Beyond RCTs: Real-World Data Reveals Common Downstream Pathways to Severe Asthma Exacerbations

Pathways that predict severe asthma attacks (exacerbations) were found to be similar, with matching strength of prediction, in both clinical trials (Randomised Controlled Trials, RCTs) and real-world data (RWD) settings in the new International Severe Asthma Registry (ISAR) study “Interactive Pathways of Key Prognostic Factors in Severe Asthma: A Bayesian Network Comparison of Clinical Trials & Real-World Data”.

Recently published in CHEST, this study performed a novel Bayesian Network (BN) analysis that integrated machine learning with expert knowledge to map how factors interact to influence exacerbation risk, addressing the important question of whether these factors may differ between RCTs and RWD settings. The RCT cohort included 345 adult patients from the placebo arms of two large international clinical trials. The real-world cohort comprised 6,814 adults not on specialist biologic therapies enrolled in ISAR. Both cohorts focused on patients with severe asthma, with a primary outcome of occurrence of severe asthma exacerbations during a 365-day follow-up period.

In both RCT and RWD settings, two clear pathways to exacerbations were found (Figure 1).  Firstly, the blood marker (biomarker) Immunoglobulin E (IgE) influenced the biomarker BEC (Blood Eosinophil Count) to predict severe exacerbations. Secondly, history of severe exacerbation directly predicted future severe exacerbations. Understanding the impact of these factors can provide critical support to decision making in clinical care, shaping patient outcomes.

Figure 1: Final Bayesian Networks learned under RCTs (A) and ISAR (B) settings

OCS: Oral Corticosteroids, BEC: Blood Eosinophil Count, IgE: Immunoglobulin E, FEV1: Forced Expiratory Volume 1 second, FVC: Forced Vital Capacity

Factors leading to these key predictors were more complex in the ISAR cohort than in the RCT population, reflecting the broader range of patient characteristics and clinical management in routine care. Importantly, these richer interactions highlight additional opportunities for reducing exacerbation risk in RWD settings, targeting clinical and biological pathways that are less visible in RCT environments.

How can this study impact care in severe asthma? Dr. Wenjia Chen, Assistant Professor of Public Health and a leading author of the study, concludes “These findings suggest that RWD does not contradict RCT evidence; rather, it extends the evidence by confirming core mechanisms while also revealing additional upstream pathways that shape risk in real-world patients. Combining both data sources may support more personalized and adaptable risk prediction and management strategies for severe asthma patients”.

To learn more about the study, please read the full publication in CHEST, as well as the accompanying slide deck.

Acknowledgement: This work was supported by the Singapore National Medical Research Council – Open Fund – Young Individual Research Grant (MOH-001337-00), the International Severe Asthma Registry (ISAR) Expert Panel and the Observational and Pragmatic Research Institute (OPRI). ISAR is operated by Optimum Patient Care Global (OPCG) and co-funded by OPCG and AstraZeneca.  We thank all investigators, collaborators, and patients who contributed to this research.

About OPRI   

The Observational and Pragmatic Research Institute (OPRI) is an internationally recognized independent research organization dedicated to providing real-world evidence that supports best practices in chronic disease management in primary care. Learn more at https://www.opri.org.uk/. For media inquiries and additional information, please contact https://www.opri.org.uk/contact.  

About ISAR 

The International Severe Asthma Registry (ISAR) is the first global adult severe asthma registry, providing a rich, standardized dataset to advance research, clinical practice, and policy in severe asthma care. It fosters international collaboration to improve outcomes for patients worldwide. ISAR is operated by Optimum Patient Care Global Ltd. (OPCG) and co-funded by OPCG and AstraZeneca. Learn more at https://www.isar.opcglobal.org.