Abstract
Background/Objectives: The overuse of short-acting β(2)-agonists (SABAs) has been associated with increased asthma morbidity and mortality, prompting changes in treatment guidelines. However, the role of frequent short-acting muscarinic antagonists (SAMAs) use remains poorly defined and unaddressed in current recommendations. This study offers the first real-world analysis of SAMA overuse in asthma, quantifying its association with exacerbation risk and healthcare utilization and comparing its predictive value to that of SABAs. Methods: A retrospective multicenter cohort study analyzed electronic health records (EHRs) from 132 adults with asthma in the Spanish National Health System (SNS). Associations between annual SAMA use and clinical outcomes were assessed using negative binomial regression and 5000-sample bootstrap simulations. Interaction and threshold models were applied to explore how SAMA use affected outcomes and identify clinically actionable cutoffs. Results: SAMA use was independently associated with a 19.2% increase in exacerbation frequency per canister and a nearly sixfold increase in the odds of experiencing ≥1 exacerbation (OR = 5.97; 95% CI: 2.43-14.66). An inflection point at 2.5 canisters/year marked the threshold beyond which annual exacerbations exceeded one. Increased SAMA use was also associated with a higher number of respiratory consultations and with more frequent prescriptions of systemic corticosteroids and antibiotics. The risk increased more sharply with SAMAs than with SABAs, and the lack of correlation between them suggests distinct clinical patterns underlying their use. Conclusions: SAMA use emerges as a digitally traceable and clinically meaningful indicator of asthma instability. While the associations observed are robust and consistent across multiple outcomes, they should be considered provisional due to the study's retrospective design and limited sample size. Replication in larger and more diverse cohorts is needed to confirm external validity. These findings support the integration of SAMA tracking into asthma management tools-alongside SABAs-to enable the earlier identification of uncontrolled disease and guide therapeutic adjustment.