Effect of Individual Patient Characteristics and Treatment Choices on Reliever Medication Use in Moderate-Severe Asthma: A Poisson Analysis of Randomised Clinical Trials

Asthma affects around 300 million individuals worldwide. It has a heterogenous clinical presentation, including cough, wheeze, dyspnoea, chest tightness or pressure as well as signs of expiratory airflow obstruction [1]. Achievement of asthma control over time, reduced dependency on reliever therapy and a reduction in exacerbation are clear goals of the clinical management of patients with moderate-severe asthma [2, 3]. Previous research has shown that in adults with moderate-severe asthma, exacerbation risk is significantly higher in women, obese subjects, smokers and those who have poor lung function, as assessed by spirometric measures; these factors have also been associated with variable or decreased symptom control [4, 5]. However, despite evidence showing that patients achieving control require less reliever medication and have a lower risk of exacerbation [6], the correlation among symptom control, reliever use and reduction in future risk has not been fully characterised.

To date, it has been shown that improvements in lung function testing are accompanied by symptom reduction and need for reliever use, but less information is available on the correlation with exacerbation risk [7]. In fact, a complex relation appears to exist between controller and reliever medication use and exacerbations [8‐11]. This complexity arises partly because of over-reliance on acute symptom improvement through reliever at the expense of inadequate controller therapy. Real-world data reveal that patients who exhibit low ICS adherence (50% or less) and rely more on reliever use are at higher risk of experiencing exacerbations [12]. Moreover, increased reliever use has been associated with higher incidence of exacerbation, independent of maintenance therapy with inhaled corticosteroids (ICS) or ICS/long-acting beta agonist (LABA) combination therapy. Whilst variable adherence to daily ICS or ICS/LABA regimens may stem from the episodic nature of asthma symptoms [13], such findings highlight the importance of ensuring bronchoprotection, irrespective of current symptoms, i.e. adherence to controller medication and maintenance therapy.

From a pharmacological perspective, the complexity in establishing a link among reliever use, symptom control and exacerbation risk may arise from the different time scales, pathways associated with the inflammatory response and airway function. Defining correlations between effects that occur over a different time scale therefore requires longitudinal data, which capture the contribution of patient-related factors and long-term effects of maintenance therapy.

Unfortunately, longitudinal data describing reliever use at individual patient level are scarce, and cross-sectional studies do not overcome this shortcoming. Consequently, there is limited insight into how the interplay among patient-, disease- and treatment-related factors affects the natural history of asthma control [14]. Instead, most reports focus primarily on the history of prior exacerbations, as asthma exacerbations are known to affect airway function and the clinical course of asthma symptoms [15]. However, data collection on reliever use is primarily qualitative or cross sectional [16]. There has been no strictly quantitative approach describing how reliever use influences long-term treatment response in patients on maintenance therapy and which factors determine interindividual variation in reliever use patterns. This represents an important gap in the clinical management of patients, as asthma symptom control and exacerbation risk reduction are directly and indirectly associated with reliever use.

To address this gap, one needs to distinguish short-term fluctuation in airway function, which may be due to a range of triggers resulting in bronchoconstriction, from asthma exacerbations and long-term symptom variation (i.e. individual trajectories), which are likely to reflect the underlying airway inflammation status [17, 18] as well as interindividual differences in demographic and clinical baseline characteristics [3, 19]. The aims of this study were three-fold: (1) to improve individualised patient care by identifying treatable traits and their effects on disease status and reliever use, (2) to quantify the effect of maintenance therapy on reliever use and (3) to understand the interplay between symptom severity and maintenance therapy selection. To this purpose, we analyse daily record data on reliever use in conjunction with a parametric Poisson model to establish the correlation between reliever use and individual patients characteristics, symptom control level and exacerbation in patients with moderate-severe asthma on regular maintenance therapy.

Despite the importance of maintenance therapy, a significant proportion of patients seems to rely on reliever to manage worsening of asthma symptoms. Indeed, a debate has been ongoing on the effect of variable adherence to maintenance therapy and implications of over-reliance on the effects of reliever medication in moderate-severe asthma, in particular short-acting beta-adrenergic agonists (SABA) [29, 30]. Whilst multiple factors may contribute to such a behaviour, there have been limited efforts to assess the interplay among reliever use, symptom control and future risk using longitudinal data. To date, very few studies have evaluated individual patient-level, longitudinal data on reliever use in asthma [31].

Given the known interindividual differences in bronchial reactivity to triggers, the contribution of airway remodelling to airflow limitation and symptoms, and drug and dose-dependent desensitisation of β-2 adrenergic receptors [32], the assessment of individual patterns of reliever use, along with its correlation with the achievement of short/long-term symptom control, and subsequent reduction in exacerbation risk may not be possible without longitudinal data and a model-based approach [33‐37]. Here we have attempted to characterise individual patterns of reliever use, mostly short-acting beta adrenergic drugs, in moderate-severe asthma over the course of run-in, titration and maintenance phases of treatment with ICS or ICS/LABA combination therapy.

Mean and individual patterns in reliever use revealed a profile that includes an initial steep drop followed by a slow, gradual decrease in reliever use, which stabilises well after 6 months after initiation of ICS monotherapy or ICS/LABA combination therapy (Figs. 2 and 3). This pattern indicates that inferences about the efficacy of the maintenance dosing regimen based on short term studies may not be accurate. In addition, patients who show poor asthma symptom control at baseline (i.e. ACQ-5 > 1.5) or experience an exacerbation during the course of treatment use significantly more reliever than those who achieve adequate level of control or do not exacerbate. Nevertheless, some reliever medication is still required even by those who achieve symptom control or do not exacerbate (Fig. 7). Such a requirement suggests that airway hyperresponsiveness may not be completely suppressed in the presence of triggers. This may be due to variable adherence to treatment or underuse of ICS, and consequently suboptimal anti-inflammatory response (i.e. bronchoprotection).

Our findings can also indicate that distinct mechanisms or pathways contribute to bronchoconstriction and airway smooth muscle (ASM) homeostasis, as observed in viral exacerbations, during which the ability to respond to bronchodilators is partially or almost completely lost [38, 39]. Loss of homeostasis results in excessive ASM contraction which, in those with poor control, is manifest by variations in airflow resistance over short periods of time [40]. Hence, overlooking the implication of impairment in ASM homeostasis, as well as the time-, drug- and dose-dependent desensitisation of β-2 adrenergic receptors, may lead to confounding and misinterpretation of data on reliever use. In addition, the reversibility of airflow resistance through smooth muscle relaxation and bronchodilation may vary according to the selectivity, potency and actual exposure to β-2 agonists reaching the airways.

Undoubtedly, the identification of asthma duration as a significant baseline covariate suggests progressive desensitisation of beta-adrenergic receptors to beta-adrenergic agonists in patients who have been diagnosed with asthma for > 5 years, leading to higher reliever use. An additional factor might be the progressive development of fixed airflow limitation as a result of airway remodelling. These effects may be further amplified by current smokers, higher BMI and other comorbidities impacting on symptom control. These factors will also vary depending on the maintenance (controller) therapy choice [41, 42].

The final model highlighted the effect of disease history (asthma duration) and interindividual differences in clinical and demographic baseline characteristics on reliever use (i.e. baseline ACQ-5, BMI, smoking status), which directly and indirectly affect airway hyperresponsiveness to environmental and other external triggers. In practice, the effect of baseline covariate factors and maintenance therapy summarised in Table 4 can be interpreted as follows: assuming the average patient requires 3.6 puffs per day at the start of treatment, each increase or decrease of 1 unit in the covariate results, respectively, in a percentage increase or reduction in the number of puffs of overnight occasions of the magnitude of the parameter point estimate (relative to its median value). For instance, for every unit increase in baseline BMI relative to the median (i.e. 26 kg/m²), the number of puffs increases by approximately 2.6% per unit BMI. Hence, a patient with baseline BMI value of 34 kg/m² (i.e. 8 units higher than the median value) will require 4.3 puffs. That means 0.7 puffs more per 24 h and approximately 22.3% more puffs than a patient with a BMI of 26 kg/m². Similarly, for every unit increase in ACQ-5, reliever use increases by 75.9%, whereas smoking is associated with 73.5% more reliever use compared to a patient who never smoked.

In contrast to the effect of baseline covariates, the extent of the effect of maintenance therapy is time-, drug- and dose-dependent, with maximum reduction in reliever use being achieved after 12 months from the start of treatment. In fact, the predicted maximum reduction in reliever use is 1.9-fold higher at 12 months than what is observed at the start of treatment. This partly explains the diverging results obtained on reliever use in observational, cross-sectional studies, where time since the onset of maintenance therapy may not be factored into the analysis [8]. Clearly, this time-dependent effect leads to important shortcomings in cross-sectional studies. Hence, whenever exploring overuse of reliever, estimates based on a single figure for the whole population are not adequate and could be misleading.

Reliever use depends not only upon a patient’s baseline characteristics and disease history but also on the duration and choice of drugs used as maintenance therapy. The availability of different FP doses allowed us to quantify the effect of salmeterol (SAL) in the ICS/LABA combination therapy. Whilst the maximum effect of FP was lower than BUD/FOR combination (i.e. a reduction of approximately 69.3%), salmeterol alone appears to contribute significantly to the effect of the combination on reliever use, with an estimated reduction of 38.1%. Furthermore, it was possible to estimate the theoretical median reliever use in the absence of the effect of maintenance controller therapy, which corresponds to 3.6 puffs per 24 h, with an average of 0.6 overnight events. This represents a theoretical consumption of 6.6 canisters per year. Consequently, this estimate provides insight into the magnitude of the effect of ICS/LABA combination therapy on reliever use reduction, which reaches 75.3% following regular dosing with FP/SAL (i.e. from 6.6 to approximately 0.9 canisters per year after the first year of treatment).

Our findings also raise further questions on the conclusions drawn by Bateman and colleagues on the association between higher prescription of short-acting β2-agonists and rates of severe asthma exacerbations [43, 44]. Even though patients exacerbating during the study period appear to use approximately twice as much reliever relative to those who do not exacerbate, such a difference is observed irrespective of treatment type (i.e. monotherapy or combination therapy) and is consistent with previous reports [12]. Hence, it is unlikely that the higher exacerbation rate observed following monotherapy is caused by variable adherence to ICS. Rather, the risk of exacerbation in this group of patients appears to be associated with clinical and demographic covariates [5], suggesting that reliever use is triggered most likely by the inadequate level of bronchoprotection in this population. We hypothesise that this pattern can be explained by distinct mechanisms underpinning the immediate and long-term symptom control in patients who exacerbate and those who do not [39, 45]. Such a distinction is critical, as it becomes evident that inflammation, currently elevated as the underlying cause of the clinical symptoms of asthma, may need to be assessed as another relatively independent component [31, 40, 46].

As schematically summarised in Fig. 7, the increased use of reliever medication in exacerbating patients or in those with a history of moderate and severe asthma exacerbations is not associated with reliever medication itself but with additional treatable traits and external factors [5]. Moreover, the evidence of a dose-dependent effect of ICS and a significantly higher decrease, rather than total suppression in reliever use following ICS/LABA combination therapy with different drugs, suggests that increased bronchial reactivity may involve other pathways than the underlying anti-inflammatory mechanisms by which inhaled corticosteroids act, highlighting that loss of normal homeostatic control of airways smooth muscle (ASM) may play an important role in long-term use of reliever. As to the direct clinical implications of this work, we foresee that evidence of the magnitude of the effect of baseline characteristics, i.e. treatable traits, on reliever use will help clinicians implement personalised interventions and identify opportunities to better manage patients. Obvious recommendations include weight loss, smoking cessation and appropriate selection and earlier initiation of maintenance therapy, considering not only the current disease status (ACQ-5) but also the patient’s disease history (time since asthma diagnosis). The quantification of these effects at individual level will allow the clinician to have a frank conversation as to the expected improvement that lifestyle and treatment choices may have on the patient’s symptoms, exacerbation risk and reliever medication use. It can be anticipated that such choices may also have repercussions on a larger scale, informing education programmes and healthcare services for patients with moderate-severe asthma.

In summary, the implementation of a Poisson model to describe individual patterns of reliever use can be compared to similar research in other therapeutic areas, such as migraine, major depression or epilepsy [32‐34], where the endpoints of interest are count or frequency data. Hence, we anticipate that our analysis will provide the basis for the evaluation of a range of clinical questions regarding reliever use in asthma and eventually support the implementation of personalised interventions.

We acknowledge that, as with any pharmacometric approach, model predictive performance and generalisability depend highly upon the data available and the clinical questions one aims to address. A few areas have been identified, which could represent a limitation to this investigation, namely, the potential for selection bias due to the limited access to a wider pool of individual patient level data, imputation of missing baseline covariates in some patients for whom information was not recorded, difficulties in discriminating the effect of patient baseline characteristics from maintenance therapy, potential impact of variable adherence and apparent estimates of reliever use rate at the start of maintenance therapy. An overview of the limitations of the clinical trial data and model parameterisation is provided in Table S5 (Supplementary Material).