Understanding relationships between asthma medication use and outcomes in a SABINA primary care database study

This study showed that both patients with an ICS adherence level of 50% or less and patients with an adherence level of over 90% were issued more SABA prescriptions. The number of SABA prescriptions was strongly associated with the occurrence of asthma exacerbations, whilst ICS adherence did not show a clear association. Patients with a higher number of SABA prescriptions in 2016 were more likely to have experienced one or more exacerbations in that year. Increased SABA use and an ICS adherence level of 50% or less were also strongly associated with self-reported uncontrolled asthma.

The SABA use of patients in our study appears to be similar to other European countries. A recent study investigating SABA overuse (at least three prescriptions per year) in the UK, Germany, Italy, Spain, and Sweden found percentages ranging from 9% in Italy up to 38% in the UK25. In our study, about 14% of patients received three or more SABA prescriptions.

In line with our study, an association between SABA use and exacerbations has been found in several studies26,27. More conflicting evidence has been found about the association between ICS adherence and exacerbations. Several studies have shown that a higher ICS adherence decreased the risk of exacerbations (e.g. refs. 9,28). However, like in our study, this association was not found in other studies13,29. It has been shown that ICS adherence fluctuates with an increase right before and after an exacerbation28. With our operationalization of ICS adherence (medication availability computed over the whole year using GP prescription data), these fluctuations could not be distinguished in the data. Our finding that self-reported uncontrolled asthma was associated with increased SABA use and low ICS adherence was in line with previous studies29,30.

The associations found in our study indicate a complex relation between controller and reliever medication use and exacerbations. On the one hand, there are patients who exhibit low ICS adherence (50% or less), and use more SABA (and who—independent of the ICS adherence level—also are at higher risk of experiencing exacerbations). These patients might either over-rely on their SABA for quick relief or they might confuse their controller and reliever medication. A recent study revealed that patients perceive their SABA as a great support in treating asthma symptoms driven by its immediate relief of symptoms31, and as such might prefer their SABA over their controller medication. This is also linked to the episodic nature of asthma; patients do not feel the need for long-term treatment with controller medication if they do not experience an impact on their daily life32. In addition, patients often do not realize that the frequent use of SABA indicates poorer asthma outcomes31. The combination of low ICS adherence and high SABA use might also be explained by patients’ confusion about their inhalers. Previous studies indicated that patients do not always know or understand the difference between their reliever medication and their controller medication to manage their asthma32. They use SABA regularly instead of their ICS medication unintentionally. A recent review showed similar or even better asthma symptom control and lower exacerbation rate in patients who use budesonide/formoterol as a maintenance and reliever therapy, compared to patients who use ICS/LABA with as-needed SABA33, also when used as as-needed medication (without maintenance)34. This as-needed combination medication, recommended for the first treatment step in the Netherlands since 202023, can especially be suitable for patients with lower ICS adherence levels (and using SABA) or those who have a limited understanding of their asthma.

On the other hand, there are patients who are highly adherent to their controller medication (ICS adherence above 90%), but still use SABA often, and are as such also at higher risk for exacerbations.

Several factors may account for this behavior, including inhaler technique, adequacy of treatment, and exposure to environmental triggers. A correct technique is crucial for the effectiveness of ICS medication, i.e., if patients do not use their inhalers correctly, the medication does not reach its target and cannot be optimally effective. Patients thus might seem highly adherent as they “use” their medication according to the prescription, but do not benefit from the medication and are thus at higher risk for increased SABA use and exacerbations. Previous studies have revealed that many patients make critical errors in inhaling their medication, which has been shown to be associated with poor asthma outcomes35,36. Another factor might be the adequacy of the treatment. Patients might be treated with an inadequate dose of controller medication to control their asthma symptoms and therefore might more often need SABA to alleviate symptoms, whilst being adherent to the controller medication.

Finally, independent of the level of ICS adherence, patients might also require SABA frequently to regain control after being exposed to environmental triggers. Dima et al.’s Asthma Care Model (2016) includes, besides regular and correct use of maintenance medication, three other types of behavior patients need to perform for managing their asthma. These are self-monitoring of symptoms, management of triggers, and management of severe exacerbations37. Thus there can be several factors contributing to patients using SABA very frequently which cannot be disentangled easily from our study. However, the recently published study by Quint et al. (2022) also confirmed across other European countries that increasing SABA exposure is associated with increasing risk of exacerbation, independent of maintenance therapy38.

A strength of our study is that it used “real-world data”, i.e., data from a large primary care database. An advantage of these data is that they reflect daily practice. Using this type of data resulted in a large cohort of patients with asthma. After data preparation steps, we were provided with robust and interpretable data. It was necessary to exclude patients for whom we could not calculate adherence to controller treatment (23%); however, this was rather due to missing or incomplete information in the GP information system than to patient-related factors. The data preparation steps appeared to have had little impact on the representativeness of our study sample. The distribution of sex39, and percentage of patients per treatment step40 resembled the Dutch asthma population. Patients aged 12–17 years were somewhat underrepresented in our sample, as the Dutch asthma population is evenly distributed amongst age groups41. The average ICS adherence of 62% in our study sample was similar to the adherence levels found over the years 2007–2013 in the Netherlands, though these were based on dispensing data (www.TherapietrouwMonitor.nl) and similar to adherence levels found in other countries (e.g. refs. 7,8). SABA use in Dutch patients resembled SABA use in patients from other European countries25.

A limitation of our study is that our study period was limited to one year. Only exacerbations occurring in 2016 were included, thus disregarding whether patients have a short or long history with either few or many prior exacerbations. It would be interesting to investigate longer periods of time to investigate the effect of prior events. However, earlier studies already showed an association between consecutive exacerbations since each exacerbation causes irreversible damage to the lungs42. Another limitation is that data on healthcare utilization, such as emergency department visits, hospital admissions, or unscheduled GP visits, which often follow a severe exacerbation were not available. Short OCS courses with ≥20 mg daily were used as a proxy for exacerbations. This approach might have underestimated the number of exacerbations (capturing only mild to moderate exacerbations, and misclassifying patients with severe exacerbations to the reference group) which might have biased our results toward the null. Another limitation is that patients starting with ICS treatment in 2016 were not excluded from our sample. Patients who initiated treatment late in 2016 might have been overrepresented in the lowest adherence category, although two prescriptions were a minimum. In addition, we might have excluded patients with milder asthma as a result of having minimally two R03A and/or R03B prescriptions in 2016. We did not have detailed data on which the asthma diagnosis was based, we used the ICPC-code R96 to select patients with asthma. However, GPs follow their professional guideline “Asthma” in diagnosing patients which indicates that medical history should be assessed and physical examination and spirometry should be conducted.

The 227 practices were not fully representative of Dutch primary care, although the practices were located in both urban and rural areas, spread throughout the Netherlands, and the age distribution of our patient population resembled that of the total Dutch population.

There might also have been some residual confounding, other factors that play a role in the associations between ICS adherence, SABA use, and asthma outcomes besides the patient and clinical characteristics that were controlled for. For example, outcomes could have been influenced by factors such as environmental triggers (allergies, air pollution), whether ICS was correctly inhaled (inhaler technique) or whether all issued SABA prescriptions were actually used. SABA use may also be overestimated when patients have multiple inhalers which they keep at different locations for their convenience.

There are many ways to calculate adherence from administrative databases, all with their own strengths and limitations43 and each providing different estimates of adherence44. For this study, a CMA was used to operationalize adherence, more specifically the CMA7. The CMA7 takes carry-over into account from before the observation window as well as within the observation window. Disregarding the carry-over would underestimate the adherence rate. This is a clear advantage of CMA7. However, since CMA7 provides information about medication availability, overuse cannot be identified. Furthermore, prescription patterns are an estimate for medication adherence but lack information about actual intake. To actually monitor medication intake behavior, other adherence measures are necessary, e.g., electronic monitoring45.

The relation between ICS adherence and the number of SABA prescriptions with the risk of exacerbations is not a simple linear relationship. For GPs it is important to recognize that according to the SABA use of their patients with asthma, different approaches to achieving optimal asthma control are needed. Our study revealed that SABA use was associated with higher odds of exacerbations and higher odds of having self-reported uncontrolled asthma. Although the odds increased with the number of SABA prescriptions, patients having one or two prescriptions already were more likely to experience exacerbations. Yet, a higher number of SABA prescriptions was also associated with being more adherent to ICS. The GINA guidelines for treatment are updated annually and since 2019 recommend low-dose ICS or as-needed low-dose ICS/formoterol as the first step in treatment instead of SABA monotherapy. Our study supports these changes.

As GPs can easily identify patients with (higher) SABA use, compared to determining adherence to ICS medication, this should provide them with a clear signal to start the conversation with these patients about their asthma self-management. Our findings indicate that for achieving optimal asthma control, it is important for GPs to discuss with patients their asthma medication use (both controller and reliever medication), to check whether their inhaler technique is correct, and to determine whether the prescribed treatment is still adequate. Moreover, GPs should not only support patients in their medication use, but also support them in identifying and avoiding environmental triggers that worsen their symptoms. These implications endorse the 2020 updated Dutch guideline for GPs for the treatment of asthma in adults23.

In conclusion, SABA use was strongly associated with exacerbations, whereas ICS adherence was not. SABA use and poor ICS adherence were associated with self-reported uncontrolled asthma. These findings indicate that SABA use is an easily identifiable and important signal for GPs to discuss asthma management with their patients. To achieve better asthma outcomes, limiting SABA use, improving ICS adherence, optimizing treatment, but also other self-management behaviors, such as identifying and avoiding triggers, need to be considered.

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