Modelling ASthma TrEatment Responses (MASTER): Effect of individual patient characteristics on the risk of exacerbation in moderate or severe asthma: A time‐to‐event analysis of randomized clinical trials

Abstract

AimsThere is limited understanding of how clinical and demographic characteristics are associated with exacerbation risk in patients with moderate‐to‐severe asthma, and how these factors correlate with symptom control and treatment response. Here we assess the relationship between baseline characteristics and exacerbation risk during regular dosing with inhaled corticosteroids (ICS) monotherapy or in combination with long‐acting beta2‐agonists (ICS/LABA) in clinical trial patients with varying levels of symptom control, as assessed by the asthma control questionnaire (ACQ‐5).MethodsA time‐to‐event model was developed using pooled patient data (N = 16 282) from nine clinical studies [Correction added on 26 July 2023, after first online publication: The N value in the preceding sentence has been corrected in this version.]. A parametric hazard function was used to describe the time‐to‐first exacerbation. Covariate analysis included the assessment of the effect of seasonal variation, clinical and demographic baseline characteristics on baseline hazard. Predictive performance was evaluated by standard graphical and statistical methods.ResultsAn exponential hazard model best described the time‐to‐first exacerbation in moderate‐to‐severe asthma patients. Body mass index, smoking status, sex, ACQ‐5, % predicted forced expiratory volume over 1 s (FEV1p) and season were identified as statistically significant covariates affecting baseline hazard irrespective of ICS or ICS/LABA use. Fluticasone propionate/salmeterol (FP/SAL) combination therapy resulted in a significant reduction in the baseline hazard (30.8%) relative to FP monotherapy.ConclusionsInterindividual differences at baseline and seasonal variation affect the exacerbation risk independently from drug treatment. Moreover, it appears that even when a comparable level of symptom control is achieved in a group of patients, each individual may have a different exacerbation risk, depending on their baseline characteristics and time of the year. These findings highlight the importance of personalized interventions in moderate‐to‐severe asthma patients.

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

“…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 ].…”

“…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.…”

“…Moreover, baseline ACQ-5 was derived from ACT scores for patients included in studies ADA109055 and ADA109057. This was required because only ACT was recorded in these studies and ACQ-5 has been identified as a covariate affecting exacerbation risk and individual symptom trajectories during the course of treatment [ 5 , 20 ]. Conversion was performed considering the symptom category and percentiles of the scores of each scale.…”

“…Further details of the evaluation steps are provided in the Supplementary Material. In addition, it should be emphasised that similar methodologies, aimed at characterising interindividual differences in disease processes, disease progression, and treatment response, have been applied elsewhere [ 5 , 28 ].…”

“…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.…”