A large-scale review has revealed that outcome measures used in clinical trials of experimental acute asthma treatments have been inconsistent, heterogeneous and narrowly focused on short-term impact on lung function.
The review’s findings, published in ERJ Open Research [link here], highlight significant limitations in the evidence and approaches that guide the current management of asthma exacerbations.
Crucially, a lack of consensus on acute asthma treatment outcomes and the tendency to undertake related research and development in the emergency care setting means there has been a missed opportunity to develop approaches for earlier intervention before severe presentation, researchers said.
The analysis included 208 randomised controlled trials from 35 countries that compared treatments for adults with asthma attacks, published in English between 1972 and 2022 in the MEDLINE, Embase, and Cochrane Library databases. Studies tended to be small but ranged from 12 to 1109 participants (median 60), and the most common settings were emergency departments (n=165) and hospital admissions (n=33).
Researchers noted that just 128 studies had clearly defined primary and secondary outcomes. Of those that did, the majority (73%) of primary endpoints focused on changes in lung function or other physiological parameters over a short period (usually less than 24 hours).
The UK authors said this is potentially problematic as lung function “correlates weakly with patient-reported recovery of symptoms and relapse” and emphasised that there is “a large degree of variability in lung function because of inconsistent testing technique and effort dependence.
In a linked editorial, Dr Richard Russell, Respiratory Speciality Registrar, Leicester University, UK, also pointed out that “lung function does not relate well to other measures of asthma control in nonexacerbating patients,” and that “whether lung function response in the first three h of an exacerbation is important to ongoing recovery, or in preventing future relapse, is unclear”.
Furthermore, the authors said that many of the trials in the review failed to consider a minimum important difference for lung function in the study’s design and powering, which limits their validity.
The short duration of lung function assessment was also an issue. “While these may be sufficient to demonstrate the efficacy of interventions in the narrow context of an emergency department presentation, they almost certainly do not capture the full recovery of a person from an asthma attack,” they noted.
The findings also revealed that patient-reported and healthcare utilisation outcomes were primary goals in less than one-third (27%) of trials included in the review. None of the studies had reliever medication use or any quality of life score as a primary outcome.
There was also “significant heterogeneity” between definitions of similar outcome measures, making it more challenging to compare treatment effects.
Consistent outcome measures needed
As such, the group called for a consensus definition of “treatment failure” for asthma attack trials, given that “types and timing of treatment failure reported varied considerably, which limits comparison between trials”.
Dr Russell suggested developing consistent outcome measures across acute asthma treatment interventions could “facilitate a more detailed evaluation of current clinical guideline recommendations, more accurate comparison between interventions regarding their magnitude of benefit and further optimisation of care pathways.
“It would also provide reference points against which future novel therapeutics can be benchmarked, allowing easier evaluation of how these should fit into clinical practice,” he said.
Overall, the review’s findings suggest that “the approaches taken by studies in acute asthma to date may lack generalisability, overlook other valid outcome measures, and hinder the evaluation and comparison of different interventions,” the researchers noted.
Also, the fact that the vast majority of trials (95%) have taken place in an emergency department or during hospital admission has played a role in shaping the outcomes studied and positioning acute asthma treatments later in the care pathway, they said.
“By trialling treatments for acute asthma predominantly in urgent and emergent care, the medical community has directed most interventions downstream to late, severe presentations of an attack. Consequently, outcome measures chosen for these studies tend to be short term and based around quick physiological wins”, according to the paper.
Looking forward, the focus of asthma attack trials should “move beyond downstream and short-term interventions”, mainly as remission is now a realistic proposition for patients.