suggested that by embedding medication use into established daily activities can effectively address issues of forgetfulness as they noted that older asthma patients who stored their ICS in the bathroom or incorporated their use into a daily routine were more likely to adhere to their medication compared to those who employed different strategies (37). Additionally, Zhang et al. described that patient adherence to medication is heavily influenced by their understanding and beliefs about their condition and the prescribed treatments. This includes their assessment of the treatment’s necessity based on the severity of their illness and their concerns about potential medication side effects. Research indicates that patients who perceive a lower need for their medication or have limited confidence in its effectiveness are more likely to be non-adherent. Addressing these factors is crucial for improving adherence rates. Additionally, factors such as low health literacy, family dynamics, and cultural considerations have been shown to affect the use of asthma controller medications. Therefore, it is important to incorporate an individual's health literacy and cultural background into the development of educational programs and self-management strategies to ensure they are personalized and effective (38). Similarly, authors from the included studies in this review recommended to enhance medication adherence, interventions including comprehensive education for both patients and healthcare providers, along with improved medication management especially with combination inhalers.

Moreover, in this study we observed that one of the studies included reported that reminders through SMS helped in achieving 15% increase in adherence rate. Similarly, a systematic review from the present time concluded that electronic approaches have repeatedly demonstrated an effective impact on monitoring adherence to inhaled treatments in asthma patients. Adherence improvement was linked to minor clinical improvements and asthma-related quality of life. Digital health helps to monitor adherence in a way that is highly customizable, low cost, and conveniently accessible (39). Similarly, another systematic review supports this finding as results revealed that text-messaging interventions were beneficial for reducing forgetfulness by reminding patients to take their medications. Even though there is limited data from studies to support the usefulness of text message reminders, such technology is an important tool for achieving optimal medication adherence among asthmatics (40).

Pharmacological insights

A considerable amount of evidence from randomized controlled trials shows that adding LABA to an existing ICS regimen is more effective than simply increasing the ICS dose alone, even when accounting for variations in individual responses to asthma medications. LABA use as a standalone treatment for asthma is not recommended due to its lower efficacy compared to ICS and potential safety concerns. Consequently, combining ICS with LABA therapy remains the preferred approach for patients needing a step-up from ICS monotherapy (41).

ICS effectively manages chronic inflammation and reduces airway hyperreactivity in asthma, usually at low doses. LABAs contribute by targeting additional aspects of asthma's pathophysiology. Besides their primary function as bronchodilators, LABAs also help inhibit mast cell mediator release, decrease plasma leakage, and may reduce sensory nerve activation. Therefore, the combination of ICS and LABAs provides a broader therapeutic approach, addressing different facets of asthma that neither medication class can fully address on its own (42). Corticosteroids influence β2-receptor-mediated signaling and can up-regulate β2-receptor gene expression in response to glucocorticoids. Long-term use of LABAs can lead to β2-receptor down-regulation and tolerance to β-agonists; however, corticosteroids help mitigate this down-regulation and preserve receptor function during β-agonist therapy (41). Studies indicate that ICS/LABA combination inhalers are more effective than using separate inhalers for each medication. Additionally, combination inhalers tend to improve adherence to the treatment regimen in real-world settings (41).

This study boasts several notable strengths. It provides a comprehensive analysis by integrating evidence from high-quality, robust studies conducted across various geographical locations, which enhances the generalizability and reliability of its findings. The review employs a systematic search methodology to identify and include relevant studies, ensuring a comprehensive and unbiased collection of data. This evidence-based approach thoroughly examines how adherence to ICS/LABA therapy impacts asthma outcomes, identifying critical patterns that influence treatment effectiveness. The review’s insights are highly relevant to clinical practice, aiding healthcare professionals in optimizing treatment strategies and patient education. The review's strengths lie in its broad scope, practical implications, and the inclusion of diverse, high-quality evidence.

Limitations and future research directions

Despite these strengths this study has several limitations. One notable limitation is the inclusion of studies with varying participant populations, including one study that focused specifically on paediatric patients (24). Although this study had paediatric-specific limitations, it was included to ensure that no potentially valuable information was overlooked. Additionally, not all studies assessed barriers to adherence, and only one study provided detailed insights into these barriers. This lack of comprehensive assessment across studies reflects that the review may not fully capture all factors affecting adherence. These limitations suggest the need for further research with more consistent approaches and broader barrier assessments to provide a more complete understanding of adherence to ICS/LABA therapy. Despite these limitations, publishing this review remains important as it provides valuable insights and in-depth analysis of the existing literature in this regard.

Future research on the impact of adherence to ICS and LABAs on asthma outcomes should delve into several critical areas to enhance understanding and improve patient care. Longitudinal studies are essential to assess the long-term effects of adherence on asthma control and disease progression. These studies can reveal how consistent use of ICS/LABA therapy influences asthma outcomes over extended periods and help identify any delayed effects of adherence. Barrier assessment is another crucial area for research. Detailed investigations into the psychological, socioeconomic, and logistical barriers to medication adherence can provide a clearer picture of why patients may struggle with their treatment regimens. Understanding these barriers will facilitate the development of targeted interventions to address specific issues affecting adherence.

Additionally, age-specific research should be prioritized to address the unique challenges faced by different patient populations. For example, pediatric studies are needed to explore adherence issues in children with asthma, while research on adult populations can identify age-related factors influencing adherence. Tailoring interventions to these age-specific needs can improve outcomes across the lifespan. Adherence-enhancing interventions should be evaluated rigorously. This includes testing new digital health tools, such as mobile apps and reminders, and assessing the effectiveness of patient education programs, simplified medication regimens, and support systems. Identifying which interventions are most effective can guide the implementation of strategies that improve adherence.

Moreover, real-world evidence is necessary to understand how adherence impacts asthma management in everyday settings outside clinical trials. Research should focus on diverse patient populations and various healthcare contexts to gather insights on adherence patterns and their practical implications. Comparative effectiveness studies should investigate the benefits of different ICS/LABA combination therapies formulations. This research will help determine which formulations are most effective in enhancing adherence and managing asthma symptoms. Furthermore, personalized medicine approaches should be explored to tailor treatment plans based on individual patient characteristics, preferences, and responses. This can include customizing medication regimens and adherence strategies to better suit each patient, thereby improving adherence and overall asthma control. These research directions aim to address existing gaps in literature, provide a more comprehensive understanding of adherence dynamics, and ultimately lead to more effective treatment strategies and improved patient outcomes in asthma management.

Conclusion

This systematic review highlights the significant impact of adherence to ICS/LABAs on asthma outcomes. Findings emphasized that higher adherence rates are consistently associated with improved asthma management, reduced exacerbations, and improved quality of life. Future research should focus on developing and testing interventions specifically designed to address adherence barriers, such as personalized education programs and reminders. Additionally, exploring the impact of different inhaler combinations on long-term adherence and asthma outcomes could provide further insights.

Disclosures

Author Contributions

All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.

Ethics Statement

Not applicable.

Consent for publications

Not applicable.

Data Availability

All data is provided within the manuscript.

Conflict of interest

The authors declare no competing interest.

Funding

All authors have declared that no financial support was received from any organization for the submitted work.

Acknowledgements

Not applicable.